Distinct genetic origins of eumelanin levels and barring patterns in cichlid fishes.

Pigment patterns are incredibly diverse across vertebrates and are shaped by multiple selective pressures from predator avoidance to mate choice. A common pattern across fishes, but for which we know little about the underlying mechanisms, is repeated melanic vertical bars. To understand the genetic factors that modify the level or pattern of vertical barring, we generated a genetic cross of 322 F2 hybrids between two cichlid species with distinct barring patterns, Aulonocara koningsi and Metriaclima mbenjii. We identify 48 significant quantitative trait loci that underlie a series of seven phenotypes related to the relative pigmentation intensity, and four traits related to patterning of the vertical bars. We find that genomic regions that generate variation in the level of eumelanin produced are largely independent of those that control the spacing of vertical bars. Candidate genes within these intervals include novel genes and those newly-associated with vertical bars, which could affect melanophore survival, fate decisions, pigment biosynthesis, and pigment distribution. Together, this work provides insights into the regulation of pigment diversity, with direct implications for an animal's fitness and the speciation process.

Assessing survival in non-small cell lung cancer brain metastases after stereotactic radiosurgery: before and after the start of the targetable mutation era.

PURPOSE: Targeted treatment options for non-small cell lung cancer (NSCLC) brain metastases (BMs) may be combined with stereotactic radiosurgery (SRS) to optimize survival. We assessed patient outcomes after SRS for NSCLC BMs, identifying survival trajectories associated with targetable mutations. METHODS: In this retrospective time-dependent analysis, we analyzed median overall survival of patients who received ≥ 1 SRS courses for BM from NSCLC from 2001 to 2021. We compared survival of patients with and without targetable mutations based on clinical variables and treatment. RESULTS: Among the 213 patients included, 87 (40.8%) had targetable mutations-primarily EGFR (22.5%)-and 126 (59.2%) did not. Patients with targetable mutations were more often female (63.2%, p <.001) and nonsmokers (58.6%, p <.001); had higher initial lung-molGPA (2.0 vs. 1.5, p <.001) and lower cumulative tumor volume (3.7 vs. 10.6 cm3, p <.001); and received more concurrent (55.2% vs. 36.5%, p =.007) and total (median 3 vs. 2, p <.001) systemic therapies. These patients had lower mortality rates (74.7% vs. 91.3%, p <.001) and risk (HR 0.298 [95%CI 0.190-0.469], p <.001) and longer median overall survival (20.2 vs. 7.4 months, p <.001), including survival ≥ 3 years (p =.001). Survival was best predicted by SRS with tumor resection in patients with non-targetable mutations (HR 0.491 [95%CI 0.318-757], p =.001) and by systemic therapy with SRS for those with targetable mutations (HR 0.124 [95%CI 0.013-1.153], p =.067). CONCLUSION: The presence of targetable mutations enhances survival in patients receiving SRS for NSCLC BM, particularly when used with systemic therapies. Survival for patients without targetable mutations was longest with SRS and surgical resection. These results inform best practices for managing patients with NSCLC BM based on driver mutation status.

Reduction in ACE2 expression in peripheral blood mononuclear cells during COVID-19 - implications for post COVID-19 conditions.

BACKGROUND: Severe COVID-19 is uncommon, restricted to 19% of the total population. In response to the first virus wave (alpha variant of SARS-CoV-2), we investigated whether a biomarker indicated severity of disease and, in particular, if variable expression of angiotensin converting enzyme 2 (ACE2) in blood might clarify this difference in risk and of post COVID -19 conditions (PCC). METHODS: The IRB-approved study compared patients hospitalized with severe COVID-19 to healthy controls. Severe infection was defined requiring oxygen or increased oxygen need from baseline at admission with positive COVID-19 PCR. A single blood sample was obtained from patients within a day of admission. ACE2 RNA expression in blood cells was measured by an RT-PCR assay. Plasma ACE1 and ACE2 enzyme activities were quantified by fluorescent peptides. Plasma TIMP-1, PIIINP and MMP-9 antigens were quantified by ELISA. Data were entered into REDCap and analyzed using STATA v 14 and GraphPad Prism v 10. RESULTS: Forty-eight patients and 72 healthy controls were recruited during the pandemic. ACE2 RNA expression in peripheral blood mononuclear cells (PBMC) was rarely detected acutely during severe COVID-19 but common in controls (OR for undetected ACE2: 12.4 [95% CI: 2.62-76.1]). ACE2 RNA expression in PBMC did not determine plasma ACE1 and ACE2 activity, suggesting alternative cell-signaling pathways. Markers of fibrosis (TIMP-1 and PIIINP) and vasculopathy (MMP-9) were additionally elevated. ACE2 RNA expression during severe COVID-19 often responded within hours to convalescent plasma. Analogous to oncogenesis, we speculate that potent, persistent, cryptic processes following COVID-19 (the renin-angiotensin system (RAS), fibrosis and vasculopathy) initiate or promote post-COVID-19 conditions (PCC) in susceptible individuals. CONCLUSIONS: This work elucidates biological and temporal plausibility for ACE2, TIMP1, PIIINP and MMP-9 in the pathogenesis of PCC. Intersection of these independent systems is uncommon and may in part explain the rarity of PCC.

Analysis of Completion Intraoperative Venography During First Rib Resection for Venous Thoracic Outlet Syndrome.

INTRODUCTION: We evaluated the impact of completion intraoperative venography on clinical outcomes for axillosubclavian vein (AxSCV) thrombosis due to venous thoracic outlet syndrome (vTOS). METHODS: We performed a retrospective, single-center review of all patients with vTOS treated with First Rib Resection and intraoperative venography from 2011 - 2023. We reviewed intraoperative venographic films to classify findings, collected demographics, clinical and perioperative variables, and clinical outcomes. Primary endpoints were symptomatic relief and primary patency at 3 months and 1 year. Secondary endpoints were time free from symptoms, reintervention rate, perioperative complications, and mortality. RESULTS: Fifty-one AxSCVs (49 patients, mean age of 31.3 ± 12.6, 52.9% female) were treated for vTOS with first rib resection and external venolysis followed by completion intraoperative venography with a mean follow up of 15.5 ± 13.5 months. Prior to FRR, 32 underwent catheter-directed thrombolysis (62.7%). Completion intraoperative venography identified 16 patients with No Stenosis (Group 1, 31.3%), 17 with No Stenosis after Angioplasty (Group 2, 33.3%), 10 with Residual Stenosis after Angioplasty (Group 3, 19.7%), and 8 with Complete Occlusion (Group 4, 15.7%). The overall symptomatic relief was 44 of 51 (86.3%) and did not differ between venographic classifications (Group 1: 14 of 16, Group 2: 13 of 17, Group 3: 10 of 10, and Group 4: 7 of 8; Log-Rank Test, p = 0.5). The overall 3-month and 1-year primary patency was 42 of 43 (97.7%) and 32 of 33 (97.0%), respectively (Group 1: 16 of 16 and 9 of 9; Group 2: 16 of 17 and 12 of 13; Group 3: 10 of 10, 5 of 5; Group 4: primary patency not obtained). There was one asymptomatic re-thrombosis that resolved with anticoagulation, and three patients underwent reintervention with venous angioplasty for significant symptom recurrence an average 2.89 ± 1.7 months after FRR. CONCLUSION: Our single-center retrospective study demonstrates that FRR with completion intraoperative venography has excellent symptomatic relief, short- and mid-term patency despite residual venous stenosis and complete occlusion. While completion intraoperative venographic classification did not correlate with adverse outcomes, this protocol yielded excellent results and provides important clinical data for postoperative management. Our results also support a conservative approach to AxSCV occlusion identified after FRR.

Organizing a Regional In-Person Medical Student Symposium in Neuroscience and Neurosurgery Research: A How-To Guide.

BACKGROUND: Medical students are increasingly seeking out research opportunities to build their skills and network with future colleagues. Medical student-led conferences are an excellent endeavor to achieve this goal. METHODS: The American Association of Neurological Surgeons (AANS) student chapter at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell designed an in-person medical student research symposium alongside the Northwell Health Department of Neurosurgery. Post-conference feedback forms were sent out digitally to student attendees to evaluate event planning and execution and responses were given on a scale of 1-5 (5 being the highest score). RESULTS: In December 2023, the Northeast Medical Student Research Symposium (NMSRS) was held with over 80 participants and 52 medical student presenters. Keynote speakers delivered lectures geared towards students interested in neurosurgery and neuroscience research, followed by an interactive poster board session and resident/attending networking dinner. After the conference, students affirmed that they learned more about neuroscience research after the event (mean: 4.3), were more inclined to attend other neuroscience research events in the future (mean: 4.7), and would attend this event if held next year (mean: 4.8). The poster sessions (mean: 4.75) and keynote lectures (mean: 5) were the highest rated events, while the resident/attending networking dinner (mean: 3.6) was a potential area for improvement. CONCLUSION: Regional in-person conferences are an excellent way to foster interest in neurosurgery and neuroscience research, network with like-minded peers, and prepare students for presentations at national meetings.

Modifiable Lifestyle Risk Factors in Adult Survivors of Childhood Cancer: A Nationally Representative Study.

OBJECTIVE: Given the vulnerable health condition of adult childhood cancer survivors, it is essential that they develop positive health behaviors to minimize controllable health risks. Therefore, we evaluated if adult survivors of non-childhood cancer and childhood cancer differ in the odds of each modifiable risk factor compared with each other and compared with the general population. METHODS: This nationally representative study leveraged the National Health Interview Survey (NHIS) sample from 2000 to 2018 and the Behavioral Risk Factor Surveillance System (BRFSS) sample from 2016 to 2021. Our study population included adults diagnosed with cancer when they were ≤14 years of age. Outcomes included physical activity, body mass index (BMI), current smoking, ever-smoking, alcohol use, and binge drinking. RESULTS: Insufficient physical activity was not statistically significant in the BRFSS, but in the NHIS, childhood cancer survivors had significantly more insufficient physical activity compared with non-childhood cancer survivors (aOR 1.29, P=0.038) and the general population (aOR 1.40, P=0.006). Childhood cancer survivors also had a higher likelihood of being significantly underweight (aOR 1.84, P=0.018) and having ever-smoked (aOR 1.42, P=0.001) compared with the general population in the NHIS. There was a significantly higher likelihood of smoking among childhood cancer survivors in the BRFSS (aOR 2.02, P=0.004). CONCLUSIONS: The likelihoods of many risky behaviors between adult childhood cancer survivors and general population controls were comparable, although rates of physical activity may be decreased, and rates of smoking may be increased among childhood cancer survivors. Targeted interventions are needed to promote healthy behaviors in this vulnerable population.

Provider perspectives on screening and treatment for opioid use disorder and mental health in HIV care: A qualitative study.

BACKGROUND: HIV, opioid use disorder (OUD), and mental health challenges share multiple syndemic risk factors. Each can be effectively treated with routine outpatient appointments, medication management, and psychosocial support, leading implementers to consider integrated screening and treatment for OUD and mental health in HIV care. Provider perspectives are crucial to understanding barriers and strategies for treatment integration. METHODS: We conducted in-depth qualitative interviews with 21 HIV treatment providers and social services providers (12 individual interviews and 1 group interview with 9 participants) to understand the current landscape, goals, and priorities for integrated OUD, mental health, and HIV care. Providers were purposively recruited from known clinics in Mecklenburg County, North Carolina, U.S.A. Data were analyzed using applied thematic analysis in the NVivo 12 software program and evaluated for inter-coder agreement. RESULTS: Participants viewed substance use and mental health challenges as prominent barriers to engagement in HIV care. However, few organizations have integrated structured screening for substance use and mental health into their standard of care. Even fewer screen for opioid use. Although medication assisted treatment (MAT) is effective for mitigating OUD, providers struggle to connect patients with MAT due to limited referral options, social barriers such as housing and food insecurity, overburdened staff, stigma, and lack of provider training. Providers believed there would be clear benefit to integrating OUD and mental health treatment in HIV care but lacked resources for implementation. CONCLUSIONS: Integration of screening and treatment for substance use and mental health in HIV care could mitigate many current barriers to treatment for all three conditions. Efforts are needed to train HIV providers to provide MAT, expand resources, and implement best practices.

Integration of passive sensing technology to enhance delivery of psychological interventions for mothers with depression: the StandStrong study.

Psychological interventions delivered by non-specialist providers have shown mixed results for treating maternal depression. mHealth solutions hold the possibility for unobtrusive behavioural data collection to identify challenges and reinforce change in psychological interventions. We conducted a proof-of-concept study using passive sensing integrated into a depression intervention delivered by non-specialists to twenty-four adolescents and young mothers (30% 15-17 years old; 70% 18-25 years old) with infants (< 12 months old) in rural Nepal. All mothers showed a reduction in depression symptoms as measured with the Beck Depression Inventory. There were trends toward increased movement away from the house (greater distance measured through GPS data) and more time spent away from the infant (less time in proximity measured with the Bluetooth beacon) as the depression symptoms improved. There was considerable heterogeneity in these changes and other passively collected data (speech, physical activity) throughout the intervention. This proof-of-concept demonstrated that passive sensing can be feasibly used in low-resource settings and can personalize psychological interventions. Care must be taken when implementing such an approach to ensure confidentiality, data protection, and meaningful interpretation of data to enhance psychological interventions.

Percutaneous Screw Distraction for Anatomic Restoration: Case Series.

BACKGROUND AND OBJECTIVES: Percutaneous pedicle screw fixation with distraction reduces morbidity after traumatic thoracolumbar burst fractures; however, there are substantial limitations, particularly for correction of kyphosis. The use of fixed-angle screws may offer improved anatomic restoration, facilitating greater postdistraction vertebral height restoration and spinal canal fragment reduction. We examined the radiographic results of distraction across fixed-angle screws immediately after surgery and in long-term follow-up. METHODS: Demographic and clinical characteristics were captured for patients with traumatic thoracolumbar fractures undergoing percutaneous pedicle screw fixation by a single surgeon. Radiographic measurements were collected at predistraction, postdistraction, and long-term follow-up time points. Paired t-tests, Student's t-tests, Mann-Whitney U tests, and χ2 tests were used to assess data where appropriate. RESULTS: The case series included 22 patients (77.3% male; mean age 42.0 ± 18.4 years). Hounsfield density consistent with osteopenia was seen in 13.6% of patients at the time of injury. Sporting injuries and motor vehicle accidents were common (both 31.8%). Most injuries occurred at L1 (45.5%). Upon long-term follow-up, the mean injured-level predistraction cross-sectional area improved from 2.1 to 2.9 cm2 (P < .01). Compared with the superadjacent level, the injured-level cross-sectional canal area improved by 28.6% (P < .01). Vertebral body index also improved significantly (18.8° mean change, P < .01). The mean bisegmental Cobb angle improved by 6.2° (P = .01), and injured vertebral body compression decreased by 22.4% (P < .01). Significant improvement in correction was achieved with experience, with final technique yielding superior cross-sectional area (P = .04) and compression ratios (P = .03). CONCLUSION: Distraction across fixed-angle percutaneous screw instrumentation systems stabilizes traumatic thoracolumbar burst fractures, corrects deformity, and decompresses the spinal canal. Further comparative research is necessary to demonstrate whether outcomes are different between percutaneous instrumentation vs open fusion for thoracolumbar trauma.

Development of Consensus-Based Best Practice Guidelines for the Peri- and Post-operative Care of Pediatric Patients with Spinal Deformity and Programmable Implanted Devices.

STUDY DESIGN: Modified Delphi consensus study. OBJECTIVE: To develop consensus-based best practices for the care of pediatric patients who have implanted programmable devices (IPDs) and require spinal deformity surgery. SUMMARY OF BACKGROUND DATA: Implanted programmable devices (IPDs) are often present in patients with neuromuscular or syndromic scoliosis who require spine surgery. Guidelines for monitoring and interrogating these devices during the peri-operative period are not available. METHODS: A panel was assembled consisting of 25 experts (i.e., spinal deformity surgeons, neurosurgeons, neuro-electrophysiologists, cardiologists, and otolaryngologists). Initial postulates were based on literature review and results from a prior survey. Postulates addressed the following IPDs: vagal nerve stimulators (VNS), programmable ventriculo-peritoneal shunts (VPS), intrathecal baclofen pumps (ITBP), cardiac pacemakers and implantable cardioverter-defibrillators (ICD), deep brain stimulators (DBS), and cochlear implants. Cardiologist and otolaryngologists participants responded only to postulates on cardiac pacemakers or cochlear implants, respectively. Consensus was defined as ≥80% agreement, items that did not reach consensus were revised and included in subsequent rounds. A total of three survey rounds and one virtual meeting were conducted. RESULTS: Consensus was reached on 39 total postulates across six IPD types. Postulates addressed general spine surgery considerations, use of intraoperative monitoring and cautery, use of magnetically-controlled growing rods (MCGRs), and use of an external remote controller to lengthen MCGRs. Across IPD types, consensus for the final postulates ranged from 94.4-100%. Overall, experts agreed that MCGRs can be surgically inserted and lengthened in patients with a variety of IPDs and provided guidance for the use of intraoperative monitoring and cautery, which varied between IPD types. CONCLUSION: Spinal deformity correction surgery often benefits from the use of intraoperative monitoring, monopolar and bipolar cautery, and MCGRs. Final postulates from this study can inform the peri- and post-operative practices of spinal deformity surgeons who treat patients with both scoliosis and IPDs. LEVEL OF EVIDENCE: V- Expert opinion.

Endogenous Opioids and Exercise-Related Hypoalgesia: Modern Models, Measurement, and Mechanisms of Action.

This chapter will focus on the role exercise appears to have on activation and modulating factors within the central nervous system related to endogenous like opioids and its possible contribution to exercise-induced hypoalgesia. The implications for the exercise-mediated alterations of CNS activation factors related to opioids, specifically endorphins and enkephalins, will be presented. In this update, we discuss utilization of new technology and methods to monitor mechanisms of opioid involvement to suggest their contribution with exercise mediated hypoalgesia as well as their relationships to alterations of perceptions of pain and mood. Several special populations were included to suggest that not all individuals will respond to the exercise by mediating hypoalgesia. Factors that may confound the current understanding and suggestions from the recent literature will be presented as well as suggestions for future investigations.

Perspectives on competency-based feedback for training non-specialists to deliver psychological interventions: multi-site qualitative study of the EQUIP competency-based approach.

BACKGROUND: The use of feedback to address gaps and reinforce skills is a key component of successful competency-based mental health and psychosocial support intervention training approaches. Competency-based feedback during training and supervision for personnel delivering psychological interventions is vital for safe and effective care. AIMS: For non-specialists trained in low-resource settings, there is a lack of standardised feedback systems. This study explores perspectives on competency-based feedback, using structured role-plays that are featured on the Ensuring Quality in Psychosocial and Mental Health Care (EQUIP) platform developed by the World Health Organization and United Nations Children's Fund. METHOD: Qualitative data were collected from supervisors, trainers and trainees from multiple EQUIP training sites (Ethiopia, Kenya, Lebanon, Peru and Uganda), from 18 key informant interviews and five focus group discussions (N = 41 participants). Qualitative analysis was conducted in Dedoose, using a codebook with deductively and inductively developed themes. RESULTS: Four main themes demonstrated how a competency-based structure enhanced the feedback process: (a) competency-based feedback was personalised and goal-specific, (b) competency-based feedback supported a feedback loop, (c) competency-based feedback supported a comfortable and objective feedback environment, and (d) competency-based feedback created greater opportunities for flexibility in training and supervision. CONCLUSIONS: A better understanding of the role of feedback supports the implementation of competency-based training that is systematic and effective for trainers and supervisors, which ultimately benefits the learning process for trainees.

Feasibility and acceptability of a mobile intervention for patients with psychosis following psychiatric hospitalization: A pilot randomized controlled trial.

This pilot randomized control trial examines the feasibility and acceptability of a novel mHealth intervention for patients with schizophrenia spectrum disorders following discharge from inpatient hospitalization. Using cognitive behavior therapy for psychosis strategies, the app provides just-in-time assessment and intervention for individuals to promote healthy coping skills and treatment adherence. We assessed the mHealth intervention relative to a comparison app that included mobile assessment plus psychoeducation alone. Patients were assessed at hospital discharge, as well as 1-, 2-, and 4-months postdischarge. Forty-two adults with schizophrenia spectrum disorders discharging from inpatient care participated in the study. Our a priori-defined feasibility and acceptability goals were mostly achieved during the study, in terms of the proposed recruitment and retention rates, mHealth app engagement, app satisfaction ratings, clinical improvement observed over time, and absence of adverse events related to the study. The participants were significantly more engaged in the mHealth intervention (74%) versus the comparison app (43%). Over the course of the study, dysfunctional coping and psychiatric symptoms significantly declined in both groups. Future larger trials are needed to confirm the efficacy of the mHealth intervention. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Inflammation and immune system pathways as biological signatures of adolescent depression-the IDEA-RiSCo study.

The biological mechanisms underlying the onset of major depressive disorder (MDD) have predominantly been studied in adult populations from high-income countries, despite the onset of depression typically occurring in adolescence and the majority of the world's adolescents living in low- and middle-income countries (LMIC). Taking advantage of a unique adolescent sample in an LMIC (Brazil), this study aimed to identify biological pathways characterizing the presence and increased risk of depression in adolescence, and sex-specific differences in such biological signatures. We collected blood samples from a risk-stratified cohort of 150 Brazilian adolescents (aged 14-16 years old) comprising 50 adolescents with MDD, 50 adolescents at high risk of developing MDD but without current MDD, and 50 adolescents at low risk of developing MDD and without MDD (25 females and 25 males in each group). We conducted RNA-Seq and pathway analysis on whole blood. Inflammatory-related biological pathways, such as role of hypercytokinemia/hyperchemokinemia in the pathogenesis of influenza (z-score = 3.464, p < 0.001), interferon signaling (z-score = 2.464, p < 0.001), interferon alpha/beta signaling (z-score = 3.873, p < 0.001), and complement signaling (z-score = 2, p = 0.002) were upregulated in adolescents with MDD compared with adolescents without MDD independently from their level of risk. The up-regulation of such inflammation-related pathways was observed in females but not in males. Inflammatory-related pathways involved in the production of cytokines and in interferon and complement signaling were identified as key indicators of adolescent depression, and this effect was present only in females.

A high-dimensional platform for observing neutrophil-parasite interactions.

Diarrheal diseases with infectious etiology remain a major cause of death globally, particularly in low-income countries. Entamoeba histolytica is a pathogenic protozoan parasite that is the causative agent of amebiasis. Amebiasis has a wide presentation in clinical severity with many factors, including the bacterial microbiota, contributing to this variation. The innate immune response also plays a critical role in regulating the severity of E. histolytica infection, with neutrophils reported to have a protective role. Despite this, the precise mechanism of how neutrophils mediate amebic killing is poorly understood. Thus, modern platforms that allow for inquiry of granulocyte-ameba interactions will increase our understanding of this disease. Herein, we describe an assay for neutrophil killing of E. histolytica by utilizing high-dimensional spectral flow cytometry. Neutrophils were isolated from wild-type 5-week-old C57BL/6 mice and co-cultured with E. histolytica at various multiplicity of infections (MOIs). After co-culture, neutrophils and E. histolytica were stained for spectral flow cytometry. Cell populations were identified using surface markers and fluorescence minus one (FMO) controls. We have previously shown that animals colonized with a component of the human microbiota, Clostridium scindens, were protected from E. histolytica. This protection was associated with elevated neutrophil count. Here, we explored amebic killing capacity and observed that neutrophils from animals with C. scindens possessed heightened amebic killing compared with controls. Thus, this study establishes a novel platform that can provide an in-depth analysis of granulocyte-parasite interactions in various contexts, including during alteration of the intestinal microbiota.IMPORTANCEThe tools for studying host immune cell-E. histolytica interactions are limited. Factors, such as parasite heterogeneity, infectivity, and difficulties with culture systems and animal models, make interrogation of these interactions challenging. Thus, Entamoeba researchers can benefit from next-generation models that allow for the analysis of both host and parasite cells. Here, we demonstrate the use of a novel platform that allows for the determination of parasite-host cell interactions and customizable high-dimensional phenotyping of both populations. Indeed, spectral flow cytometry can approach >40 markers on a single panel and can be paired with custom-developed parasite antibodies that can be conjugated to fluorochromes via commercially available kits. This platform affords researchers the capability to test highly precise hypotheses regarding host-parasite interactions.

In vivo editing of lung stem cells for durable gene correction in mice.

In vivo genome correction holds promise for generating durable disease cures; yet, effective stem cell editing remains challenging. In this work, we demonstrate that optimized lung-targeting lipid nanoparticles (LNPs) enable high levels of genome editing in stem cells, yielding durable responses. Intravenously administered gene-editing LNPs in activatable tdTomato mice achieved >70% lung stem cell editing, sustaining tdTomato expression in >80% of lung epithelial cells for 660 days. Addressing cystic fibrosis (CF), NG-ABE8e messenger RNA (mRNA)-sgR553X LNPs mediated >95% cystic fibrosis transmembrane conductance regulator (CFTR) DNA correction, restored CFTR function in primary patient-derived bronchial epithelial cells equivalent to Trikafta for F508del, corrected intestinal organoids and corrected R553X nonsense mutations in 50% of lung stem cells in CF mice. These findings introduce LNP-enabled tissue stem cell editing for disease-modifying genome correction.

Translation, cultural adaptation and validation of Patient Health Questionnaire and generalized anxiety disorder among adolescents in Nepal.

BACKGROUND: Depression and anxiety are significant contributors to the global burden of disease among young people. Accurate data on the prevalence of these conditions are crucial for the equitable distribution of resources for planning and implementing effective programs. This study aimed to culturally adapt and validate data collection tools for measuring depression and anxiety at the population level. METHODS: The study was conducted in Kathmandu, Nepal, a diverse city with multiple ethnicities, languages, and cultures. Ten focus group discussions with 56 participants and 25 cognitive interviews were conducted to inform adaptations of the Patient Health Questionnaire adapted for Adolescents (PHQ-A) and Generalized Anxiety Disorder (GAD-7). To validate the tools, a cross-sectional survey of 413 adolescents (aged 12-19) was conducted in three municipalities of Kathmandu district. Trained clinical psychologists administered the Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS-DSM 5 version) to survey participants. RESULTS: A number of cultural adaptations were required, such as changing statements into questions, using a visual scale (glass scale) to maintain uniformity in responses, and including a time frame at the beginning of each item. For younger adolescents aged 12 to 14 years, a PHQ-A cut-off of > = 13 had a sensitivity of 0.93, specificity of 0.80, positive predictive value (PPV) of 0.33, and negative predictive value (NPV) of 0.99. For older adolescents aged 15-19, a cut-off of > = 11 had a sensitivity of 0.89, specificity of 0.70, PPV of 0.32, and NPV of 0.97. For GAD-7, a cut-off of > = 8 had a sensitivity of 0.70 and specificity of 0.67 for younger adolescents and 0.71 for older adolescents, with a PPV of 0.39 and NPV of 0.89. The individual symptom means of both PHQ-A and GAD-7 items showed moderate ability to discriminate between adolescents with and without depression and anxiety. CONCLUSION: The PHQ-A and GAD-7 demonstrate fair psychometric properties for screening depression but performed poorly for anxiety, with high rates of false positives. Even when using clinically validated cut-offs, population prevalence rates would be inflated by 2-4 fold with these tools, requiring adjustment when interpreting epidemiological findings.

Prospective Follow-Up of Adolescents With and at Risk for Depression: Protocol and Methods of the Identifying Depression Early in Adolescence Risk Stratified Cohort Longitudinal Assessments.

Objective: To present the protocol and methods for the prospective longitudinal assessments-including clinical and digital phenotyping approaches-of the Identifying Depression Early in Adolescence Risk Stratified Cohort (IDEA-RiSCo) study, which comprises Brazilian adolescents stratified at baseline by risk of developing depression or presence of depression. Method: Of 7,720 screened adolescents aged 14 to 16 years, we recruited 150 participants (75 boys, 75 girls) based on a composite risk score: 50 with low risk for developing depression (LR), 50 with high risk for developing depression (HR), and 50 with an active untreated major depressive episode (MDD). Three annual follow-up assessments were conducted, involving clinical measures (parent- and adolescent-reported questionnaires and psychiatrist assessments), active and passive data sensing via smartphones, and neurobiological measures (neuroimaging and biological material samples). Retention rates were 96% (Wave 1), 94% (Wave 2), and 88% (Wave 3), with no significant differences by sex or group (p > .05). Participants highlighted their familiarity with the research team and assessment process as a motivator for sustained engagement. Discussion: This protocol relied on novel aspects, such as the use of a WhatsApp bot, which is particularly pertinent for low- to-middle-income countries, and the collection of information from diverse sources in a longitudinal design, encompassing clinical data, self-reports, parental reports, Global Positioning System (GPS) data, and ecological momentary assessments. The study engaged adolescents over an extensive period and demonstrated the feasibility of conducting a prospective follow-up study with a risk-enriched cohort of adolescents in a middle-income country, integrating mobile technology with traditional methodologies to enhance longitudinal data collection.

This article details the study protocol and methods used in the longitudinal assessment of 150 Brazilian teenagers with depression and at risk for depression as part of the Identifying Depression Early in Adolescence Risk Stratified Cohort (IDEA-RiSCo). Over 3 years, the authors collected clinical and digital data using innovative mobile technology, including a WhatsApp bot. Most adolescents participated in all the study phases, showing feasibility of prospective follow-up in a middle-income country. This approach allowed for a deeper understanding of depression in young populations, particularly in areas where mental health research is scarce.

"Let him die. He caused it": A qualitative study on cancer stigma in Tanzania.

Cancer stigma presents a critical barrier to care seeking, contributing to delayed presentation and poor cancer outcomes worldwide. The burden of cancer in Tanzania is on the rise, with cancer being the third-leading cause of death in the country. Despite rising incidence and poor outcomes of cancer, cancer-related stigma interventions have received low prioritization. There is a need for sound research that focuses on understanding attitudes driving stigma, its impact on care-seeking and treatment adherence, and intervention models to reduce stigma. We used a cross-sectional qualitative study design. We administered three open-ended qualitative questions to 140 adults newly diagnosed with cancer in Moshi, Tanzania. The questions explored common attitudes toward people with cancer, the perceived impact of cancer-related stigma on care engagement, and ideas for reducing cancer stigma. Patients were recruited during routine appointments at the Cancer Center at Kilimanjaro Christian Medical Center. Data were analyzed using a team-based, applied thematic approach and NVivo 12 software. All participants described stigma as a significant challenge for treatment and receiving support from their social networks. Perceptions of financial burden, misconceptions about cancer, such as the belief that it is contagious, and fear of death, were common attitudes driving cancer stigma. Most participants feared that symptoms would prevent them from being able to work and that the cost of cancer care would drive away loved ones. Stigma was not a ubiquitous response, as some participants reported increased care and social support from family members after a cancer diagnosis. Experiences of stigma contributed to feelings of shame, fear of burdening the family, reduced resources to access treatment, and disengagement from care. Common substitutes to medical therapies included religious interventions and traditional medicine, perceived as less expensive and less stigmatizing. Many participants felt they would benefit from improved financial support, professional counseling, and education for families and communities to reduce stigmatizing attitudes and enhance social support. There is a need for intervention studies focused on improving cancer literacy, community advocacy to reduce cancer stigma, and increasing emotional and practical support for people with cancer and their families. There is also a clear need for policy efforts to make cancer care more affordable and accessible to reduce the financial burden on patients and families.