Clinical and Translational Oncology

Correction to: SEOM Clinical Guideline for treatment of muscle-invasive and metastatic urothelial bladder cancer (2016) Due to a technical issue, the family name of the author

Omitting the lower neck and sparing the glottic larynx in node-negative nasopharyngeal carcinoma was safe and feasible, and improved patient-reported voice outcomes Abstract Background Worsening voice and speech quality was frequently reported in head-and-neck patients after radiotherapy to the neck; omitting the lower neck and sparing the glottic larynx in node-negative nasopharyngeal carcinoma (NPC) patients might be safe and feasible, and improve voice and speech outcomes. Methods From January 2009 to January 2013, 71 patients were analyzed. All patients received bilateral neck irradiation. Upper group (UG) patients spared the glottic larynx while lower group (LG) patients did not. Voice and speech quality were evaluated at two time-points (T1 and T2) using the Communication Domain of the Head and Neck Quality of Life (HNQOL) instrument and the Speech question of the University of Washington Quality of Life instrument. Results At a median follow-up time of 32 months (T1),71.6% of patients reported worsened voice and speech quality. UG patients resulted in significant decreases in glottic larynx dose. With a median follow-up time of 71 months (T2), no patients experienced out-of-field nodal recurrence;there was no difference in the 5-year overall survival and nodal recurrence-free survival between two groups (P = 0.235 and 0.750, respectively). At T1, in patients who without concurrent chemotherapy (CCT), UG patients showed significantly better patient-reported voice quality, (P = 0.022). UG patients without CCT also showed higher scores in the HNQOL communication domain and pain domain (P = 0.012 and P = 0.019). Conclusions For node-negative NPC patients, omitting the lower neck and sparing the glottic larynx was safe and feasible, and better voice outcomes were achieved in patients without CCT. Further prospective longitudinal studies to investigate whether this approach would be beneficial to node-negative patients are warranted.

Laparoscopy adjuvant total colorectal resection for the treatment of familial adenomatous polyposis (FAP) Abstract Objective To discuss and evaluate the safety and value of laparoscopy adjuvant total colorectal resection for the treatment of familial adenomatous polyposis (FAP). Methods From March 2010 to June 2015, 38 cases were retrospectively analyzed and divided into 2 groups, of which 17 cases used laparoscopy adjuvant total colorectal resection, and 21 cases used conventional laparotomy. Clinical data were obtained, and the safety and prognosis were observed. Results Seventeen cases using laparoscopy adjuvant total colorectal resection achieved success with no conversion to laparotomy and intraoperative complications. There was no significant difference in operation time between the two groups. There were significant differences in blood loss, the length of incision, postoperative recovery time of intestinal function and postoperative hospital stay between the two groups (P < 0.05). The trauma in laparoscopy group was less, and could recover faster, and there was no significant difference in complications between the two groups. In addition, there were no recurrence, distant metastasis and death in the follow-up period from 6 to 56 months. Conclusion Laparoscopy adjuvant total colorectal resection is more safe and feasible, which has minimal invasion and can recover fast.

Active surveillance as a successful management strategy for patients with clinical stage I germ cell testicular cancer Abstract Background Cancer-specific survival for patients with clinical stage I (CSI) germ cell testicular cancer (GCTC) is outstanding after inguinal orchidectomy regardless the treatment utilized. This study evaluated whether active surveillance (AS) of such patients yielded similar health outcomes to other therapeutic strategies such as adjuvant chemotherapy, radiotherapy or primary retroperitoneal lymphadenectomy as described in the literature. Patients and methods Patients with CSI GCTC were screened between January 2012 and December 2016. Patients had previously undergone inguinal orchidectomy as the primary treatment and chosen AS as their preferred management strategy after receiving information about all available strategies. Results Out of 91 patients screened, 82 patients selected AS as their preferred management strategy. Relapse rate in the overall population was 20% (95% CI 12–30) and median time to relapse was 11.5 months (range 1.0–35.0). In patients with seminomatous tumors, relapse rate decreased to 13% and median time to relapse was 13 months; whereas in patients with non-seminomatous tumors, relapse rate was 33% (IA) or 29% (IB) and median time to relapse was 12 months in stage IA and 4.5 months in stage IB patients. All relapses were rescued with three or four cycles of chemotherapy and two also required a retroperitoneal lymphadenectomy. All patients are currently alive and free of disease. Conclusions The clinical outcomes of patients with CSI GCTC managed by AS in this series were excellent. This strategy limited the administration of active treatments specifically to the minority of patients who relapsed without compromising performance.

Improvement of appropriate pharmacological prophylaxis in hospitalised cancer patients with a multiscreen e-alert system: a single-centre experience Abstract Purpose Thromboprophylaxis use among medical inpatients, including cancer patients, is suboptimal. We aimed to evaluate the impact of a novel multiscreen version (v2.0) of an e-alert system for VTE prevention in hospitalised cancer medical patients compared to the original software. Methods Prospective study including 989 consecutive adult cancer patients with high-risk of VTE. Patients were followed-up 30 days post-discharge. Two periods were defined, according to the operative software. Results E-alert v2.0 was associated with an increase in the use of LMWH prophylaxis (65.5% vs. 72.0%); risk difference (95% CI) 0.064 (0.0043–0.12). Only 16% of patients in whom LMWH prophylaxis was not prescribed lacked a contraindication. No significant differences in the rates of VTE (2.9% vs. 3.2%) and major bleeding (2.7% vs. 4.0%) were observed. Conclusions E-alert v2.0 further increased the use of appropriate thromboprophylaxis in hospitalised cancer patients, although was not associated with a reduction in VTE incidence.

The dual effect of morphine on tumor development Abstract Morphine is a classic opioid drug used for reducing pain and is commonly prescribed as an effective drug to control cancer pain. Morphine has a direct role in the central nervous system to relieve pain, but because of its peripheral functions, morphine also has some side effects, such as nausea, constipation, and addiction (Gupta et al. in Sci World J 2015:10, 2015). In addition to its analgesic effect, the role of morphine in tumor development is an important question that has been investigated for many years with conflicting results. Numerous studies suggest that morphine has a role in both promoting and inhibiting tumor growth. In this extensive review, we attempt to comprehensively understand the effects of morphine and summarize both its positive and negative influences on various aspects of tumors, including tumor growth, angiogenesis, metastasis, inflammation, and immunomodulation.

Cancer immunotherapy of patients with HIV infection Abstract Cancer immunotherapy with antibodies against immune checkpoints has made impressive advances in the last several years. The most relevant drugs target programmed cell death 1 (PD-1) expressed on T cells or its ligand, the programmed cell death ligand 1 (PD-L1), expressed on cancer cells, and cytotoxic T lymphocyte-associated protein 4 (CTLA-4). Unfortunately, cancer patients with HIV infection are usually excluded from cancer clinical trials, because there are concerns about the safety and the anti-tumoral activity of these novel therapies in patients with HIV infection. Several retrospective studies and some case reports now support the notion that antibodies against immune checkpoints are safe and active in cancer patients with HIV infection, but prospective data in these patients are lacking. In addition, signs of antiviral activity with increase in CD4 T cell counts, plasma viremia reduction or decrease in the viral reservoir have been reported in some of the patients treated, although no patient achieved a complete clearance of the viral reservoir. Here we briefly summarize all clinical cases reported in the literature, as well as ongoing clinical trials testing novel immunotherapy drugs in cancer patients with HIV infection.

The protective effects of melatonin on blood cell counts of rectal cancer patients following radio-chemotherapy: a randomized controlled trial Abstract Purpose We aimed to examine the radioprotective effects of melatonin on the blood cell counts of patients with rectum cancer undergoing radiotherapy. Materials and methods This double-blind placebo-controlled study was conducted on 60 rectal cancer patients who were referred to Rajaii Hospital of Babolsar, Iran. An equal number of patients were randomly assigned to the control group which received placebo and study group which received 20 mg melatonin a day as an intervention. The melatonin was administered 5 days a week for 28 days. Blood samples were taken before melatonin received on day 1 and also day 28; then, to measure the changes in blood cell counts representing our primary outcomes, the samples were analyzed by Sysmex K810i auto-analyzer. Results Our results showed that the platelet, white blood cells, lymphocyte, and neutrophil population reduction induced by radiotherapy were slighter or even insignificant in melatonin recipients compared to control. However, the difference between red blood cells in both groups was not significant. Conclusion Our results are indicating that melatonin could prevent or minimize the unfavorable effects of radiotherapy on blood cell count reductions by attenuating the adverse influence of radiation, probably through stimulation of cellular antioxidant potential as previously reported in animal models. Iranian Registry of Clinical Trials (IRCT) Registry No. IRCT2016021626586N1.

Oncologic outcomes of nephron-sparing surgery in patients with T1 multifocal renal cell carcinoma Abstract Objective This study is performed to explore the pathological characteristics and oncologic outcomes of T1 multifocal renal cell carcinoma (RCC). Methods The clinical data of 600 patients (442 males and 158 females) between the age of 29 and 73 years, diagnosed with T1 RCC were collected from three hospitals in China, out of which 421 cases had undergone nephron-sparing surgery (NSS) and 179 cases had undergone radical nephrectomy (RN) between December 2010 and January 2015. Results Tumor was identified with multifocality in 32 patients (5.33%), out of which 21 were set to receive NSS, and 11 to receive RN, respectively; 21 cases of clear cell tumor, 8 cases of papillary tumor, 1 case of chromophobe tumor and 2 cases of Xp.11.2 translocation RCC. Among 568 cases of monofocal tumors, 400 patients underwent NSS, and the remaining 168 patients underwent RN, respectively. After a median follow-up of 5 years, 13 patients were found with recurrent tumors out of those who had undergone NSS, 11 with monofocal tumors and 2 with multifocal tumors containing satellite tumor nodules (p = 0.13). Out of the 32 individuals with multifocal RCC, 4 cases were reported to have died of cancer, 2 of NSS and 2 of RN. From these findings, the cancer-specific survival for NSS and RN was estimated to be 90.48% and 81.82%, respectively (p = 0.48). Conclusion The findings from the study suggested that there were pathological differences in multifocal renal tumors, and that papillary carcinoma may be more common than clear cell carcinoma. The recurrence rate and survival rate of multifocal RCC were similar to monofocal tumors. Tumor recurrence may be related to satellite tumor nodules, which can only be detected once surgery is performed.

Metronomic oral vinorelbine for the treatment of advanced non-small cell lung cancer: a multicenter international retrospective analysis Abstract Purpose Metronomic oral vinorelbine (MOV) could be a treatment option for unfit patients with advanced non-small cell lung cancer (NSCLC) based on its safety profile and high patient compliance. Methods We retrospectively collected data on 270 patients [median age 76 (range 48–92) years, M/F 204/66, PS 0 (27)/1 (110)/≥ 2 (133), median of 3 serious comorbidities] with stage IIIB-IV NSCLC treated with MOV as first (T1) (67%), second (T2) (19%) or subsequent (T3) (14%) line. Schedules consisted of vinorelbine 50 mg (138), 40 mg (68) or 30 mg (64) three times a week continuously. Results Patients received an overall median of 6 (range 1–25) cycles with a total of 1253 cycles delivered. The overall response rate was 17.8% with 46 partial and 2 complete responses and 119 patients (44.1%) experienced stable disease > 12 weeks with an overall disease control rate of 61.9%. Median overall time to progression was 5 (range 1–21) months [T1 7 (1–21), T2 5.5 (1–19) and T3 4 (1–19) months] and median overall survival 9 (range 1–36) months [T1 10 (1–31), T2 8 (1–36) and T3 6.5 (2–29) months]. Treatment was extremely well tolerated with 2% (25/1253) G3/4 toxicity (mainly G3 fatigue and anemia) and no toxic deaths. We observed the longer OS 14 (range 7–36) months in a subset of squamous NSCLC patients receiving immunotherapy after metronomic oral vinorelbine. Conclusion We confirmed MOV as an extremely safe treatment in a large real world population of advanced NSCLC with an interesting activity mainly consisting of long-term disease stabilization. We speculate the possibility of a synergistic effect with subsequent immunotherapy.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Parasitology Research

First report of a Hypoderma diana infestation in alpaca ( Vicugna pacos ) in Germany Abstract A Hypoderma larva was removed from a painful swelling in the lumbar region of a 17-month-old male alpaca kept on a farm in the Brandenburg district, eastern Germany. Morphological analysis and sequencing of the 18S rRNA gene demonstrated it was a second instar larvae of Hypoderma diana. The main host of H. diana is the roe deer (Capreolus capreolus). This is the first description of hypodermosis caused by H. diana in a camelid species.

Is species identification of Echinostoma revolutum using mitochondrial DNA barcoding feasible with high-resolution melting analysis? Abstract The taxonomic evaluation of Echinostoma species is controversial. Echinostoma species are recognized as complex, leading to problems associated with accurate identification of these species. The aim of this study was to test the feasibility of using DNA barcoding of cytochrome c oxidase subunit I (COI) and NADH dehydrogenase subunit 1 (ND1) conjugated with high-resolution melting (HRM) analysis to identify Echinostoma revolutum. HRM using COI and ND1 was unable to differentiate between species in the "revolutum complex" but did distinguish between two isolates of 37-collar-spined echinostome species, including E. revolutum (Asian lineage) and Echinostoma sp. A from different genera, e.g., Hypoderaeum conoideum, Haplorchoides mehrai, Fasciola gigantica, and Thapariella anastomusa, based on the Tm values derived from HRM analysis. Through phylogenetic analysis, a new clade of the cryptic species known as Echinostoma sp. A was identified. In addition, we found that the E. revolutum clade of ND1 phylogeny obtained from the Thailand strain was from a different lineage than the Eurasian lineage. These findings reveal the complexity of the clade, which is composed of 37-collar-spined echinostome species found in Southeast Asia. Taken together, the systematic aspects of the complex revolutum group are in need of extensive investigation by integrating morphological, biological, and molecular features in order to clarify them, particularly in Southeast Asia.

Protein extract from head-foot tissue of Oncomelania hupensis promotes the growth and development of mother sporocysts of Schistosoma japonicum via upregulation of parasite aldolase gene Abstract Previous studies showed that protein extract from head-foot tissue of Oncomelania hupensis (O. hupensis) (PhfO), when cocultured with mother sporocysts of Schistosoma japonicum (S. japonicum), was beneficial for parasite's growth and development but the underlying mechanisms remain unclear. One possible strategy for PhfO to promote the growth and development of mother sporocysts of S. japonicum is to upregulate parasite's survival genes. Fructose-1,6-bisphosphate aldolase (ALD), an essential enzyme of glycometabolism in the energy metabolism process, plays an important role in the survival and the growth and development of schistosomes. Using an in vitro coculture system, in this study, we analyzed the potential involvement of the ald gene in the growth and development of mother sporocysts of S. japonicum following coculture with PhfO. We found that coculture with PhfO promoted the growth and development and the survival of mother sporocysts, and increased parasites' ATP consumption level. Mother sporocysts cocultured with PhfO showed a significantly increased expression of the ald gene at both RNA and protein levels. The ALD protein mainly expressed in the cytoplasm of mother sporocysts. Knockdown of ald gene in parasites decreased the ALD protein expression and the ATP consumption level, suppressed the growth and development, and attenuated the survival of mother sporocysts. In ald knockdown mother sporocysts, the effects of PhfO on the ALD expression, the ATP consumption level, the growth and development, and the survival of larvae were significantly abolished. Therefore, the data suggest that PhfO could promote the growth and development, and the survival of mother sporocysts of S. japonicum via upregulating the expression of the ald gene.

Novel data from Italian Vermamoeba vermiformis isolates from multiple sources add to genetic diversity within the genus Abstract Vermamoeba vermiformis represents one of the most common free-living amoebae identified in worldwide environmental surveys. We analyzed 56 water samples with varying characteristics, including temperature and the particular settings in which humans may be exposed to water, plus one corneal scraping from a keratitis patient, with the following aims: (i) to investigate the presence of V. vermiformis; (ii) to identify the isolate subtypes; (iii) to place the Italian isolates in the broader picture of the genetic diversity within V. vermiformis. Twenty-two isolates were identified upon culturing and sequencing of > 600 bp in the 18S ribosomal RNA (rRNA) gene sequence, bringing to 27 the number of sequences recovered from Italian sources. By adding deposited sequences, we assembled a dataset of 74 isolates. Three of our isolates were characterized by allelic code 7-5-1-1, never reported before, and two showed 100% identity with an uncultured eukaryote and carried the 719T>C variant. We show that the variable segments E5, E3, F, and G convey most of the information on diversity, enabling the clustering of the isolates in a replicable fashion. The presence of different strains in natural thermal waters and in distribution systems indicated heterogeneity of the amoebic populations. Also, ours and the only other sequence from human infection were mapped in different clades. Overall, we enlarged the repertoire of single nucleotide and indel variants and the list of allelic codes, proceeding one step further in the description of the diversity within the genus.

Efficacy of silver nanoparticles against the adults and eggs of monogenean parasites of fish Abstract Monogeneans are a diverse group of parasites that are commonly found on fish. Some monogenean species are highly pathogenic to cultured fish. The present study aimed to determine the in vitro anthelmintic effect of silver nanoparticles (AgNPs) against adults and eggs of monogeneans in freshwater using Cichlidogyrus spp. as a model organism. We tested two types of AgNPs with different synthesis methodologies and size diameters: ARGOVIT (35 nm) and UTSA (1–3 nm) nanoparticles. Damage to the parasite tegument was observed by scanning electron microscopy. UTSA AgNPs were more effective than ARGOVIT; in both cases, there was a concentration-dependent effect. A concentration of 36 μg/L UTSA AgNPs for 1 h was 100% effective against eggs and adult parasites, causing swelling, loss of corrugations, and disruption of the parasite's tegument. This is an interesting result considering that monogenean eggs are typically tolerant to antiparasite drugs and chemical agents. To the best of our knowledge, no previous reports have assessed the effect of AgNPs on any metazoan parasites of fish. Therefore, the present work provides a basis for future research on the control of fish parasite diseases.

Cloning, expression, characterization, and immunological properties of citrate synthase from Echinococcus granulosus Abstract The larval stages of the tapeworm Echinococcus granulosus (Cestoda: Taeniidae) are the causative agent of cystic echinococcosis, one of the most important parasitic zoonoses worldwide. E. granulosus has a complete pathway for the tricarboxylic acid cycle (TCA), in which citrate synthase (CS) is the key enzyme. Here, we cloned and expressed CS from E. granulosus (Eg-CS) and report its molecular characterization. The localization of this protein during different developmental stages and mRNA expression patterns during H2O2 treatment were determined. We found that Eg-CS is a highly conserved protein, consisting of 466 amino acids. In western blotting assays, recombinant Eg-CS (rEg-CS) reacted with E. granulosus-positive sheep sera and anti-rEg-CS rabbit sera, indicating that Eg-CS has good antigenicity and immunoreactivity. Localization studies, performed using immunohistochemistry, showed that Eg-CS is ubiquitously expressed in the larva, germinal layer, and adult worm sections of E. granulosus. Eg-CS mRNA expression levels increased following H2O2 exposure. In conclusion, citrate synthase might be involved in the metabolic process in E. granulosus. An assessment of the serodiagnostic potential of rEg-CS based on indirect ELISA showed that, although sensitivity (93.55%) and specificity (80.49%) are high, cross-reactivity with other parasites precludes its use as a diagnostic antigen.

Detection and genotypic characterization of Toxoplasma gondii DNA within the milk of Mongolian livestock Abstract Toxoplasma gondii is a global, zoonotic parasite capable of infecting any warm-blooded host. Toxoplasmosis can cause a variety of illnesses including abortions and congenital defects in humans, sheep, and goats. Congenital toxoplasmosis is considered to have the highest global disease burden of any foodborne illness in humans. This study examined the potential role of milk as a route of T. gondii transmission between livestock and humans within Mongolian herders, a little-studied population which relies heavily on animals. Milk of Mongolian sheep, goats and Bactrian camels was tested for the presence of T. gondii DNA, and a survey was conducted to ascertain what behavioral and environmental factors were present that might potentiate T. gondii infection within these Mongolian communities. T. gondii DNA was detected in samples from one sheep and five camels. Sequence analysis of DNA from camel milk revealed that two were from potentially virulent T. gondii genotypes. This has implications for public health in the region, as milk is an extremely important source of nutrition and our survey results imply that some people believe consumption of raw camel milk carries health benefits. This is the first report of T. gondii DNA in Bactrian camel milk as well as the first genotypic characterization of T. gondii within Mongolia.

Synthesis and in vitro activity of new biguanide-containing dendrimers on pathogenic isolates of Acanthamoeba polyphaga and Acanthamoeba griffini Abstract The genus Acanthamoeba can cause Acanthamoeba keratitis (AK) and granulomatous amoebic encephalitis (GAE). The treatment of these illnesses is hampered by the existence of a resistance stage that many times causes infection relapses. In an attempt to add new agents to our chemotherapeutic arsenal against acanthamebiasis, two Acanthamoeba isolates were treated in vitro with newly synthesized biguanide dendrimers. Trophozoite viability analysis and ultrastructural studies showed that dendrimers prevent encystment by lysing the cellular membrane of the amoeba. Moreover, one of the dendrimers showed low toxicity when tested on mammalian cell cultures, which suggest that it might be eventually used as an amoebicidal drug or as a disinfection compound in contact lens solutions.

Molecular characterization of a new Trypanosoma (Megatrypanum) theileri isolate supports the two main phylogenetic lineages of this species in Japanese cattle Abstract Trypanosoma (Megatrypanum) theileri is a cosmopolitan, usually non-pathogenic, trypanosome of cattle transmitted by blood-sucking arthropods, mainly tabanid flies. Several T. theileri strains isolated from domestic and wild ruminants via co-culturing with mammalian feeder cells or blood cells have been characterized morphologically and genetically. Here, we cultured a new trypanosome isolate from a Holstein cow in Hokkaido, Japan, and performed morphological and molecular characterization studies. The new isolate (Obihiro strain) was co-cultivated with Madin–Darby bovine kidney (MDBK) cells in GIT medium supplemented with 10% fetal bovine serum. Trypomastigotes and epimastigotes, but not intracellular parasites, were identified in the culture. Analysis of the V7-V8 region of 18S rRNA sequences showed that the Obihiro strain is positioned within the subgenus Megatrypanum. A dendrogram based on whole internal transcribed spacer rDNA sequence showed that the Obihiro strain clustered in the lineage TthII together with the Japanese isolates of T. theileri, Esashi 9, and Esashi 12, and isolates from Zambia and the USA. T. theileri of the KM strain and a T. theileri-like trypanosome isolated from deer (TSD1 strain) clustered in the lineage TthI, separate from the Obihiro strain. Based on a partial cathepsin L-like protein gene analysis, the Obihiro strain clustered with isolates of the TthIIF genotype, which includes T. theileri from Vietnam, Sri Lanka, and Brazil. Our analyses of the T. theileri Obihiro strain provide relevant insights into its genetic diversity in Japanese cattle and corroborate the host specificity of cattle and deer trypanosomes of the subgenus Megatrypanum.

CpG enhances the immunogenicity of heterologous DNA-prime/protein-boost vaccination with the heavy chain myosin of Brugia malayi in BALB/c mice Abstract The recombinant heavy chain myosin of Brugia malayi (Bm-Myo) has earlier been reported as a potent vaccine candidate in our lab. Subsequently, we further enhanced its efficacy employing heterologous DNA prime/protein boost (Myo-pcD+Bm-Myo) immunization approach that produced superior immune-protection than protein or DNA vaccination. In the present study, we evaluated the efficacy of heterologous prime boost vaccination in combination with CpG, synthetic oligodeoxynucleotides (ODN) adjuvant in BALB/c mice. The results showed that CpG/Myo-pcD+Bm-Myo conferred 84.5 ± 0.62% protection against B. malayi infective larval challenge which was considerably higher than Myo-pcD+Bm-Myo (75.6 ± 1.10%) following immunization. Although, both the formulations of immunization elicited robust production of specific IgG antibody and their isotypes (IgG1, IgG2a, IgG2b, and IgG3); however, CpG/Myo-pcD+Bm-Myo predominantly enhanced the level of IgG2a suggesting Th1 biased immune response in presence of CpG. Furthermore, spleen isolated from mice that immunized with CpG/Myo-pcD+Bm-Myo had greater accumulation of CD4+, CD8+, and CD19+ B cells and there was an augmented expression of co-stimulatory molecules CD40, CD86 on host dendritic cells (DCs). In contrast to Myo-pcD+Bm-Myo group, the splenocytes of CpG/Myo-pcD+Bm-Myo immunized mice developed comparatively higher pro-inflammatory cytokines IL-2 and IFN-γ leaving anti-inflammatory cytokine levels unchanged. Moreover, CpG formulation also upregulated the RNA expression of IL-12 and TNF-α in spleenocytes. The current findings suggest that the use of CpG would be more advantageous as an adjuvant predominantly in DNA/protein prime boost vaccine against Bm-Myo and presumably also for filarial infection.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Human Ecology

Historical Ecologies of Pastoralist Overgrazing in Kenya: Long-Term Perspectives on Cause and Effect Abstract The spectre of 'overgrazing' looms large in historical and political narratives of ecological degradation in savannah ecosystems. While pastoral exploitation is a conspicuous driver of landscape variability and modification, assumptions that such change is inevitable or necessarily negative deserve to be continuously evaluated and challenged. With reference to three case studies from Kenya – the Laikipia Plateau, the Lake Baringo basin, and the Amboseli ecosystem – we argue that the impacts of pastoralism are contingent on the diachronic interactions of locally specific environmental, political, and cultural conditions. The impacts of the compression of rangelands and restrictions on herd mobility driven by misguided conservation and economic policies are emphasised over outdated notions of pastoralist inefficiency. We review the application of 'overgrazing' in interpretations of the archaeological record and assess its relevance for how we interpret past socio-environmental dynamics. Any discussion of overgrazing, or any form of human-environment interaction, must acknowledge spatio-temporal context and account for historical variability in landscape ontogenies.

Local Fishers' Knowledge of Target and Incidental Seahorse Catch in Southern Vietnam Abstract Many vulnerable marine species are caught in small-scale fisheries that lack long-term records, thereby limiting the development of effective evidence-based management measures. To uncover recent trends in fish landings and value in the absence of historical data, we interviewed 77 fishers and five buyers on Phu Quoc Island in Southern Vietnam regarding their current and past fishing practices, with a focus on seahorse catches. Seahorses (Hippocampus spp.) are caught using multiple gear types (including trawls, crab nets, and compressor diving) and have both cultural and financial value. Most fishers catch seahorses incidentally, though 14 targeted them and made the majority of their income from their sale. Fishers reported that seahorse catch rates decreased by 86–95% from 2004 to 2014, while landed value simultaneously increased by 534%. If these reports are accurate, seahorse fishing on Phu Quoc is unsustainable and requires immediate management controls.

Correction to: Hiding in the Dark: Local Ecological Knowledge about Slow Loris in Sarawak Sheds Light on Relationships between Human Populations and Wild Animals The article Hiding in the dark: Local ecological knowledge about slow loris in Sarawak sheds light on relationships between human populations and wild animals, written by Priscillia Miard, K. A. I. Nekaris and Hatta Ramlee, was originally published electronically with open access.

Pumping Yemen Dry: A History of Yemen's Water Crisis Abstract Yemen, located on the southwestern corner of the Arabian Peninsula, is one of the most water-scarce countries in the world. Quite apart from the continuing catastrophic conflict, the massive overdraw of existing groundwater due to unregulated drilling of tube wells since the 1970s has created a major water crisis that affects the future of the county's estimated 28 million people. While once known for its rich traditions of agriculture due to its extensive highland terrace systems, spate flow and runoff water harvesting, Yemen is now food insecure, relying almost entirely on food imports. This article surveys the range of water resources in Yemen and their sustainability in light of climate change predictions. I examined government and development aid reports to highlight the causes of the water crisis and the failure of previous governments to resolve it. The situation is even more critical today, given the ongoing war between a Saudi-led coalition and a Huthi alliance that has created one of the worst humanitarian crises in the world. I conclude with priorities for mitigating the water crisis and promoting sustainable agriculture for Yemen's post-conflict future.

Greg Mitman, Marco Armiero, Robert S. Emmett, Editors. Future Remains: a Cabinet of Curiosities for the Anthropocene

Andy Bruno: The Nature of Soviet Power. An Arctic Environmental History

Divine Placebo: Health and the Evolution of Religion Abstract In this paper, I draw on knowledge from several disciplines to explicate the potential evolutionary significance of health effects of religiosity. I present three main observations. First, traditional methods of religious healers seldom rely on active remedies, but instead focus on lifestyle changes or spiritual healing practices that best can be described as placebo methods. Second, actual health effects of religiosity are thus mainly traceable to effects from a regulated lifestyle, social support networks, or placebo effects. Third, there are clear parallels between religious healing practices and currently identified methods that induce placebo effects. Physiological mechanisms identified to lie behind placebo effects activate the body's own coping strategies and healing responses. In combination, lifestyle, social support networks, and placebo effects thus produce both actual and perceived health effects of religiosity. This may have played an important role in the evolution and diffusion of religion through two main pathways. First, any real positive health effects of religiosity would have provided a direct biological advantage. Second, any perceived health effects, both positive and negative, would further have provided a unique selling point for 'religiosity' per se. Actual and perceived health effects of religiosity may therefore have played an underestimated role during the evolution of religiosity through both biological and cultural pathways.

Spatial Distribution and Abundance of Acacia mangium on Indigenous Lands in the Serra da Lua Region, Roraima State, Brazil

Variability and Change in Maasai Views of Wildlife and the Implications for Conservation Abstract Surveys conducted across sections of the pastoral Maasai of Kenya show a wide variety of values for wildlife, ranging from utility and medicinal uses to environmental indicators, commerce, and tourism. Attitudes toward wildlife are highly variable, depending on perceived threats and uses. Large carnivores and herbivores pose the greatest threats to people, livestock, and crops, but also have many positive values. Attitudes vary with gender, age, education, and land holding, but most of all with the source of livelihood and location, which bears on relative abundance of useful and threatening species. Traditional pastoral practices and cultural views that accommodated coexistence between livestock and wildlife are dwindling and being replaced by new values and sensibilities as pastoral practices give way to new livelihoods, lifestyles, and aspirations. Human-wildlife conflict has grown with the transition from mobile pastoralism to sedentary livelihoods. Unless the new values offset the loss of traditional values, wildlife will continue to decline. New wildlife-based livelihoods show that continued coexistence is possible despite the changes underway.

Exploring Diversity in Forest Management Outlooks of African American Family Forest Landowners for Ensuring Sustainability of Forestry Resources in the Southern United States Abstract African American forest landowners in the southern United States (US) are typically considered a homogenous group in current studies. Our research challenges this assumption by identifying four distinct forest management outlooks among African American forest landowners using Q Method. Sustainable Harvesters focus on balanced land use with a long-term outlook; Back 40ers appreciate the presence of forests on their property but focus on alternative land use; Land Use Pragmatists are also interested in alternative land use and primarily view forest as an economic resource; Recreationalists value their forestland not for economic value but as a place for personal use. Finally, Indecisive landowners are not sure about how to best manage their forestland. We argue that an understanding of different forest management outlooks will improve sustainable forest management by better targeting extension and outreach efforts for African American forest landowners.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Health Economics

The economics of antibiotic resistance: a claim for personalised treatments

Patient responsiveness to a differential deductible: empirical results from The Netherlands Abstract Health insurers may use financial incentives to encourage their enrollees to choose preferred providers for medical treatment. Empirical evidence whether differences in cost-sharing rates across providers affects patient choice behavior is, especially from Europe, limited. This paper examines the effect of a differential deductible to steer patient provider choice in a Dutch regional market for varicose veins treatment. Using individual patients' choice data and information about their out-of-pocket payments covering the year of the experiment and 1 year before, we estimate a conditional logit model that explicitly controls for pre-existing patient preferences. Our results suggest that in this natural experiment designating preferred providers and waiving the deductible for enrollees using these providers significantly influenced patient choice. The average cross-price elasticity of demand is found to be 0.02, indicating that patient responsiveness to the cost-sharing differential itself was low. Unlike fixed cost-sharing differences, the deductible exemption was conditional on the patient's other medical expenses occurring in the policy year. The differential deductible did, therefore, not result in a financial benefit for patients with annual costs exceeding their total deductible.

Including intangible costs into the cost-of-illness approach: a method refinement illustrated based on the PM 2.5 economic burden in China Abstract The concentrations of particulate matter with aerodynamic diameters less than 2.5 µm (PM2.5) and 10 µm (PM10) is a widespread concern and has been demonstrated for 103 countries. During the past few years, the exposure–response function (ERf) has been widely used to estimate the health effects of air pollution. However, past studies are either based on the cost-of-illness or the willingness-to-pay approach, and therefore, either do not cover intangible costs or costs due to the absence of work. To address this limitation, a hybrid health effect and economic loss model is developed in this study. This novel approach is applied to a sample of environmental and cost data in China. First, the ERf is used to link PM2.5 concentrations to health endpoints of chronic mortality, acute mortality, respiratory hospital admission, cardiovascular hospital admission, outpatient visits—internal medicine, outpatient visits—pediatrics, asthma attack, acute bronchitis, and chronic bronchitis. Second, the health effect of PM2.5 is monetized into the economic loss. The mean economic loss due to PM2.5was much heavier in the North than the South of China. Furthermore, the empirical results from 76 cities in China show that the health effects and economic losses were over 4.98 million cases and 382.30 billion-yuan in 2014 and decreased dramatically compared with those in 2013.

Unemployment and suicide in Italy: evidence of a long-run association mitigated by public unemployment spending Abstract From the mid-1990s on, the suicide rate in Italy declined steadily, then apparently rose again after the onset of the Great Recession, along with a sharp increase in unemployment. The aim of this study is to test the association between the suicide rate and unemployment (i.e., the unemployment rate for males and females in the period 1977–2015, and the long-term unemployment rate in the period 1983–2012) in Italy, by means of cointegration techniques. The analysis was adjusted for public unemployment spending (referring to the period 1980–2012). The study identified a long-run relationship between the suicide rate and long-term unemployment. On the other hand, an association between suicide and unemployment rate emerged, though statistically weaker. A 1% increase in long-term unemployment increases the suicide rate by 0.83%, with a long-term effect lasting up to 18 years. Public unemployment spending (as percentage of the Italian gross domestic product) may mitigate this association: when its annual growth rate is higher than 0.18%, no impact of unemployment on suicide in detectable. A decrease in the suicide rate is expected for higher amounts of social spending, which may be able to compensate for the reduced level of social integration resulting from unemployment, helping the individual to continue to integrate into society. A corollary of this is that austerity in times of economic recession may exacerbate the impact of the economic downturn on mental health. However, a specific "flexicurity" system (intended as a combination of high employment protection, job satisfaction and labour-market policies) may have a positive impact on health.

Income distribution and health: can polarization explain health outcomes better than inequality? Abstract Utilizing data from the China Health and Nutrition Survey (CHNS) from 1991 to 2011, we aim to analyze the effects of income distribution on two risks for chronic diseases: body mass index (BMI) and blood pressure. Unlike the previous studies, we consider two different kinds of indicators of income distribution: inequality and polarization. Different from relative inequality indicators such as the Gini index, which measure income gaps only, the recently developed polarization indicator captures group clustering and social alienation, in addition to income gaps. Our empirical results demonstrate that both BMI and blood pressure are positively correlated with income polarization, while inequality is a weaker predictor of these health outcomes. Thus, polarization, rather than inequality, should be used when analyzing the relationship between health outcomes and income distribution. We also examine the polarization-to-health transmission mechanism using mediation and moderation analytic frameworks. The results suggest that social networks mediate the effect of polarization on BMI and neutralize the effect on blood pressure.

Co-ordination of health care: the case of hospital emergency admissions Abstract The recognition that chronic care delivery is suboptimal has led many health authorities around the world to redesign it. In Norway, the Department of Health and Care Services implemented the Coordination Reform in January 2012. One policy instrument was to build emergency bed capacity (EBC) as an integrated part of primary care service provided by municipalities. The explicit aim was to reduce the rate of avoidable admissions to state-owned hospitals. Using five different sources of register data and a quasi-experimental framework—the "difference-in-differences" regression approach—we estimated the association between changes in EBC on changes in aggregate emergency hospital admissions for eight ambulatory care sensitive conditions (ACSC). The results show that EBC is negatively associated with changes in aggregate ACSC emergency admissions. The associations are largely consistent with alternative model specifications. We also estimated the relationship between changes in EBC on changes in each ACSC condition separately. Our results are mixed. EBC is negatively associated with emergency hospital admissions for asthma, angina and chronic obstructive pulmonary disease but not congestive heart failure and diabetes. The main implication of the study is that EBC within primary care is potentially a sensible way of redesigning chronic care.

Impact of early primary care follow-up after discharge on hospital readmissions Abstract Reducing repeated hospitalizations of patients with chronic conditions is a policy objective for improving system efficiency. We test the hypothesis that the risk of readmission is associated with the timing and intensity of primary care follow-up after discharge, focusing on patients hospitalized for heart failure in France. We propose a discrete-time model which takes into account that primary care treatments have a lagged and cumulative effect on readmission risk, and an instrumental variable approach, exploiting geographical differences in availability of generalists. We show that the early consultations with a GP after discharge can reduce the 28-day readmission risk by almost 50%, and that patients with higher ambulatory care utilization have smaller odds of readmission. Furthermore, geographical disparities in primary care affect indirectly the readmission risk. These results suggest that interventions which strengthen communication between hospitals and generalists are elemental for reducing readmissions and for developing effective strategies at the hospital level, it is also necessary to consider primary care resources that are available to patients.

The Great Recession, financial strain and self-assessed health in Ireland Abstract In this paper, we study the effects of the 2008 economic crisis on general health in one of the most severely affected EU economies—Ireland. We examine the relationship between compositional changes in demographic and socio-economic factors, such as education, income, and financial strain, and changes in the prevalence of poor self-assessed health over a 5-year period (2008–2013). We apply a generalised Oaxaca–Blinder decomposition approach for non-linear regression models proposed by Fairlie (1999, 2005). Results show that the increased financial strain explained the largest part of the increase in poor health in the Irish population and different sub-groups. Changes in the economic activity status and population structure also had a significant positive effect. The expansion of education had a significant negative effect, preventing further increases in poor health. Wealthier and better educated individuals experienced larger relative increases in poor health, which led to reduced socio-economic health inequalities.

An evaluation of the 1987 French Disabled Workers Act: better paying than hiring Abstract This paper presents the first evaluation of the French Disabled Workers Act of 1987, which aimed to promote the employment of disabled people in the private sector. We use a panel data set, which includes both the health and the labour market histories of workers. We account both for unobserved heterogeneity and for the change in the disabled population over time. We find that the law had a negative impact on the employment of disabled workers in the private sector. This counterproductive effect likely comes from the possibility to pay a fine instead of hiring disabled workers.

Denosumab versus bisphosphonates for the treatment of bone metastases from solid tumors: a systematic review Abstract Background Bone metastases are highly prevalent in breast, prostate, lung and colon cancers. Their symptoms negatively affect quality of life and functionality and optimal management can mitigate these problems. There are two different targeted agents to treat them: bisphosphonates (pamidronate and zoledronic acid) and the monoclonal antibody denosumab. Estimates of cost-effectiveness are still mixed. Objective To conduct a systematic review of economic studies that compares these two options. Method Literature search comprised eight databases and keywords for bone metastases, bisphosphonates, denosumab, and economic studies were used. Data were extracted regarding their methodologic characteristics and cost-effectiveness analyses. All studies were evaluated regarding to its methodological quality. Results A total of 263 unique studies were retrieved and six met inclusion criteria. All studies were based on clinical trials and other existing literature data, and they had high methodological quality. Most found unfavorable cost-effectiveness for denosumab compared with zoledronic acid, with adjusted ICERS that ranged from $4638–87,354 per SRE avoided and from US$57,274–4.81 M. per QALY gained, which varied widely according to type of tumor, time horizon, among others. Results were sensitive to drug costs, time to first skeletal-related event (SRE), time horizon, and utility. Conclusions Denosumab had unfavorable cost-effectiveness compared with zoledronic acid in most of the included studies. New economic studies based on real-world data and longer time horizons comparing these therapeutic options are needed.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Public Health

Direct healthcare costs of spinal disorders in Brazil Abstract Objectives To estimate the direct healthcare costs of spinal disorders in Brazil over 2016. Methods This is a prevalence-based cost-of-illness study with a top-down approach from the perspective of the public healthcare system. All international Classification of Diseases codes related to spinal disorders were included. The following costs were obtained: (1) hospitalization; medical professional service costs; intensive care unit costs; companion daily stay; (2) outpatient (services/procedures). Data were analyzed descriptively and costs presented in US$. Results The healthcare system spent US$ 71.4 million, and inpatient care represented 58%. The number of inpatient days was 250,426, and there were 36,654 hospital admissions (dorsalgia and disk disorders representing 70% of the costs). More than 114,000 magnetic resonance scans and 107,000 computerized tomography scans were adopted. Men had more inpatient days (138,215) than women (112,211). Overall, the inpatient/outpatient cost ratio was twice as high for men. Conclusions We demonstrated that the direct costs of spinal disorders in Brazil in 2016 were considerable. We also found a substantial amount of financial resources spent on diagnostic imaging. This is relevant as the routine use of diagnostic imaging for back pain is discouraged in international guidelines.

Roma health: Do we know enough?

Reducing socioeconomic inequalities in life expectancy among municipalities: the Brazilian experience Abstract Objectives This study analyzed the evolution of regional and socioeconomic inequality in life expectancy (LE) at birth and the probability of living up to 40 (LU40) and up to 60 years of age (LU60) in Brazilian municipalities between 1991 and 2010. Methods We analyzed data from the last three national census (1991, 2000 and 2010) computed for the 5565 Brazilian municipalities. They were divided into centiles according to the average per capita income. Poisson regression was performed to calculate the ratios between the poorest and the richest centiles. Results The average LE (+ 8.8 years), LU40 [6.7 percentage points (pp)] and LU60 increased (12.2 pp) between 1991 and 2010. The ratio of LE between the 1% of richest counties and the 1% of poorest counties decreased from 1.20 in 1991 to 1.09 in 2010. While in the poorest municipalities there was a gain of around 12 years of life, among the richest this increase was around 7 years. Conclusions There was a remarkable decrease in regional and socioeconomic inequality in LE, LU40 and LU60 in Brazil between 1991 and 2010.

Clusters of risk behaviors for noncommunicable diseases in the Brazilian adult population Abstract Objectives To identify clusters of risk behaviors among Brazilian adults, by sex, and to associate clusters with sociodemographic factors and self-perception of health. Methods We assessed 46,785 adults from the Brazilian National Health Survey. The risk behaviors were low consumption of fruits and vegetables—LFV (< 5 times/week), physical inactivity—PI (< 150 min/week), smoking (yes/no) and excessive consumption of alcohol—EA (5 doses for male, 4 doses for female). We used Venn diagram, cluster analysis and multinomial regression models. Results We found 9 clusters. The cluster of four risk behaviors was more common in males (3.2% vs. 0.83%). Despite a greater potential for aggregation of behaviors in females (O/E = 2.48) than in males (O/E = 1.62), the women were less likely to have all risk behaviors jointly (OR 0.24, 95% CI 0.19; 0.31), and this was found for the other clusters. In general, Brazilian black/brown, younger, with low education level and who had a self-perception of bad health, were more likely to engage in clusters of risk behaviors. Conclusions The prevalence of Brazilian adults engaging in clusters of risk behaviors is high, mainly among males, those who reported a bad health and with low socioeconomic status.

Palliative care in universal health coverage: What about humanitarian emergency assistance?

Migrant mental health, Hickam's dictum, and the dangers of oversimplification

Road map towards a harmonized pan-European surveillance of obesity-related lifestyle behaviours and their determinants in children and adolescents Abstract Objectives To develop a road map towards a harmonized pan-European surveillance system for children and adolescents. Methods Representatives of five European surveillance systems and the German Health Interview and Examination Survey for Children and Adolescents contributed to the road map through a structured workshop in 2016. Results A conceptual framework for this road map was developed with seven action points (APs) guiding the successive cross-country harmonization. First, key indicators of health behaviour and their determinants in children and adolescents will be identified (AP1, 2); short screening instruments will be developed and implemented to assess and monitor key indicators (AP3, 4). In parallel, optional supplementary modules could be implemented to provide objective data (AP5). This would allow mutual calibration and improvement of existing instruments before their progressive replacement by more comparable measurement tools (AP6). The establishment of a competence platform is envisaged for guiding the harmonization process (AP7). Conclusions This approach builds on existing systems, provides comparable key health indicators across European regions, helps to assess temporal trends and—once in place—will facilitate health reporting and monitoring of national and international health targets.

Association of objectively measured and perceived environment with accelerometer-based physical activity and cycling: a Swiss population-based cross-sectional study of children Abstract Objectives We tested whether objectively assessed neighbourhood characteristics are associated with moderate-to vigorous physical activity (MVPA) and cycling in Swiss children and adolescents and assessed the mediating role of the perception of the environment. Methods The cross-sectional analyses were based on data of 1306 participants aged 6–16 years of the population-based SOPHYA study. MVPA was measured by accelerometry, time spent cycling and the perceived environment by questionnaire. Objective environmental parameters at the residential address were GIS derived. In all analyses, personal, social and environmental factors were considered. Results MVPA showed significant positive associations with perceived personal safety and perceived access to green spaces but not with respective objective parameters. Objectively assessed main street density and shorter distance to the next public transport were associated with less cycling in adolescents. Parents' perceptions did not mediate the observed associations of the objectively assessed environment with MVPA and cycling. Conclusions Associations between the environment and physical activity differ by domain. In spatial planning efforts to improve objective environments should be complemented with efforts to increase parental sense of security.

Obesity risk in women of childbearing age in New Zealand: a nationally representative cross-sectional study Abstract Objectives To investigate risk factors for women with obesity of childbearing age. Methods A cross-sectional survey of New Zealand women (15–49 years) with measured height and weight was used [unweighted (n = 3625) and weighted analytical sample (n = 1,098,372)] alongside sociodemographic-, behavioural- and environmental-level predictors. Multilevel logistic regression weighted for non-response of height and weight data was used. Results Meeting physical activity guidelines (AOR (adjusted odds ratio) 0.66, 95% CI 0.54–0.80), Asian (AOR 0.15, 95% CI 0.10–0.23) and European/other ethnicity (AOR 0.46, 95% CI 0.36–0.58) and an increased availability of public greenspace (Q4 AOR 0.55, 95% CI 0.41–0.75) were related to decreased obesity risk. Older age (45–49 years AOR 3.01, 95% CI 2.17–4.16), Pacific ethnicity (AOR 2.81, 95% CI 1.87–4.22), residing in deprived areas (AOR 1.65, 95% CI 1.16–2.35) or secondary urban areas (AOR 1.49, 95% CI 1.03–2.18) were related to increased obesity risk. When examined by rural/urban classification, private greenspace was only related to increased obesity risk in main urban areas. Conclusions This study highlights factors including but not limited to public greenspace, which inform obesity interventions for women of childbearing age in New Zealand.

Source-country individualism, cultural shock, and depression among immigrants Abstract Objectives To determine whether there is a relationship between source-country individualism and depression among different immigrant groups. Methods Pooled data from the 2009–2014 waves of the Canadian Community Health Survey (CCHS) were used. The CCHS is a cross-sectional, nationally representative household survey. A sample of 4347 immigrants in Canada were studied, representing 101 source countries. Results Multi-level logistic regression analysis showed a curvilinear relationship between source-country individualism and depression. A positive relationship was found among immigrants from countries with mid- to high levels of individualism. However, an inverse relationship was observed among immigrants from countries with low to mid-levels of individualism. Depression was significantly associated with the linear form of the source-country individualism measure [odds ratio (OR) 0.950; 95% confidence interval (CI) 0.915–0.987] and its squared term (OR 1.063; 95% CI 1.026–1.102). Conclusions A high level of source-country individualism tends to increase the prevalence of depression among immigrants. There is also a cultural shock effect: the prevalence of depression was stronger in the initial years after immigration for those who migrated from countries with low levels of individualism.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Pediatric Critical Care Medicine

Antibiotic Prophylaxis for Open Chest Management After Pediatric Cardiac Surgery Objectives: Although open chest management optimizes hemodynamics after cardiac surgery, it increases postoperative infections and leads to increased mortality. Despite the importance of antibiotic prophylaxis during open chest management, no specific recommendations exist. We aimed to compare the occurrence rates of bloodstream infection and surgical site infection between the different prophylactic antibiotic regimens for open chest management after pediatric cardiac surgery. Design: Retrospective, single-center, observational study. Setting: PICU at a tertiary children's hospital. Patients: Consecutive patients less than or equal to 18 years old with open chest management after cardiac surgery followed by delayed sternal closure, between January 2012 and June 2018. Interventions: None. Measurements and Main Results: We compared the composite occurrence rate of postoperative bloodstream infection and surgical site infection within 30 days after cardiac surgery between three prophylactic antibiotic regimens: 1) cefazolin, 2) cefazolin + vancomycin, and 3) vancomycin + meropenem. In 63 pediatric cardiac surgeries with open chest management, 17 bloodstream infections, and 12 surgical site infections were identified postoperatively. The composite occurrence rates of bloodstream infection and surgical site infection were 10 of 15 (67%), 10 of 19 (53%), and nine of 29 (31%) in the cefazolin, cefazolin + vancomycin, and vancomycin + meropenem regimens, respectively (p = 0.07). After adjusting for age, open chest management duration, extracorporeal membrane oxygenation use, and nasal methicillin-resistant Staphylococcus aureus colonization in multivariable analysis, there was no significant difference between the cefazolin and the cefazolin + vancomycin regimens (p = 0.19), while the vancomycin + meropenem regimen had a lower occurrence rate of bloodstream infection and surgical site infection than the cefazolin regimen (odds ratio, 0.0885; 95% CI, 0.0176–0.446; p = 0.003). Conclusions: In this study, a lower occurrence rate of postoperative bloodstream infection and surgical site infection was observed among patients with broad-spectrum antibiotic regimen after pediatric cardiac surgery with open chest management. Further studies, ideally randomized controlled studies investigating the efficacy of broad-spectrum antibiotics and their complications, are warranted before routine implementation of broad-spectrum prophylactic antibiotic regimen. The authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: hatachi@wch.opho.jp ©2019The Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies

Noninvasive Determination of Blood Pressure by Heart Sound Analysis Compared With Intra-Arterial Monitoring in Critically Ill Children—A Pilot Study of a Novel Approach Objectives: To develop a novel device to predict systolic and diastolic blood pressure based on measured heart sound signals and evaluate its accuracy in comparison to intra-arterial blood pressure readings. Study Design: Prospective, observational pilot study. Setting: PICU. Patients: Critically ill children (0–18 yr) undergoing continuous blood pressure monitoring via radial artery intra-arterial catheters were enrolled in the study after informed consent. The study included medical, cardiac, and surgical PICU patients. Interventions: Along with intra-arterial blood pressure, patient's heart sounds were recorded simultaneously by a highly sensitive sensor taped to the chest. Additional hardware included a data acquisition unit and laptop computer. Subsequently, advanced signal processing technologies were used to minimize random interfering signals and extract and separate S1 and S2 signals. A computerized model was then developed using artificial neural network systems to estimate blood pressure from the extracted heart sound analysis. Measurements and Main Outcomes: We found a statistically significant correlation for systolic (r = 0.964; R2 = 0.928) and diastolic (r = 0.935; R2 = 0.868) blood pressure readings (n = 491) estimated by the novel heart-sound signal–based method and those recorded by intra-arterial catheters. The mean difference of the individually paired determinations of the blood pressure between the heart-sound–based method and intra-arterial catheters was 0.6 ± 7 mm Hg for systolic blood pressure and –0.06 ± 5 mm Hg for diastolic blood pressure, which was within the recommended range of 5 ± 8 mm Hg for any new blood pressure devices. Conclusions: Our findings provide proof of concept that the heart-sound signal-based method can provide accurate, noninvasive blood pressure monitoring. Drs. Kapur and Chen contributed equally to the article. This work was supported by the 21st Century Jobs Trust Fund received through the Michigan Strategic Fund from the State of Michigan and administered by the Michigan Economic Development Corporation (www.michiganbusiness.org). Dr. Kapur's institution received funding from Alexion; a nonprovisional patent (number PCT/US18/17178) titled, "Method and Apparatus for Determining Blood Pressure on Measured Heart Sounds," based on this research was submitted on 02/07/2018 (to Drs. Kapur, Chen, Xu, and Wu listed as co-inventors); and he disclosed off-label product use of the technology reported in the article, which is currently investigational and not approved by the U.S. Food and Drug Administration for any purposes. Drs. Kapur and Chen disclosed that this work was supported by the 21st Century Jobs Trust Fund received through the Michigan Strategic Fund from the State of Michigan and administered by the Michigan Economic Development Corporation. Dr. Xu disclosed work for hire. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: gkapur@med.wayne.edu ©2019The Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies

Relationship Between Diaphragmatic Electrical Activity and Esophageal Pressure Monitoring in Children Objectives: Mechanical ventilation is an essential life support technology, but it is associated with side effects in case of over or under-assistance. The monitoring of respiratory effort may facilitate titration of the support. The gold standard for respiratory effort measurement is based on esophageal pressure monitoring, a technology not commonly available at bedside. Diaphragmatic electrical activity can be routinely monitored in clinical practice and reflects the output of the respiratory centers. We hypothesized that diaphragmatic electrical activity changes accurately reflect changes in mechanical efforts. The objectives of this study were to characterize the relationship between diaphragmatic electrical activity and esophageal pressure. Design: Prospective crossover study. Setting: Esophageal pressure and diaphragmatic electrical activity were simultaneously recorded using a specific nasogastric tube in three conditions: in pressure support ventilation and in neurally adjusted ventilatory support in a random order, and then after extubation. Patients: Children in the weaning phase of mechanical ventilation. Interventions: The maximal swing in esophageal pressure and esophageal pressure-time product, maximum diaphragmatic electrical activity, and inspiratory diaphragmatic electrical activity integral were calculated from 100 consecutive breaths. Neuroventilatory efficiency was estimated using the ratio of tidal volume/maximum diaphragmatic electrical activity. Measurements and Main Results: Sixteen patients, with a median age of 4 months (interquartile range, 0.5–13 mo), and weight 5.8 kg (interquartile range, 4.1–8 kg) were included. A strong linear correlation between maximum diaphragmatic electrical activity and maximal swing in esophageal pressure (r2 > 0.95), and inspiratory diaphragmatic electrical activity integral and esophageal pressure-time product (r2 > 0.71) was observed in all ventilatory conditions. This correlation was not modified by the type of ventilatory support. Conclusions: On a short-term basis, diaphragmatic electrical activity changes are strongly correlated with esophageal pressure changes. In clinical practice, diaphragmatic electrical activity monitoring may help to inform on changes in respiratory efforts. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://journals.lww.com/pccmjournal). Dr. Baudin received funding from Maquet Critical Care (speaking fees and nonfinancial support). Dr. Beck received funding from Maquet Critical Care (she and her husband have made inventions related to neural control of mechanical ventilation that are patented. The patents are assigned to the academic institution[s] where inventions were made. The license for these patents belongs to Maquet Critical Care. Future commercial uses of this technology may provide financial benefit to them through royalties) and Neurovent Research Inc (NVR) (she and her husband own 50% of NVR, which is a research and development company that builds the equipment and catheters for research studies. NVR has a consulting agreement with Maquet Critical Care). Dr. Jouvet's institution received funding from Air Liquide Santé (grant and lecture), and he received salary and grant funding from the Ministry of Health of Quebec, Sainte Justine Hospital, and Public Research Agency of Quebec. Dr. Emeriaud's institution received funding from Fonds de Recherche du Québec—Santé and Maquet Critical Care (currently supporting a feasibility study in neonatal ventilation which Dr. Emeriaud is leading). The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: sandrine.essouri.hsj@ssss.gouv.qc.ca ©2019The Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies

International Study of the Epidemiology of Platelet Transfusions in Critically Ill Children With an Underlying Oncologic Diagnosis Objectives: To describe the epidemiology of platelet transfusions in critically ill children with an underlying oncologic diagnosis and to examine effects of prophylactic versus therapeutic transfusions. Design: Subgroup analysis of a prospective, observational study. Setting: Eighty-two PICUs in 16 countries. Patients: All children (3 d to 16 yr old) who received a platelet transfusion during one of the six predefined screening weeks and had received chemotherapy in the previous 6 months or had undergone hematopoietic stem cell transplantation in the last year. Interventions: None. Measurements and Main Results: Of the 548 patients enrolled in the parent study, 237 (43%) had an underlying oncologic diagnosis. In this population, 71% (168/237) of transfusions were given prophylactically, and 59% (139/237) of transfusions were given at a total platelet count greater than 20 × 109/L, higher than the current recommendations. Those with an underlying oncologic diagnosis were significantly older, and received less support including less mechanical ventilation, fewer medications that affect platelet function, and less use of extracorporeal life support than those without an underlying oncologic diagnosis. In this subpopulation, there were no statistically significant differences in median (interquartile range) platelet transfusion thresholds when comparing bleeding or nonbleeding patients (50 × 109/L [10–50 × 109/L] and 30 × 109/L [10–50 × 109/L], respectively [p = 0.166]). The median (interquartile range) interval transfusion increment in children with an underlying oncologic diagnosis was 17 × 109/L (6–52 × 109/L). The presence of an underlying oncologic diagnosis was associated with a poor platelet increment response to platelet transfusion in this cohort (adjusted odds ratio, 0.46; 95% CI, 0.22–0.95; p = 0.035). Conclusions: Children with an underlying oncologic diagnosis receive nearly half of platelet transfusions prescribed by pediatric intensivists. Over half of these transfusions are prescribed at total platelet count greater than current recommendations. Studies must be done to clarify appropriate indications for platelet transfusions in this vulnerable population. The Point Prevalence Study of Platelet Transfusions in Critically Ill Children (P3T) Investigators are listed in the Acknowledgments. Dr. Cushing received funding from Cerus Corporation, Octapharma, and Instrumentation Laboratory. Dr. Steiner's institution received funding from the National Institutes of Health and Boeringer-Ingelheim, and she received funding from Cerus (travel for study design consultation regarding pathogen-inactivated red cells). The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: man9026@med.cornell.edu ©2019The Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies

Parent Medical Traumatic Stress and Associated Family Outcomes After Pediatric Critical Illness: A Systematic Review Objectives: To critically review, analyze, and synthesize the literature on parent medical traumatic stress from a child's critical illness requiring PICU admission and its association with outcomes of parent mental and physical health, and family functioning. Data Sources: Systematic literature search of Pubmed, Embase, CINAHL, and PsychInfo. Study Selection: Two reviewers identified peer-reviewed published articles with the following criteria: 1) published between January 1, 1980, and August 1, 2018; 2) published in English; 3) study population of parents of children with a PICU admission; and 4) quantitative studies examining factors associated with outcomes of parent mental health, parent physical health, or family functioning. Data Extraction: Literature search yielded 2,476 articles, of which 23 studies met inclusion criteria. Study data extracted included study characteristics, descriptive statistics of parent outcomes after critical illness, and variables associated with parent and family outcomes. Data Synthesis: Studies examined numerous variables associated with parent and family outcomes and used multiple survey measures. These variables were categorized according to their phase in the Integrative Trajectory Model of Pediatric Medical Traumatic Stress, which included peri-trauma, acute medical care, and ongoing care or discharge from care. The majority of objective elements of a child's illness, such as severity of illness and length of hospitalization, did not have a clear relationship with parent and family outcomes. However, familial preexisting factors, a parent's subjective experience in the PICU, and family life stressors after discharge were often associated with parent and family outcomes. Conclusions: This systematic literature review suggests that parent and family outcomes after pediatric critical illness are impacted by familial preexisting factors, a parent's subjective experience in the PICU, and family life stressors after discharge. Developing parent interventions focused on modifying the parent's subjective experience in the PICU could be an effective approach to improve parent outcomes. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://journals.lww.com/pccmjournal). This work was supported by the Department of Pediatrics at Children's Hospital of Michigan and the Department of Pediatrics at the University of Michigan. The authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: lyagiela@dmc.org ©2019The Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies

Severe Sepsis in Pediatric Liver Transplant Patients: The Emergence of Multidrug-Resistant Organisms Objectives: To describe characteristics of liver transplant patients with severe sepsis in the PICU. Design: Retrospective descriptive analysis. Setting: Tertiary children's hospital PICU. Patients: Liver transplant recipients admitted January 2010 to July 2016 for pediatric severe sepsis. Interventions: None. Measurements and Main Results: Between January 2010 and July 2016, 173 liver transplants were performed, and 36 of these patients (21%) were admitted with severe sepsis (54 episodes total). Median age at admission was 2 years (1–6.5 yr), 47.2% were male. Bacterial infections were the most common (77.8%), followed by culture negative (12.9%) and viral infections (7.4%). Fungal infections accounted for only 1.9%. Median time from transplant for viral and culture negative infections was 18 days (8.25–39.75 d) and 25 days (9–41 d), whereas 54.5 days (17–131.25 d) for bacterial infections. Bloodstream and intra-abdominal were the most common bacterial sites (45% and 22.5%, respectively). Multidrug-resistant organisms accounted for 47.6% of bacterial sepsis. Vancomycin-resistant Enterococcus and extended-spectrum beta-lactamase producers were the most frequently identified multidrug-resistant organisms. Patients with multidrug-resistant organism sepsis demonstrated higher admission Pediatric Logistic Organ Dysfunction scores (p = 0.043) and were noted to have an odds ratio of 3.8 and 3.6 for mechanical ventilation and multiple organ dysfunction syndrome, respectively (p = 0.047 and p = 0.044). Overall mortality was 5.5% (n = 2 patients), with both deaths occurring in multidrug-resistant organism episodes. Conclusions: We report that multidrug-resistant organisms are increasingly being identified as causative pathogens for sepsis in pediatric liver transplant recipients and are associated with significantly higher odds for mechanical ventilation and higher organ failure. The emergence of multidrug-resistant organism infections in pediatric liver transplant patients has implications for patient outcomes, antibiotic stewardship, and infection prevention strategies. Supported, in part, by grant from National Institutes of Health (NIH) T32-HD40686 (to Dr. Alcamo) and NIH R01-GM108618 (to Dr. Carcillo). Dr. Alcamo's institution received funding from National Institutes of Health (NIH) T32 HD040686. Drs. Alcamo, Carcillo, and Aneja received support for article research from the NIH. Dr. Carcillo's institution received funding from the NIH/National Institute of General Medical Sciences. Dr. Michaels' institution received funding from Pfizer (unrelated study grant), and she received funding as an American Society of Transplantation board member (travel and room for meetings, no honoraria) and from National Institute of Allergy and Infectious Diseases (honoraria and travel and room for Data and Safety Monitoring Board meetings). Dr. Aneja received royalties from UpToDate. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: Alicia.Alcamo@chp.edu ©2019The Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies

State of the Unit: Physician Gender Diversity in Pediatric Critical Care Medicine Leadership Gender disparities in leadership are receiving increased attention throughout medicine and medical subspecialties. Little is known about the disparities in Pediatric Critical Care Medicine. In this piece, we explore gender disparities in Pediatric Critical Care Medicine physician leadership. We examine physician leadership in the Accreditation Council for Graduate Medical Education fellowship programs, as well as a limited sample of major Pediatric Critical Care Medicine textbooks and societies. Overall, the gender composition of division directors is not significantly different from that of workforce composition, although regional differences exist. More women than men lead fellowship programs, at a higher ratio compared with workforce composition. However, greater gender disparities are present in editorial leadership in this limited analysis. We conclude by recommending potential paths forward for further study and intervention, such as tracking gender diversity and being cognizant of the unique challenges that women currently experience in professional advancement. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://journals.lww.com/pccmjournal). Dr. Riley receives support from the Institute for Healthcare Improvement to develop measurement framework and measures for the 100 Million Healthier Lives Initiative. Dr. Stalets received funding from Fisher & Paykel (hotel and flight accommodations to attend a conference). The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: Andrea.Maxwell@cchmc.org ©2019The Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies

Association of Organ Dysfunction Scores and Functional Outcomes Following Pediatric Critical Illness Objectives: Short-term and long-term morbidity and mortality are common following pediatric critical illness. Severe organ dysfunction is associated with significant in-hospital mortality in critically ill children; however, the performance of pediatric organ dysfunction scores as predictors of functional outcomes after critical illness has not been previously assessed. Design: Secondary analysis of a prospective observational cohort. Setting: A multidisciplinary, tertiary, academic PICU. Patients: Patients less than or equal to 18 years old admitted between June 2012 and August 2012. Interventions: None. Measurements and Main Results: The maximum pediatric Sequential Organ Failure Assessment and Pediatric Logistic Organ Dysfunction-2 scores during admission were calculated. The Functional Status Scale score was obtained at baseline, 6 months and 3 years following discharge. New morbidity was defined as a change in Functional Status Scale greater than or equal to 3 points from baseline. The performance of organ dysfunction scores at discriminating new morbidity or mortality at 6 months and 3 years was measured using the area under the curve. Seventy-three patients met inclusion criteria. Fourteen percent had new morbidity or mortality at 6 months and 23% at 3 years. The performance of the maximum pediatric Sequential Organ Failure Assessment and Pediatric Logistic Organ Dysfunction-2 scores at discriminating new morbidity or mortality was excellent at 6 months (areas under the curves 0.9 and 0.88, respectively) and good at 3 years (0.82 and 0.79, respectively). Conclusions: Severity of organ dysfunction is associated with longitudinal change in functional status and short-term and long-term development of new morbidity and mortality. Maximum pediatric Sequential Organ Failure Assessment and Pediatric Logistic Organ Dysfunction-2 scores during critical illness have good to excellent performance at predicting new morbidity or mortality up to 3 years after critical illness. Use of these pediatric organ dysfunction scores may be helpful for prognostication of longitudinal functional outcomes in critically ill children. All authors conceptualized, designed, analyzed, drafted the article for important intellectual content, and collected the data. The authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: travis.matics@advocatehealth.com ©2019The Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies

The Inadequate Oxygen Delivery Index and Low Cardiac Output Syndrome Score As predictors of Adverse Events Associated With Low Cardiac Output Syndrome Early After Cardiac Bypass Objectives: To evaluate the effectiveness of two scoring systems, the inadequate oxygen delivery index, a risk analytics algorithm (Etiometry, Boston, MA) and the Low Cardiac Output Syndrome Score, in predicting adverse events recognized as indicative of low cardiac output syndrome within 72 hours of surgery. Design: A retrospective observational pair-matched study. Setting: Tertiary pediatric cardiac ICU. Patients: Children undergoing cardiac bypass for congenital heart defects. Cases experienced an adverse event linked to low cardiac output syndrome in the 72 hours following surgery (extracorporeal membrane oxygenation, renal replacement therapy, cardiopulmonary resuscitation, and necrotizing enterocolitis) and were matched with a control patient on criteria of procedure, diagnosis, and age who experienced no such event. Interventions: None. Measurements and Main Results: Of a total 536 bypass operations in the study period, 38 patients experienced one of the defined events. Twenty-eight cases were included in the study after removing patients who suffered an event after 72 hours or who had insufficient data. Clinical and laboratory data were collected to derive scores for the first 12 hours after surgery. The inadequate oxygen delivery index was calculated by Etiometry using vital signs and laboratory data. A modified Low Cardiac Output Syndrome Score was calculated from clinical and therapeutic markers. The mean inadequate oxygen delivery and modified Low Cardiac Output Syndrome Score were compared within each matched pair using the Wilcoxon signed-rank test. Inadequate oxygen delivery correctly differentiated adverse events in 13 of 28 matched pairs, with no evidence of inadequate oxygen delivery being higher in cases (p = 0.71). Modified Low Cardiac Output Syndrome Score correctly differentiated adverse events in 23 of 28 matched pairs, with strong evidence of a raised score in low cardiac output syndrome cases (p < 0.01). Conclusions: Although inadequate oxygen delivery is an Food and Drug Administration approved indicator of risk for low mixed venous oxygen saturation, early postoperative average values were not linked with medium-term adverse events. The indicators included in the modified Low Cardiac Output Syndrome Score had a much stronger association with the specified adverse events. This work was undertaken at Great Ormond Street Hospital/UCL Institute of Child Health, which received a proportion of funding from the Department of Health's National Institute of Health Research Biomedical Research Centre's funding scheme. Drs. Ray and Peters' institutions received funding from Great Ormond Street Hospital Children's Charity (GOSHCC). Dr. Peters received funding from Faron pharmaceuticals (advisory board) and Therakind. Drs. Peters and Brown received support for article research from GOSHCC. Dr. Brown received other support from GOSHCC PICU infrastructure grant supporting Libby Rogers. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: samiran.ray@gosh.nhs.uk ©2019The Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies

Decision-Making About Intracranial Pressure Monitor Placement in Children With Traumatic Brain Injury Objectives: Little is known about how clinicians make the complex decision regarding whether to place an intracranial pressure monitor in children with traumatic brain injury. The objective of this study was to identify the decisional needs of multidisciplinary clinician stakeholders. Design: Semi-structured qualitative interviews with clinicians who regularly care for children with traumatic brain injury. Setting: One U.S. level I pediatric trauma center. Subjects: Twenty-eight clinicians including 17 ICU nurses, advanced practice providers, and physicians and 11 pediatric surgeons and neurosurgeons interviewed between August 2017 and February 2018. Interventions: None. Measurements and Main Results: Participants had a mean age of 43 years (range, 30–66 yr), mean experience of 10 years (range, 0–30 yr), were 46% female (13/28), and 96% white (27/28). A novel conceptual model emerged that related the difficulty of the decision about intracranial pressure monitor placement (y-axis) with the estimated outcome of the patient (x-axis). This model had a bimodal shape, with the most difficult decisions occurring for patients who 1) had a good opportunity for recovery but whose neurologic examination had not yet normalized or 2) had a low but uncertain likelihood of neurologically functional recovery. Emergent themes included gaps in medical knowledge and information available for decision-making, differences in perspective between clinical specialties, and ethical implications of decision-making about intracranial pressure monitoring. Experienced clinicians described less difficulty with decision-making overall. Conclusions: Children with severe traumatic brain injury near perceived transition points along a spectrum of potential for recovery present challenges for decision-making about intracranial pressure monitor placement. Clinician experience and specialty discipline further influence decision-making. These findings will contribute to the design of a multidisciplinary clinical decision support tool for intracranial pressure monitor placement in children with traumatic brain injury. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://journals.lww.com/pccmjournal). Dr. Bennett's institution also received funding from the National Institutes of Health (NIH) Eunice Kennedy Shriver National Institute of Child Health and Human Development and NIH/National Center for Advancing Translational Science. Drs. Bennett's and Rutebemberwa's institutions received funding from Mindsource Brain Injury Network of the Colorado Department of Human Services. Ms. Marsh's and Dr. Maertens's institutions received funding from the Colorado Department of Human Services. Dr. Hankinson's institution received funding from Colorado Traumatic Brain Injury Trust Fund. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: tell.bennett@ucdenver.edu ©2019The Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies

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