Optimising rabies vaccination of dogs in India.

Dog vaccination is the key to controlling rabies in human populations. However, in countries like India, with large free-roaming dog populations, vaccination strategies that rely only on parenteral vaccines are unlikely to be either feasible or successful. Oral rabies vaccines could be used to reach these dogs. We use cost estimates for an Indian city and linear optimisation to find the most cost-effective vaccination strategies. We show that an oral bait handout method for dogs that are never confined can reduce the per dog costs of vaccination and increase vaccine coverage. This finding holds even when baits cost up to 10x the price of parenteral vaccines, if there is a large dog population or proportion of dogs that are never confined. We suggest that oral rabies vaccine baits will be part of the most cost-effective strategies to eliminate human deaths from dog-mediated rabies by 2030.

Evaluating Responses to Gluten Challenge: A Randomized, Double-Blind, 2-Dose Gluten Challenge Trial.

BACKGROUND & AIMS: Gluten challenge is used to diagnose celiac disease (CeD) and for clinical research. Sustained gluten exposure reliably induces histologic changes but is burdensome. We investigated the relative abilities of multiple biomarkers to assess disease activity induced by 2 gluten doses, and aimed to identify biomarkers to supplement or replace histology. METHODS: In this randomized, double-blind, 2-dose gluten-challenge trial conducted in 2 US centers (Boston, MA), 14 adults with biopsy-proven CeD were randomized to 3 g or 10 g gluten/d for 14 days. The study was powered to detect changes in villous height to crypt depth, and stopped at planned interim analysis on reaching this end point. Additional end points included gluten-specific cluster of differentiation (CD)4 T-cell analysis with HLA-DQ2-gluten tetramers and enzyme-linked immune absorbent spot, gut-homing CD8 T cells, interleukin-2, symptoms, video capsule endoscopy, intraepithelial leukocytes, and tissue multiplex immunofluorescence. RESULTS: All assessments showed changes with gluten challenge. However, time to maximal change, change magnitude, and gluten dose-response relationship varied. Villous height to crypt depth, video capsule endoscopy enteropathy score, enzyme-linked immune absorbent spot, gut-homing CD8 T cells, intraepithelial leukocyte counts, and HLA-DQ2-restricted gluten-specific CD4 T cells showed significant changes from baseline at 10 g gluten only; symptoms were significant at 3 g. Symptoms and plasma interleukin-2 levels increased significantly or near significantly at both doses. Interleukin-2 appeared to be the earliest, most sensitive marker of acute gluten exposure. CONCLUSIONS: Modern biomarkers are sensitive and responsive to gluten exposure, potentially allowing less invasive, lower-dose, shorter-duration gluten ingestion. This work provides a preliminary framework for rational design of gluten challenge for CeD research. ClinicalTrials.gov number, NCT03409796.

Using "Markers of Harm" to Track Risky Gambling in Two Cohorts of Online Sports Bettors.

Online gambling poses novel risks for problem gambling, but also unique opportunities to detect and intervene with at-risk users. A consortium of gambling companies recently committed to using nine behavioral "Markers of Harm'' that can be calculated with online user data to estimate risk for gambling-related harm. The current study evaluates these markers in two independent samples of sports bettors, collected ten years apart. We find over a two-year period that most users never had high enough overall risk scores to indicate that they would have received an intervention. This observation is partly due to characteristics of our samples that are associated with lower risk for gambling-related harm, but might also be due to overly high risk thresholds or flaws in the design of some markers. Users with higher average risk scores had more intraindividual variability in risk scores. Younger age and male gender were not associated with higher average risk scores. The most active users were more likely than other users to have ever exceeded risk thresholds. Several risk scores significantly predicted proxies of gambling-related harm (e.g., account closure). Overall, the current Markers of Harm system has some correctable limitations that future risk detection systems should consider adopting.

Is Empathy the Default Response to Suffering? A Meta-Analytic Evaluation of Perspective Taking's Effect on Empathic Concern.

We conducted a series of meta-analytic tests on experiments in which participants read perspective-taking instructions-that is, written instructions to imagine a distressed persons' point of view ("imagine-self" and "imagine-other" instructions), or to inhibit such actions ("remain-objective" instructions)-and afterwards reported how much empathic concern they experienced upon learning about the distressed person. If people spontaneously empathize with others, then participants who receive remain-objective instructions should report less empathic concern than do participants in a "no-instructions" control condition; if people can deliberately increase how much empathic concern they experience, then imagine-self and imagine-other instructions should increase empathic concern relative to not receiving any instructions. Random-effects models revealed that remain-objective instructions reduced empathic concern, but "imagine" instructions did not significantly increase it. The results were robust to most corrections for bias. Our conclusions were not qualified by the study characteristics we examined, but most relevant moderators have not yet been thoroughly studied.

Moral reasoning performance determines epistemic peerdom.

We offer a friendly criticism of May's fantastic book on moral reasoning: It is overly charitable to the argument that moral disagreement undermines moral knowledge. To highlight the role that reasoning quality plays in moral judgments, we review literature that he did not mention showing that individual differences in intelligence and cognitive reflection explain much of moral disagreement. The burden is on skeptics of moral knowledge to show that moral disagreement arises from non-rational origins.

Fibroadipose vascular anomaly treated with sirolimus: Successful outcome in two patients.

Fibroadipose vascular anomaly (FAVA) is a rare, complex mesenchymal malformation combining fibrofatty replacement of the affected muscles and slow-flow vascular malformation. The condition is characterized by localized swelling, severe pain, phlebectasia, and contracture of the affected limb. Treatment paradigms are not well established for this rare, recently recognized condition. We report two cases of FAVA in which treatment with sirolimus produced rapid, dramatic improvement in pain and quality of life.

Does empathy promote helping by activating altruistic motivation or concern about social evaluation? A direct replication of Fultz et al. (1986).

When people experience empathy for a needy stranger, efforts to help are often not far behind. But does empathy actually cause prosocial behavior? And if so, does it activate genuine concern or more self-interested motivations? To rule out the alternative hypothesis that empathy motivates prosocial behavior by generating fear of social disapproval for acting selfishly, Fultz et al. (1986) manipulated empathy for a lonely stranger using perspective-taking instructions; they also manipulated whether subjects believed their decision to help would remain anonymous. However, Fultz et al. conducted their experiment decades ago, with few subjects, and before some potentially important cultural changes in college students' values and social lives. Here, in a preregistered replication with 280 undergraduates, we tested Fultz et al.'s key assertions. The perspective-taking and social evaluation manipulations influenced scores on the manipulation check measures mostly in theory-consistent ways but did not significantly influence helping. Consistent with theory, empathy was positively associated with prosocial behavior. We also found evidence that endorsement of the principle of care reflects genuine concern for needy strangers and that moral identity symbolization reflects a desire to help in order to avoid social disapproval. We consider these results a partially successful replication of key tenets of the empathy-altruism hypothesis, though questions remain about the conditions under which perspective-taking promotes prosocial behavior and about the generalizability of our findings to populations beyond undergraduate women circa 1986. Our results also help illuminate the motivational underpinnings of two individual differences that predicted prosocial behavior in previous research. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

The persistent trigeminal artery: development, imaging anatomy, variants, and associated vascular pathologies.

The persistent trigeminal artery (PTA) is the most common and most cephalad-located embryological anastomosis between the developing carotid artery and vertebrobasilar system to persist into adulthood. As such, it is frequently reported as an incidental finding in computed tomography angiography and magnetic resonance angiography studies. Here, we review the embryology, anatomy, and angiographic imaging findings, including important variants of this commonly encountered cerebrovascular anomaly (reported incidence of PTA/PTA variants ranges from 0.1% to 0.76%). Further, the aim is to present the range of associated arterial anomalies or syndromes, as well as pathologies that are associated with a PTA: aneurysms, trigeminal cavernous fistulas, and trigeminal nerve compression. Besides summarizing the risks and clinical presentation of such pathologies, their management is discussed with endovascular strategies mostly being the primary choice for aneurysms and trigeminal cavernous fistulas. Symptomatic trigeminal nerve compression can be treated with microvascular decompression surgery. As an illustrative example, a case of a trigeminal cavernous fistula on a PTA variant is included, mainly to emphasize the importance of understanding the variant anatomy for treatment planning in such pathologies. Finally, recommendations on how to manage patients with PTA-associated vascular pathologies are advanced.

Intracranial venous stenting for idiopathic intracranial hypertension.

INTRODUCTION: There is increasing evidence in the literature to support venous sinus stenting in patients with idiopathic intracranial hypertension who fail first-line therapy. Venous sinus stenting is a safe and successful technique compared with cerebrospinal fluid diversion procedures. This study examines the clinical outcomes of patients post intracranial venous stenting for intracranial hypertension across three tertiary hospitals in Western Australia. METHODS: A retrospective analysis was performed on 83 consecutive patients treated with intracranial venous stenting for IIH at three tertiary hospitals from October 2013 to March 2020. Data were collected from outpatient clinic letters, electronic discharge letters, electronic radiological imaging and procedural reports. RESULTS: 89.2% patients were able to cease Acetazolomide post stenting. 78.3% patients reported resolution of headaches. 84.3% patients demonstrated resolution of their papilloedema. 91.6% patients demonstrated improvement of their visual acuity. Compared with a recent meta-analysis by Satti and Chaudry in 2015, our results demonstrated a higher technical success rate and lower complication rates. CONCLUSION: Our study findings support the paradigm shift from CSF diversion procedures to venous sinus stenting in patients with IIH who fail first-line therapy. Venous sinus stenting has a high technical success rate and significantly lower complication rates than other invasive treatments.

A meta-analytic investigation of problem gambling and self-harm: A causal inference perspective.

OBJECTIVE: Problem gambling may be an underappreciated treatment target for reducing self-harm. Multivariate studies examining the relationship between problem gambling and self-harm have returned inconsistent results, perhaps due to insufficient power or differences in study quality. METHOD: We conducted a series of meta-analyses examining the effect of problem gambling on self-harm outcomes of varying severity. We assessed the sensitivity of results to study characteristics, publication bias, and influential cases. To highlight threats to causal inference, we evaluated each study for residual confounding bias. RESULTS: In total, two types of meta-analyses were adequately powered: those assessing (a) the effect of problem gambling (binary) on suicide ideation and (b) problem gambling (binary) on suicide attempt (k = 14 unique studies between the two meta-analyses). For both meta-analyses, we found a positive, statistically significant average effect of problem gambling on the respective self-harm outcome. We did not detect any influential studies among these two meta-analyses, nor residual confounding. However, these findings are limited by the overall quality of included literature. PET-PEESE analysis detected substantial potential publication bias in the main results, with both meta-analytic effects being reduced to statistical nonsignificance. All included studies also used a cross-sectional design for their analysis of interest, thus simultaneity bias cannot be ruled out. CONCLUSION: While these findings suggest there is an appreciable relationship between problem gambling and at least two forms of self-harm (suicide ideation and attempts), well-designed longitudinal research is needed to make more firm conclusions. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

A phase II, single-arm study of the anti-α5ß1 integrin antibody volociximab as monotherapy in patients with platinum-resistant advanced epithelial ovarian or primary peritoneal cancer.

OBJECTIVE: This phase II, multicenter, single-arm, two-stage study in platinum-resistant, advanced epithelial ovarian or primary peritoneal cancer evaluated the efficacy, safety, and tolerability of weekly single-agent volociximab. Pharmacokinetic/pharmacodynamic (PK/PD) studies were also performed. METHODS: Sixteen patients were enrolled in Stage 1. Volociximab was administered at 15mg/kg IV qwk until progression of disease or drug intolerability. Tumor response was assessed every 8weeks. Serum samples for PK or whole blood for the evaluation of circulating tumor cells, endothelial cells, and endothelial progenitor cells were obtained on Days 1, 8, 15, 29, and 50. Ascites from one patient was collected for volociximab concentration analysis. Archived tumor tissue was analyzed by immunohistochemistry (IHC) for α5 integrin expression. RESULTS: Safety data are available on all 16 patients; 14 were evaluable for efficacy. One patient had stable disease at 8weeks. The remaining 13 progressed on treatment. Twelve patients (75%) experienced study-related adverse events (AEs); the most common (≥20%) were headache and fatigue. Three patients experienced possible study-related serious AEs (SAEs): reversible posterior leukoencephalopathy syndrome, pulmonary embolism, and hyponatremia. Peak serum concentrations of volociximab increased 2-3 fold from Day 1 to Day 50. Clinically relevant trough levels were achieved (>150µg/mL). IHC analysis of archived tumor sections showed low-to-moderate expression of α5 integrin on all ovarian cancer tissue evaluated. CONCLUSION: Despite insufficient clinical activity in this refractory patient population to continue the study, weekly volociximab was well tolerated, and the gained understanding of the mechanism of action of volociximab will inform future development efforts.

Development and validation of a high-parameter mass cytometry workflow to decipher immunomodulatory changes in celiac disease.

The advent of time-of-flight mass cytometry (CyTOF) has enabled high dimensional and unbiased examination of the immune system to simultaneous interrogate a multitude of parameters and gain a better understanding of immunologic data from clinical trial samples. Here we describe the development and validation of a 33-marker mass cytometry workflow for measuring gastrointestinal (GI) trafficking peripheral blood mononuclear cells (PBMCs) in patients with celiac disease (CeD). This panel builds upon identification of well-characterized immune cells and expands to include markers modulated in response to gluten challenge in patients with CeD. The CeD panel was optimized and validated according to accepted industry practice for validation of flow cytometry assays and builds upon established sample processing workflows for mass cytometry studies. Several critical parameters were evaluated during the assay development phase of this study including optimization of the sample processing steps, antibody specificity, and ensuring the panel as a whole performed to expectation. The panel was then validated using a fit-for-purpose approach tailored to the intended use of the data in the clinical trial. Validation included assessment of analytical parameters essential to understanding the reliability and robustness of the CeD panel such as intra-assay precision, inter-assay precision, inter-operator precision and sample processing stability. Together, this validated mass cytometry workstream provides robust and reproducible high-dimensional analysis of human peripheral blood immune cells to characterize patient samples from clinical trials.

Responsible product design to mitigate excessive gambling: A scoping review and z-curve analysis of replicability.

OBJECTIVES: Systematic mapping of evaluations of tools and interventions that are intended to mitigate risks for gambling harm. DESIGN: Scoping Review and z-curve analysis (which estimates the average replicability of a body of literature). SEARCH STRATEGY: We searched 7 databases. We also examined reference lists of included studies, as well as papers that cited included studies. Included studies described a quantitative empirical assessment of a game-based (i.e., intrinsic to a specific gambling product) structural feature, user-directed tool, or regulatory initiative to promote responsible gambling. At least two research assistants independently performed screening and extracted study characteristics (e.g., study design and sample size). One author extracted statistics for the z-curve analysis. RESULTS: 86 studies met inclusion criteria. No tools or interventions had unambiguous evidence of efficacy, but some show promise, such as within-session breaks in play. Pre-registration of research hypotheses, methods, and analytic plans was absent until 2019, reflecting a recent embracement of open science practices. Published studies also inconsistently reported effect sizes and power analyses. The results of z-curve provide some evidence of publication bias, and suggest that the replicability of the responsible product design literature is uncertain but could be low. CONCLUSION: Greater transparency and precision are paramount to improving the evidence base for responsible product design to mitigate gambling-related harm.

Mechanical thrombectomy is efficacious in patients with pre-stroke moderate disability.

INTRODUCTION: Patients with ischaemic stroke due to large vessel occlusion (LVO) can be treated successfully with mechanical thrombectomy (MT) and/or intravenous thrombolysis. In the landmark trials, MT was only performed for those with no functional disability prior to stroke (mRS 0-2). There are limited data available regarding clinical outcomes for patients with pre-stroke moderate disability (mRS ≥ 3). The aims of this study were to analyse the clinical outcomes and financial implications in regard to accommodation costs of performing MT in patients with pre-stroke mRS = 3. METHODS: An observational cohort study was performed of 802 patients with anterior circulation LVO ischaemic stroke who underwent MT between October 2016 and January 2020 at three tertiary hospitals. Patient demographics, premorbid mRS, stroke and interventional data, 90-day mRS and accommodation situation were recorded. RESULTS: Eighty-two patients with anterior circulation LVO ischaemic stroke were pre-stroke mRS 3. 38% had a good clinical outcome, as defined by mRS 3 at 90 days. Mortality rate was 38%. The majority of patients presented from home (83%) and greater than one third of those returned home during the 90 days post treatment. 81% of patients had no increase in accommodation cost at 90 days. CONCLUSION: Patients with pre-stroke moderate disability may benefit from MT if they are appropriately selected. This may result in fewer patients requiring nursing home placement and less financial burden on the public health system, indicating significant savings are possible.

Transradial versus transfemoral access for anterior circulation mechanical thrombectomy: analysis of 375 consecutive cases.

OBJECTIVE: To compare transradial artery access (TRA) to the gold standard of transfemoral artery access (TFA) in mechanical thrombectomy (MT) for stroke caused by anterior circulation large vessel occlusion. METHODS: The clinical outcomes, procedural speed, angiographic efficacy and safety of both techniques were analysed in 375 consecutive cases over an 18-month period in a high volume statewide neurointerventional service. RESULTS: There was no significant difference in patient characteristics, stroke parameters, imaging techniques or intracranial techniques. The median time elapsed between CT scanning and reperfusion was 96.5 min (IQR 68-123) in the TFA group and 95 min (IQR 68-123) in the TRA group (p=0.456). Of 336 patients who were independent at presentation 58% (124/214) of the TFA group and 67% (82/122) of the TRA group had a modified Rankin score of 0-2 at 90-day follow-up (p=0.093). Cross-over from radial to femoral was 4.6% (4/130) compared with 1.6% cross-over from femoral to radial (4/245), but did not meet the predetermined level of statistical significance (OR 2.92, 95% CI 0.81 to 10.52), p=0.088) and did not impact median procedural speed. Adequate angiographic reperfusion, first pass reperfusion, embolisation to new territory and symptomatic intracranial haemorrhage were similar in both groups. There was a significant difference in major access site complications requiring an additional procedure. None of the TRA cases had a major access site complication but 6.5% (16/245) of the TFA cases did (p=0.003). CONCLUSION: This study suggests that using TRA for anterior circulation MT is fast, efficacious, safe and not inferior to the gold standard of TFA.

First line transradial access for posterior circulation stroke intervention; initial 12-month experience at a high volume thrombectomy center.

BACKGROUND: The Neurointerventional Surgery Standards and Guidelines Committee has advocated the use of transradial access in the setting of posterior circulation stroke intervention, however there is a paucity of published data on this approach. The purpose of this study is to present 12-months of prospectively collected data from a high volume thrombectomy center following the adoption of a first line transradial approach for posterior circulation stroke intervention. METHODS: A range of data on patient characteristics, procedural metrics, complications and outcomes was prospectively collected between August 2018 - August 2019 following the adoption of first line transradial access for posterior circulation stroke intervention at a high volume thrombectomy center. RESULTS: Transradial access was successful in 22/23 cases (96%), median arteriotomy to reperfusion time was 24 min (IQR 18-40), good angiographic outcome (mTICI 2b-3) was achieved in all cases and good clinical outcome (mRs 0-2) was achieved in 61% of cases. No intracranial or radial artery access site complications occurred. CONCLUSION: The fast procedure times, excellent outcomes and low complication rates achieved in this prospective 12-month study indicate that transradial access is a viable first line strategy in posterior circulation stroke intervention.

Using Administrative Data to Predict Suicide After Psychiatric Hospitalization in the Veterans Health Administration System.

There is a very high suicide rate in the year after psychiatric hospital discharge. Intensive postdischarge case management programs can address this problem but are not cost-effective for all patients. This issue can be addressed by developing a risk model to predict which inpatients might need such a program. We developed such a model for the 391,018 short-term psychiatric hospital admissions of US veterans in Veterans Health Administration (VHA) hospitals 2010-2013. Records were linked with the National Death Index to determine suicide within 12 months of hospital discharge (n=771). The Super Learner ensemble machine learning method was used to predict these suicides for time horizon between 1 week and 12 months after discharge in a 70% training sample. Accuracy was validated in the remaining 30% holdout sample. Predictors included VHA administrative variables and small area geocode data linked to patient home addresses. The models had AUC=.79-.82 for time horizons between 1 week and 6 months and AUC=.74 for 12 months. An analysis of operating characteristics showed that 22.4%-32.2% of patients who died by suicide would have been reached if intensive case management was provided to the 5% of patients with highest predicted suicide risk. Positive predictive value (PPV) at this higher threshold ranged from 1.2% over 12 months to 3.8% per case manager year over 1 week. Focusing on the low end of the risk spectrum, the 40% of patients classified as having lowest risk account for 0%-9.7% of suicides across time horizons. Variable importance analysis shows that 51.1% of model performance is due to psychopathological risk factors accounted, 26.2% to social determinants of health, 14.8% to prior history of suicidal behaviors, and 6.6% to physical disorders. The paper closes with a discussion of next steps in refining the model and prospects for developing a parallel precision treatment model.