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Abstract Background In Malawi, approximately 25% of adolescents living with HIV (ALWH) also suffer from depression. Not only is HIV stigma a major contributor to depression but it also adversely impacts HIV care engagement. ALWH can experience HIV stigma as stereotyping, social exclusion, low social support, and abuse, and these experiences are associated with poor mental health. Despite recognition of the deleterious effects of HIV stigma, we have limited knowledge of how stigma is experienced by ALWH with comorbid depression. Guided by the Health Stigma and Discrimination Framework, we describe stigma faced by ALWH and comorbid depression in Malawi and its implications for future interventions. Methods As part of a larger formative study to adapt a mental health counseling intervention, we conducted in-depth interviews, social support mapping sessions, and focus-group discussions with 25 ALWH, 4 caregivers of ALWH, 3 HIV providers, and 5 participants and 5 staff of a prior mental health counseling intervention. After analyzing the stigma codes, we used the Health Stigma and Discrimination Framework to organize the data into four key domains: drivers, manifestations, outcomes, and health and social impacts. Results Major drivers of HIV stigma included fear of HIV transmission, negative effects of antiretroviral therapy (ART), association with death, inaccurate knowledge, and negative attitudes towards ALWH. The most common manifestations of HIV stigma were gossip, insults and mocking, and physical and social distancing. Decreased ART adherence and missed HIV appointments were commonly cited outcomes of HIV stigma. Broader health impacts of HIV stigma were notable for mental health comorbidities including depression, anxiety, substance use, and suicidality. Identified resilience strategies included support for HIV care engagement and psychosocial support from family and friends. Conclusions This study systematically describes the stigmatization process faced by ALWH and experiencing depressive symptoms in Malawi. Notably, HIV stigma continues to disrupt HIV care and detrimentally impacts mental health during adolescent development. Further studies focused specifically on stigma are needed to better characterize this process and identify additional resilience factors. Investment in stigma-reduction interventions for ALWH is needed to avert poor mental health and HIV outcomes.

A long-standing question concerns whether sensory input can reach semantic stages of processing in the absence of attention and awareness. Here, we examine whether the N400, an event related potential associated with semantic processing, can occur under conditions of inattentional blindness. By employing a novel three-phase inattentional blindness paradigm designed to maximise the opportunity for detecting an N400, we found no evidence for it when participants were inattentionally blind to the eliciting stimuli (related and unrelated word pairs). In contrast, participants noticed the same task-irrelevant word pairs when minimal attention was allocated to them, and a small N400 became evident. When the same stimuli were fully attended and relevant to the task, a robust N400 was observed. In addition to univariate ERP measures, multivariate decoding analyses were unable to classify related from unrelated word pairs when observers were inattentionally blind to the words, with decoding reaching above-chance levels only when the words were (at least minimally) attended. By comparison, decoding reached above-chance levels when contrasting word pairs with non-word stimuli, even when participants were inattentionally blind to these stimuli. Our results also replicated several previous studies by finding a “visual awareness negativity” (VAN) that distinguished task-irrelevant stimuli that participants noticed compared with those that were not perceived, and a P3b (or “late positivity”) that was evident only when the stimuli were task relevant. Together, our findings suggest that semantic processing might require at least a minimal amount of attention.

Background and purpose: Epilepsy is a complex neurological disorder affecting 50 million people worldwide. Persistent seizures may correlate with neural network, microstructural, and vascular changes within the thalamus. These thalamic changes may result from seizure activity or broader alterations involving neuronal vasculature and neuroinflammatory processes linked to glymphatic drainage. Improved resolution with Ultra-high field (UHF) magnetic resonance imaging (MRI) may be useful in identifying possible thalamic vascular abnormalities not otherwise detectable at lower field strengths. Materials and methods: We outline a novel method which leverages UHF neuroimaging for detection and quantification of vessels and perivascular spaces (PVS) within the thalamus in 25 epilepsy patients and 16 controls, to uncover possible underlying imaging biomarkers of epilepsy. In our analysis, we optimize a MATLAB-based Frangi-based detection tool called Perivascular Space Semi-Automated Segmentation (PVSSAS) to detect thalamic PVSs, and additionally use a second Frangi-based segmentation tool method to automate detection of vascular structures in the thalamus. The resulting PVS and vessel masks were used to quantify differences in the number of vessels, PVS, overlaps, and number of PVS overlaps per vessel detected between groups, using a Hessian detection filter linked on an 18-connected network. Results: We found significantly more thalamic PVS (p = 0.0307) and a significant increase in the number of thalamic vessels (p = 0.038) in patients compared to controls. Conclusion: Here we have developed a novel process which leverages UHF MRI to quantify and detect thalamic vessels and PVS that may provide a potential neuroimaging biomarker of epilepsy. Statement of Significance: We use 7T, ultra-high field MRI and employed an innovative combination of semi-automated perivascular space segmentation and automated vessel segmentation to visualize and quantify vessels and perivascular spaces (PVS) within the thalamus, a highly cited region of interest in epilepsy. To our knowledge, this is the first study to semi-automatically visualize and segment PVS in the thalamus and automatically detect thalamic vessels. We uncovered detectable differences in thalamic vasculature and PVS. These findings suggests that increases in the number of thalamic PVS and vessels may be a potential neuroimaging biomarker in epilepsy. This tool may be useful in the detection of subtle vascular changes in other regions of the brain related to epilepsy or can be employed in other neurological conditions.

Abstract Background Low- and middle-income countries often lack access to mental health services, leading to calls for integration within other primary care systems. In sub-Saharan Africa, integration of depression treatment in non-communicable disease (NCD) settings is feasible, acceptable, and effective. However, leadership and implementation climate challenges often hinder effective integration and quality of services. The aim of this study was to identify discrete leadership strategies that facilitate overcoming barriers to the integration of depression care in NCD clinics in Malawi and to understand how clinic leadership shapes the implementation climate. Methods We conducted 39 in-depth interviews with the District Medical Officer, the NCD coordinator, one NCD provider, and the research assistant from each of the ten Malawian NCD clinics (note one District Medical Officer served two clinics). Based on semi-structured interview guides, participants were asked their perspectives on the impact of leadership and implementation climate on overcoming barriers to integrating depression care into existing NCD services. Thematic analysis used both inductive and deductive approaches to identify emerging themes and compare among participant type. Results The results revealed how engaged leadership can fuel a positive implementation climate where clinics had heightened capacity to overcome implementation barriers. Effective leaders were approachable and engaged in daily operations of the clinic and problem-solving. They held direct involvement with and mentorship during the intervention, providing assistance in patient screening and consultation with treatment plans. Different levels of leadership utilized their respective standings and power dynamics to influence provider attitudes and perceptions surrounding the intervention. Leaders acted by informing providers about the intervention source and educating them on the importance of mental healthcare, as it was often undervalued. Lastly, they prioritized teamwork and collective ownership for the intervention, increasing provider responsibility. Conclusion Training that prioritizes leadership visibility and open communication will facilitate ongoing Malawi Ministry of Health efforts to scale up evidence-based depression treatment within NCD clinics. This proves useful where extensive and external monitoring may be limited. Ultimately, these results can inform successful strategies to close implementation gaps to achieve integration of mental health services in low-resource settings through improved leadership and implementation climate. Trial registration These findings are reported from ClinicalTrials.gov, NCT03711786. Registered on 18/10/2018. https://clinicaltrials.gov/ct2/show/NCT03711786 .

Abstract Background Option B + offers lifelong ART to pregnant or breastfeeding mothers, but postpartum loss to HIV care, partially driven by perinatal depression (PND), threatens the impact of this policy. This study aims to understand women’s and providers’ preferences for developing a feasible intervention to address PND and support engagement in HIV care among women living with PND and HIV. Methods We conducted a total of 6 focus group discussions (FGDs) involving 4 clinics in Lilongwe District from December 2018 through February 2019. We conducted 2 FGDs each among 3 stakeholder groups: clinical staff, prenatal women, and postnatal women. Perinatal participants were living with HIV and screened positively for PND using the validated Edinburgh Postnatal Depression Scale (EPDS). Clinical staff were nurses who were trained antiretroviral therapy (ART) providers. Interviewers led FGDs in Chichewa using a semi-structured guide. Data were analyzed using deductive and inductive coding in NVivo 12 software. Results Women favored ART linkage services, but providers said they already offered such services, with mixed results. Individual counselling was universally supported. A perceived benefit of group counselling was peer support, but there were concerns among women regarding confidentiality and stigma. Women liked mobile appointment reminders but identified low phone ownership as a barrier. Participants recommended home visits as an additional care engagement strategy. Women consistently discussed the need for social support from family members and friends to address PND and support engagement in HIV care. Conclusion This study highlights the importance of peer encouragement to support perinatal HIV care engagement among women with HIV and PND. The results from this study can be used to support intervention development to increase HIV care engagement and improve long-term HIV outcomes in women with PND.

Background Currently, endovascular treatment of intracranial aneurysms is limited by low complete occlusion rates. The advent of novel endovascular technology has expanded the applicability of endovascular therapies; however, the superiority of novel embolic devices over the traditional Guglielmi detachable coils is still debated. We performed a systematic review of literature that reported the Raymond–Roy occlusion classification (RROC) rates of modern endovascular devices to determine their immediate and follow‐up occlusion effectivenesses for the treatment of unruptured saccular intracranial aneurysms. Methods A search was conducted using electronic databases (PUBMED, Cochrane, ClinicalTrials.gov, and Web of Science). We retrieved studies published between 2000 and 2022, reporting immediate and follow‐up RROC rates of subjects treated with different endovascular intracranial aneurysm therapies. We extracted demographic information of the treated patients and their reported angiographic RROC rates. Results A total of 80 studies from 15 countries were included for data extraction. The RROC rates determined from angiogram were obtained for 21 331 patients (72.5% women, pooled mean age: 58.2 [95% CI]: 56.8–59.6), harboring 22 791 aneurysms. The most frequent aneurysm locations were the internal carotid artery (46.4%, 95% CI: 41.9%–50.9%), the anterior communicating artery (26.4%, 95% CI: 22.5%–30.8%), the middle cerebral artery (24.5%, 95% CI: 19.2%–30.8%), and the basilar tip (14.4%, 95% CI: 11.3%–18.3%). The complete occlusion probability (RROC‐I) was analyzed for Guglielmi detachable coils, the Woven EndoBridge, and flow diverters. The RROC‐I rate was the highest in balloon‐assisted coiling (73.9%, 95% CI: 65.0%–81.2%) and the lowest in the Woven EndoBridge (27.8%, 95% CI: 13.2%–49.2%). The follow‐up RROC‐I probability was homogenous in all analyzed devices. Conclusion We observed that the coil‐based endovascular therapy provides acceptable rates of complete occlusion, and these rates are improved in balloon‐assisted coils. Out of the analyzed devices, the Woven EndoBridge exhibited the shortest time to achieve >90% probability of follow‐up complete occlusion (∼18 months). Overall, the Guglielmi detachable coils remain the gold standard for endovascular treatment of unruptured saccular aneurysms.

[This corrects the article DOI: 10.1371/journal.pone.0279619.].

Depressive disorders are leading contributors to morbidity in low- and middle-income countries and are particularly prevalent among people with non-communicable diseases (NCD). Stressful life events (SLEs) are risk factors for, and can help identify those at risk of, severe depressive illness requiring more aggressive treatment. Yet, research on the impact of SLEs on the trajectory of depressive symptoms among NCD patients indicated for depression treatment is lacking, especially in low resource settings. This study aims to estimate the longitudinal association of SLEs at baseline with depression remission achievement at three, six, and 12 months among adults with either hypertension or diabetes and comorbid depression identified as being eligible for depression treatment. Participants were recruited from 10 NCD clinics in Malawi from May 2019-December 2021. SLEs were measured by the Life Events Survey and depression remission was defined as achieving a Patient Health Questionaire-9 (PHQ-9) score

Abstract Rectal cancer ranks as the second leading cause of cancer-related deaths. Neoadjuvant therapy for rectal cancer patients often results in individuals that respond well to therapy and those that respond poorly, requiring life-altering excision surgery. It is inadequately understood what dictates this responder/nonresponder divide. Our major aim is to identify what factors in the tumor microenvironment drive a fraction of rectal cancer patients to respond to radiotherapy. We also sought to distinguish potential biomarkers that would indicate a positive response to therapy and design combinatorial therapeutics to enhance radiotherapy efficacy. To address this, we developed an orthotopic murine model of rectal cancer treated with short course radiotherapy that recapitulates the bimodal response observed in the clinic. We utilized a robust combination of transcriptomics and protein analysis to identify differences between responding and nonresponding tumors. Our mouse model recapitulates human disease in which a fraction of tumors respond to radiotherapy (responders) while the majority are nonresponsive. We determined that responding tumors had increased damage-induced cell death, and a unique immune-activation signature associated with tumor-associated macrophages, cancer-associated fibroblasts, and CD8+ T cells. This signature was dependent on radiation-induced increases of Type I Interferons (IFNs). We investigated a therapeutic approach targeting the cGAS/STING pathway and demonstrated improved response rate following radiotherapy. These results suggest that modulating the Type I IFN pathway has the potential to improve radiation therapy efficacy in RC.

Background: Globally, mental health disorders rank as the greatest cause of disability. Low and middle-income countries (LMICs) hold a disproportionate share of the mental health burden, especially as it pertains to depression. Depression is highly prevalent among those with non-communicable diseases (NCDs), creating a barrier to successful treatment. While some treatments have proven efficacy in LMIC settings, wide dissemination is challenged by multiple factors, leading researchers to call for implementation strategies to overcome barriers to care provision. However, implementation strategies are often not well defined or documented, challenging the interpretation of study results and the uptake and replication of strategies in practice settings. Assessing implementation strategy fidelity (ISF), or the extent to which a strategy was implemented as designed, overcomes these challenges. This study assessed fidelity of two implementation strategies (a ‘basic’ champion strategy and an ‘enhanced’ champion ​+ ​audit and feedback strategy) to improve the integration of a depression intervention, measurement based care (MBC), at 10 NCD clinics in Malawi. The primary goal of this study was to assess the relationship between the implementation strategies and MBC fidelity using a mixed methods approach. Methods: We developed a theory-informed mixed methods fidelity assessment that first combined an implementation strategy specification technique with a fidelity framework. We then created corresponding fidelity indicators to strategy components. Clinical process data and one-on-one in-depth interviews with 45 staff members at 6 clinics were utilized as data sources. Our final analysis used descriptive statistics, reflexive-thematic analysis (RTA), data merging, and triangulation to examine the relationship between ISF and MBC intervention fidelity. Results: Our mixed methods analysis revealed how ISF may moderate the relationship between the strategies and MBC fidelity. Leadership engagement and implementation climate were critical for clinics to overcome implementation barriers and preserve implementation strategy and MBC fidelity. Descriptive statistics determined champion strategy fidelity to range from 61 to 93% across the 10 clinics. Fidelity to the audit and feedback strategy ranged from 82 to 91% across the 5 clinics assigned to that condition. MBC fidelity ranged from 54 to 95% across all clinics. Although correlations between ISF and MBC fidelity were not statistically significant due to the sample of 10 clinics, associations were in the expected direction and of moderate effect size. A coefficient for shared depression screening among clinicians had greater face validity compared to depression screening coverage and functioned as a proximal indicator of implementation strategy success. Conclusion: Fidelity to the basic and enhanced strategies varied by site and were influenced by leadership engagement and implementation climate. Champion strategies may benefit from the addition of leadership strategies to help address implementation barriers outside the purview of champions. ISF may moderate the relationship between strategies and implementation outcomes.

Transient terahertz time-domain spectroscopy (THz-TDS) imaging has emerged as a novel non-ionizing and noninvasive biomedical imaging modality, designed for the detection and characterization of a variety of tissue malignancies due to their high signal-to-noise ratio and submillimeter resolution. We report our design of a pair of aspheric focusing lenses using a commercially available lens-design software that resulted in about 200 × 200-μm2 focal spot size corresponding to the 1-THz frequency. The lenses are made of high-density polyethylene (HDPE) obtained using a lathe fabrication and are integrated into a THz-TDS system that includes low-temperature GaAs photoconductive antennae as both a THz emitter and detector. The system is used to generate high-resolution, two-dimensional (2D) images of formalin-fixed, paraffin-embedded murine pancreas tissue blocks. The performance of these focusing lenses is compared to the older system based on a pair of short-focal-length, hemispherical polytetrafluoroethylene (TeflonTM) lenses and is characterized using THz-domain measurements, resulting in 2D maps of the tissue refractive index and absorption coefficient as imaging markers. For a quantitative evaluation of the lens effect on the image resolution, we formulated a lateral resolution parameter, R2080, defined as the distance required for a 20–80% transition of the imaging marker from the bare paraffin region to the tissue region in the same image frame. The R2080 parameter clearly demonstrates the advantage of the HDPE lenses over TeflonTM lenses. The lens-design approach presented here can be successfully implemented in other THz-TDS setups with known THz emitter and detector specifications.

Patients who undergo resection for non-invasive IPMN are at risk for long-term recurrence. Further evidence is needed to identify evidence-based surveillance strategies based on the risk of recurrence. We performed a systematic review of the current literature regarding recurrence patterns following resection of non-invasive IPMN to summarize evidence-based recommendations for surveillance. Among the 61 studies reviewed, a total of 8779 patients underwent resection for non-invasive IPMN. The pooled overall median follow-up time was 49.5 months (IQR: 38.5–57.7) and ranged between 14.1 months and 114 months. The overall median recurrence rate for patients with resected non-invasive IPMN was 8.8% (IQR: 5.0, 15.6) and ranged from 0% to 27.6%. Among the 33 studies reporting the time to recurrence, the overall median time to recurrence was 24 months (IQR: 17, 46). Existing literature on recurrence rates and post-resection surveillance strategies for patients with resected non-invasive IPMN varies greatly. Patients with resected non-invasive IPMN appear to be at risk for long-term recurrence and should undergo routine surveillance.

Abstract Background Perinatal depression (PND) is prevalent and negatively impacts HIV care among women living with HIV (WLHIV), yet PND remains under-identified in Malawian WLHIV. Accordingly, this formative study explored perceptions of the feasibility and acceptability of an integrated, task-shifted approach to PND screening and treatment in maternity clinics. Methods We completed consecutive PND screenings of HIV+ women attending pre- or post-natal appointments at 5 clinics in Lilongwe district, Malawi. We conducted in-depth interviews with the first 4-5 women presenting with PND per site (n = 24 total) from July to August 2018. PND classification was based on a score ≥ 10 on the Edinburgh Postnatal Depression Scale (EPDS). We conducted 10 additional in-depth interviews with HIV and mental health providers at the 5 clinics. Results Most participants endorsed the feasibility of integrated PND screening, as they believed that PND had potential for significant morbidity. Among providers, identified barriers to screening were negative staff attitudes toward additional work, inadequate staffing numbers and time constraints. Suggested solutions to barriers were health worker training, supervision, and a brief screening tool. Patient-centered counselling strategies were favored over medication by WLHIV as the acceptable treatment of choice, with providers supporting the role of medication to be restricted to severe depression. Providers identified nurses as the most suitable health workers to deliver task-shifted interventions and emphasized further training as a requirement to ensure successful task shifting. Conclusion Improving PND in a simple, task-shifted intervention is essential for supporting mental health among women with PND and HIV. Our results suggest that an effective PND intervention for this population should include a brief, streamlined PND screening questionnaire and individualized counselling for those who have PND, with supplemental support groups and depression medication readily available. These study results support the development of a PND intervention to address the gap in treatment of PND and HIV among WLHIV in Malawi.

Abstract Background Stigma around human immunodeficiency virus (HIV), injection drug use (IDU), and mental health disorders can be co-occurring and have different impacts on the well-being of people living with HIV (PWH) who use drugs and have mental health disorders. This stigma can come from society, health professionals, and internalized stigma. A person who has more than one health condition can experience overlapping health-related stigma and levels of stigma which can prevent them from receiving necessary support and healthcare, serving to intensify their experience with stigma. This study investigates HIV, drug use, and mental health stigmas in three dimensions (social, internalized, and professional) around PWH on methadone maintenance treatment (MMT) who have common mental disorders (CMDs) including depression, anxiety, and stress-related disorders in Hanoi, Vietnam.Please check and confirm whether corresponding author's email id is correctly identified.The cooresponding author's email is correct Methods We conducted semi-structured, in-depth interviews (IDIs) (n = 21) and two focus group discussions (FGDs) (n = 10) with PWH receiving MMT who have CMD symptoms, their family members, clinic health care providers, and clinic directors. We applied thematic analysis using NVIVO software version 12.0, with themes based on IDI and FGD guides and emergent themes from interview transcripts. Results The study found evidence of different stigmas towards HIV, IDU, and CMDs from the community, family, health care providers, and participants themselves. Community and family members were physically and emotionally distant from patients due to societal stigma around illicit drug use and fears of acquiring HIV. Participants often conflated stigmas around drug use and HIV, referring to these stigmas interchangeably. The internalized stigma around having HIV and injecting drugs made PWH on MMT hesitant to seek support for CMDs. These stigmas compounded to negatively impact participants’ health. Conclusions Strategies to reduce stigma affecting PWH on MMT should concurrently address stigmas around HIV, drug addiction, and mental health. Future studies could explore approaches to address internalized stigma to improve self-esteem, mental health, and capacities to cope with stigma for PWH on MMT. Trial registration: NCT04790201, available at clinicaltrials.gov.

Abstract Background Global pandemics have occurred with increasing frequency over the past decade reflecting the sub-optimum operationalization of surveillance systems handling human health data. Despite the wide array of current surveillance methods, their effectiveness varies with multiple factors. Here, we perform a systematic review of the effectiveness of alternative infectious diseases Early Warning Systems (EWSs) with a focus on the surveillance data collection methods, and taking into consideration feasibility in different settings. Methods We searched PubMed and Scopus databases on 21 October 2022. Articles were included if they covered the implementation of an early warning system and evaluated infectious diseases outbreaks that had potential to become pandemics. Of 1669 studies screened, 68 were included in the final sample. We performed quality assessment using an adapted CASP Checklist. Results Of the 68 articles included, 42 articles found EWSs successfully functioned independently as surveillance systems for pandemic-wide infectious diseases outbreaks, and 16 studies reported EWSs to have contributing surveillance features through complementary roles. Chief complaints from emergency departments’ data is an effective EWS but it requires standardized formats across hospitals. Centralized Public Health records-based EWSs facilitate information sharing; however, they rely on clinicians’ reporting of cases. Facilitated reporting by remote health settings and rapid alarm transmission are key advantages of Web-based EWSs. Pharmaceutical sales and laboratory results did not prove solo effectiveness. The EWS design combining surveillance data from both health records and staff was very successful. Also, daily surveillance data notification was the most successful and accepted enhancement strategy especially during mass gathering events. Eventually, in Low Middle Income Countries, working to improve and enhance existing systems was more critical than implementing new Syndromic Surveillance approaches. Conclusions Our study was able to evaluate the effectiveness of Early Warning Systems in different contexts and resource settings based on the EWSs’ method of data collection. There is consistent evidence that EWSs compiling pre-diagnosis data are more proactive to detect outbreaks. However, the fact that Syndromic Surveillance Systems (SSS) are more proactive than diagnostic disease surveillance should not be taken as an effective clue for outbreaks detection.

Abstract Background The acceptability of teachers delivering task-shifted mental health care to their school-aged students is understudied. Here, we evaluate teachers’, students’, and caregivers’ acceptability of Tealeaf (Teachers Leading the Frontlines), an alternative system of care in which teachers are trained and supervised to deliver transdiagnostic, non-manualized task-shifted care to their students. Methods In a 2019 single-arm, mixed methods, pragmatic acceptability pilot study in Darjeeling, India, 13 teachers delivered task-shifted child mental health care to 26 students in need. Teachers delivered care through using a transdiagnostic, non-manualized therapy modality, “education as mental health therapy” (Ed-MH). Measured with validated scales, teachers’ and students’ acceptability were compared after teacher training (PRE) and at the end of intervention (POST) using paired t tests. Teachers (n = 7), students (n = 7), and caregivers (n = 7) completed semi-structured interviews POST. Results Teachers’ quantitative measures indicated moderate acceptability PRE and POST and did not change PRE to POST. Children’s measures showed acceptability PRE and POST but decreased PRE to POST. Teachers and caregivers universally expressed acceptability in interviews. Facilitators of acceptability included impact, trust of teachers, and teachers’ ability to make adaptations. Conditions required for acceptability included supervision and teachers emphasizing academics benefits over mental health benefits to caregivers. Barriers to acceptability included a lack of teacher time and stigma. Interviewed students universally were unaware of receiving care; teachers intentionally avoided singling them out. Conclusion Teachers, caregivers, and children found teacher delivering task-shifted care acceptable, a key factor in care adoption and sustainability, though interviewed children were unaware of receiving care. Trial registration The trial was registered on January 01, 2018 with Clinical Trials Registry—India (CTRI), Reg. No. CTRI/2018/01/011471, Ref. No. REF/2017/11/015895. http://ctri.nic.in/Clinicaltrials/pdf_generate.php?trialid=21129&EncHid=&modid=&compid=%27,%2721129det%27

Background: Recent literature suggests wide variations exist in the international management of locally advanced pancreatic cancer. This study sought to evaluate how geography contributes to variations in management of locally advanced pancreatic cancer. Methods: An electronic survey investigating preferences for the evaluation and management of locally advanced pancreatic cancer was distributed to an international cohort of pancreatic surgeons. Surgeons were classified according to geographic location of practice, and survey responses were compared across locations. Results: A total of 153 eligible responses were received from 4 continents: North and South America (n = 94, 61.4%), Europe (n = 25, 16.3%), and Asia (n = 34, 22.2%). Preferences for the use and duration of neoadjuvant chemotherapy and radiotherapy varied widely. For example, participants in Asia commonly preferred 2 months of neoadjuvant chemotherapy (61.8%), whereas North and South American participants preferred 4 months (52.1%), and responses in Europe were mixed (P = .006). Participants in Asia were less likely to consider isolated liver or lung metastases contraindications to exploration and consequently had a greater propensity to consider exploration in a vignette of oligometastatic disease (56.7% vs North and South America: 25.6%, Europe: 43.5%; P = .007). Conclusion: In an international survey of pancreatic surgeons, attitudes regarding locally advanced pancreatic cancer and metastatic disease management varied widely across geographic locations. Better evidence is needed to define optimal management of locally advanced pancreatic cancer.

Introduction Adverse childhood experiences (ACEs) are stressful or traumatic events experienced before the age of 18 years old. ACEs have been associated with an increased risk for substance use in adulthood. While an abundance of research has examined psychosocial factors that explain the link between ACEs and psychoactive substance use, little is known about the additional influence of the urban neighbourhood environment, including community-level factors, that influence the risk of substance use among populations with a history of ACEs.Methods and analysis The following databases will be systematically searched: PubMed, Embase, Web of Science, Cochrane, PsycInfo, CINAHL, Clinicaltrials.gov and TRIP medical databases. After the title and abstract screening and full-text screening, we will also conduct a manual search of the reference sections of included articles and include relevant citations. Eligibility criteria include peer-reviewed articles that focus on populations with at least one ACE, factors from the urban neighbourhood community, such as elements from the built environment, presence of community service programmes, quality and vacancy of housing, neighbourhood level social cohesion, and neighbourhood level collective efficacy or crime. Included articles should also include terms such as ‘substance abuse’, ‘prescription misuse’ and ‘dependence’. Only studies written or translated into the English language will be included.Ethics and dissemination This systematic and scoping review will focus on peer-reviewed publications and does not require ethics approval. Findings will be available for clinicians, researchers and community members via publications and social media. This protocol describes the rationale and methods for the first scoping review to inform future research and community-level intervention development that targets substance use among populations who have experienced ACEs.PROSPERO registration number CRD42023405151.

Abstract Background Worsening of the overdose crisis in the USA has been linked to the continuing proliferation of non-pharmaceutical fentanyl (NPF). The recent wave of NPF spread in the USA has been fueled by an increased presence of counterfeit pills that contain NPF. This qualitative study aims to characterize the motivation and practices of counterfeit NPF pill initiation and use among individuals using illicit opioids in Arizona. Methods Between October 2020 and May 2021, semi-structured interviews were conducted with 22 individuals meeting the following eligibility criteria: (1) 18 years or older; (2) residence in Arizona; and (3) use of illicit opioids in the past 30 days and/or opioid use disorder treatment in the past 12 months. Participants were recruited through referrals by a harm reduction organization, craigslist ads, and referrals by other participants. Interviews were conducted virtually via Zoom. Qualitative interviews were transcribed and analyzed thematically using NVivo. Results Out of 22 participants, 64% were male, and 45% were ethnic minorities. Age ranged between 25 and 51 years old. Participants noted significant recent increases in the availability of counterfeit NPF pills (“blues,” “dirty oxys”) that were most commonly used by smoking. The majority indicated first trying NPF pills in the past year, and the first use often occurred in situations of reduced access to heroin or pharmaceutical opioids. Participant decisions to switch over to more frequent NPF pill use or to maintain some levels of heroin use were shaped by local drug availability trends and personal experiences with NPF effects. They were also influenced by conflicting views of social acceptability of pharmaceutical-like drugs, perceived harms of NPF in terms of overdose risks and increased difficulty of quitting, and perceived benefits of switching to the non-injection route of opioid administration (e.g., from injecting heroin to smoking NPF pills). Conclusion Our findings highlight the need for the implementation of novel policy, treatment, and harm reduction approaches to address the growing unpredictability of drug supply and NPF pill-specific risks, attitudes, and behaviors.

Abstract Background Of the 1.8 million adolescents between the ages of 10 and 19 living with HIV globally in 2020; approximately 1.5 million of these live in sub-Saharan Africa. These adolescents living with HIV (ALHIV) are at higher risk of experiencing mental health problems than those without; in Malawi, 18.9% have a depressive disorder. ALHIV can face numerous psychosocial challenges, but little is known about how ALHIV in Malawi perceive these stressors. Understanding psychosocial challenges of ALHIV is a key step in ensuring good mental health care. The aim of this study was to assess the psychosocial challenges faced by ALHIV attending adolescent-specific ART program in Zomba, Malawi. Methods Between April and May 2019, we engaged a purposive sample of ALHIV ages 12–18 (n = 80) in a series of eight focus groups drawing from four Teen Clubs linked to an adolescent-specific ART program. Data were analyzed inductively and deductively to identify themes related to ALHIV psychosocial experiences. Results Two themes that emerged from the study include: 1) stigma and discrimination within communities and families; 2) non-adherence to medications. HIV-related stigma was associated with increased psychological distress; physical and emotional/verbal abuse; low social support, isolation, and a feeling of rejection; and risky health behaviors such as medication hiding and non-adherence to ART. Discriminatory actions were manifested in a form of being given separate utensils for their meals and mistreatment at school. Furthermore, some parents did not allow their children to play with the participants out of fear that HIV transmission. Conclusions Stigma and discrimination are overlooked potential barriers to HIV treatment and care. If HIV services are to effectively meet ALHIVs' needs, mental health interventions are needed to prevent and manage depression and improve adherence to ART. These findings highlight the crucial need to develop culturally relevant mental interventions aimed at helping ALHIV to cope with these diverse challenges.

Introduction Endovascular coiling for intracerebral aneurysms has been evolving. Yet, large, and giant aneurysms (LAGA) remain a significant challenge for treatment and carry a high rate of morbidity and mortality. Previous studies have demonstrated 72–76% long‐term adequate occlusion and up to 34% retreatment rate in patients undergoing reconstructive treatment for LAGA. Methods The SMART registry, a prospective, multicenter outcome trial was used to identify patients with LAGA (Sac 10–24mm for large and ≥ 25mm for giant aneurysms) treated with the Penumbra SMART COIL® (SMART) system in the US and Canada. Patients’ characteristics and outcomes were then compared to patients with smaller aneurysms (SA) (Sac≤10mm). Primary effectiveness endpoint was aneurysm occlusion using Raymond‐Roy (RR) scale and safety endpoints included mortality and stroke outcomes. Fisher exact test and T‐test were used to compare categorical and continuous variables, respectively. P‐value

BackgroundMajor depressive disorder (MDD) is a prevalent health problem with complex pathophysiology that is not clearly understood. Prior work has implicated the hippocampus in MDD, but how hippocampal subfields influence or are affected by MDD requires further characterization with high-resolution data. This will help ascertain the accuracy and reproducibility of previous subfield findings in depression as well as correlate subfield volumes with MDD symptom scores. The objective of this study was to assess volumetric differences in hippocampal subfields between MDD patients globally and healthy controls (HC) as well as between a subset of treatment-resistant depression (TRD) patients and HC using automatic segmentation of hippocampal subfields (ASHS) software and ultra-high field MRI.MethodsThirty-five MDD patients and 28 HC underwent imaging using 7-Tesla MRI. ASHS software was applied to the imaging data to perform automated hippocampal segmentation and provide volumetrics for analysis. An exploratory analysis was also performed on associations between symptom scores for diagnostic testing and hippocampal subfield volumes.ResultsCompared to HC, MDD and TRD patients showed reduced right-hemisphere CA2/3 subfield volume (p = 0.01, η2 = 0.31 and p = 0.3, η2 = 0.44, respectively). Additionally, negative associations were found between subfield volumes and life-stressor checklist scores, including left CA1 (p = 0.041, f2 = 0.419), left CA4/DG (p = 0.010, f2 = 0.584), right subiculum total (p = 0.038, f2 = 0.354), left hippocampus total (p = 0.015, f2 = 0.134), and right hippocampus total (p = 0.034, f2 = 0.110). Caution should be exercised in interpreting these results due to the small sample size and low power.ConclusionDetermining biomarkers for MDD and TRD pathophysiology through segmentation on high-resolution MRI data and understanding the effects of stress on these regions can enable better assessment of biological response to treatment selection and may elucidate the underlying mechanisms of depression.

Depression is common among people living with HIV (PLWH). Measurement-based care models that measure depression severity and antidepressant side effects, and use an algorithm to guide antidepressant prescription by non-specialized health workers represent an evidence-based treatment for severe depression in sub-Saharan Africa. We conducted in-depth interviews from June to December 2018 with eleven patients enrolled in Project SOAR-Mental Health, a pilot project integrating depression treatment into HIV care in Malawi. Patients treated with amitriptyline or fluoxetine participated in interviews exploring antidepressant acceptability through patient knowledge, side effect severity, pill burden, adherence, perceived efficacy, and tolerability. Patients described a lack of detailed antidepressant education from their providers. Variable, typically self-limiting side effects were reported from both amitriptyline and fluoxetine. While most side effects were mild, three patients reported functional impairment. Patients reported high adherence, though the additional pill burden was a challenge. Most patients found the antidepressants efficacious, tolerable, beneficial and acceptable. Although patient psychoeducation is notably lacking as a facet of clinical management, antidepressant prescription by primary care providers appears acceptable for comorbid severe depression in PLWH initiating HIV care in sub-Saharan Africa. Health workers should be mindful of dosing to minimise side effects and considerate of the additional pill burden. Trial registration: ClinicalTrials.gov ID [NCT03555669]. Retrospectively registered on 13 June 2018.

BackgroundThe COVID-19 pandemic has created an epidemic of distress-related mental disorders such as depression, while simultaneously necessitating a shift to virtual domains of mental health care; yet, the evidence to support the use of virtual interventions is unclear. ObjectiveThe purpose of this study was to evaluate the efficacy of virtual interventions for depressive disorders by addressing three key questions: (1) Does virtual intervention provide better outcomes than no treatment or other control conditions (ie, waitlist, treatment as usual [TAU], or attention control)? (2) Does in-person intervention provide better outcomes than virtual intervention? (3) Does one type of virtual intervention provide better outcomes than another? MethodsWe searched the PubMed, EMBASE, and PsycINFO databases for trials published from January 1, 2010, to October 30, 2021. We included randomized controlled trials of adults with depressive disorders that tested a virtual intervention and used a validated depression measure. Primary outcomes were defined as remission (ie, no longer meeting the clinical cutoff for depression), response (ie, a clinically significant reduction in depressive symptoms), and depression severity at posttreatment. Two researchers independently selected studies and extracted data using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Risk of bias was evaluated based on Agency for Healthcare and Research Quality guidelines. We calculated odds ratios (ORs) for binary outcomes and standardized mean differences (SMDs) for continuous outcomes. ResultsWe identified 3797 references, 24 of which were eligible. Compared with waitlist, virtual intervention had higher odds of remission (OR 10.30, 95% CI 5.70-18.60; N=619 patients) and lower posttreatment symptom severity (SMD 0.81, 95% CI 0.52-1.10; N=1071). Compared with TAU and virtual attention control conditions, virtual intervention had higher odds of remission (OR 2.27, 95% CI 1.10-3.35; N=512) and lower posttreatment symptom severity (SMD 0.25, 95% CI 0.09-0.42; N=573). In-person intervention outcomes were not significantly different from virtual intervention outcomes (eg, remission OR 0.84, CI 0.51-1.37; N=789). No eligible studies directly compared one active virtual intervention to another. ConclusionsVirtual interventions were efficacious compared with control conditions, including waitlist control, TAU, and attention control. Although the number of studies was relatively small, the strength of evidence was moderate that in-person interventions did not yield significantly better outcomes than virtual interventions for depressive disorders.

Mental illness stigma research is sparse in Malawi. Our team previously analyzed the reliability and statistical validity of a quantitative tool to measure depression-related stigma among participants with depressive symptoms using quantitative psychometric methods. This analysis aims to further evaluate the content validity of the stigma tool by comparing participants' quantitative responses with qualitative data. The SHARP project conducted depression screening and treatment at 10 noncommunicable disease clinics across Malawi from April 2019 through December 2021. Eligible participants were 18-65 years with depressive symptoms indicated by a PHQ-9 score ≥5. Questionnaires at each study timepoint included a vignette-based quantitative stigma instrument with three thematic domains: disclosure carryover (i.e., concerns about disclosure), treatment carryover (i.e., concerns about external stigma because of receiving depression treatment), and negative affect (i.e., negative attitudes about people having depression). Sub-scores were aggregated for each domain, with higher scores indicating greater stigma. To better understand participants' interpretation of this quantitative stigma questionnaire, we asked a subset of six participants a parallel set of questions in semi-structured qualitative interviews in a method similar to cognitive interviewing. Qualitative responses were linked with participants' most recent quantitative follow-up interviews using Stata 16 and NVivo software. Participants with lower quantitative stigma disclosure sub-scores had qualitative responses that indicated less stigma around disclosure, while participants with higher quantitative stigma sub-scores had qualitative responses indicating greater stigma. Similarly, in the negative affect and treatment carryover domains, participants had parallel quantitative and qualitative responses. Further, participants identified with the vignette character in their qualitative interviews, and participants spoke about the character's projected feelings and experiences based on their own lived experiences. The stigma tool was interpreted appropriately by participants, providing strong evidence for the content validity of the quantitative tool to measure these stigma domains.

IntroductionCoronavirus 2019 (COVID-19) is known to affect the central nervous system. Neurologic morbidity associated with COVID-19 is commonly attributed to sequelae of some combination of thrombotic and inflammatory processes. The aim of this retrospective observational study was to evaluate neuroimaging findings in hospitalized COVID-19 patients with neurological manifestations in cancer versus non-cancer patients, and in patients with versus without ventilatory support (with ventilatory support defined as including patients with intubation and noninvasive ventilation). Cancer patients are frequently in an immunocompromised or prothrombotic state with side effects from chemotherapy and radiation that may cause neurological issues and increase vulnerability to systemic illness. We wanted to determine whether neurological and/or neuroimaging findings differed between patients with and without cancer.MethodsEighty adults (44 male, 36 female, 64.5 ±14 years) hospitalized in the Mount Sinai Health System in New York City between March 2020 and April 2021 with reverse-transcriptase polymerase chain reaction-confirmed COVID-19 underwent magnetic resonance imaging (MRI) during their admissions. The cohort consisted of four equal subgroups based on cancer and ventilatory support status. Clinical and imaging data were acquired and analyzed.ResultsNeuroimaging findings included non-ischemic parenchymal T2/FLAIR signal hyperintensities (36.3%), acute/subacute infarcts (26.3%), chronic infarcts (25.0%), microhemorrhages (23.8%), chronic macrohemorrhages (10.0%), acute macrohemorrhages (7.5%), and encephalitis-like findings (7.5%). There were no significant differences in neuroimaging findings between cancer and non-cancer subgroups. Clinical neurological manifestations varied. The most common was encephalopathy (77.5%), followed by impaired responsiveness/coma (38.8%) and stroke (26.3%). There were significant differences between patients with versus without ventilatory support. Encephalopathy and impaired responsiveness/coma were more prevalent in patients with ventilatory support (p = 0.02). Focal weakness was more frequently seen in patients without ventilatory support (p = 0.01).DiscussionThis study suggests COVID-19 is associated with neurological manifestations that may be visible with brain imaging techniques such as MRI. In our COVID-19 cohort, there was no association between cancer status and neuroimaging findings. Future studies might include more prospectively enrolled systematically characterized patients, allowing for more rigorous statistical analysis.

The SARS-CoV-2 pandemic led to the rapid transition of many research studies from in-person to telephone follow-up globally. For mental health research in low-income settings, tele-follow-up raises unique safety concerns due to the potential of identifying suicide risk in participants who cannot be immediately referred to in-person care. We developed and iteratively adapted a telephone-delivered protocol designed to follow a positive suicide risk assessment (SRA) screening. We describe the development and implementation of this SRA protocol during follow-up of a cohort of adults with depression in Malawi enrolled in the Sub-Saharan Africa Regional Partnership for Mental Health Capacity Building (SHARP) randomized control trial during the COVID-19 era. We assess protocol feasibility and performance, describe challenges and lessons learned during protocol development, and discuss how this protocol may function as a model for use in other settings. Transition from in-person to telephone SRAs was feasible and identified participants with suicidal ideation (SI). Follow-up protocol monitoring indicated a 100% resolution rate of SI in cases following the SRA during this period, indicating that this was an effective strategy for monitoring SI virtually. Over 2% of participants monitored by phone screened positive for SI in the first six months of protocol implementation. Most were passive risk (73%). There were no suicides or suicide attempts during the study period. Barriers to implementation included use of a contact person for participants without personal phones, intermittent network problems, and pre-paid phone plans delaying follow-up. Delays in follow-up due to challenges with reaching contact persons, intermittent network problems, and pre-paid phone plans should be considered in future adaptations. Future directions include validation studies for use of this protocol in its existing context. This protocol was successful at identifying suicide risk levels and providing research assistants and participants with structured follow-up and referral plans. The protocol can serve as a model for virtual SRA development and is currently being adapted for use in other contexts.

PurposeWhile mental health stigma research is sparse in Malawi, research in other settings suggests that stigma represents a barrier to mental health treatment and recovery. Accordingly, we conducted an analysis to understand the role of treatment-related stigma in depression care in Malawi by estimating the effect of patients' baseline anticipated treatment-related stigma on their 3-month probability of depression remission when newly identified with depression.MethodsWe conducted depression screening and treatment at 10 noncommunicable disease (NCD) clinics across Malawi from April 2019 through December 2021. Eligible cohort participants were 18-65 years with depressive symptoms indicated by a PHQ-9 score ≥5. Questionnaires at the baseline and 3-month interviews included a vignette-based quantitative stigma instrument that measured treatment-related stigma, i.e., concerns about external stigma because of receiving depression treatment. Using inverse probability weighting to adjust for confounding and multiple imputation to account for missing data, this analysis relates participants' baseline levels of anticipated treatment stigma to the 3-month probability of achieving depression remission (i.e., PHQ-9 score < 5).ResultsOf 743 included participants, 273 (37%) achieved depression remission by their 3-month interview. The probability of achieving depression remission at the 3-month interview among participants with high anticipated treatment stigma (0.31; 95% Confidence Interval [CI]: 0.23, 0.39)) was 10 percentage points lower than among the low/neutral stigma group (risk: 0.41; 95% CI: 0.36, 0.45; RD: -0.10; 95% CI: -0.19, -0.003).ConclusionIn Malawi, a reduction in anticipated depression treatment-related stigma among NCD patients initiating depression treatment could improve depression outcomes. Further investigation is necessary to understand the modes by which stigma can be successfully reduced to improve mental health outcomes and quality of life among people living with depression.

The phenomenon of sensory self-suppression - also known as sensory attenuation - occurs when a person generates a perceptible stimulus (such as a sound) by performing an action (such as speaking). The sensorimotor control system is thought to actively predict and then suppress the vocal sound in the course of speaking, resulting in lowered cortical responsiveness when speaking than when passively listening to an identical sound. It has been hypothesized that auditory hallucinations in schizophrenia result from a reduction in self-suppression due to a disruption of predictive mechanisms required to anticipate and suppress a specific, self-generated sound. It has further been hypothesized that this suppression is evident primarily in theta band activity. Fifty-one people, half of whom had a diagnosis of schizophrenia, were asked to repeatedly utter a single syllable, which was played back to them concurrently over headphones while EEG was continuously recorded. In other conditions, recordings of the same spoken syllables were played back to participants while they passively listened, or were played back with their onsets preceded by a visual cue. All participants experienced these conditions with their voice artificially shifted in pitch and also with their unaltered voice. Suppression was measured using event-related potentials (N1 component), theta phase coherence and power. We found that suppression was generally reduced on all metrics in the patient sample, and when voice alteration was applied. We additionally observed reduced theta coherence and power in the patient sample across all conditions. Visual cueing affected theta coherence only. In aggregate, the results suggest that sensory self-suppression of theta power and coherence is disrupted in schizophrenia.

The effect of stress on honey bee drone survival and physiology are largely unknown, but it is hypothesized that increased stress would reduce their survival. Surprisingly, although drones are more likely to die from some stressors than workers, they exhibit higher baseline stress response proteins.

Cancer cells producing ligands for the immune checkpoint molecules PD-1 and CTLA-4 is an important mechanism of tumour immune resistance. Here authors show that BTNL2 expression on cancer cells generates a dysfunctional tumour immune microenvironment via promoting IL-17A-producing γδ T cells.

Abstract Background Adolescents living with HIV (ALHIV) are at high risk of experiencing mental health problems. Depression is a major contributor to the burden of HIV-related disease amongst ALHIV and is significantly linked to non-adherence to anti-retroviral therapy (ART), yet it is under-recognized. In 2015, the Baylor College of Medicine International Pediatric AIDS Initiative (BIPAI) recommended that the psychosocial screening tool Home, Education, Activities, Drugs, Sexuality, Suicide/Depression (HEADSS) be used to screen ALHIV in Malawi who were part of an adolescent antiretroviral therapy program termed “Teen Club”. However, the HEADSS tool has been substantially under-utilized. This study assessed barriers and facilitators to implementing HEADSS for ALHIV attending Teen Club Program in four selected health facilities in Malawi. Methods We conducted a qualitative study using semi-structured interviews at four program sites (one district hospital and one health center each in two districts) between April and May 2019. Twenty key informants were purposively selected to join this study based on their role and experiences. We used the five domains of the Consolidated Framework for Implementation Research (CFIR) to guide the development of the interview guides, analysis and interpretation of results. Results Barriers included inadequate planning for integration of the HEADSS approach; concerns that the HEADSS tool was too long, time consuming, lacked appropriate cultural context, and increased workload; and reports by participants that they did not have knowledge and skills to screen ALHIV using this tool. Facilitators to implementing the screening were that health care providers viewed screening as a guide to better systematic counselling, believed that screening could build better client provider relationship, and thought that it could fit into the existing work practice since it is not complex. Conclusions A culturally adapted screening tool, especially one that can be used by non-clinicians such as lay health workers, would improve the ability to address mental health needs of ALHIV in many primary care and social service settings where resources for professional mental health staff are limited. These findings are a springboard for efforts to culturally adapt the HEADSS screening tool for detection of mental and risky behaviors among ALHIV attending ART program in Malawi.

Abstract Background Chronic conditions are common and require ongoing continuous management and preventive measures. The COVID-19 pandemic may have affected the management of chronic conditions by delaying care. We sought to understand the impact of personal characteristics (i.e., age) and healthcare factors (i.e., access to a provider) on healthcare access in a sample of Americans 50 years of age or older during COVID-19. Method Participants completed an online survey at the start of the COVID-19 pandemic – the Aging in the Time of COVID Survey. Questions focused on health status, health care access, COVID-19 fear, and social connectedness. Participants were recruited through social media advertisements, list serves, and snowball sampling. Data collection started in early April 2020 and concluded in late May 2020. Logistic regression models examined the results of two key access points: healthcare provider/doctor (n = 481) and medication (n = 765), with 56 and 93% of participants reporting access to a provider and medications, respectively. Results Individuals with an established primary care provider were much more likely to obtain access to a healthcare provider, OR = 3.81 (95% CI: 1.69, 8.77), and to receive medication, OR = 4.48 (95% CI: 1.61, 11.48), during the time of COVID-19. In addition, access to medication was (a) higher for those who were older, OR = 1.05 (95% CI: 1.01, 1.09), had a higher income (greater than 100 k compared to less than 50 k, OR = 3.04 (95% CI: 1.11, 8.98), and (b) lower for those having caregiving responsibilities, OR = 0.41 (95% CI: 0.21, 0.78), or greater social isolation, OR = 0.93 (95% CI: 0.87, 0.98). Conclusions Although most participants had access to medication, just over half had access to a healthcare provider when needed. Notably, health-seeking behaviors for individuals who do not have an established primary care providers as well as those who provide unpaid care, are socially isolated, and younger may require more proactive approaches to care monitoring, management, and maintenance.

Abstract In recent years, new human magnetic resonance imaging systems operating at static magnetic fields strengths of 7 Tesla or higher have become available, providing better signal sensitivity compared with lower field strengths. However, imaging human-sized objects at such high field strength and associated precession frequencies is limited due to the technical challenges associated with the wavelength effect, which substantially disturb the transmit field uniformity over the human body when conventional coils are used. Here we report a novel passive inductively-coupled radiofrequency resonator array design with a simple structure that works in conjunction with conventional coils and requires only to be tuned to the scanner’s operating frequency. We show that inductive-coupling between the resonator array and the coil improves the transmit efficiency and signal sensitivity in the targeted region. The simple structure, flexibility, and cost-efficiency make the proposed array design an attractive approach for altering the transmit field distribution specially at high field systems, where the wavelength is comparable with the tissue size.

Abstract Background Common mental health disorders (CMDs), including depression, anxiety and post-traumatic stress disorder (PTSD) may worsen both HIV and drug use outcomes, yet feasible tools to accurately identify CMDs have received limited study in this population. We aimed to validate the Patient Health Questionnaire (PHQ-9), Generalized Anxiety Disorder screen (GAD-7) and Primary Care PTSD screen for DSM-5 (PC-PTSD-5) in a methadone maintenance therapy (MMT) patient population in Hanoi, Vietnam. Methods We conducted a cross-sectional survey. The PHQ-9, GAD-7, and PC-PTSD-5 were administered to MMT patients. A blinded interviewer administered the Mini-International Neuropsychiatric Interview (MINI) as the reference gold standard. Total scores of each tool were compared with the MINI diagnoses using a receiver operating characteristic curves, and we identified the optimal respective cut-off scores using the Youden’s Index. Results We enrolled 400 MMT patients. Approximately 99.3% were male (n = 397) and 21.8% (n = 87) were HIV positive. The prevalence of major depressive disorder, generalized anxiety disorder and PTSD, respectively, was 10.5, 4 and 2%. Optimal cut-off scores for the PHQ-9, GAD-7 and PC-PTSD were ≥ 5, ≥3, and ≥ 4 with a sensitivity/specificity of 95.2%/91.9, 93.8%/87.5, and 62.5%/95.2%. Conclusions The prevalence of CMDs in the MMT population was lower than expected. A lower cut-off score may be considered when screening for CMDs in this population. Further research should investigate the validity of somatic symptom-based screening tools among other drug-using or MMT populations.

Objective The authors systematically reviewed evidence on pharmacotherapy for perinatal mental health disorders. Methods The authors searched for studies of pregnant, postpartum, or reproductive‐age women with mental health disorders treated with pharmacotherapy in MEDLINE, EMBASE, PsycINFO, the Cochrane Library, and trial registries from database inception through June 5, 2020 and surveilled literature through March 2, 2021. Outcomes included symptoms; functional capacity; quality of life; suicidal events; death; and maternal, fetal, infant, or child adverse events. Results 164 studies were included. Regarding benefits, brexanolone for third‐trimester or postpartum depression onset may be associated with improved depressive symptoms at 30 days when compared with placebo. Sertraline for postpartum depression may be associated with improved response, remission, and depressive symptoms when compared with placebo. Discontinuing mood stabilizers during pregnancy may be associated with increased recurrence of mood episodes for bipolar disorder. Regarding adverse events, most studies were observational and unable to fully account for confounding. Evidence on congenital and cardiac anomalies for treatment compared with no treatment was inconclusive. Brexanolone for depression onset in the third trimester or the postpartum period may be associated with risk of sedation or somnolence, leading to dose interruption or reduction when compared with placebo. Conclusions Evidence from few studies supports the use of pharmacotherapy for perinatal mental health disorders. Although many studies report on adverse events, they could not rule out underlying disease severity as the cause of the association between exposures and adverse events. Patients and clinicians need to make informed, collaborative decisions on treatment choices.

Abstract Background Trigeminal Neuralgia (TN) is a chronic neurological disease that is strongly associated with neurovascular compression (NVC) of the trigeminal nerve near its root entry zone. The trigeminal nerve at the site of NVC has been extensively studied but limbic structures that are potentially involved in TN have not been adequately characterized. Specifically, the hippocampus is a stress-sensitive region which may be structurally impacted by chronic TN pain. As the center of the emotion-related network, the amygdala is closely related to stress regulation and may be associated with TN pain as well. The thalamus, which is involved in the trigeminal sensory pathway and nociception, may play a role in pain processing of TN. The objective of this study was to assess structural alterations in the trigeminal nerve and subregions of the hippocampus, amygdala, and thalamus in TN patients using ultra-high field MRI and examine quantitative differences in these structures compared with healthy controls. Methods Thirteen TN patients and 13 matched controls were scanned at 7-Tesla MRI with high resolution, T1-weighted imaging. Nerve cross sectional area (CSA) was measured and an automated algorithm was used to segment hippocampal, amygdaloid, and thalamic subregions. Nerve CSA and limbic structure subnuclei volumes were compared between TN patients and controls. Results CSA of the posterior cisternal nerve on the symptomatic side was smaller in patients (3.75 mm2) compared with side-matched controls (5.77 mm2, p = 0.006). In TN patients, basal subnucleus amygdala volume (0.347 mm3) was reduced on the symptomatic side compared with controls (0.401 mm3, p = 0.025) and the paralaminar subnucleus volume (0.04 mm3) was also reduced on the symptomatic side compared with controls (0.05 mm3, p = 0.009). The central lateral thalamic subnucleus was larger in TN patients on both the symptomatic side (0.033 mm3) and asymptomatic side (0.035 mm3), compared with the corresponding sides in controls (0.025 mm3 on both sides, p = 0.048 and p = 0.003 respectively). The inferior and lateral pulvinar thalamic subnuclei were both reduced in TN patients on the symptomatic side (0.2 mm3 and 0.17 mm3 respectively) compared to controls (0.23 mm3, p = 0.04 and 0.18 mm3, p = 0.04 respectively). No significant findings were found in the hippocampal subfields analyzed. Conclusions These findings, generated through a highly sensitive 7 T MRI protocol, provide compelling support for the theory that TN neurobiology is a complex amalgamation of local structural changes within the trigeminal nerve and structural alterations in subnuclei of limbic structures directly and indirectly involved in nociception and pain processing.

Long-term anticoagulation in the treatment of Cerebral Venous Sinus Thrombosis (CVST) has revolved around the use of warfarin. The relatively recent introduction of Direct Oral Anticoagulants (DOACs), such as Factor Xa inhibitors, in treating CVSTs promises to offer numerous patient benefits. We aimed to examine the efficacy of Factor Xa inhibitors in comparison to warfarin in the long-term treatment of CVSTs. A single-center retrospective analysis was conducted in which 49 eligible patients having presented with a first-time CVST were identified. Long-term anticoagulation was achieved with Warfarin (n = 23) or Factor Xa Inhibitors (n = 26; Apixaban or Rivaroxaban). Outcomes of interest were improvements in patient functional status, modified Ranking Scores (mRS), and radiographic improvement/resolution in sinus thromboses. Secondary comparisons included complication rates, particularly recurring venous thrombotic events. Patient mRS scores by 7-to-18-month follow-up all fell within the extremely favorable range of 0–1 regardless of the long-term anticoagulant (P-value = 0.3591). Proportion of patients with radiographic improvement/resolution of thrombosed sinuses trended towards being higher in the Factor Xa Inhibitor group at the 12-month follow-up period, Warfarin and Factor Xa inhibitor groups had similar rates of radiographic sinus improvement – 76.9% versus 71.4%, respectively (P-value = 0.6298). No statistically significant differences were documented between groups regarding complications. Factor Xa inhibitors are equally as effective as Warfarin in the long-term treatment of CVSTs, whether it be restoring patient functional status, sinus thrombus burden reduction, or minimizing bleeding complications whilst preventing recurrent venous thrombosis.

Background Honey bee males (drones) exhibit life histories that enable a high potential for pre- or post-copulatory sperm competition. With a numerical sex ratio of ∼11,000 drones for every queen, they patrol flyways and congregate aerially to mate on the wing. However, colonies and in fact drones themselves may benefit from a relative lack of competition, as queens are highly polyandrous, and colonies have an adaptive advantage when headed by queens that are multiply mated. Previous research has shown that larger drones are more likely to be found at drone congregation areas, more likely to mate successfully, and obtain a higher paternity share. However, the reproductive quality and size of drones varies widely within and among colonies, suggesting adaptive maintenance of drone quality variation at different levels of selection. Methods We collected drones from six colony sources over the course of five days. We paint marked and individually tagged drones after taking body measurements at emergence and then placed the drones in one of two foster colonies. Using an entrance cage, we collected drones daily as they attempted flight. We collected 2,420 drones live or dead, analyzed 1,891 for attempted flight, collected emergence data on 207 drones, and dissected 565 upon capture to assess reproductive maturity. We measured drone body mass, head width, and thorax width at emergence, and upon dissection we further measured thorax mass, seminal vesicle length, mucus gland length, sperm count, and sperm viability from the seminal vesicles. Results We found that drones that were more massive at emergence were larger and more fecund upon capture, suggesting that they are of higher reproductive quality and therefore do not exhibit a trade-off between size and fecundity. However, smaller drones tended to attempt initial flight at a younger age, which suggests a size trade-off not with fecundity but rather developmental maturation. We conclude that smaller drones may take more mating flights, each individually with a lower chance of success but thereby increasing their overall fitness. In doing so, the temporal spread of mating attempts of a single generation of drones within a given colony increases colony-level chances of mating with nearby queens, suggesting an adaptive rationale for high variation among drone reproductive quality within colonies.

BackgroundThe prevalence of common mental disorders (CMDs) among people living with HIV and people who inject drugs is high worldwide and in Vietnam. However, few evidence-informed CMD programs for people living with HIV who inject drugs have been adapted for use in Vietnam. We adapted the Friendship Bench (FB), a problem-solving therapy (PST)–based program that was successfully implemented among patients with CMDs in primary health settings in Zimbabwe and Malawi for use among people living with HIV on methadone maintenance treatment (MMT) with CMDs in Hanoi, Vietnam. ObjectiveThis study aimed to describe the adaptation process with a detailed presentation of 4 phases from the third (adaptation) to the sixth (integration) of the Assessment-Decision-Adaptation-Production-Topical Experts-Integration-Training-Testing (ADAPT-ITT) framework. MethodsThe adaptation phase followed a qualitative study design to explore symptoms of CMDs, facilitators, and barriers to conducting FB for people living with HIV on MMT in Vietnam, and patient, provider, and caretaker concerns about FB. In the production phase, we revised the original program manual and developed illustrated PST cases. In the topical expert and integration phases, 2 investigators (BNG and BWP) and 3 subject matter experts (RV, DC, and GML) reviewed the manual, with reviewer comments incorporated in the final, revised manual to be used in the training. The draft program will be used in the training and testing phases. ResultsThe study was methodologically aligned with the ADAPT-ITT goals as we chose a proven, effective program for adaptation. Insights from the adaptation phase addressed the who, where, when, and how of FB program implementation in the MMT clinics. The ADAPT-ITT framework guided the appropriate adaptation of the program manual while maintaining the core components of the PST of the original program throughout counseling techniques in all program sessions. The deliverable of this study was an adapted FB manual to be used for training and piloting to make a final program manual. ConclusionsThis study successfully illustrated the process of operationalizing the ADAPT-ITT framework to adapt a mental health program in Vietnam. This study selected and culturally adapted an evidence-informed PST program to improve CMDs among people living with HIV on MMT in Vietnam. This adapted program has the potential to effectively address CMDs among people living with HIV on MMT in Vietnam. Trial RegistrationClinicalTrials.gov NCT04790201; https://clinicaltrials.gov/ct2/show/NCT04790201

Abstract Introduction Emerging evidence in depression suggests that blood–brain barrier (BBB) breakdown and elevated inflammatory cytokines in states of persistent stress or trauma may contribute to the development of symptoms. Signal‐to‐noise ratio afforded by ultra‐high field MRI may aid in the detection of maladaptations of the glymphatic system related to BBB integrity that may not be visualized at lower field strengths. Methods We investigated the link between glymphatic neuroanatomy via perivascular spaces (PVS) and trauma experience in patients with major depressive disorder (MDD) and in healthy controls using 7‐Tesla MRI and a semi‐automated segmentation algorithm. Results After controlling for age and gender, the number of traumatic events was correlated with total PVS volume in MDD patients (r = 0.50, p = .028) and the overall population (r = 0.34, p = .024). The number of traumatic events eliciting horror was positively correlated with total PVS volume in MDD patients (r = 0.50, p = .030) and the overall population (r = 0.32, p = .023). Age correlated positively with PVS count, PVS total volume, and PVS density in all participants (r > 0.35, p

Background Stereotactic body radiotherapy (SBRT) has been increasingly used as adjuvant therapy in pancreatic ductal adenocarcinoma (PDAC), and induces immunogenic cell death, which leads to the release of tumor antigen and damage-associated molecular patterns. However, this induction often fails to generate sufficient response to overcome pre-existing tumor microenvironment (TME) immunosuppression. Toll-like receptor (TLR) 7/8 ligands, such as R848, can amplify the effect of tumor vaccines, with recent evidence showing its antitumor effect in pancreatic cancer by modulating the immunosuppressive TME. Therefore, we hypothesized that the combination of R848 and SBRT would improve local and systemic antitumor immune responses by potentiating the antitumor effects of SBRT and reversing the immunosuppressive nature of the PDAC TME.Methods Using murine models of orthotopic PDAC, we assessed the combination of intravenous TLR7/8 agonist R848 and local SBRT on tumor growth and immune response in primary pancreatic tumors. Additionally, we employed a hepatic metastatic model to investigate if the combination of SBRT targeting only the primary pancreatic tumor and systemic R848 is effective in controlling established liver metastases.Results We demonstrated that intravenous administration of the TLR7/8 agonist R848, in combination with local SBRT, leads to superior tumor control compared with either treatment alone. The combination of R848 and SBRT results in significant immune activation of the pancreatic TME, including increased tumor antigen-specific CD8+ T cells, decreased regulatory T cells, and enhanced antigen-presenting cells maturation, as well as increased interferon gamma, granzyme B, and CCL5 along with decreased levels of interleukin 4 (IL-4), IL-6, and IL-10. Importantly, the combination of SBRT and systemic R848 also resulted in similar immunostimulatory changes in liver metastases, leading to improved metastatic control. CD8+ T cell depletion studies highlighted the necessity of these effector cells at both the local and hepatic metastatic sites. T cell receptor (TCR) clonotype analysis indicated that systemic R848 not only diversified the TCR repertoire but also conditioned the metastatic foci to facilitate entry of CD8+ T cells generated by SBRT therapy.Conclusions These findings suggest that systemic administration of TLR7/8 agonists in combination with SBRT may be a promising avenue for metastatic PDAC treatment.

Abstract Aberrantly expressed fused in sarcoma (FUS) is a hallmark of FUS-related amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Wildtype FUS localises to synapses and interacts with mitochondrial proteins while mutations have been shown to cause to pathological changes affecting mitochondria, synapses and the neuromuscular junction (NMJ). This indicates a crucial physiological role for FUS in regulating synaptic and mitochondrial function that is currently poorly understood. In this paper we provide evidence that mislocalised cytoplasmic FUS causes mitochondrial and synaptic changes and that FUS plays a vital role in maintaining neuronal health in vitro and in vivo. Overexpressing mutant FUS altered synaptic numbers and neuronal complexity in both primary neurons and zebrafish models. The degree to which FUS was mislocalised led to differences in the synaptic changes which was mirrored by changes in mitochondrial numbers and transport. Furthermore, we showed that FUS co-localises with the mitochondrial tethering protein Syntaphilin (SNPH), and that mutations in FUS affect this relationship. Finally, we demonstrated mutant FUS led to changes in global protein translation. This localisation between FUS and SNPH could explain the synaptic and mitochondrial defects observed leading to global protein translation defects. Importantly, our results support the ‘gain-of-function’ hypothesis for disease pathogenesis in FUS-related ALS.

Stereotactic Radiotherapy (SRT) over 5-15 days can be interdigitated without delaying chemotherapy. Bridging chemotherapy may allow for extended intervals to surgery, potentially improving sterilization of surgical margins and overall survival. SRT for pancreatic adenocarcinoma should not be limited to the tumor, and should consider hypofractionated approaches to regional nodes.

Abstract Background The optimal type of operative drainage following pancreaticoduodenectomy (PD) remains unclear. Our objective is to investigate risk associated with closed drainage techniques (passive [gravity] vs. suction) after PD. Methods We assessed operative drainage techniques utilized in patients undergoing PD in the ACS-NSQIP pancreas-targeted database from 2016 to 2018. Using multivariable logistic regression to adjust for characteristics of the patient, procedure, and pancreas, we examined the association between use of gravity drainage and postoperative outcomes. Results We identified 9665 patients with drains following PD from 2016 to 2018, of which 12.7% received gravity drainage. 61.0% had a diagnosis of adenocarcinoma or pancreatitis, 26.5% had a duct

Abstract Background Injection drug use drives HIV transmission in Southeast Asia, where around a quarter of users are living with HIV. Vietnam developed Methadone Maintenance Therapy (MMT) programs to reduce unsafe drug abuse. Common mental health disorders (CMD), including depression, anxiety and post-traumatic stress disorder (PTSD), can worsen MMT outcomes and are highly prevalent among people living with HIV (PLH). We aimed to characterize HIV and CMD among MMT patients and assess the impact of HIV and CMD on MMT engagement outcomes in Hanoi, Vietnam. Methods This cross-sectional study was conducted at an urban MMT clinic in Hanoi. Participants were screened for CMD with the relevant sections of the Mini International Neuropsychiatric Interview (MINI). Tabular comparisons and regression models were used to understand the association of HIV and CMD with substance use and methadone compliance. Results Of the 400 MMT participants, 22% were living with HIV, 11% a CMD, 27% reported injection drug use, and 27% reported methadone noncompliance. Around 17% of those with HIV also had a CMD. Reporting non injection and injection drug use were each higher among those with CMD regardless of HIV status. In addition, reporting any drug use was much higher among those with both HIV and CMD than among those with neither (73% vs 31%, p value 0.001). While methadone noncompliance was lower among PLH than among those without HIV (16.3% vs 30.1%, p value 0.010), noncompliance was higher among those with CMD than among those without (40.5% vs 25.6%, p value 0.045). Among those without HIV, noncompliance was higher among those with CMD than among those without, but among those with HIV, the opposite relationship was observed. Conclusion There is complex overlap between substance use and methadone noncompliance among MMT patients living with HIV, CMD or both. In this population, we found a high prevalence of CMD and substance use among PLH, and a high prevalence of substance use and methadone noncompliance among those with CMD. Prioritizing provision of mental health care services to MMT patients living with HIV can help improve engagement with substance use disorder treatment and reduce the risk of HIV transmission.

Abstract Background Low and middle-income countries (LMICs) lack trained child mental health professionals. While teachers’ child development experience potentially positions them to fill the gap as lay mental health counselors, they have rarely delivered indicated child mental health care in LMICs. As part of assessing the feasibility of teachers serving as lay counselors, we explored teachers’ perceptions of serving as lay counselors and their mental health attitudes and knowledge. Methods In 2018, with training and supervision, 19 primary school teachers from five rural, low cost private schools in Darjeeling, India, served as lay counselors in their classrooms. Using mixed methods, we examined teacher perceptions of serving as lay counselor and mental health attitudes and knowledge through a survey (n = 15), a summative assessment (n = 14), and semi-structured interviews (n = 17). For the survey and summative assessment, pre-training, post-training, and post-intervention mean scores were compared using paired t tests. Post-intervention interviews were coded for teachers’ perceptions of serving as lay counselor and mental health attitudes and knowledge. Results Qualitatively, teachers expressed being willing to serve as lay counselor, having more inclusive mental health attitudes, and retaining mental health knowledge as applicable to use during instructional time or incorporation into the knowledge transfer process, their primary duty. By contrast, quantitatively, teachers’ attitudes appeared to become more inclusive on the study-specific survey pre versus post-training, but reverted to pre-training levels post-intervention. Teachers’ mental health knowledge on the summative assessment did not change pre-training versus post-training versus post-intervention. Conclusions Training, supervision, and serving as lay counselors led to teachers’ willingness to serve as lay counselors. Teachers served as lay counselors by utilizing therapeutic techniques during class time and incorporating them into their typical instruction, not through delivering traditional office-like care. Teacher practices may be pointing to the potential emergence of an “education as mental health therapy” system of care. Their changes in attitudes and knowledge reflected their emerging practices. Quantitative measures of knowledge and attitude changes did not capture these nuanced changes. Trial Registration The parent feasibility trial was registered on January 01, 2018 with Clinical Trials Registry – India (CTRI), reg. no. CTRI/2018/01/011471, ref. no. REF/2017/11/015895. http://ctri.nic.in/Clinicaltrials/pdf_generate.php?trialid=21129&EncHid=&modid=&compid=%27,%2721129det%27. .

The Gulf Cooperation Council (GCC) countries – Bahrain, Kuwait, Oman, Qatar, Saudi Arabia, and the United Arab Emirates (UAE) – ratified the Framework Convention on Tobacco Control (FCTC) in 2006. Yet, GCC countries predict a slight reduction in tobacco use compared to the Eastern Mediterranean region’s significant downward trend. The purpose of this study was to examine changes in self-reported intention to initiating tobacco use (susceptibility) among youth over time in five GCC countries and the relationship between susceptibility and key FCTC provisions. Complex sample logistic regression analyses were conducted using data from the 2001 to 2018 Global Youth Tobacco Survey (n = 349,878 adolescents). Since the ratification of FCTC in GCC countries, susceptibility to initiate tobacco use significantly decreased in Bahrain and Qatar while it increased in UAE (P

While COVID-19 is primarily considered a respiratory disease, it has been shown to affect the central nervous system. Mounting evidence shows that COVID-19 is associated with neurological complications as well as effects thought to be related to neuroinflammatory processes. Due to the novelty of COVID-19, there is a need to better understand the possible long-term effects it may have on patients, particularly linkage to neuroinflammatory processes. Perivascular spaces (PVS) are small fluid-filled spaces in the brain that appear on MRI scans near blood vessels and are believed to play a role in modulation of the immune response, leukocyte trafficking, and glymphatic drainage. Some studies have suggested that increased number or presence of PVS could be considered a marker of increased blood-brain barrier permeability or dysfunction and may be involved in or precede cascades leading to neuroinflammatory processes. Due to their size, PVS are better detected on MRI at ultrahigh magnetic field strengths such as 7 Tesla, with improved sensitivity and resolution to quantify both concentration and size. As such, the objective of this prospective study was to leverage a semi-automated detection tool to identify and quantify differences in perivascular spaces between a group of 10 COVID-19 patients and a similar subset of controls to determine whether PVS might be biomarkers of COVID-19-mediated neuroinflammation. Results demonstrate a detectable difference in neuroinflammatory measures in the patient group compared to controls. PVS count and white matter volume were significantly different in the patient group compared to controls, yet there was no significant association between PVS count and symptom measures. Our findings suggest that the PVS count may be a viable marker for neuroinflammation in COVID-19, and other diseases which may be linked to neuroinflammatory processes.