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Although the precise underlying cause(s) of autism spectrum disorder remain unclear, more than 1000 rare genetic variations are associated with the condition. For a large number of people living with profound autism, this genetic heterogeneity has impeded the identification of common biological targets for therapy development for core and comorbid traits that include significant impairments in social communication, and repetitive and restricted behaviors. A substantial number of genes associated with autism encode proteins involved in signal transduction and synaptic transmission that are critical for brain development and function. CAMK4 is an emerging risk gene for autism spectrum disorder that encodes the Ca 2+ -calmodulin-dependent protein kinase-4 (CaMK4) enzyme. CaMK4 is a key component of a Ca 2+ -activated signaling pathway that regulates neurodevelopment and synaptic plasticity. In this review, we discuss three genetic variants of CAMK4 found in individuals with hyperkinetic movement disorder and comorbid neurological symptoms including autism spectrum disorder that are likely pathogenic with monogenic effect. We also comment on four other genetic variations in CAMK4 that display associations with autism spectrum disorder, as well as twelve examples of autism-associated variations in other genes that impact CaMK4 signaling pathways. Finally, we highlight three environmental risk factors that impact CaMK4 signaling based on studies in preclinical models of autism and/or clinical cohorts. Overall, we review molecular, genetic, physiological, and environmental evidence that suggest defects in the CaMK4 signaling pathway may play an important role in a common autism pathogenesis network across numerous patient groups, and propose CaMK4 as a potential therapeutic target., (Copyright © 2024. Published by Elsevier Inc.)

Landfills and wastewater treatment plants (WWTP) are point sources for many emerging contaminants, including microplastics and per- and polyfluoroalkyl substances (PFAS). Previous studies have estimated the abundance and transport of microplastics and PFAS separately in landfills and WWTPs. In addition, previous studies typically report concentrations of microplastics as particle count/L or count/g sediment, which do not provide the information needed to calculate mass balances. We measured microplastics and PFAS in four landfill-WWTP systems in Illinois, USA, and quantified mass of both contaminants in landfill leachate, WWTP influent, effluent, and biosolids. Microplastic concentrations in WWTP influent were similar in magnitude to landfill leachates, in the order of 10 2  μg plastic/L (parts-per-billion). In contrast, PFAS concentrations were higher in leachates (parts-per-billion range) than WWTP influent (parts-per-trillion range). After treatment, both contaminants had lower concentrations in WWTP effluent, although were abundant in biosolids. We concluded that WWTPs reduce PFAS and microplastics, lowering concentrations in the effluent that is discharged to nearby surface waters. However, partitioning of both contaminants to biosolids may reintroduce them as pollutants when biosolids are landfilled or used as fertilizer., Competing Interests: Declaration of competing interest There is no conflict of interest associated with this manuscript., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Disposable e-cigarettes (vapes) are becoming increasingly popular but there are concerns about their impacts on human health, the environment and resource sustainability. A better understanding of these impacts and potential solutions requires characterisation and quantification of the materials and chemicals used in their construction. In the present study we dismantle nine types of popular, single-use vapes and analyse the components by X-ray fluorescence spectrometry and pyrolysis-gas chromatography mass spectrometry. The median dry mass of vapes was about 50 g, and the main material contribution was either plastic (up to about 80 %) or metal (up to about 85 %, and including the battery). Polycarbonate was the principal plastic used in the casing and nylon was always employed in the wick, but a range of other polymers were identified in other components used in wire insulation, sleeving, packaging, bundling and sealing. Various elements, as additives, residues or contaminants, were encountered in these parts that included As, Ba, Bi, Cr, Hg, Pb and Sb. Metal components were constructed of Al (often with Ti), stainless steel or Ni-based alloys (mainly in the coils), but other metals were often incorporated in alloys (e.g., Bi, Pb, W) or were present in trace quantities (including Co and Nb). Common metals in the Al-plastic-laminated Li-ion batteries were Cu, Co, Fe and Ni, but Au, Ba, Hg and Pb were also detected, while additional metals in the Cu-based printed circuit boards included Ag, Al, Ni, Sn, Ti and V, with traces of Ag, Bi, Mn, Nb and Pb present. The presence of toxic or potentially toxic metals in the vapes poses an environmental hazard through leaching after littering or landfilling, while metals within or in contact with the wick raise concerns about transfer to the e-liquid and exposure to the user. The overall material and chemical complexity of vapes presents challenges for safe disposal and component recycling, but the presence of critical elements, like Bi, Co, Nb, Sb, Sn, V and W, has additional implications for resource management., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: Pediatric cholestasis is the phenotypic expression of clinically and genetically heterogeneous disorders of bile acid synthesis and flow. Although a growing number of monogenic causes of pediatric cholestasis have been identified, the majority of cases remain undiagnosed molecularly., Methods: In a cohort of 299 pediatric participants (279 families) with intrahepatic cholestasis, we performed exome sequencing as a first-tier diagnostic test., Results: A likely causal variant was identified in 135 families (48.56%). These comprise 135 families that harbor variants spanning 37 genes with established or tentative links to cholestasis. In addition, we propose a novel candidate gene (PSKH1) (HGNC:9529) in 4 families. PSKH1 was particularly compelling because of strong linkage in 3 consanguineous families who shared a novel hepatorenal ciliopathy phenotype. Two of the 4 families shared a founder homozygous variant, whereas the third and fourth had different homozygous variants in PSKH1. PSKH1 encodes a putative protein serine kinase of unknown function. Patient fibroblasts displayed abnormal cilia that are long and show abnormal transport. A homozygous Pskh1 mutant mouse faithfully recapitulated the human phenotype and displayed abnormally long cilia. The phenotype could be rationalized by the loss of catalytic activity observed for each recombinant PSKH1 variant using in vitro kinase assays., Conclusion: Our results support the use of genomics in the workup of pediatric cholestasis and reveal PSKH1-related hepatorenal ciliopathy as a novel candidate monogenic form., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2024 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Biosolids and sewage effluent application to agricultural fields is becoming a win-win practice as both an economical waste management strategy and a source of nutrients and organic matter for plant growth. However, these organic wastes contain a variety of trace chemicals of environmental concern such as pharmaceuticals and personal care products (PPCPs), which may pose a risk to agricultural fields and ecosystems. This work aims to investigate the sorption of sitagliptin on four agricultural soils, evaluate the effects of biosolids and sewage effluent application, and elucidate the main sorption mechanism of the pharmaceutical on soils. The sorption study revealed that the sorption capacities of sitagliptin on different soils were positively related to the contents of soil organic matter and negatively associated with soil pH values. The application of biosolids and sewage effluent decreased the sorption capacity of sitagliptin, which may be attributed to the loading of dissolved organic matter derived from organic wastes. The Freundlich isotherm model demonstrated that the addition of biosolids from 0 to 100 % (W/W) consistently decreased the sorption affinity (K f ) of sitagliptin from 1.69 × 10 2 to 3.82 × 10 1  mg (1-n) L n kg -1 . Sewage application at 0, 10, 50, and 100 % (V/V) also reduced the K f values from 1.69 × 10 2 to 9.17 × 10 1  mg (1-n) L n kg -1 . Attenuated Total Reflection (ATR)-Infrared (IR) spectroscopy analyses suggested that electrostatic interactions between carbonyl and amino groups of sitagliptin and the negatively charged soil surface are the main sorption mechanisms. In a co-solute system, the sorption affinity of sitagliptin on the soil decreased with increasing metformin concentrations, suggesting that competitive sorption may reduce the sorption capacity of individual contaminants in soil systems containing multiple PPCPs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

In urban areas, exposure to greenspace has been found to be beneficial to human health. The biodiversity hypothesis proposed that exposure to diverse ambient microbes in greener areas may be one pathway leading to health benefits such as improved immune system functioning, reduced systemic inflammation, and ultimately reduced morbidity and mortality. Previous studies observed differences in ambient outdoor bacterial diversity between areas of high and low vegetated land cover but didn't focus on residential environments which are important to human health. This research examined the relationship between vegetated land and tree cover near residence and outdoor ambient air bacterial diversity and composition. We used a filter and pump system to collect ambient bacteria samples outside residences in the Raleigh-Durham-Chapel Hill metropolitan area and identified bacteria by 16S rRNA amplicon sequencing. Geospatial quantification of total vegetated land or tree cover was conducted within 500 m of each residence. Shannon's diversity index and weighted UniFrac distances were calculated to measure α (within-sample) and β (between-sample) diversity, respectively. Linear regression for α-diversity and permutational analysis of variance (PERMANOVA) for β-diversity were used to model relationships between vegetated land and tree cover and bacterial diversity. Data analysis included 73 ambient air samples collected near 69 residences. Analysis of β-diversity demonstrated differences in ambient air microbiome composition between areas of high and low vegetated land (p = 0.03) and tree cover (p = 0.07). These relationships remained consistent among quintiles of vegetated land (p = 0.03) and tree cover (p = 0.008) and continuous measures of vegetated land (p = 0.03) and tree cover (p = 0.03). Increased vegetated land and tree cover were also associated with increased ambient microbiome α-diversity (p = 0.06 and p = 0.03, respectively). To our knowledge, this is the first study to demonstrate associations between vegetated land and tree cover and the ambient air microbiome's diversity and composition in the residential ecosystem., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Polypropylene (PP) inkjet cartridges spilled during January 2014 in the northwest Atlantic Ocean from a container ship and subsequently retrieved from beaches around Europe and the Azores along with a matching reference cartridge that had not been exposed to the environment were physically and chemically characterized. Compared with the reference, the cartridges retrieved from the marine environment exhibited considerable cracking-fracturing, discoloration, surface roughness, loss of gloss and staining. Infrared analysis revealed that weathering was highly heterogeneous, with the carbonyl index ranging from <0.1 to >0.9 over areas of sub-mm-dimensions. The high degree of weathering was partly attributed to the presence, quality, and distribution of the titanium dioxide pigment, TiO 2 . Thus, in the absence of sufficient protection by encapsulation or addition of antioxidants, the ultraviolet light-absorbing pigment promoted the formation of free radicals and photocatalytic oxidation. The results of this study show that consumer plastics containing TiO 2 for coloration or tinting purposes, when not designed for exterior use (in the absence of encapsulation or antioxidants), may experience accelerated weathering in the marine environment, and that estimates of plastic persistence should factor in the role of additives that promote photoactivity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Traumatic spinal cord injury (TSCI) constitutes a considerable portion of the global injury burden, disproportionately affecting low- and middle-income countries (LMICs). Prehospital care can address TSCI morbidity and mortality, but emergency medical services are lacking in LMICs. The current standard of prehospital care for TSCI in sub-Saharan Africa and other LMICs is unknown., Methods: This review sought to describe the state of training and resources for prehospital TSCI management in sub-Saharan Africa and other LMICs. Articles published between 1 January 1995 and 1 March 2020 were identified using PMC, MEDLINE, and Scopus databases following PRISMA-ScR guidelines. Inclusion criteria spanned first responder training programs delivering prehospital care for TSCI. Two reviewers assessed full texts meeting inclusion criteria for quality using the Newcastle-Ottawa Scale and extracted relevant characteristics to assess trends in the state of prehospital TSCI care in sub-Saharan Africa and other LMICs., Results: Of an initial 482 articles identified, 23 met inclusion criteria, of which ten were set in Africa, representing eight countries. C-spine immobilization precautions for suspected TSCI patients is the most prevalent prehospital TSCI intervention for and is in every LMIC first responder program reviewed, except one. Numerous first responder programs providing TSCI care operate without C-collar access (n = 13) and few teach full spinal immobilization (n = 5). Rapid transport is most frequently reported as the key mortality-reducing factor (n = 11). Despite more studies conducted in the Southeast Asia/Middle East (n = 13), prehospital TSCI studies in Africa are more geographically diverse, but responder courses are shorter, produce fewer professional responders, and have limited C-collar availability., Discussion: Deficits in training and resources to manage TSCI highlights the need for large prospective trials evaluating alternative C-spine immobilization methods for TCSI that are more readily available across diverse LMIC environments and the importance of understanding resource variability to sustainably improve prehospital TSCI care., Competing Interests: The authors declared no conflicts of interest., (© 2018 Published by Elsevier Ltd. CC BY-NC-ND 4.0.)

Because of their unique properties, rare earth elements (REEs), comprising the lanthanide elements plus Sc and Y, have a variety of integral applications in modern electronic equipment. Consequently, it has been suggested that REEs may act as contaminants of and tracers for recycled electrical and electronic plastics in consumer goods. In this study, REEs have been determined in a range of consumer plastics of different polymeric makeup (n = 31), and purchased new and in societal circulation, by inductively coupled plasma-mass spectrometry following acid digestion. Samples were also screened by X-ray fluorescence spectrometry for Br and Sb as markers of brominated flame retardants and the retardant synergist, Sb 2 O 3 , respectively. One or more REE was detected in 24 samples, with four samples returning detectable concentrations of all REEs analysed and with total REE concentrations up to 8 mg kg -1 . REEs were most commonly observed in samples containing Br and Sb at levels insufficient to effect flame retardancy and, therefore, likely derived from recycled electronic plastic, but were not detectable in new electrical plastics. Various REEs were also present in plastics with no detectable Br and Sb, however, and where unregulated recycling is prohibited (e.g. food packaging). This observation, and correlations between pairs of REEs for all samples considered, suggests a more generic source of these elements in consumer plastics in addition to the recycling of electrical and electronic waste. REEs reported in the literature for beached marine plastics were characterised by similar concentrations and inter-element correlations, suggesting that REEs are ubiquitous and pervasive contaminants of both contemporary and historical consumer and environmental plastics., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Introduction: Ghana implemented a National Health Insurance Scheme (NHIS) in 2003 as a step toward universal health coverage. We aimed to determine the effect of the NHIS on timeliness of care, mortality, and catastrophic health expenditure (CHE) among children with serious injuries at a trauma center in Ghana., Methods: We performed a retrospective cohort study of injured children aged <18 years who required surgery (i.e., proxy for serious injury) at Komfo Anokye Teaching Hospital from 2015 to 2016. Household income data was obtained from the Ghana Statistical Service. CHE was defined as out-of-pocket payments to annual household income ≥10%. Differences in insured and uninsured children were described. Multivariable regression was used to assess the effect of NHIS on time to surgery, length of stay, in-hospital mortality, out-of-pocket expenditure and CHE., Results: Of the 263 children who met inclusion criteria, 70% were insured. Mechanism of injury, triage scores and Kampala Trauma Score II were similar in both groups (all p  > 0.10). Uninsured children were more likely to have a delay in care for financial reasons (17.3 vs 6.4%, p  < 0.001) than insured children, and the families of uninsured children paid a median of 1.7 times more out-of-pocket costs than families with insured children (p < 0.001). Eighty-six percent of families of uninsured children experienced CHE compared to 54% of families of insured children (p < 0.001); however, 64% of all families experienced CHE. Insurance was protective against CHE (aOR 0.21, 95%CI 0.08-0.55)., Conclusions: NHIS did not improve timeliness of care, length of stay or mortality. Although NHIS did provide some financial risk protection for families, it did not eliminate out-of-pocket payments. The families of most seriously injured children experienced CHE, regardless of insurance status. NHIS and similar financial risk pooling schemes could be strengthened to better provide financial risk protection and promote quality of care for injured children., Competing Interests: The authors declared no conflict of interest., (© 2020 African Federation for Emergency Medicine. Publishing services provided by Elsevier.)

Introduction: Few countries in Sub-Saharan Africa have robust emergency medical services (EMS). The World Health Organization (WHO) recommends scaling-up lay first responder programs as the first step toward formal EMS development., Materials and Methods: We trained and equipped 4,529 lay first responders (LFRs) between June-December 2019 in Bombali District, Sierra Leone, with a 5-hour hands-on, contextually-adapted prehospital trauma course to cover 535,000 people. Instructors trained 1,029 LFRs and 50 local trainers in a training-of-trainers (TOT) model, who then trained an additional 3,500 LFRs. A validated, 23-question pre-/post-test measured knowledge improvement, while six- and nine-month follow-up tests measured knowledge retention. Incident reports tracked patient encounters to assess longitudinal impact., Results: Median pre-/post-test scores improved by 43.5 percentage points (34.8% vs. 78.3%, p<0.0001). Knowledge retention was assessed at six months, with median score dropping to 60.9%, while at nine months, median score dropped to 43.5%. Lay first responders participating in courses led by TOT trainers had a pre-/post-test median score improvement of 30.4 percentage points (21.7% vs. 52.2%, p<0.0001). LFRs treated 1,850 patients over six months, most frequently utilizing hemorrhage control skills in 61.2% of encounters (1,133/1,850). The plurality of patients were young adult males (36.8%) and 48.7% of encounters were motorcycle injury-related., Conclusion: A 5-hour first responder course targeting laypeople demonstrates significant emergency care knowledge improvement and retention. By training networks of transportation providers, lay first responder programs represent a robust and scalable prehospital emergency care alternative for low-resource settings., Competing Interests: Declaration of Competing Interest Declarations of interest: none., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective: Breast cancer is the most common cancer diagnosed in low and middle-income countries. Growing the number of health care personnel trained in diagnostic procedures like breast core needle biopsy (BCNB) is critical. We developed a BCNB simulation-training course that evaluated skill acquisition, confidence, and safety, comparing low-cost low fidelity (LF) models to expensive high fidelity (HF) models., Design: A single-center randomized education crossover trial was implemented. Participants were randomized to HF or LF groups. A preintervention baseline exam followed by lectures and training sessions with a HF or LF model was implemented. A postintervention simulation exam was conducted, and participants crossed over to the other simulation model., Setting: The study was implemented at the University Teaching Hospital, Kigali (CHUK) in Rwanda, Africa from October 2014 to March 2015., Participants: Residents training in surgery or obstetrics and gynecology participated in a 1-day BCNB training course., Results: A total of 36 residents were analyzed, 19 in the HF arm and 17 in the LF arm. Mean difference in exam scores for HF and LF groups in the baseline exam (exam 1) (0.067, p = 0.94, standard error [SE] of 1.57) postintervention exam (exam 2) (1.85, SE 1.46, p = 0.33), and the crossover exam (exam 3) (4.39, SE = 1.90, p = 0.11) were not significantly different between HF and LF. Overall exam scores improved from pre- to postintervention., Conclusions: Our results indicate that mean difference in exams scores were not significantly different between residents trained with HF versus LF models. In resources poor areas-LF models can be utilized as effective teaching tools for skill acquisition for diagnostic surgical procedures., (Copyright © 2019 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

Introduction: Induction of programmed death ligand 1 (PD-L1) expression due to constitutive oncogenic signaling has been reported in NSCLC models harboring echinoderm microtubule associated protein like 4 gene (EML4)-ALK receptor tyrosine kinase gene (ALK) rearrangements. We assessed the safety and activity of ceritinib plus nivolumab in these patients., Methods: In this open-label, phase 1B, multicenter, dose escalation and expansion study, previously treated (with ALK receptor tyrosine kinase [ALK] inhibitor [ALKI]/chemotherapy) or treatment-naive patients with stage IIIB or IV ALK-rearranged NSCLC received nivolumab, 3 mg/kg intravenously every 2 weeks, plus ceritinib, 450 mg/300 mg daily, with a low-fat meal., Results: In total, 36 patients were treated (a 450-mg cohort [n=14] and a 300-mg cohort [n=22]). In the 450-mg cohort, four patients experienced dose-limiting toxicities. In the 300-mg cohort, two patients experienced dose-limiting toxicities. Among ALKI-naive patients, the overall response rate (ORR) was 83% (95% confidence interval [CI]: 35.9-99.6) in the 450-mg cohort and 60% (95% CI: 26.2-87.8) in the 300-mg cohort. Among ALKI-pretreated patients, the ORR was 50% (95% CI: 15.7-84.3) in the 450-mg cohort and 25% (95% CI: 5.5-57.2) in the 300-mg cohort. The ORR point estimate was observed to be greater in patients who were positive for PD-L1 than in those who were negative for PD-L1, with overlapping CIs (e.g., at a cutoff ≥1% PD-L1, 64% of patients [95% CI: 35.1-87.2] had confirmed responses as compared with those with negative PD-L1 staining (31% [95% CI: 11.0-58.7]). The most frequently reported grade 3 or 4 adverse events were increased alanine aminotransferase level (25%), increased gamma-glutamyl transferase level (22%), increased amylase level (14%), increased lipase level (11%), and maculopapular rash (11%). The incidence of all-grade rash (grouped term) was 64% in both cohorts; grade 3 rash was reported in 29% and 14% of patients in the 450-mg and 300-mg cohorts, respectively; no grade 4 rash was reported., Conclusion: Ceritinib plus nivolumab has activity; ORR appears to correlate with PD-L1 at baseline. Toxicity, especially rash, is more common than with either single agent., (Copyright © 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Injuries are a leading cause of death and disability globally. Over 90% of injury-related mortality happens in low- and middle- income countries (LMICs). Rwanda's pre-hospital emergency system - Service d'Aide Medicale Urgente (SAMU) - and their partners created an electronic pre-hospital registry and Continuous Quality Improvement (CQI) project in 2014. The CQI showed progress in quality of care, sparking interest in factors enabling the project's success. Healthcare workers (HCW) are critical pieces of this success, yet we found a void of information linking pre-hospital HCW motivation to CQI programs like SAMU's., Methods: Our mixed methods approach included a 40-question survey using questions regarding HCW motivation. We scored the surveys to compare SAMU staff motivation with other HCWs in LMICs, and used a Likert scale to elicit agreement or disagreement. A semi-structured interview based on employee motivation theory qualitatively explored SAMU staff motivation using constructivist grounded theory. To find interview themes, two researchers independently performed line-by-line analysis., Results: SAMU staff received 5-21% higher motivation scores relative to other cohorts of HCWs in LMICs. Questions showing disagreement (five) asked about reprimand, damaged social standing, and ease of using the CQI technology. Three questions did not show consensus. Questions showing agreement (23) and strong agreement (nine) asked about organizational commitment, impact, and research improving patient care. Major themes were: improvements in quality of care, changes in job expectations, views on research, and positive experiences with data feedback., Conclusions: The CQI project provides constant feedback vital to building and sustaining successful health systems. It encourages communication, collaboration, and personal investment, which increase organizational commitment. Continuous feedback provides opportunities for personal and professional development by uncovering gaps in knowledge, patient care, and technological understanding. Complete, personalized data input encouraged by the CQI improves resource allocation, building robust health systems that improve HCW agency and motivation., (© 2020 African Federation for Emergency Medicine. Publishing services provided by Elsevier.)

Objective: A substantial proportion of adverse intraoperative events are attributed to failures in nontechnical skills. To strengthen these skills and improve surgical safety, the Non-Technical Skills for Surgeons (NOTSS) taxonomy was developed as a common framework. The NOTSS taxonomy was adapted for low- and middle-income countries, where variable resources pose a significant challenge to safe surgery. The NOTSS for variable-resource contexts (VRC) curriculum was developed and implemented in Rwanda, with the aim of enhancing knowledge and attitudes about nontechnical skills and promoting surgical safety., Design: The NOTSS-VRC curriculum was developed through a rigorous process of integrating contextually appropriate values. It was implemented as a 1-day training course for surgical and anesthesia postgraduate trainees. The curriculum comprises lectures, videos, and group discussions. A pretraining and posttraining questionnaire was administered to compare knowledge and attitudes regarding nontechnical skills, and their potential to improve surgical safety., Setting: The setting of this study was in the tertiary teaching hospital of Kigali, Rwanda., Participants: Participants were residents of the University of Kigali. A total of 55 residents participated from general surgery (31.4%), obstetrics (25.5%), anesthesia (17.6%), and other surgical specialties (25.5%)., Results: In a paired analysis, understanding of NOTSS improved significantly (55.6% precourse, 80.9% postcourse, p<0.01). All residents reported that the course would improve their ability to provide safer patient care, and 97.4% believed developing nontechnical skills would improve patient outcomes., Conclusions: Nontechnical skills must be highlighted in surgical training in low- and middle-income countries. The NOTSS-VRC curriculum can be implemented without additional technology or significant financial cost. Its deliberate design for resource-constrained settings allows it to be used both as an educational course and a quality improvement strategy. Our research demonstrates it is feasible to improve knowledge and attitudes about NOTSS through a 1-day course, and represents a novel approach to improving global surgical safety., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Ceritinib, 750 mg fasted, is approved for treatment of patients with ALK receptor tyrosine kinase gene (ALK)-rearranged (ALK-positive) NSCLC previously treated with crizotinib. Part 1 of the ASCEND-8 study determined whether administering ceritinib, 450 mg or 600 mg, with a low-fat meal may enhance gastrointestinal (GI) tolerability versus 750 mg fasted in patients with ALK-positive NSCLC while maintaining similar exposure., Methods: ASCEND-8 is a multicenter, randomized, open-label, phase 1 study. Part 1 investigated the steady-state pharmacokinetics (PK) and safety of ceritinib, 450 mg or 600 mg, taken with a low-fat meal versus 750 mg fasted in patients with advanced ALK-positive NSCLC who were either treatment naive or pretreated with chemotherapy and/or crizotinib. Part 2 will assess efficacy and safety of ceritinib in treatment-naive patients., Results: As of June 16, 2016, 137 patients were randomized (450 mg fed [n = 44], 600 mg fed [n = 47], and 750 mg fasted [n = 46]); 135 patients received ceritinib. Median follow-up duration was 4.14 months. At steady state, relative to 750 mg fasted, 450 mg with food demonstrated comparable PK as assessed by maximum (peak) concentration of drug in plasma and area under the plasma concentration-time curve from time zero to 24 hours, whereas 600 mg with food demonstrated approximately 25% higher PK. Relative to 750 mg fasted, 450 mg with food was associated with a lower proportion of patients with GI toxicities, mostly grade 1 (diarrhea [43.2%], nausea [29.5%], and vomiting [18.2%]); there were no grade 3 or 4 events, study drug discontinuations, or serious AEs due to GI toxicities., Conclusion: Ceritinib, 450 mg with food, had similar exposure and a more favorable GI safety profile than ceritinib, 750 mg in fasted patients with ALK-positive NSCLC., (Copyright © 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Introduction: Injury is a major cause of premature death and disability in East Africa, and high-quality pre-hospital care is essential for optimal trauma outcomes. The Rwandan pre-hospital emergency care service (SAMU) uses an electronic database to evaluate and optimize pre-hospital care through a continuous quality improvement programme (CQIP), beginning March 2014., Materials and Methods: The SAMU database was used to assess pre-hospital quality metrics including supplementary oxygen for hypoxia (O2), intravenous fluids for hypotension (IVF), cervical collar placement for head injuries (c-collar), and either splinting (splint) or administration of pain medications (pain) for long bone fractures. Targets of >90% were set for each metric and daily team meetings and monthly feedback sessions were implemented to address opportunities for improvement. These five pre-hospital quality metrics were assessed monthly before and after implementation of the CQIP. Met and unmet needs for O2, IVF, and c-collar were combined into a summative monthly SAMU Trauma Quality Scores (STQ score). An interrupted time series linear regression model compared the STQ score during 14 months before the CQIP implementation to the first 14 months after., Results: During the 29-month study period 3,822 patients met study criteria. 1,028 patients needed one or more of the five studied interventions during the study period. All five endpoints had a significant increase between the pre-CQI and post-CQI periods (p<0.05 for all), and all five achieved a post-CQI average of at least 90% completion. The monthly composite STQ scores ranged from 76.5 to 97.9 pre-CQI, but tightened to 86.1-98.7 during the post-CQI period. Interrupted time series analysis of the STQ score showed that CQI programme led to both an immediate improvement of +6.1% (p=0.017) and sustained monthly improvements in care delivery-improving at a rate of 0.7% per month (p=0.028)., Conclusion: The SAMU experience demonstrates the utility of a responsive, data-driven quality improvement programme to yield significant immediate and sustained improvements in pre-hospital care for trauma in Rwanda. This programme may be used as an example for additional efforts engaging frontline staff with real-time data feedback in order to rapidly translate data collection efforts into improved care for the injured in a resource-limited setting., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Introduction: Injury accounts for 9.6% of the global mortality burden, disproportionately affecting those living in low- and middle-income countries. In an effort to improve trauma care in Rwanda, the Ministry of Health developed a prehospital service, Service d'Aide Médicale Urgente (SAMU), and established an emergency medicine training program. However, little is known about patients receiving prehospital and emergency trauma care or their outcomes. The objective was to develop a linked prehospital-hospital database to evaluate patient characteristics, mechanisms of injury, prehospital and hospital resource use, and outcomes among injured patients receiving acute care in Kigali, Rwanda., Methods: A retrospective cohort study was conducted at University Teaching Hospital - Kigali, the primary trauma centre in Rwanda. Data was included on all injured patients transported by SAMU from December 2012 to February 2015. SAMU's prehospital database was linked to hospital records and data were collected using standardised protocols by trained abstractors. Demographic information, injury characteristics, acute care, hospital course and outcomes were included., Results: 1668 patients were transported for traumatic injury during the study period. The majority (77.7%) of patients were male. The median age was 30 years. Motor vehicle collisions accounted for 75.0% of encounters of which 61.4% involved motorcycles. 48.8% of patients sustained injuries in two or more anatomical regions. 40.1% of patients were admitted to the hospital and 78.1% required surgery. The overall mortality rate was 5.5% with nearly half of hospital deaths occurring in the emergency centre., Conclusion: A linked prehospital and hospital database provided critical epidemiological information describing trauma patients in a low-resource setting. Blunt trauma from motor vehicle collisions involving young males constituted the majority of traumatic injury. Among this cohort, hospital resource utilisation was high as was mortality. This data can help guide the implementation of interventions to improve trauma care in the Rwandan setting.

Academic global surgery is a nascent field focused on improving surgical care in resource-poor settings through a broad-based scholarship agenda. Although there is increasing momentum to expand training opportunities in low-resource settings among academic surgical programs, most focus solely on establishing short-term elective rotations rather than fostering research or career development. Given the complex nature of surgical care delivery and programmatic capacity building in the resource-poor settings, many challenges remain before global surgery is accepted as an academic discipline and an established career path. Brigham and Women's Hospital has established a specialized global surgery track within the general surgery residency program to develop academic leaders in this growing area of need and opportunity. Here we describe our experience with the design and development of the program followed by practical applications and lessons learned from our early experiences., (Copyright © 2015 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

The AMP-activated protein kinase (AMPK) is a metabolic stress-sensing αβγ heterotrimer responsible for energy homeostasis. Pharmacological inhibition of AMPK is regarded as a therapeutic strategy in some disease settings including obesity and cancer; however, the broadly used direct AMPK inhibitor compound C suffers from poor selectivity. We have discovered a dihydroxyquinoline drug (MT47-100) with novel AMPK regulatory properties, being simultaneously a direct activator and inhibitor of AMPK complexes containing the β1 or β2 isoform, respectively. Allosteric inhibition by MT47-100 was dependent on the β2 carbohydrate-binding module (CBM) and determined by three non-conserved CBM residues (Ile81, Phe91, Ile92), but was independent of β2-Ser108 phosphorylation. Whereas MT47-100 regulation of total cellular AMPK activity was determined by β1/β2 expression ratio, MT47-100 augmented glucose-stimulated insulin secretion from isolated mouse pancreatic islets via a β2-dependent mechanism. Our findings highlight the therapeutic potential of isoform-specific AMPK allosteric inhibitors., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Billions of people worldwide lack access to surgical care; this is in part driven by severe shortages in the global surgical workforce. Task shifting, the movement of tasks to associate clinicians or non-specialist physicians, is a commonly implemented yet often contentious strategy to expand the surgical workforce. A more complete understanding of the global distribution and use of surgical and anaesthetic task shifting is needed to strengthen strategic planning efforts to bridge the gap between surgical and anaesthetic providers. We aimed to document the use of task shifting worldwide with an in-depth review of the literature and subsequent confirmation of practices through a provider survey., Methods: We did a literature search according to PRISMA guidelines. We searched PubMed, Embase, The Cochrane Library, CINAHL, WHOLIS, and five regional databases for journal articles published between Jan 1, 1995, and Aug 29, 2014, for titles or abstracts mentioning surgical or anaesthetic care provision by associate clinicians or non-specialist physicians. We also searched article references and online resources. We extracted data for health cadres performing task shifting, the types of tasks performed, training programmes, and supervision of those performing tasks and compared these across regions and income groups. Additionally, we then undertook an unvalidated survey to investigate the use of task shifting at the country level, which was sent to surgeons and anaesthetists in 19 countries across all major regions of the world., Findings: We identified 62 studies. The review and survey provided data for 163 and 51 countries respectively, totalling 174 countries. Surgical task shifting occured in 30 (33%) of 92 countries. Anaesthetic task shifting occured in 108 (65%) of 165 countries. Task shifting was documented across all World Bank income groups. Where relevant data were available, in high-income countries, associate clinicians were commonly supervised (100% [four countries] for surgery and 90% [20 countries] for anaesthesia). In low-income countries, associate clinicians undertook surgical and anaesthetic procedures without supervision (100% for surgery [five countries] and 100% for anaesthesia [22 countries])., Interpretation: Task shifting is used to augment the global surgical workforce across all geographical regions and income groups. Associate clinicians are ubiquitous among the global surgical workforce and should be considered in plans to scale up the surgical workforce in countries with workforce shortages. Reporting bias is likely to have favoured the more novel and successful task shifting initiatives, which could have caused our results to underestimate the absolute number of countries that use task shifting. Although surgical and anaesthetic task shifting has been described in many countries, further research is required to assess outcomes, especially in low-income and middle-income countries where supervision is less robust., Funding: None., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The AMP-activated protein kinase (AMPK) is a metabolic stress-sensing αβγ heterotrimer responsible for energy homeostasis, making it a therapeutic target for metabolic diseases such as type 2 diabetes and obesity. AMPK signaling is triggered by phosphorylation on the AMPK α subunit activation loop Thr172 by upstream kinases. Dephosphorylated, naive AMPK is thought to be catalytically inactive and insensitive to allosteric regulation by AMP and direct AMPK-activating drugs such as A-769662. Here we show that A-769662 activates AMPK independently of α-Thr172 phosphorylation, provided β-Ser108 is phosphorylated. Although neither A-769662 nor AMP individually stimulate the activity of dephosphorylated AMPK, together they stimulate >1,000-fold, bypassing the requirement for β-Ser108 phosphorylation. Consequently A-769662 and AMP together activate naive AMPK entirely allosterically and independently of upstream kinase signaling. These findings have important implications for development of AMPK-targeting therapeutics and point to possible combinatorial therapeutic strategies based on AMP and AMPK drugs., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

The AMP-activated protein kinase (AMPK) regulates cellular and whole-body energy balance in response to changes in adenylate charge and hormonal signals. Activation of AMPK in tissues such as skeletal muscle and liver reverses many of the metabolic defects associated with obesity and Type 2 diabetes. Here we report a bi-quinoline (JJO-1) that allosterically activates all AMPK αβγ isoforms in vitro except complexes containing the γ3 subunit. JJO-1 does not directly activate the autoinhibited α subunit kinase domain and differs among other known direct activators of AMPK in that allosteric activation occurs only at low ATP concentrations, and is not influenced by either mutation of the γ subunit adenylate-nucleotide binding sites or deletion of the β subunit carbohydrate-binding module. Our findings indicate that AMPK has multiple modes of allosteric activation that may be exploited to design isoform-specific activators as potential therapeutics for metabolic diseases., (Copyright © 2013 Elsevier Inc. All rights reserved.)

We describe a new method of selective regional perfusion during arch reconstruction in the Norwood procedure. The strategy involves direct sequential perfusion of the coronary and splanchnic circulations coupled with continuous cerebral perfusion, while repairing the arch in a distal to proximal fashion. This technique provides the potential for decreased coronary and splanchnic ischemic times, which in combination with continuous selective cerebral perfusion may further allow for warmer operating temperatures and decreased overall bypass times., (Copyright © 2011 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

The purpose of this project was to compare the ability of chlorine (HOCl/OCl(-)) and monochloramine (NH(2)Cl) to mobilize mercury from dental amalgam. Two types of amalgam were used in this investigation: laboratory-prepared amalgam and samples obtained from dental-unit wastewater. For disinfectant exposure simulations, 0.5 g of either the laboratory-generated or clinically obtained amalgam waste was added to 250 mL amber bottles. The amalgam samples were agitated by end-over-end rotation at 30 rpm in the presence of 1 mg/L chlorine, 10 mg/L chlorine, 1 mg/L monochloramine, 10 mg/L monochloramine, or deionized water for intervals of 0 h, 2 h, 4 h, 8 h, and 24 h for the clinically obtained amalgam waste samples and 4 h and 24 h for the laboratory-prepared samples. Chlorine and monochloramine concentrations were measured with a spectrophotometer. Samples were filtered through a 0.45 microm membrane filter and analyzed for mercury with USEPA standard method 245.7. When the two sample types were combined, the mean mercury level in the 1 mg/L chlorine group was 0.020 mg/L (n=25, SD=0.008). The 10 mg/L chlorine group had a mean mercury concentration of 0.59 mg/L (n=25, SD=1.06). The 1 mg/L chloramine group had a mean mercury level of 0.023 mg/L (n=25, SD=0.010). The 10 mg/L chloramine group had a mean mercury level of 0.024 mg/L (n=25, SD=0.011). Independent samples t-tests showed that there was a significant difference between the natural log mercury measurements of 10 mg/L chlorine compared to those of 1 mg/L and 10 mg/L chloramine. Changing from chlorine to chloramine disinfection at water treatment plants would not be expected to produce substantial increases in dissolved mercury levels in dental-unit wastewater.

The AMP-activated protein kinase (AMPK) is an alphabetagamma heterotrimer that plays a pivotal role in regulating cellular and whole-body metabolism. Activation of AMPK reverses many of the metabolic defects associated with obesity and type 2 diabetes, and therefore AMPK is considered a promising target for drugs to treat these diseases. Recently, the thienopyridone A769662 has been reported to directly activate AMPK by an unexpected mechanism. Here we show that A769662 activates AMPK by a mechanism involving the beta subunit carbohydrate-binding module and residues from the gamma subunit but not the AMP-binding sites. Furthermore, A769662 exclusively activates AMPK heterotrimers containing the beta1 subunit. Our findings highlight the regulatory role played by the beta subunit in modulating AMPK activity and the possibility of developing isoform specific therapeutic activators of this important metabolic regulator.

Objectives: To report the Mayo Clinic experience of Q fever endocarditis., Background: Q fever endocarditis is rare in North America with few case reports in the literature. The Centers for Disease Control lists Q fever as a reportable illness but does not differentiate endocarditis as a syndrome in its database., Methods: A search of the database for elevated Q fever IgG serology at our institution was conducted from December 1980 to December 2005. Patients with elevated serologies were retrospectively identified and their medical records were reviewed to determine which cases met criteria for a diagnosis of endocarditis., Results: Eight patients with elevated serology were identified. One case failed to meet criteria and was therefore excluded. All patients presented with fever and had previously diagnosed valvular disease. Only 3 patients had valvular vegetations on transesophageal echocardiography. All 7 patients were treated with antimicrobial therapy, which was not uniform. Six required surgical intervention on the affected valves, and 2 required multiple valve surgeries. Follow-up ranged from 1 to 17 years., Conclusions: Q fever endocarditis is a rare disease in the United States, where no reliable reporting exists. Q fever endocarditis involves underlying abnormal native valves or prosthetic valves. Vegetations are small or absent. Relapses are common. Surgeries are common adding to morbidity and cost. The chronicity of the syndrome and its high morbidity mandate an increased awareness of the condition in patients with culture-negative endocarditis or unexplained perivalvular leaks detected by echocardiography. Appropriate diagnosis and tailored treatment are likely to reduce the need for repeat surgeries.

Left pulmonary artery hypoplasia in the setting of Fontan circulation predisposes to pulmonary artery discontinuity. We describe a novel approach to correct post-Fontan left pulmonary artery discontinuity by a strategy to produce isolated left pulmonary artery growth, followed by a catheter-based reincorporation of the left pulmonary artery into the Fontan circuit.

We have expressed a truncated form of the alpha1 kinase domain of AMP-activated protein kinase (AMPK) in Escherichia coli as a glutathione-S-transferase fusion (GST-KD). A T172D mutant version did not require prior phosphorylation and was utilized for most subsequent studies. We have also created a recombinant substrate (GST-ACC) by expressing 34 residues around the major phosphorylation site (Ser79) on rat acetyl-CoA carboxylase-1/alpha (ACC1) as a GST fusion. This was an excellent substrate that was phosphorylated with similar kinetic parameters to ACC1 by both native AMPK and the bacterially expressed kinase domain. We also constructed a structural model for the binding of the ACC1 sequence to the kinase domain, based on crystal structures for related protein kinases. The model was tested by making a total of 25 mutants of GST-ACC and seven mutants of GST-KD, and measuring kinetic parameters with different combinations. The results reveal that AMPK and ACC1 interact over a much wider region than previously realized (>20 residues). The features of the interaction can be summarised as follows: (i) an amphipathic helix from P-16 to P-5 on the substrate binds in a hydrophobic groove on the large lobe of the kinase; (ii) basic residues at P-6 and P-4 bind to two acidic patches (D215/D216/D217 and E103/D100/E143, respectively), on the large lobe; (iii) a histidine at P+3 interacts with D56 on the small lobe; (iv) the side-chain of P+4 leucine could not be precisely positioned, but a new finding was that asparagine or glutamine could replace a hydrophobic residue at this position. These interactions position the serine residue to be phosphorylated in close proximity to the gamma-phosphate group of ATP. Although based on modelling rather than a determined structure, this represents one of the most detailed studies of the interaction between a kinase and its substrate achieved to date., (Copyright 2002 Elsevier Science Ltd.)

CL 306,293, a substituted quinoline carboxylic acid, is a potent inhibitor of dihydroorotic acid dehydrogenase, an enzyme essential for the biosynthesis of pyrimidines. In mammalian cell culture, the agent exhibits antiproliferative properties that can be reversed by the addition of uridine. CL 306,293 inhibits the development of the clinical disease in a murine model of immunodeficiency induced by a mixture of LP-BM5 retroviruses. In infected mice, the agent prevents the development of hypergammaglobulinemia, lymphadenopathy, splenomegaly and induction of an IL-2 deficiency. The CD4/CD8 ratio and the number of B cells in the lymph nodes are decreased if the infected animals are treated with CL 306,293. CL 306,293 was more efficacious and potent than 3'-azido-3'-deoxythymidine. The beneficial effects of CL 306,293 observed in this model are most probably related to its antiproliferative properties.

Management of heart transplant patients who are being given cyclosporine is complicated by the variety of methods available for measuring cyclosporine levels and the current trend toward exclusive use of monoclonal assays. To facilitate clinical decisions regarding cyclosporine levels when converting from a polyclonal system to monoclonal system, 79 heart transplant patients underwent a prospective study to compare the polyclonal radioimmunoassay with the monoclonal-specific parent compound and nonspecific radioimmunoassays. Multivariable regression analyses were performed to generate best-fit equations for conversion of one assay to another. The closest correlation was noted in converting the measurement of cyclosporine parent compound with metabolites by the polyclonal method to the monoclonal method (nonspecific), R2 = 0.93. Considerable variability existed in the relationship between polyclonal and monoclonal-specific levels (R2 = 0.66) and between monoclonal-nonspecific and monoclonal-specific levels (R2 = 0.66), and both relationships were affected by hepatic function. Inferences: (1) The conversion of numeric cyclosporine levels from parent compound to parent plus metabolites is not completely predictable and must be empirically determined with the generation of appropriate regression equations. (2) Caution is advisable when a transplant team adopts a new cyclosporine assay for clinical use; formal study between existing assay methods and any newly adopted assay is warranted to prevent inadvertent underdosing or overdosing with cyclosporine.