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Assessing the foraging ecology of a threatened species is necessary to understand their movement behaviour and habitat use patterns, which are essential for developing effective protection strategies. Here, the foraging ecology of reef manta rays (Mobula alfredi) in the Chagos Archipelago, a region encompassed by a vast no-take marine protected area (MPA), was investigated using stable isotope analysis of skin and muscle tissue. Enriched δ13C values suggest the population predominantly forages in nearshore environments. Skin δ13C values increased with increased rainfall, likely associated with the boosts in primary production and zooplankton biomass due to the coastal advection of seabird guano. Annual variations in δ13C values of skin and muscle were observed and are consistent with reduced nutrient transport associated with the effects of Indian Ocean Dipole oscillations, including a deepening of the thermocline, a suppression of cold-water upwelling, and reduced rainfall. Short- and long-term foraging strategies and locations were identified by applying hierarchical clustering, isotopic niche analysis, and Bayesian stable isotope mixing models to δ13C and δ15N of paired skin and muscle tissue samples. Two isotopically distinct groups of M. alfredi were identified, employing either local foraging strategies restricted to specific locations or wide-ranging strategies that likely mean they engage in regular migrations throughout the archipelago. Ninety-eight percent of M. alfredi were estimated to switch between strategies utilising and connecting multiple discrete nearshore habitats, emphasising their role in ecosystem functioning by facilitating the transport of nutrients across ecosystem boundaries. However, illegal, unreported, and unregulated fishing and lost or abandoned fishing gear commonly occur within the MPA. Locations of particular concern are Egmont Atoll as it is a highly active aggregation location and Peros Banhos Atoll where IUU frequently occurs and M. alfredi are estimated to be heavily reliant upon for foraging. Frequent migrations between atolls by M. alfredi also raises concern over their vulnerability to these activities along migration corridors. This research bridges current knowledge gaps in this population's foraging ecology and concomitant movement patterns, which should inform conservation strategies in the region.

Noonan syndrome (NS) is a genetic disorder with distinctive physical features and often multiple organ involvement. Bleeding disorders are reported in over half of patients with NS, including thrombocytopenia and platelet dysfunction. Neonatal alloimmune thrombocytopenia (NAIT) is an alloantigenic thrombocytopenia that can present with severe bleeding. Here, we present a case of intracranial hemorrhage and severe thrombocytopenia in a neonate found to have both NAIT and a de novo heterozygous pathogenic variant in PTPN11, consistent with Noonan syndrome.

The purpose of the study was to characterize a detection system based on inorganic scintillators and determine its suitability for dosimetry in preclinical radiation research. Dose rate, linearity, and repeatability of the response (among others) were assessed for medium-energy X-ray beam qualities. The response’s variation with temperature and beam angle incidence was also evaluated. Absorbed dose quality-dependent calibration coefficients, based on a cross-calibration against air kerma secondary standard ionization chambers, were determined. Relative output factors (ROF) for small, collimated fields (≤10 mm × 10 mm) were measured and compared with Gafchromic film and to a CMOS imaging sensor. Independently of the beam quality, the scintillator signal repeatability was adequate and linear with dose. Compared with EBT3 films and CMOS, ROF was within 5% (except for smaller circular fields). We demonstrated that when the detector is cross-calibrated in the user’s beam, it is a useful tool for dosimetry in medium-energy X-rays with small fields delivered by Image-Guided Small Animal Radiotherapy Platforms. It supports the development of procedures for independent “live” dose verification of complex preclinical radiotherapy plans with the possibility to insert the detectors in phantoms.

Abstract Background The Democratic Republic of the Congo (DRC) boasts one of the highest rates of institutional deliveries in sub-Saharan Africa (80%), with eight out of every ten births also assisted by a skilled provider. However, the maternal and neonatal mortality are still among the highest in the world, which demonstrates the poor in-facility quality of maternal and newborn care. The objective of this ongoing project is to design, implement, and evaluate a clinical mentorship program in 72 health facilities in two rural provinces of Kwango and Kwilu, DRC. Methods This is an ongoing quasi-experimental study. In the 72 facilities, 48 facilities were assigned to the group where the clinical mentorship program is being implemented (intervention group), and 24 facilities were assigned to the group where the clinical mentorship program is not being implemented (control group). The groups were selected and assigned based on administrative criteria, taking into account the number of deliveries in each facility, the coverage of health zones, accessibility, and ease of implementation of a clinical mentorship program. The main activities are organizing and training a national team of mentors (including senior midwives, obstetricians, and pediatricians) in clinical mentoring, deploying them to mentor all health providers (mentees) performing maternal and newborn health (MNH) services, and providing in-service training in routine and Emergency Obstetrical and Newborn Care (EmONC) to the mentees in health facilities over an 18-month period. Baseline and endline assessments are carried out to evaluate the effectiveness of the clinical mentorship program on the quality of MNH care and the effective coverage of key interventions to reduce maternal and neonatal mortality. Findings will be disseminated nationwide and internationally, as scientific evidence is scarce. A national strategy, guidelines, and tools for clinical mentorship in MNH will be developed for replication in other provinces, thus benefitting the entire country. Discussion This is the largest project on clinical mentorship aimed to improving the quality of MNH care in Africa. This program is expected to generate one of the first pieces of scientific evidence on the effectiveness of a clinical mentorship program in MNH on a scientifically designed and sustainable model.

African spitting cobras are unique among cobras for their potent anticoagulant venom activity arising from strong inhibition of Factor Xa. This anticoagulant effect is exerted by venom phospholipase A2 (Group I PLA2) toxins whose activity contributes to the lethality of these species. This anticoagulant toxicity is particularly problematic as it is not neutralized by current antivenoms. Previous work demonstrated this trait for Naja mossambica, N. nigricincta, N. nigricollis, and N. pallida. The present work builds upon previous research by testing across the full taxonomical range of African spitting cobras, demonstrating that N. ashei, N. katiensis, and N. nubiae are also potently anticoagulant through the inhibition of Factor Xa, and therefore the amplification of potent anticoagulant activity occurred at the base of the African spitting cobra radiation. Previous work demonstrated that the enzyme-inhibitor varespladib was able to neutralize this toxic action for N. mossambica, N. nigricincta, N. nigricollis, and N. pallida venoms. The current work demonstrates that varespladib was also able to neutralize N. ashei, N. katiensis, and N. nubiae. Thus varespladib is shown to have broad utility across the full range of African spitting cobras. In addition, we examined the cross-reactivity of the metalloprotease inhibitor prinomastat, which had been previously intriguingly indicated as being capable of neutralizing viperid venom PLA2 (Group II PLA2). In this study prinomastat inhibited the FXa-inhibiting PLA2 toxins of all the African spitting cobras at the same concentration at which it has been shown to inhibit metalloproteases, and thus was comparably effective in its cross-reactivity. In addition we showed that the metalloprotease-inhibitor marimastat was also able to cross-neutralize PLA2 but less effectively than prinomastat. Due to logistical (cold-chain requirement) and efficacy (cross-reactivity across snake species) limitations of traditional antivenoms, particularly in developing countries where snakebite is most common, these small molecule inhibitors (SMIs) might hold great promise as initial, field-based, treatments for snakebite envenoming as well as addressing fundamental limitations of antivenom in the clinical setting where certain toxin effects are unneutralized.

The African viperid snake genera Atheris, Cerastes, and Proatheris are closely related, similar in size, but occupy extremely divergent ecological niches (arboreal in tropical rainforests, fossorial in deserts, and swamp-dwelling, respectively). Their venoms have not previously been subjected to comparative analyses for their action upon the coagulation of blood, most notably with significant data deficiencies from Atheris and Proatheris. In contrast, the closely related genus Echis is well-documented as capable of producing potent procoagulant effects. In light of this, we set out to compare the coagulotoxic actions of Atheris ceratophora, A. chlorechis, A. desaixi, A. nitschei, A. squamigera, C. cerastes, C. cerastes gasperettii, C. vipera, and Proatheris superciliaris and explore potential pharmacological interventions to reestablish normal blood coagulation. All venoms displayed extremely potent procoagulant effects, over twice as fast as the most potent Echis reported to date. Although Cerastes is used in the immunising mixture of two different regionally available antivenoms (Inoserp-MENA with C. cerastes, C. cerastes gasperettii, C. vipera and Saudi Arabian polyvalent with C. cerastes), none of the other species in this study are included in the immunising mixture of any antivenom. Notably, all the Cerastes species were only neutralised by the Inoserp-MENA antivenom. C. cerastes venom was not neutralised well by the Saudi Arabian antivenom, with the low levels of recognition for any of the Cerastes venoms suggesting a strong regional variation in the venom of this species, as the C. cerastes venom tested was of African (Tunisian) origin versus Saudi locality used in that antivenom’s production. The other antivenoms (Micropharm EchiTAbG, ICP EchiTAb-Plus-ICP, Inosan Inoserp Pan-Africa, Premium Serums PANAF Sub-Sahara Africa, South African Vaccine Producers Echis, South African Vaccine Producers Polyvalent) all displayed trivial-to-no ability to neutralise the procoagulant toxicity of any of the Atheris, Cerastes, or Proatheris venoms. Comparative testing of the enzyme inhibitors DMPS, marimastat, and prinomastat, revealed a very potent neutralising capacity of marimastat, with prinomastat showing lower but still significant potency at the same molar concentration, while a 5× molar concentration of DMPS had no apparent effect on procoagulant venom effects normalized by the other inhibitors. These results and methods contribute to the body of knowledge of potential clinical effects and data necessary for evidence-based advancement of clinical management strategies.

Within Neotropical pit-vipers, the Mexican/Central-American clade consisting of Atropoides, Cerrophidion, Metlapilcoatlus, and Porthidium is a wide-ranging, morphologically and ecologically diverse group of snakes. Despite their prevalence, little is known of the functional aspects of their venoms. This study aimed to fill the knowledge gap regarding coagulotoxic effects and to examine the potential of different therapeutic approaches. As a general trait, the venoms were shown to be anticoagulant but were underpinned by diverse biochemical actions. Pseudo-procoagulant activity (i.e., thrombin-like), characterized by the direct cleavage of fibrinogen to form weak fibrin clots, was evident for Atropoides picadoi, Cerrophidiontzotzilorum, Metlapilcoatlus mexicanus, M. nummifer, M. occiduus, M. olmec, and Porthidium porrasi. In contrast, other venoms cleaved fibrinogen in a destructive (non-clotting) manner, with C. godmani and C. wilsoni being the most potent. In addition to actions on fibrinogen, clotting enzymes were also inhibited. FXa was only weakly inhibited by most species, but Cerrophidion godmani and C. wilsoni were extremely strong in their inhibitory action. Other clotting enzymes were more widely inhibited by diverse species spanning the full taxonomical range, but in each case, there were species that had these traits notably amplified relatively to the others. C. godmani and C. wilsoni were the most potent amongst those that inhibited the formation of the prothrombinase complex and were also amongst the most potent inhibitors of Factor XIa. While most species displayed only low levels of thrombin inhibition, Porthidium dunni potently inhibited this clotting factor. The regional polyvalent antivenom produced by Instituto Picado Clodomiro was tested and was shown to be effective against the diverse anticoagulant pathophysiological effects. In contrast to the anticoagulant activities of the other species, Porthidium volcanicum was uniquely procoagulant through the activation of Factor VII and Factor XII. This viperid species is the first snake outside of the Oxyuranus/Pseudonaja elapid snake clade to be shown to activate FVII and the first snake venom of any kind to activate FXII. Interestingly, while small-molecule metalloprotease inhibitors prinomastat and marimastat demonstrated the ability to prevent the procoagulant toxicity of P. volcanicum, neither ICP antivenom nor inhibitor DMPS showed this effect. The extreme variation among the snakes here studied underscores how venom is a dynamic trait and how this can shape clinical outcomes and influence evolving treatment strategies.

Palearctic vipers are medically significant snakes in the genera Daboia, Macrovipera, Montivipera, and Vipera which occur throughout Europe, Central Asia, Near and Middle East. While the ancestral condition is that of a small-bodied, lowland species, extensive diversification has occurred in body size, and niche specialization. Using 27 venom samples and a panel of in vitro coagulation assays, we evaluated the relative coagulotoxic potency of Palearctic viper venoms and compared their neutralization by three antivenoms (Insoserp Europe, VIPERFAV and ViperaTAb) and two metalloprotease inhibitors (prinomastat and DMPS). We show that variation in morphology parallels variation in the Factor X activating procoagulant toxicity, with the three convergent evolutions of larger body sizes (Daboia genus, Macrovipera genus, and Vipera ammodytes uniquely within the Vipera genus) were each accompanied by a significant increase in procoagulant potency. In contrast, the two convergent evolutions of high altitude specialization (the Montivipera genus and Vipera latastei uniquely within the Vipera genus) were each accompanied by a shift away from procoagulant action, with the Montivipera species being particularly potently anticoagulant. Inoserp Europe and VIPERFAV antivenoms were both effective against a broad range of Vipera species, with Inoserp able to neutralize additional species relative to VIPERFAV, reflective of its more complex antivenom immunization mixture. In contrast, ViperaTAb was extremely potent in neutralizing V. berus but, reflective of this being a monovalent antivenom, it was not effective against other Vipera species. The enzyme inhibitor prinomastat efficiently neutralized the metalloprotease-driven Factor X activation of the procoagulant venoms. In contrast, DMPS (2,3-dimercapto-1-propanesulfonic acid), which as been suggested as another potential treatment option in the absence of antivenom, DMPS failed against all venoms tested. Overall, our results highlight the evolutionary variations within Palearctic vipers and help to inform clinical management of viper envenomation.

Objective Patients with BRAF-mutant colorectal cancer (CRC) have a poor prognosis. Molecular status is not currently used to select which drug to use in combination with radiotherapy. Our aim was to identify drugs that radiosensitise CRC cells with known BRAF status.Methods We screened 298 oncological drugs with and without ionising radiation in colorectal cancer cells isogenic for BRAF. Hits from rank product analysis were validated in a 16-cell line panel of human CRC cell lines, using clonogenic survival assays and xenograft models in vivo.Results Most consistently identified hits were drugs targeting cell growth/proliferation or DNA damage repair. The most effective class of drugs that radiosensitised wild-type and mutant cell lines was PARP inhibitors. In clonogenic survival assays, talazoparib produced a radiation enhancement ratio of 1.9 in DLD1 (BRAF-wildtype) cells and 1.8 in RKO (BRAF V600E) cells. In DLD1 xenografts, talazoparib significantly increased the inhibitory effect of radiation on tumour growth (P ≤ 0.01). Conclusions Our method for screening large drug libraries for radiosensitisation has identified PARP inhibitors as promising radiosensitisers of colorectal cancer cells with wild-type and mutant BRAF backgrounds.

Snakebite remains a significant public health burden globally, disproportionately affecting low-income and impoverished regions of the world. Recently, researchers have begun to focus on the use of small-molecule inhibitors as potential candidates for the neutralisation of key snake venom toxins and as potential field therapies. Bitis vipers represent some of the most medically important as well as frequently encountered snake species in Africa, with a number of species possessing anticoagulant phospholipase A2 (PLA2) toxins that prevent the prothrombinase complex from inducing clot formation. Additionally, species within the genus are known to exert pseudo-procoagulant activity, whereby kallikrein enzymatic toxins cleave fibrinogen to form a weak fibrin clot that rapidly degrades, thereby depleting fibrinogen levels and contributing to the net anticoagulant state. Utilising well-validated coagulation assays measuring time until clot formation, this study addresses the in vitro efficacy of three small molecule enzyme inhibitors (marimastat, prinomastat and varespladib) in neutralising these aforementioned activities. The PLA2 inhibitor varespladib showed the greatest efficacy for the neutralisation of PLA2-driven anticoagulant venom activity, with the metalloproteinase inhibitors prinomastat and marimastat both showing low and highly variable degrees of cross-neutralisation with PLA2 anticoagulant toxicity. However, none of the inhibitors showed efficacy in neutralising the pseudo-procoagulant venom activity exerted by the venom of B. caudalis. Our results highlight the complex nature of snake venoms, for which single-compound treatments will not be universally effective, but combinations might prove highly effective. Despite the limitations of these inhibitors with regards to in vitro kallikrein enzyme pseudo-procoagulant venom activity, our results further support the growing body of literature indicating the potential use of small molecule inhibitors to enhance first-aid treatment of snakebite envenoming, particularly in cases where hospital and thus antivenom treatment is either unavailable or far away.

Background . Pediatric obesity has become a significant public health concern. Pediatricians are the ideal group to help identify and treat this epidemic, but unfortunately, many pediatricians are not trained to discuss obesity with patients and their families. Standardized training initiatives for pediatric residents on prevention and/or management of obesity are needed to equip emerging pediatricians to combat the obesity epidemic. Objectives . This systematic literature review aims to examine the effectiveness of childhood obesity prevention/counseling resident training interventions. Methods . A comprehensive literature search was performed using preidentified search terms and limited to articles published prior to November 6, 2019. Articles were analyzed by 2 reviewers with a standardized evaluation tool. Results . A total of 698 articles were identified by the search. These were reduced to 111 articles after title review and 11 articles following abstract/full paper review. The 11 articles described 10 different obesity training interventions for residents. The articles varied in their size, length of training session, and study design. Despite these variations, all articles outlined positive outcomes, including an increase in physician confidence, positive changes in behavior, and/or improved electronic medical record documentation. Conclusions . With the continued increase in pediatric obesity, there is a need for practical, easy-to-implement, standardized trainings for pediatric residents on obesity prevention and treatment. More investigation needs to be done to look at long-term results of current interventions as well as other outcomes such as whether physicians are correctly identifying patients who are overweight or obese and whether there is improvement in patient follow-up.

Background: Current facility conditions, obstetric and neonatal care practices, and availability of emergency obstetric and neonatal care (EmONC) were assessed in the Kwango and Kwilu provinces of the Democratic Republic of the Congo (DRC). Methods: This is an analysis of the baseline survey data from an ongoing clinical mentoring program among 72 rural health facilities in the DRC. Data collectors visited each of the facilities and collected data through a pre-programmed smartphone. Frequencies of selected indicators were calculated by province and facility type—general referral hospital (GRH) and primary health centers (HC). Results: Facility conditions varied across province and facility type. Maternity wards and delivery rooms were available in the highest frequency of rooms assessed (>95% of all facilities). Drinking water was available in 25.0% of all facilities; electricity was available in 49.2% of labor rooms and 67.6% of delivery rooms in all facilities. Antenatal, delivery, and postnatal care services were available but varied across facilities. While the proportion of blood pressure measured during antenatal care was high (94.9%), the antenatal screening rate for proteinuria was low (14.7%). The use of uterotonics immediately after birth was observed in high numbers across both provinces (94.4% in Kwango and 75.6% in Kwilu) and facility type (91.3% in GRH and 81.4% in HC). The provision of immediate postnatal care to mothers every 15 minutes was provided in less than 50% of all facilities. GRH facilities generally had higher frequencies of available equipment and more services available than HC. GRH facilities provided an average of 6 EmONC signal functions (range: 2-9). Conclusions: Despite poor facility conditions and a lack of supplies, GRH and HC facilities were able to provide EmONC care in rural DRC. These findings could guide the provision of essential needs to the health facilities for better delivery of maternal and neonatal care.

Objective . To evaluate the impact of an obesity didactic session for pediatric physicians on confidence in counseling and identified overweight/obesity and follow-up recommendations. Methods . Pediatric residents underwent training and completed pre/post online surveys evaluating confidence in obesity prevention and identification. A booster training occurred 1 year later. Pre-/post-training scores were compared using χ 2 or Fisher’s exact tests. Electronic medical records data for patients ≥3 years with BMI-for-age percentile ≥85 during 3 months prior/following the training/booster compared frequency of overweight/obesity identification and follow-up recommendations (≤3 months recommended vs longer) using logistic regression adjusting for age and overweight/obese status. Results . Post trainings, improvements in confidence to define/screen for obesity were observed, with a decline between trainings. Overweight/obese identification and follow-up time recommendations improved post-training (identification: 14.2% to 27.4%, adjusted odds ratio [aOR] = 3.16, 95% confidence interval [CI] = 1.54-6.51; follow-up: 48.9% to 58.9%, aOR = 1.63, 95% CI = 1.01-2.64), aOR = 1.77, 95% CI = 1.10-2.85, and identification remained stable/above pre-training rates both pre-/post-booster (25.8%, aOR = 3.14, 95% CI = 1.53-6.45; and 22.1%, aOR = 2.57, 95% CI = 1.25-5.30, respectively). Recommended follow-up time rates continued to rise when measured pre-booster (60.6%, aOR = 1.77, 95% CI = 1.10-2.85), then declined (46.0%, aOR = 0.95, 95% CI = 0.60-1.52). Conclusion . This didactic session improved resident confidence in defining/screening, identification of overweight/obesity and follow-up recommendations; however, rates of identification remained low. The successes of this intervention support similar didactic sessions in residency programs and identifies opportunities for improved resident/attending education.

In 2015, Steve and I traveled together to Ithaca from Pittsburgh for a workshop on differential privacy (DP). This is one of my fondest memories with Steve for many reasons. The trip involved many of my favorite things, which Steve and I both shared --- statistics, hockey, great food, and good conversation. For me, this is one of my most memorable trips with Steve, as I learned so much from our conversations together.

Differential privacy has emerged as a popular model to provably limit privacy risks associated with a given data release. However releasing high dimensional synthetic data under differential privacy remains a challenging problem. In this paper, we study the problem of releasing synthetic data in the form of a high dimensional histogram under the constraint of differential privacy. We develop an $(\epsilon, \delta)$-differentially private categorical data synthesizer called \emph{Stability Based Hashed Gibbs Sampler} (SBHG). SBHG works by combining a stability based sparse histogram estimation algorithm with Gibbs sampling and feature selection to approximate the empirical joint distribution of a discrete dataset. SBHG offers a competitive alternative to state-of-the art synthetic data generators while preserving the sparsity structure of the original dataset, which leads to improved statistical utility as illustrated on simulated data. Finally, to study the utility of the resulting synthetic data sets generated by SBHG, we also perform logistic regression using the synthetic datasets and compare the classification accuracy with those from using the original dataset.

Hepatocellular Carcinoma (HCC) is increasing in incidence worldwide and requires new approaches to therapy. The combination of anti-angiogenic drug therapy and radiotherapy is one promising new approach. The anti-angiogenic drug vandetanib is a tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2) and RET proto-oncogene with radio-enhancement potential. To explore the benefit of combined vandetanib and radiotherapy treatment for HCC, we studied outcomes following combined treatment in pre-clinical models. Methods: Vandetanib and radiation treatment were combined in HCC cell lines grown in vitro and in vivo. In addition to 2D migration and clonogenic assays, the combination was studied in 3D spheroids and a syngeneic mouse model of HCC. Results: Vandetanib IC 50 s were measured in 20 cell lines and the drug was found to significantly enhance radiation cell kill and to inhibit both cell migration and invasion in vitro. In vivo, combination therapy significantly reduced cancer growth and improved overall survival, an effect that persisted for the duration of vandetanib treatment. Conclusion: In 2D and 3D studies in vitro and in a syngeneic model in vivo, the combination of vandetanib plus radiotherapy was more efficacious than either treatment alone. This new combination therapy for HCC merits evaluation in clinical trials.

Antibiotic resistance among enterococci and γ-proteobacteria is an increasing problem in healthcare settings. Dense colonization of the gut by antibiotic-resistant bacteria facilitates their spread between patients and also leads to bloodstream and other systemic infections. Antibiotic-mediated destruction of the intestinal microbiota and consequent loss of colonization resistance are critical factors leading to persistence and spread of antibiotic-resistant bacteria. The mechanisms underlying microbiota-mediated colonization resistance remain incompletely defined and are likely distinct for different antibiotic-resistant bacterial species. It is unclear whether enterococci or γ-proteobacteria, upon expanding to high density in the gut, confer colonization resistance against competing bacterial species. Herein, we demonstrate that dense intestinal colonization with vancomycin-resistant Enterococcus faecium (VRE) does not reduce in vivo growth of carbapenem-resistant Klebsiella pneumoniae. Reciprocally, K. pneumoniae does not impair intestinal colonization by VRE. In contrast, transplantation of a diverse fecal microbiota eliminates both VRE and K. pneumoniae from the gut. Fluorescence in situ hybridization demonstrates that VRE and K. pneumoniae localize to the same regions in the colon but differ with respect to stimulation and invasion of the colonic mucus layer. While VRE and K. pneumoniae occupy the same three-dimensional space within the gut lumen, their independent growth and persistence in the gut suggests that they reside in distinct niches that satisfy their specific in vivo metabolic needs.