Natural malaria infection elicits rare but potent neutralizing antibodies to the blood-stage antigen RH5.

Plasmodium falciparum reticulocyte-binding protein homolog 5 (RH5) is the most advanced blood-stage malaria vaccine candidate and is being evaluated for efficacy in endemic regions, emphasizing the need to study the underlying antibody response to RH5 during natural infection, which could augment or counteract responses to vaccination. Here, we found that RH5-reactive B cells were rare, and circulating immunoglobulin G (IgG) responses to RH5 were short-lived in malaria-exposed Malian individuals, despite repeated infections over multiple years. RH5-specific monoclonal antibodies isolated from eight malaria-exposed individuals mostly targeted non-neutralizing epitopes, in contrast to antibodies isolated from five RH5-vaccinated, malaria-naive UK individuals. However, MAD8-151 and MAD8-502, isolated from two malaria-exposed Malian individuals, were among the most potent neutralizers out of 186 antibodies from both cohorts and targeted the same epitopes as the most potent vaccine-induced antibodies. These results suggest that natural malaria infection may boost RH5-vaccine-induced responses and provide a clear strategy for the development of next-generation RH5 vaccines.

Analysis of the diverse antigenic landscape of the malaria protein RH5 identifies a potent vaccine-induced human public antibody clonotype.

The highly conserved and essential Plasmodium falciparum reticulocyte-binding protein homolog 5 (PfRH5) has emerged as the leading target for vaccines against the disease-causing blood stage of malaria. However, the features of the human vaccine-induced antibody response that confer highly potent inhibition of malaria parasite invasion into red blood cells are not well defined. Here, we characterize 236 human IgG monoclonal antibodies, derived from 15 donors, induced by the most advanced PfRH5 vaccine. We define the antigenic landscape of this molecule and establish that epitope specificity, antibody association rate, and intra-PfRH5 antibody interactions are key determinants of functional anti-parasitic potency. In addition, we identify a germline IgG gene combination that results in an exceptionally potent class of antibody and demonstrate its prophylactic potential to protect against P. falciparum parasite challenge in vivo. This comprehensive dataset provides a framework to guide rational design of next-generation vaccines and prophylactic antibodies to protect against blood-stage malaria.

Feasibility of safe outpatient treatment in pediatric patients following intraventricular radioimmunotherapy with 131I-omburtamab for leptomeningeal disease.

BACKGROUND: Radiolabeled antibody 131I-omburtamab was administered intraventricularly in patients with leptomeningeal disease under an institutionally approved study (#NCT03275402). Radiation safety precautions were tailored for individual patients, enabling outpatient treatment based on in-depth, evidence-based recommendations for such precautions. The imperative advancement of streamlined therapeutic administration procedures, eliminating the necessity for inpatient isolation and resource-intensive measures, holds pivotal significance. This development bears broader implications for analogous therapies within the pediatric patient demographic. METHODS: Intraventricular radioimmunotherapy (RIT) with 925-1850 MBq (25-50 mCi) of 131I-omburtamab was administered via the Ommaya reservoir, in designated rooms within the pediatric ambulatory care center. Dosimeters were provided to staff involved in patient care to evaluate exposure during injection and post-administration. Post-administration exposure rate readings from the patient on contact, at 0.3 m, and at 1 m were taken within the first 30 min, and the room was surveyed after patient discharge. Duration of radiation exposure was calculated using standard U.S. Nuclear Regulatory Commission (US NRC) regulatory guidance recommendations combined with mean exposure rates and whole-body clearance estimates. Exposure rate measurements and clearance data provided patient-specific precautions for four cohorts by age: < 3 y/o, 3-10 y/o, 10-18 y/o, and 18+. RESULTS: Post-administration exposure rates for patients ranged from 0.16 to 0.46 µSv/hr/MBq at 0.3 m and 0.03-0.08 µSv/hr/MBq at 1 m. Radiation exposure precautions ranged from 1 to 10 days after release for the four evaluated cohorts. Based on the highest measured exposure rates and slowest whole-body clearance, the longest precautions were approximately 78% lower than the regulatory guidance recommendations. Radiation exposure to staff associated with 131I-omburtamab per administration was substantially below the annual regulatory threshold for individual exposure monitoring. CONCLUSION: 131I-omburtamab can be administered on an outpatient basis, using appropriate patient-based radiation safety precautions that employ patient-specific exposure rate and biological clearance parameters. This trial is registered with the National Library of Medicine's ClinicalTrials.gov. The registration number is NCT03275402, and it was registered on 7 September 2017. The web link is included here. https://clinicaltrials.gov/study/NCT03275402 .

Associations of Long-term Sleep Duration Trajectories with Overall and Cause-Specific Mortality Among Middle-to-older Aged Black and White Adults.

Background: Both short and long sleep durations are adversely associated with numerous chronic conditions, including cardiovascular disease (CVD), diabetes, hypertension, and mortality. The American Academy of Sleep Medicine recommends adults in the United States sleep at least 7 hours and less than 9 hours per night to maintain optimal health. It remains unclear how sleep duration trajectories over time are associated with mortality. Methods: This observational cohort study includes 46,928 Black and White adults (mean age: 53 ± 9 years) who enrolled in the Southern Community Cohort Study between 2002-2009 and completed a follow-up survey in 2008-2013. Participants were categorized into nine sleep duration trajectory categories based on the reported average sleep duration between study enrollment and at follow-up. Participant vital status and date and cause of death were ascertained via linkage to the National Death Index through 2022. Cox regression analysis was performed to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association between sleep duration trajectory and all-cause and cause-specific mortality (CVD, cancer, and neurodegenerative disease) after adjustment for sociodemographic characteristics, health behaviors, and clinical factors. Results: During a median 12.6 years of follow-up, we documented 13,579 deaths, including 4,135 from CVD, 3,067 from cancer, and 544 from neurodegenerative diseases. Compared to the optimal sleep duration trajectory (maintaining 7-9 hours), all sub-optimal trajectories were associated with significant 6 to 33% greater risk of all-cause mortality in fully adjusted models. Compared to the optimal sleep trajectory, three of the sub-optimal trajectories were associated with increased CVD mortality, with HRs ranging from 1.20 to 1.34. The short-long trajectory was associated with the greatest risk of all-cause mortality (HR:1.33; 95%CI: 1.21, 1.46) and the long-short trajectory was associated with the greatest CVD mortality risk (HR:1.34; 95%CI: 1.10, 1.65). The healthy-long trajectory was associated with the greatest risk of cancer mortality (HR: 1.19; 95%CI:1.00, 1.41). None of the sub-optimal trajectories was associated with neurodegenerative disease mortality. Conclusions: Suboptimal sleep duration trajectories were associated with increased risk of all-cause mortality as well as CVD mortality. Findings highlight the importance of maintaining healthy sleep duration throughout midlife to reduce mortality risk.

The Prevalence of Caregiving among Young People.

With the increasing number of people with chronic diseases and disabilities, the number of family members as caregivers have also been growing. Despite the attention paid to caregiving in recent years, little is known about caregiving among young people, particularly its global prevalence. The lack of information has important implications for health policy and management, resulting in the inability to form appropriate evidence-based policies and managerial decision making. This study aims to derive an estimate of the prevalence of caregiving among young people through a systematic review of the current literature. The results of this study revealed a prevalence of caregiving among younger adolescents of between 1.1% (1.06-1.14%) and 12.0% (11.02-12.98%). However, the assessment of caregiving varies across studies, and all were conducted in developed countries. These results provide information on the burden of caregiving in young people and reveal the lack of global information, calling for more research on and attention to this specific population.

A Web-Based and Mobile Intervention Program Using a Spaced Education Approach for Workplace Mental Health Literacy: Cluster Randomized Controlled Trial.

Background: Workplace mental health is an important global health concern. objectives: This unblinded, phase-III, wait-listed cluster randomized controlled trial aimed to examine the effectiveness of a mobile health (mHealth) psychoeducation program using a spaced education approach on mental health literacy (MHL) in the workplace. The main interest of this paper was the immediate and 3-month medium-term effect of the program on the MHL of workers. The purposely built mHealth platform was also evaluated as a health-related app. Methods: The mHealth platform was designed using the principle of spaced education as a psychoeducation intervention program, with various modules of web-based and mobile materials presented to the participant in a progressive manner. Short quizzes at the end of each module ensured adequate learning, and successful completion qualified the learner to progress to the next level. The trial recruited 456 employees of specific industries with high levels of work-related stress. Participants who were nested in different offices or units were allocated into the intervention and wait-listed control groups using a block randomization process, with the office or unit as the cluster. A separate sample of 70 individual raters were used for the evaluation of the mHealth platform. The Australian National MHL and Stigma Survey and the Mobile Apps Rating Scale were completed through a web-based self-reported survey to assess MHL and evaluate the app. The trial and follow-up data were analyzed by a generalized linear latent and mixed model with adjustments for the clustering effect of work sites and repeated measures. Results: Of the 456 participants in the trial, 236 (51.8%) responded to the follow-up survey. Most MHL outcomes obtained significant results immediately after the intervention and across time. After adjusting for the clustering effect, the postintervention weighted mean scores were significantly higher in the intervention group than the control group for correct recognition of a mental health problem, help seeking, and stigmatization by 0.2 (SE 0.1; P=.003), 0.9 (SE 0.2; P<.001), and 1.8 (SE 0.4; P<.001), respectively. After adjusting for the clustering effect, significant differences across time were found in help-seeking intention (P=.01), stigmatization (P<.001), and social distancing (P<.001). The evaluation of the mHealth program resulted in average scores of the 4 major domains ranging from 3.8 to 4.2, with engagement having the lowest score. Conclusions: The mHealth psychoeducation intervention program using this platform had immediate and 3-month medium-term effects of retaining and improving MHL. The platform was evaluated to have satisfactory performance in terms of functionality, aesthetics, information content, and utility in enhancing MHL. It is anticipated that ongoing development in digital health will provide great benefits in improving the mental health of the global population.

A cultural models approach to understanding body fatness perceptions and disordered eating in young South Korean men.

OBJECTIVE: The eating disorders field has been limited by a predominant focus on White, Western women, and there is growing recognition of the need to understand cross-cultural variation in key constructs (i.e., ideal body types). A transdisciplinary, cultural models approach systematizes the incorporation of an "emic" perspective (a culture's own understandings of phenomena) into assessments of relationships between body shapes and eating disorders. METHOD: Eighty-one young South Korean men aged 19-34 years living in Seoul participated in this research. A cultural model of body fatness was identified using cultural consensus analysis during 18 months of ethnographic, mixed-methods fieldwork. Participants also completed questionnaires assessing age, height, weight, sexual identity, university prestige, body dissatisfaction, eating disorder symptoms, and cultural consonance with the Korean cultural model of the ideal male body. Variation in these factors was analyzed using a series of chi-squares and analyses of variance with the culturally defined categories of body fatness as the independent variables. RESULTS: Cultural consensus analysis found that young South Korean men are consistent in identifying categories of "too thin," "balanced," and "too fat." The "balanced" category contained the lowest proportion of high-prestige university attendees and the highest average cultural consonance. The "too fat" category was characterized by the highest levels of body dissatisfaction and dieting, as well as proportion of probable eating disorders. DISCUSSION: A cultural models approach identified culturally important factors and patterns in disordered eating among young South Korean men and may be effective for understanding eating disorders in other populations not typically studied. PUBLIC SIGNIFICANCE: This study applies a systematic, "emic" perspective to young South Korean men's body ideals. Young Korean men share a cultural model of body fatness, and this model frames how they experience risk for eating disorders. This study demonstrates a method for incorporating culture into research on eating disorder risk.

Gut resident Escherichia coli profile predicts the eighteen-month probability and antimicrobial susceptibility of urinary tract infections.

Background: Community-acquired UTI is the most common bacterial infection managed in general medical practice that can lead to life-threatening outcomes. While UTIs are primarily caused by Escherichia coli colonizing the patient's gut, it is unclear whether the gut resident E. coli profiles can predict the person's risks for UTI and optimal antimicrobial treatments. Thus, we conducted an eighteen-month long community-based observational study of fecal E. coli colonization and UTI in women aged 50 years and above. Methods and Findings: We enrolled a total of 1,804 women distributed among age groups 50-59 yo (437 participants), 60-69 yo (632), 70-79 yo (532), and above 80 yo (203), lacking antibiotic prescriptions for at least one year. The provided fecal samples were plated for the presence of E. coli and other enterobacteria resistant to trimethoprim/sulfamethoxazole (TMP/STX), ciprofloxacin (CIP) and 3rd generation cephalosporins (3GC). E. coli was also characterized as belonging to the pandemic multi-drug resistant clonal groups ST131 (subclone H30) and ST1193. Following sample collection, the women were monitored for 18 months for occurrence of UTI.E. coli was cultured from 90.8% fecal samples, with 24.1% containing bacteria resistant to TMP/STX, 19.4% to CIP, and 7.9% to 3GC. In 62.5% samples, only all-susceptible E. coli were present. Overall, there were no age-related differences in resistance prevalence. However, while the total E. coli H30 and ST1193 carriage rates were similar (4.3% and 4.2%, respectively), there was a notable increase of H30 carriage with age (P = .001), while carriage decreased with age for ST1193 (P = .057).Within 18 months, 184 women (10.2%) experienced at least one episode of UTI - 10.9% among the gut E. coli carriers and 3.0% among the non-carriers (P=.0013). The UTI risk among carriers of E. coli H30 but not ST1193 was significantly above average (24.3%, P = .0004). The UTI probability increased with age, occurring in 6.4% of 50-59 yo and 19.7% of 80+ yo (P<.001), with the latter group being especially at high risk for UTI, if they were colonized by E. coli H30 (40.0%, P<.001).E. coli was identified in 88.1% of urine samples, with 16.1% resistant to TMP/STX, 16.1% to CIP, 4.2% to 3GC and 73.1% to none of the antibiotics. Among tested urinary E. coli resistant to antibiotics, 86.1% matched the resistance profile of E. coli in the fecal samples, with the clonotyping and whole genome sequencing confirming the matching strains' identity. Positive predictive value (PPV) of using gut resistance profiles to predict UTI pathogens' susceptibility to TMP/STX, CIP, 3GC and all three antibiotics were 98.4%, 98.3%, 96.6% and 95.3%, respectively. Corresponding negative predictive values (NPV) were 63.0%, 54.8%, 44.4% and 75.8%, respectively. The AUC ROC curve values for the accuracy of fecal diagnostic testing for the prediction of UTI resistance ranged .86-.89. The fecal test-guided drug-bug mismatch rate for empirical (pre-culture) prescription of TMP-SXT or CIP is reduced to ≤2% in 89.6% of patients and 94.8% of patients with an optional 3GC prescription. Conclusion: The resistance profile and clonal identity of gut colonizing E. coli, along with the carrier's age, can inform personalized prediction of a patients' UTI risk and the UTI pathogen's antibiotic susceptibility within an 18-month period.

Feasibility of safe outpatient treatment in pediatric patients following intraventricular radioimmunotherapy with 131I-omburtamab for leptomeningeal disease.

Background: Radiolabeled antibody 131I-omburtamab was administered intraventricularly in patients with leptomeningeal disease under an institutionally approved study (#NCT03275402). Radiation safety precautions were tailored for individual patients, enabling outpatient treatment based on in-depth, evidence-based recommendations for such precautions. The imperative advancement of streamlined therapeutic administration procedures, eliminating the necessity for inpatient isolation and resource-intensive measures, holds pivotal significance. This development bears broader implications for analogous therapies within the pediatric patient demographic. Methods: Intraventricular radioimmunotherapy (RIT) with 925-1850 MBq (25-50 mCi) of 131I-omburtamab was administered via the Ommaya reservoir, in designated rooms within the pediatric ambulatory care center. Dosimeters were provided to staff involved in patient care to evaluate exposure during injection and post-administration. Post-administration exposure rate readings from the patient on contact, at 0.3 m, and at 1 m were taken within the first 30 minutes, and the room was surveyed after patient discharge. Duration of radiation exposure was calculated using standard U.S. Nuclear Regulatory Commission (US NRC) regulatory guidance recommendations combined with mean exposure rates and whole-body clearance estimates. Exposure rate measurements and clearance data provided patient-specific precautions for four cohorts by age: < 3 y/o, 3-10 y/o, 10-18 y/o, and 18+. Results: Post-administration exposure rates for patients ranged from 0.16-0.46 µSv/hr/MBq at 1 ft and 0.03-0.08 µSv/hr/MBq at 1 m. Radiation exposure duration ranged from 1-10 days after release for the four evaluated cohorts. Based on the highest measured exposure rates and slowest whole-body clearance, the longest precautions were approximately 78% lower than the regulatory guidance recommendations. Radiation exposure to staff associated with 131I-omburtamab per administration was substantially below the annual regulatory threshold for individual exposure monitoring. Conclusion: 131I-omburtamab can be administered on an outpatient basis, using appropriate patient-based radiation safety precautions that employ patient-specific exposure rate and biological clearance parameters. This trial is registered with the National Library of Medicine's ClinicalTrials.gov. The registration number is NCT03275402, and it was registered on 7 September 2017. The web link is included here. https://clinicaltrials.gov/study/NCT03275402.

Glial expression of Drosophila UBE3A causes spontaneous seizures modulated by 5-HT signaling.

Misexpression of the E3 ubiquitin ligase UBE3A is thought to contribute to a range of neurological disorders. In the context of Dup15q syndrome, excess genomic copies of UBE3A is thought to contribute to the autism, muscle tone and spontaneous seizures characteristic of the disorder. In a Drosophila model of Dup 15q syndrome, it was recently shown glial-driven expression of the UBE3A ortholog dube3a led to a "bang-sensitive" phenotype, where mechanical shock triggers convulsions, suggesting glial dube3a expression contributes to hyperexcitability in flies. Here we directly compare the consequences of glial- and neuronal-driven dube3a expression on motor coordination and neuronal excitability in Drosophila. We utilized IowaFLI tracker and developed a hidden Markov Model to classify seizure-related immobilization. Both glial and neuronal driven dube3a expression led to clear motor phenotypes. However, only glial-driven dube3a expression displayed spontaneous immobilization events, that were exacerbated at high-temperature (38 °C). Using a tethered fly preparation we monitored flight muscle activity, we found glial-driven dube3a flies display spontaneous spike discharges which were bilaterally synchronized indicative of seizure activity. Neither control flies, nor neuronal- dube3a overexpressing flies display such firing patterns. Prior drug screen indicated bang-sensitivity in glial-driven dube3a expressing flies could be suppressed by certain 5-HT modulators. Consistent with this report, we found glial-driven dube3a flies fed the serotonin reuptake inhibitor vortioxetine and the 5HT 2A antagonist ketanserin displayed reduced immobilization and spike bursting. Together these findings highlight the potential for glial pathophysiology to drive Dup15q syndrome-related seizure activity.

The association between Long-COVID symptomology, perceived symptom burden and mental health in COVID-19 patients in Shijiazhuang, China: a population-based health survey.

Background: Long-COVID (LC) refers to post-acute COVID-19 symptoms that can last for months or longer after the initial infection, affecting the physical health of infected patients. This study aims to investigate the association between the symptomology of LC and the mental health of patients in China. It also aims to examine the relationship between the perceived symptom burden and mental health of these patients. Methods: A population-based stratified cluster sample was recruited, using a standard sampling procedure, from a prefecture-level city in Northern China. Participants included patients who had tested positive for COVID-19 after December 2022. LC symptomology was assessed using a LC symptoms checklist where the perceived symptom burden was measured by the included 5-point Likert scales. Mental health of patients was measured using the Depression, Anxiety, and Stress Scale (DASS), the original Connor-Davidson Resilience Scale (CD-RISC), and the Duke-UNC Functional Social Support Questionnaire (DUFSS). Data were analysed using multiple linear regression models. Results: About 25% of respondents, experienced COVID symptoms lasting longer than two months that could only be explained by the infection. Post-exertional malaise (22.2%) and fatigue (21.2%) were the most common symptoms. After controlling for potential confounding variables, LC symptomology was significantly and positively associated with depression (t=2.09, p=0.037) and anxiety (t=4.51, p<0.001), but not stress. Perceived symptoms burden was also positively and significantly related to depression (ß=0.35, p<0.001), anxiety (ß=0.54, p<0.001), and stress (ß=0.35, p<0.001), suggesting a dose-response relationship between perceived symptom burden and mental ill health. Conclusion: This study highlights the importance of recognising the risk of LC, patients' perception of the symptom burden and its potential impact on mental health. Healthcare professionals should be aware of the complexity of psychological comorbidities among infected patients reporting prolonged symptoms, and be able to give advice regarding long-term management of the symptoms.

A Rare Presentation of Idiopathic Unilateral Hypertrophic Olivary Degeneration.

Hypertrophic olivary degeneration (HOD) is a rare form of trans-synaptic degeneration affecting the inferior olivary nucleus (ION). Its classical description involves a lesion in the Guillain-Mollaret triangle (GMT), characteristic imaging findings, and associated oculopalatal tremor. However, understanding of this disease entity is incomplete, as its overall rarity has limited strong classification. Case reports and small studies indicate that a variety of presentations can occur, including non-existent or non-classical lesions as well as variations in physical symptoms. Here we report the exceedingly rare case of idiopathic, nonlesional, unilateral HOD in a female patient.

Digital Multiphase Composites via Additive Manufacturing.

Mechanical properties of traditional engineering materials are typically coupled to each other, presenting a challenge to practitioners with multi-dimensional material property requirements. In this work, continuous, independent control over multiple mechanical properties is demonstrated in composite materials realized using additive manufacturing. For the first time, composites additively manufactured from rigid plastic, soft elastomer, and liquid constituents are experimentally characterized, demonstrating materials which span four orders of magnitude in modulus and two orders of magnitude in toughness. By forming analytical mappings between relative concentrations of constituents at the microscale and resulting macroscale material properties, inverse material design is enabled; the method is showcased by printing artifacts with prescribed toughness and elasticity distributions. The properties of these composites are placed in the context of biological tissues, showing they have promise as mechanically plausible tissue mimics.

Moon, Mars and Minds: Evaluating Parkinson's disease mortality among U.S. radiation workers and veterans in the million person study of low-dose effects.

BACKGROUND: Radiation is one of the most important stressors related to missions in space beyond Earth's orbit. Epidemiologic studies of exposed workers have reported elevated rates of Parkinson's disease. The importance of cognitive dysfunction related to low-dose rate radiation in humans is not defined. A meta-analysis was conducted of six cohorts in the Million Person Study (MPS) of low-dose health effects to learn whether there is consistent evidence that Parkinson's disease is associated with radiation dose to brain. MATERIALS AND METHODS: The MPS evaluates all causes of death among U.S. radiation workers and veterans, including Parkinson's disease. Systematic and consistent methods are applied to study all categories of workers including medical radiation workers, industrial radiographers, nuclear power plant workers, atomic veterans, and Manhattan Projects workers at the Los Alamos National Laboratory and at Rocky Flats. Consistent methods for all cohorts are used to estimate organ-specific doses and to obtain vital status and cause of death. RESULTS: The meta-analysis include 6 cohorts within the MPS, consisting of 517,608 workers and 17,219,001 person-years of observation. The mean dose to brain ranged from 6.9 to 47.6 mGy and the maximum dose from 0.76 to 2.7 Gy. Five of the 6 cohorts revealed positive associations with Parkinson's disease. The overall summary estimate from the meta-analysis was statistically significant based on 1573 deaths due to Parkinson's disease. The summary excess relative risk at 100 mGy was 0.17 (95% CI: 0.05; 0.29). CONCLUSIONS: Parkinson's disease was positively associated with radiation in the MPS cohorts indicating the need for careful evaluation as to causality in other studies, delineation of possible mechanisms, and assessing possible implications for space travel as well as radiation protection guidance for terrestrial workers.

Expression of the Calcium-Sensing Receptor on Normal and Abnormal Parathyroid and Thyroid Tissue.

INTRODUCTION: Current imaging techniques have several limitations in detecting parathyroid glands. We have investigated the calcium-sensing receptor (CaSR) as a potential target for specifically labeling parathyroid glands for radiologic detection. For accurate imaging it is vital that a large differential expression exists between the target tissue and adjacent structures. We sought to investigate the relative abundance of the CaSR in normal and abnormal parathyroid tissue, as well as normal and abnormal thyroid. METHODS: Existing clinical specimens were selected that represented a wide variety of pathologically and clinically confirmed malignant and benign thyroid and parathyroid specimens. Sections were stained for the CaSR using immunohistochemistry and scored for intensity and abundance of expression. (H score = intensity scored from 0 to 3 multiplied by the % of cells at each intensity. Range 0-300). RESULTS: All parathyroid specimens expressed the CaSR to a high degree. Normal parathyroid had the highest H score (271, s.d. 25.4). Abnormal parathyroid specimens were slightly lower but still much higher than normal thyroid (H score 38.3, s.d. 23.3). Medullary thyroid cancer also expressed the CaSR significantly higher than normal thyroid (H score 182, s.d. 69.1, P < 0.001) but below parathyroid levels. Hürthle cell carcinoma expressed the CaSR to a lesser degree but higher than normal thyroid (H score 101, s.d. 46.4, P = 0.0037). CONCLUSIONS: The CaSR is differentially expressed on parathyroid tissue making it a feasible target for parathyroid imaging. False positives might be anticipated with medullary and Hürthle cell cancers.

HIV vaccines induce CD8+ T cells with low antigen receptor sensitivity.

Current HIV vaccines designed to stimulate CD8+ T cells have failed to induce immunologic control upon infection. The functions of vaccine-induced HIV-specific CD8+ T cells were investigated here in detail. Cytotoxic capacity was significantly lower than in HIV controllers and was not a consequence of low frequency or unaccumulated functional cytotoxic proteins. Low cytotoxic capacity was attributable to impaired degranulation in response to the low antigen levels present on HIV-infected targets. The vaccine-induced T cell receptor (TCR) repertoire was polyclonal and transduction of these TCRs conferred the same reduced functions. These results define a mechanism accounting for poor antiviral activity induced by these vaccines and suggest that an effective CD8+ T cell response may require a vaccination strategy that drives further TCR clonal selection.

Using Social Influence Strategies to Improve Rates of Online Mental Health Survey Participation: Results from Two Experiments.

Online surveys are routinely used in mental health screening and treatment follow-up assessment, though they can yield low response rates. We tested the effects of social psychology-informed influence strategies for increasing rates of participation in an online mental health screening survey (Experiment 1) and a treatment follow-up survey (Experiment 2). In Experiment 1 (N = 45,569), embedding one or any combination of three motivational appeals (personal gain, community gain, and inclusivity) in screening survey invitation and reminder emails unexpectedly led to lower rates of survey participation compared to when the appeals were not included (overall participation rate = 12.02%, ORs = 0.75 to 0.97, ps < .001). In Experiment 2 (N = 873), a video of a TikTok influencer encouraging survey participation embedded in treatment follow-up survey invitation and reminder emails did not significantly affect survey completion compared to a humorous gif unrelated to survey participation (overall participation rate = 47.88%, OR = 1.18, p = .200). Moderator analyses revealed that the video led to higher rates of participation than the gif among White participants (OR = 1.39, p = .031) and non-Hispanic participants (OR = 1.35, p = .029) only, whereas the video led to lower rates of participation than the gif among students who did not disclose their race (OR = 0.31, p = .010). Results suggested that efforts to improve online survey participation should be balanced with possible downsides (e.g., added email length) and should be evaluated for differential performance among population subgroups prior to widespread implementation.

An Open-Label Study of Adjunctive Dextromethorphan/Quinidine in Treatment-Resistant Depression.

BACKGROUND: Approximately one third of individuals with major depressive disorder have treatment-resistant depression (TRD). Glutamatergic modulators such as the N -methyl- d -aspartate receptor antagonist ketamine have rapid and robust antidepressant effects, but their use has been limited by accessibility and route of administration. This open-label pilot study assessed the adjunctive antidepressant efficacy of dextromethorphan/quinidine (DM/Q) in TRD. METHODS: Inpatients with TRD (n = 17, 40.8 ± 12.3 years; 9 females/8 males) received adjunctive open-label DM/Q (20 mg/10 mg) up to 3 times daily. The study had no set endpoint; participants were followed until they discontinued DM/Q or were discharged. Montgomery-Asberg Depression Rating Scale (MADRS) scores were obtained at baseline (before DM/Q administration) and regularly during hospitalization. Full response was defined as a ≥50% reduction in baseline MADRS score, partial response as a 25% to 50% decrease in baseline MADRS score, and nonresponse as a <25% reduction or an increase in baseline MADRS score. RESULTS: The 17 inpatients received open-label DM/Q for 5.1 ± 2.7 weeks. Forty-seven percent of participants responded to DM/Q-12% achieved a full response and 35% achieved a partial response. The largest MADRS difference observed at any time point was -6.4 ± 8.4 (-21.0% ± 29.9%), and the MADRS difference observed at time of DM/Q discontinuation or hospital discharge was -4.8 ± 8.4 (-15.9% ± 29.7%). Twenty-four percent of participants experienced a nonserious adverse event; none experienced a serious adverse event. CONCLUSIONS: In this open-label pilot study, 47% of participants responded to adjunctive DM/Q, which was well tolerated. Larger placebo-controlled trials are needed to determine the real-world efficacy of DM/Q.

Evidence Base Update on Behavioral Treatments for Overweight and Obesity in Children and Adolescents.

OBJECTIVE: This review provides an update to a previous Evidence Base Update addressing behavioral treatments for overweight and obesity in children and adolescents. METHOD: Articles were identified through a systematic search of the biomedical literature in PubMed/MEDLINE (1946-), Elsevier EMBASE (1947-), SCOPUS (1823-), Clarivate Web of Science Core Collection (WOS, 1900-), PsycINFO (1800-), The Cochrane Library and Clinicaltrials.gov published between June 2014 and August 2022. RESULTS: Family-based treatment (FBT) remains a well-established treatment for overweight and obesity in children and is now well-established in adolescents and toddlers. Parent-only behavioral treatment remains well-established in children and is now well-established among adolescents and children. Possibly effective treatments continue to include FBT-parent only for adolescents, and behavioral weight loss (BWL) with a family component for adolescents, children, and toddlers. Several variations of FBT and BWL can now be considered possibly effective including FBT+motivational interviewing, FBT+social facilitation maintenance, group-based FBT, low-dose FBT, BWL+stress management, and camp-based BWL. Cognitive behavioral treatment (CBT) for adolescents also met criteria for possibly effective treatments. Current research has also established that behavioral treatments can be effectively delivered in alternative settings (e.g. primary care) and through alternative mediums (e.g. telehealth). CONCLUSIONS: Research continues to support the use of multicomponent lifestyle interventions in accordance with recent recommendations from the American Academy of Pediatrics, the American Psychological Association, and the United State Preventative Services Task Force. However, more work is needed to ensure appropriate access for children with comorbid medical and psychiatric disorders and children from socially, politically, and economically marginalized groups.

Trends in Radiation Dose to the Contralateral Breast During Breast Cancer Radiation Therapy.

Over 4 million survivors of breast cancer live in the United States, 35% of whom were treated before 2009. Approximately half of patients with breast cancer receive radiation therapy, which exposes the untreated contralateral breast to radiation and increases the risk of a subsequent contralateral breast cancer (CBC). Radiation oncology has strived to reduce unwanted radiation dose, but it is unknown whether a corresponding decline in actual dose received to the untreated contralateral breast has occurred. The purpose of this study was to evaluate trends in unwanted contralateral breast radiation dose to inform risk assessment of second primary cancer in the contralateral breast for long-term survivors of breast cancer. Individually estimated radiation absorbed doses to the four quadrants and areola central area of the contralateral breast were estimated for 2,132 women treated with radiation therapy for local/regional breast cancers at age <55 years diagnosed between 1985 and 2008. The two inner quadrant doses and two outer quadrant doses were averaged. Trends in dose to each of the three areas of the contralateral breast were evaluated in multivariable models. The population impact of reducing contralateral breast dose on the incidence of radiation-associated CBC was assessed by estimating population attributable risk fraction (PAR) in a multivariable model. The median dose to the inner quadrants of the contralateral breast was 1.70 Gy; to the areola, 1.20 Gy; and to the outer quadrants, 0.72 Gy. Ninety-two percent of patients received ≥1 Gy to the inner quadrants. For each calendar year of diagnosis, dose declined significantly for each location, most rapidly for the inner quadrants (0.04 Gy/year). Declines in dose were similar across subgroups defined by age at diagnosis and body mass index. The PAR for CBC due to radiation exposure >1 Gy for women <40 years of age was 17%. Radiation dose-reduction measures have reduced dose to the contralateral breast during breast radiation therapy. Reducing the dose to the contralateral breast to <1 Gy could prevent an estimated 17% of subsequent radiation-associated CBCs for women treated under 40 years of age. These dose estimates inform CBC surveillance for the growing number of breast cancer survivors who received radiation therapy as young women in recent decades. Continued reductions in dose to the contralateral breast could further reduce the incidence of radiation-associated CBC.