Barriers and facilitators in the implementation of youth and young adult models of mental health care.

AIM: It is increasingly recognised that traditional models of mental health (MH) care, with a service transition at age 18 years, may not reflect best practice. The literature supports a move towards youth and young adult focused models of MH care, for young people up to the age of 25, which specifically cater to the unique psychosocial and developmental needs of this population. This service evaluation aimed to explore the facilitators and barriers to the implementation of youth models of MH care across England (UK). METHODS: Six services participated in separate focus groups pertaining to their experience of implementing youth models of MH care. The interview guide for the focus groups was informed by the Consolidated Framework for Implementation Research (CFIR) and explored barriers and facilitators to implementation and sustainment. The focus groups were recorded, transcribed verbatim and analysed thematically. RESULTS: Seven key themes relevant to the implementation of youth models of MH care were identified: a clear rationale for doing things differently, for young people by young people, "building those relationships is key", service identity development, resource and infrastructure, leadership at multiple levels, and valuing and developing staff. CONCLUSIONS: The findings suggest effective communication and leadership, co-production and cross system collaboration contribute to successful implementation of youth models of MH care. The findings will be of interest to those involved in informing and supporting successful implementation and delivery of youth models of mental health care at local and national levels.

Retromer Stabilization Improves Cognitive Function and Synaptic Plasticity in a Mouse Model of Down Syndrome.

BACKGROUND: Retromer complex proteins are decreased in postmortem brain tissues from Down syndrome subjects and inversely correlate with the Alzheimer's disease-like neuropathology. However, whether targeting in vivo the retromer system affects cognitive deficits and synaptic function in Down syndrome remains unknown. OBJECTIVE: The aim of the current study was to examine the effects of pharmacological retromer stabilization on cognitive and synaptic functions in a mouse model of Down syndrome. METHODS: Ts65dn mice were administered the pharmacological chaperone, TPT-172, or vehicle from 4 to 9 months of age and then assessed for changes in cognitive function. To assess the effects of TPT-172 on synaptic plasticity, hippocampal slices from Ts65dn mice were incubated in TPT-172 and used for field potential recordings. RESULTS: Chronic TPT-172 treatment improved performance in cognitive function tests, its incubation with hippocampal slices ameliorated synaptic function response. CONCLUSION: Pharmacological stabilization of the retromer complex improves synaptic plasticity and memory in a mouse model of Down syndrome. These results support the therapeutic potential of pharmacological retromer stabilization for individual with Down syndrome.

Stener-Like Lesions in the Hand: A Qualitative Review.

A Stener-like lesion is defined as the interposition of the sagittal band between the torn collateral ligament of the metacarpophalangeal (MCP) joint of a finger and its origin or insertion. Owing to the rarity of this injury, standardized protocols on the diagnosis and care of these injuries are not currently available. PubMed Central and Google Scholar were searched for published studies from 1962 to 2022. Inclusion criteria admitted any injury of the MCP joints of any nonthumb fingers involving a torn collateral ligament with sagittal band injury that trapped the collateral ligament. Eight studies were ultimately included in our analysis and contained 11 cases of Stener-like lesions. Eight of the 11 cases presented radial collateral ligament injury to the ring and little fingers. All 11 cases presented showed that detailed physical examination was a primary step in diagnosis of these lesions. Metacarpophalangeal joint laxity was present in all cases reported. Imaging-aided diagnosis was used in majority of the cases presented and included arthrography, ultrasound, or magnetic resonance imaging. All cases presented in this review were managed surgically. Following surgical repair, a majority of authors opted to use immobilization techniques immediately postoperatively. As awareness of this injury pattern increases, a standardized treatment algorithm may develop.

Intracranial Cannula Implantation for Serial Locoregional Chimeric Antigen Receptor (CAR) T Cell Infusions in Mice.

Pediatric CNS tumors are responsible for the majority of cancer-related deaths in children and have poor prognoses, despite advancements in chemotherapy and radiotherapy. As many tumors lack efficacious treatments, there is a crucial need to develop more promising therapeutic options, such as immunotherapies; the use of chimeric antigen receptor (CAR) T cell therapy directed against CNS tumors is of particular interest. Cell surface targets such as B7-H3, IL13RA2, and the disialoganglioside GD2 are highly expressed on the surface of several pediatric and adult CNS tumors, raising the opportunity to use CAR T cell therapy against these and other surface targets. To evaluate the repeated locoregional delivery of CAR T cells in preclinical murine models, an indwelling catheter system that recapitulates indwelling catheters currently being used in human clinical trials was established. Unlike stereotactic delivery, the indwelling catheter system allows for repeated dosing without the use of multiple surgeries. This protocol describes the intratumoral placement of a fixed guide cannula that has been used to successfully test serial CAR T cell infusions in orthotopic murine models of pediatric brain tumors. Following orthotopic injection and engraftment of the tumor cells in mice, intratumoral placement of a fixed guide cannula is completed on a stereotactic apparatus and secured with screws and acrylic resin. Treatment cannulas are then inserted through the fixed guide cannula for repeated CAR T cell delivery. Stereotactic placement of the guide cannula can be adjusted to deliver CAR T cells directly into the lateral ventricle or other locations in the brain. This platform offers a reliable mechanism for the preclinical testing of repeated intracranial infusions of CAR T cells and other novel therapeutics for these devastating pediatric tumors.

Patient's experience and satisfaction with self-administered subcutaneous depot medroxyprogesterone acetate use during the first year of COVID-19.

OBJECTIVES: Self-administered subcutaneous (SC) depot medroxyprogesterone acetate (DMPA) can improve contraception access by eliminating a health center visit for administration. For patients at our New York City health centers who were offered a switch to self-administered DMPA-SC at the onset of the coronavirus 2019 (COVID-19) pandemic, we sought to understand their experience of choosing to switch, of accessing and using the method, and their method satisfaction. STUDY DESIGN: Individual interview study of 22 patients using intramuscular DMPA prior to the start of the pandemic. All had a telehealth visit to discuss switching to self-administered DMPA-SC and received a DMPA-SC prescription during the first months of COVID-19. We used a grounded theory analysis approach. RESULTS: Respondents viewed switching to self-administered DMPA-SC as a decision they had to make if they wanted to continue DMPA. Most respondents experienced logistical challenges acquiring DMPA-SC from their pharmacy. Issues around convenience were important to respondents; however what respondents found convenient varied. Despite all this, respondents appreciated having the option of DMPA-SC and felt it to be overall empowering. CONCLUSIONS: This study exploring patients' experience with self-administered DMPA-SC during the initial year of the COVID-19 pandemic found that, notwithstanding initial hesitation about self-administered injections and logistical challenges getting the SC formulation, many found the experience of trying self-administered DMPA-SC to be empowering and appreciated having this option. Thus, self-administered DMPA-SC should be included in clinicians' routine contraception counseling and provision, insurance companies should cover DMPA-SC without requiring prior authorization, and pharmacies should consistently stock DMPA-SC. IMPLICATIONS: Self-administered DMPA-SC is an acceptable contraception option that provides an opportunity to maintain contraception access while eliminating need for an in-person visit. Thus, self-administered DMPA-SC should be included in clinicians' routine contraception counseling and provision, insurance companies need to cover this contraceptive without need for prior authorization, and pharmacies should consistently stock DMPA-SC.

The Relative Citation Ratio: Evaluating a New Measure of Scientific Influence Among Academic Sports Medicine Surgeons.

Background: Objective measures of research influence are being increasingly utilized to evaluate and compare academic faculty. However, traditional bibliometrics, such as the Hirsch index and article citation count, are biased by time-dependent factors and are limited by a lack of field normalization. The relative citation ratio (RCR) is a new field- and time-normalized article-level metric developed by the National Institutes of Health (NIH). Purpose/Hypothesis: The purpose of this study was to evaluate the RCR among fellowship-trained academic sports medicine surgeons and to analyze physician factors associated with RCR values. We hypothesized that the mean RCR score for fellowship-trained academic sports medicine surgery faculty will fall above the NIH standard. Study Design: Cross-sectional study. Methods: A retrospective data analysis was performed using the iCite database for all fellowship-trained sports medicine surgery faculty associated with Accreditation Council for Graduate Medical Education-accredited orthopaedic surgery residency programs in December 2021. In eligible faculty, the mean RCR, weighted RCR, and total publication count were compared by sex, career duration, academic rank, and presence of additional degrees. A mean RCR value of 1.0 is the NIH-funded field-normalized standard. The data herein are presented as the median and interquartile range, in addition to the mean and standard deviation, to account for outliers of the mean and weighted RCR scores. Results: A total of 624 fellowship-trained sports medicine surgery faculty members from 160 orthopaedic surgery residency programs were included in the analysis. Overall, faculty produced impactful research, with a median RCR of 1.6 (interquartile range, 1.0-2.2) and a median weighted RCR of 19.3 (interquartile range, 5.1-69.3). Advanced academic rank and career longevity were associated with increased weighted RCR and total publication count. All subgroups analyzed had an RCR value >1.0. Conclusion: Study findings indicate that fellowship-trained academic sports medicine surgery faculty are highly productive and produce impactful research, as evidenced by the high median RCR value relative to the benchmark NIH RCR value of 1.0.

Optimizing an Outpatient mHealth Intervention for Children with Burns: A Convergent Mixed-Methods Study.

Burn injury is one of the most common traumatic injuries in childhood. Fortunately, 90% of pediatric burns may be treated in the outpatient setting after appropriate burn triage. Patients with burns face significant geographic disparities in accessing expert burn care due to regionalized care. To aid patients and their families during acute outpatient burn recovery, we developed a smartphone app, Telemedicine Optimized Burn Intervention (TOBI). With this app, we aimed to increase access to care by allowing secure, streamlined communication between patients and burn providers, including messaging and wound image transfer. The purpose of this study was to systematically evaluate user feedback to optimize the patient and provider experience. TOBI was evaluated using a convergent mixed-methods approach consisting of qualitative semi-structured interviews and quantitative measurements of app usability via the mHealth App Usability Questionnaire. Participants included 15 caregivers of pediatric patients with burns who used TOBI during treatment and ten burn providers. Users found TOBI to be a highly usable application in terms of usefulness, ease of use, satisfaction, and functionality. Qualitative data provided insight into user experience, satisfaction and preferences, difficulty navigating, usability and acceptability, and potential improvements. Although most users were highly satisfied, improvements were needed to optimize the burn app. We systematically made these improvements before we released TOBI for routine patient use. This study uncovered helpful recommendations for app improvements that can be generalized to other mobile health apps to increase their appeal and adoption.

Virtual Family Play Therapy: A Clinician's Guide to using Directed Family Play Therapy in Telemental Health.

The field of marriage and family therapy was founded by innovators and pioneers, taking the practice of individual psychotherapy and making it systemic. Due to the impact of COVID-19, we now need further advancement by systemic therapists for telemental health services. The purpose of this paper is to propose recommendations and guidelines for adapting directed family play therapy from the same physical location services to telemental health. The article discusses recommendations for assessment, therapy structure, therapist roles, session preparation, and how to use virtual tools to enhance treatment. Systemic play therapy in a virtual format can work well if therapists make appropriate adjustments and rely on their creativity, high regard for ethics, and innovation.

A phase I trial of metformin in combination with vincristine, irinotecan, and temozolomide in children with relapsed or refractory solid and central nervous system tumors: A report from the national pediatric cancer foundation.

BACKGROUND: Patients with relapsed and refractory solid and central nervous system (CNS) tumors have poor outcomes and need novel therapeutic options. Vincristine, irinotecan, and temozolomide (VIT) is a common chemotherapy regimen in relapsed pediatric tumors with an established toxicity profile. Metformin shows preclinical anti-cancer activity through multiple pathways. METHODS: The objective of this Phase I trial was to establish the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) of metformin in combination with VIT in children with relapsed and refractory solid and CNS tumors. A 3 + 3 design was used to test the addition of metformin at five dose levels (666, 999, 1333, 1666, and 2000 mg/m2 /day). Therapy toxicity, pharmacokinetics, and radiologic response to treatment were evaluated. RESULTS: Twenty-six patients (median age 13 years, range 2-18 years) were enrolled with 22 evaluable for toxicity. The most common diagnoses were Ewing sarcoma (n = 8), rhabdomyosarcoma (n = 3) and atypical teratoid/rhabdoid tumor (n = 3). The MTD was exceeded at Dose Level 5 due to two dose-limiting toxicities; both were Grade 3 diarrhea requiring prolonged hospitalization and intravenous fluids. The MTD was not determined due to study closure with less than six patients enrolled at Dose Level 4. Frequently observed toxicities were gastrointestinal (most notably diarrhea) and hematologic. Amongst 16 patients evaluable for best overall response, there was one complete response (Ewing sarcoma), three partial responses (Ewing sarcoma, glioblastoma multiforme, and alveolar rhabdomyosarcoma), and five patients with stable disease. CONCLUSIONS: The MTD of VIT with metformin was not determined due to premature study closure. We recommend an RP2D of Dose Level 4, 1666 mg/m2 /day. Radiographic responses were seen in multiple tumor types. Further evaluation for efficacy could be investigated in a Phase II trial.

Management of an Ingested Foreign Body in a COVID-Positive Patient.

This case report describes a 51-year-old man who swallowed an amalgam fragment dislodged during dental treatment performed without a throat screen. The patient was transferred to the emergency department, where the foreign body was confirmed to be in the esophagus following radiographic imaging. Foreign body removal from the esophagus is routinely achieved via esophagogastroduodenoscopy (EGD). However, this incident occurred in September 2020, at the height of the COVID-19 pandemic. Because of the patient's preoperative positive COVID-19 test, the option for EGD retrieval was eliminated per hospital protocol. Instead, a noninvasive approach with serial radiographic monitoring was deemed mandatory to observe the fragment as it passed through the gastrointestinal tract, warranted by the small size of the foreign body and the patient's lack of signs and symptoms of respiratory distress. This case report reinforces the importance of using airway protection during every dental procedure. Furthermore, reevaluation of EGD as the gold standard for treatment of ingested small materials may be warranted.

Discovery and functional characterization of the oncogenicity and targetability of a novel NOTCH1-ROS1 gene fusion in pediatric angiosarcoma.

Angiosarcomas are rare, malignant soft tissue tumors in children that arise in a wide range of anatomical locations and have limited targeted therapies available. Here, we report a rare case of a pediatric angiosarcoma (pAS) with Li-Fraumeni syndrome (LFS) expressing a novel NOTCH1-ROS1 gene fusion. Although both NOTCH1 and ROS1 are established proto-oncogenes, our study is the first to describe the mechanistic role of NOTCH1-ROS1 fusion arising via intrachromosomal rearrangement. NOTCH1-ROS1 displayed potent neoplastic transformation propensity in vitro, and harbors tumorigenic potential in vivo, where it induced oncogenic activation of the MAPK, PI3K/mTOR, and JAK-STAT signaling pathways in a murine allograft model. We found an unexpected contribution of the NOTCH1 extracellular region in mediating NOTCH1-ROS1 activation and oncogenic function, highlighting the contribution of both NOTCH1 and ROS1 fusion partners in driving tumorigenicity. Interestingly, neither membrane localization nor fusion protein dimerization were found to be essential for NOTCH1-ROS1 fusion oncogenicity. To target NOTCH1-ROS1-driven tumors, we tested both NOTCH1-directed inhibitors and ROS1-targeted tyrosine kinase inhibitors (TKI) in heterologous models (NIH3T3, Ba/F3). Although NOTCH1 inhibitors did not suppress NOTCH1-ROS1-driven oncogenic growth, we found that oral entrectinib treatment effectively suppressed the growth of NOTCH-ROS1-driven tumors. Taken together, we report the first known pAS case with a novel NOTCH1-ROS1 alteration along with a detailed report on the function and therapeutic targeting of NOTCH1-ROS1. Our study highlights the importance of genomic profiling of rare cancers such as pAS to reveal actionable drivers and improve patient outcomes.

Development of GPC2-directed chimeric antigen receptors using mRNA for pediatric brain tumors.

BACKGROUND: Pediatric brain tumors are the leading cause of cancer death in children with an urgent need for innovative therapies. Glypican 2 (GPC2) is a cell surface oncoprotein expressed in neuroblastoma for which targeted immunotherapies have been developed. This work aimed to characterize GPC2 expression in pediatric brain tumors and develop an mRNA CAR T cell approach against this target. METHODS: We investigated GPC2 expression across a cohort of primary pediatric brain tumor samples and cell lines using RNA sequencing, immunohistochemistry, and flow cytometry. To target GPC2 in the brain with adoptive cellular therapies and mitigate potential inflammatory neurotoxicity, we used optimized mRNA to create transient chimeric antigen receptor (CAR) T cells. We developed four mRNA CAR T cell constructs using the highly GPC2-specific fully human D3 single chain variable fragment for preclinical testing. RESULTS: We identified high GPC2 expression across multiple pediatric brain tumor types including medulloblastomas, embryonal tumors with multilayered rosettes, other central nervous system embryonal tumors, as well as definable subsets of highly malignant gliomas. We next validated and prioritized CAR configurations using in vitro cytotoxicity assays with GPC2-expressing neuroblastoma cells, where the light-to-heavy single chain variable fragment configurations proved to be superior. We expanded the testing of the two most potent GPC2-directed CAR constructs to GPC2-expressing medulloblastoma and high-grade glioma cell lines, showing significant GPC2-specific cell death in multiple models. Finally, biweekly locoregional delivery of 2-4 million GPC2-directed mRNA CAR T cells induced significant tumor regression in an orthotopic medulloblastoma model and significantly prolonged survival in an aggressive orthotopic thalamic diffuse midline glioma xenograft model. No GPC2-directed CAR T cell related neurologic or systemic toxicity was observed. CONCLUSION: Taken together, these data show that GPC2 is a highly differentially expressed cell surface protein on multiple malignant pediatric brain tumors that can be targeted safely with local delivery of mRNA CAR T cells, laying the framework for the clinical translation of GPC2-directed immunotherapies for pediatric brain tumors.

Dysfunction of the retromer complex system contributes to amyloid and tau pathology in a stem cell model of Down syndrome.

Introduction: Retromer complex proteins are decreased in Down syndrome (DS) brains and correlate inversely with brain amyloidosis. However, whether retromer dysfunction contributes to the amyloid beta (Aß) and tau neuropathology of DS remains unknown. Methods: Human trisomic induced Pluripotent Stem Cells (iPSCs) and isogenic controls were differentiated into forebrain neurons, and changes in retromer proteins, tau phosphorylated epitopes, and Aß levels were assessed in euploid and trisomic neurons using western blot and enzyme-linked immunosorbent assay (ELISA). Genetic overexpression and pharmacological retromer stabilization were used to determine the functional role of the retromer complex system in modulating amyloid and tau pathology. Results: Trisomic neurons developed age-dependent retromer core protein deficiency associated with accumulation of Aß peptides and phosphorylated tau isoforms. Enhancing retromer function through overexpression or pharmacological retromer stabilization reduced amyloid and tau pathology in trisomic neurons. However, the effect was greater using a pharmacological approach, suggesting that targeting the complex stability may be more effective in addressing this neuropathology in DS. Discussion: Our results demonstrate that the retromer complex is directly involved in the development of the neuropathologic phenotype in DS, and that pharmacological stabilization of the complex should be considered as a novel therapeutic tool in people with DS.

Evaluation of the National Institutes of Health-supported relative citation ratio among American orthopedic spine surgery faculty: A new bibliometric measure of scientific influence.

Background: Publication metrics have been traditionally used to compare research productivity amongst academic faculty. However, traditional bibliometrics lack field-normalization and are often biased towards time-dependent publication factors. The National Institutes of Health (NIH) has developed a new, field-normalized, article-level metric, known as the "relative citation ratio" (RCR), that can be used to make accurate self, departmental, and cross-specialty comparisons of research productivity. This study evaluates the use of the RCR amongst academic orthopedic spine surgery faculty and analyzes physician factors associated with RCR values. Methods: A retrospective data analysis was performed using the iCite database for all fellowship trained orthopedic spine surgery (OSS) faculty associated with Accreditation Council for Graduate Medical Education (ACGME)-accredited orthopedic surgery residency program. Mean RCR, weighted RCR, and total publication count were compared by sex, career duration, academic rank, and presence of additional degrees. A value of 1.0 is the NIH-funded field-normalized standard. Student t-tests were used for two-group analyses whereas the analysis of variance tests (ANOVA) was used for between-group comparisons of three or more subgroups. Statistical significance was achieved at P < 0.05. Results: A total of 502 academic OSS faculty members from 159 institutions were included in the analysis. Overall, OSS faculty were highly productive, with a median RCR of 1.62 (IQR 1.38-2.32) and a median weighted RCR of 68.98 (IQR 21.06-212.70). Advancing academic rank was associated with weighted RCR, career longevity was associated with mean RCR score, and male sex was associated with having increased mean and weighted RCR scores. All subgroups analyzed had an RCR value above 1.0. Conclusions: Academic orthopedic spine surgery faculty produce impactful research as evidenced by the high median RCR relative to the standard value set by the NIH of 1.0. Our data can be used to evaluate research productivity in the orthopedic spine community.

Successful Non-operative Management of Metacarpophalangeal Collateral Ligament and Sagittal Band Rupture of the Long Finger: A Case Report.

The metacarpophalangeal (MCP) joint is surrounded by various structures critical to its stability and function. Though the ligamentous injury to the digits is common, rupture of the metacarpophalangeal collateral ligament and a sagittal band of the same finger is not well represented in the literature. We report a chronic case of a concurrent metacarpophalangeal collateral ligament and sagittal band injury. Though surgery would have been the most appropriate treatment soon after the injury, restrictions on elective procedures due to the COVID-19 pandemic precluded surgical treatment. The patient was alternatively treated with buddy tape, and a close follow-up was done. This is the first reported case of a concurrent metacarpophalangeal collateral ligament, and sagittal band injury successfully treated using nonoperative management.

Prospects of viral vector-mediated delivery of sequences encoding anti-HBV designer endonucleases.

Available treatment for chronic hepatitis B virus (HBV) infection offers modest functional curative efficacy. The viral replicative intermediate comprising covalently closed circular DNA (cccDNA) is responsible for persistent chronic HBV infection. Hence, current efforts have focused on developing therapies that disable cccDNA. Employing gene editing tools has emerged as an attractive strategy, with the end goal of establishing permanently inactivated cccDNA. Although anti-HBV designer nucleases are effective in vivo, none has yet progressed to clinical trial. Lack of safe and efficient delivery systems remains the limiting factor. Several vectors may be used to deliver anti-HBV gene editor-encoding sequences, with viral vectors being at the forefront. Despite the challenges associated with packaging large gene editor-encoding sequences into viral vectors, advancement in the field is overcoming such limitations. Translation of viral vector-mediated gene editing against HBV to clinical application is within reach. This review discusses the prospects of delivering HBV targeted designer nucleases using viral vectors.

A Rapid Literature Review of Multi-Criteria Decision Support Methods in the Context of One Health for All-Hazards Threat Prioritization.

Background: Multi-Criteria Decision Analysis (MCDA) is a decision support tool that can be used in public health emergency management. The use of a One Health lens in MCDA can support the prioritization of threats and interventions which cut across the human, animal, and environmental domains. Previous literature reviews have focused on creating a snapshot of MCDA methodological trends. Our study provides an update to the MCDA methods literature with key considerations from a One Health perspective and addresses the application of MCDA in an all-hazards decision-making context. Methods: We conducted a literature search on MEDLINE, EMBASE, SCOPUS, the CAB database, and a limited online gray literature search in partnership with a librarian from Health Canada. Articles were limited to those published in the year 2010 or later in a high-income setting (OECD member countries). Results: Sixty-two articles were included for synthesis. Of these articles, most were Canadian studies (20%); and prioritized health risks, threats, and interventions in the human domain (69%). Six commonly used prioritization criteria were identified: threat, health, intervention, strategic, social, and economic impact. Stakeholders were engaged in 85% of studies and commonly consisted of government groups, non-governmental groups, subject matter experts, and the public. While most articles (65%) included elements of One Health based on our definition, only 5 studies (9%) explicitly acknowledged One Health as a guiding principle for the study. Forty seven percentage of studies noted that MCDA was beneficial in supporting the decision-making process. Conclusion: Current literature on health prioritization presents some variability in the depth of integration of the One Health framework and on the use of various MCDA methodologies given prioritization objectives. Studies which applied a comprehensive One Health approach, prioritized disparate threats, or conducted cyclical prioritizations for governing bodies were broad in scope, but sparse. The results of our review indicate the need for better guidance on the integration of a One Health approach and the use of various MCDA methods given the main prioritization objectives.

Association of Retromer Deficiency and Tau Pathology in Down Syndrome.

Retromer deficiency is reported in Down syndrome and correlates with amyloidosis, however, its association with tau neuropathology remains unclear. Down syndrome and control brain tissues were evaluated for phosphorylated tau, tau modulators, and cathepsin-D activity. Several kinases and phosphatase PP2A were unchanged, but tau phosphorylation was elevated, and cathepsin-D activity decreased in aged patients with Down syndrome. Retromer proteins positively associated with soluble tau, whereas pathogenic tau negatively correlated with retromer proteins and cathepsin-D activity. Retromer deficiency and consequent reduction of cathepsin-D activity may contribute to pathogenic tau accumulation, thus, retromer represents a viable therapeutic target against tau pathology in Down syndrome. ANN NEUROL 2022;91:561-567.

Assessment of Cervical Cancer Prevention and Treatment Infrastructure in Belize.

PURPOSE: Belize has one of the highest cervical cancer burdens among Latin American and Caribbean countries, despite the implementation of national policies to increase access to prevention and treatment services. This study evaluates the policies, infrastructure, and workforce of the cervical cancer management system in Belize to inform capacity building efforts. METHODS: In 2018, health facility assessments were conducted across all six districts of Belize at the national pathology facility and 12 public facilities identified as critical to cervical cancer control. Human and infrastructure resource availability and existing policies related to cervical cancer screening and treatment services were assessed through a structured instrument. RESULTS: The public cervical cancer screening workforce in Belize consists of 75 primary care nurses and physicians-one per 1,076 screening-eligible women, with 44% conducting rural outreach. All districts have at least one screening facility, but 50% perform screening services only once per week. Colposcopy and loop electrical excision procedures are available in three and four districts, respectively; radical hysterectomy and chemotherapy are available in two districts; and radiation therapy is unavailable. Of essential pathology equipment, 38.5% were present and functional, 23% were present but nonfunctional, and 38.5% were unavailable. Additionally, 35% of supplies were unavailable at the time of assessment, and 75% were unavailable at least once in the 12 months before assessment. CONCLUSION: Public-sector cervical cancer management services differ among districts of Belize, with tertiary service availability concentrated in the largest district. Screening, outreach, and pathology are limited mostly by resource availability. This study characterizes the current capacity of services in Belize and pinpoints health system components for future investment and capacity-building efforts.

Improved Specificity and Safety of Anti-Hepatitis B Virus TALENs Using Obligate Heterodimeric FokI Nuclease Domains.

Persistent hepatitis B virus (HBV) infection remains a serious medical problem worldwide, with an estimated global burden of 257 million carriers. Prophylactic and therapeutic interventions, in the form of a vaccine, immunomodulators, and nucleotide and nucleoside analogs, are available. Vaccination, however, offers no therapeutic benefit to chronic sufferers and has had a limited impact on infection rates. Although immunomodulators and nucleotide and nucleoside analogs have been licensed for treatment of chronic HBV, cure rates remain low. Transcription activator-like effector nucleases (TALENs) designed to bind and cleave viral DNA offer a novel therapeutic approach. Importantly, TALENs can target covalently closed circular DNA (cccDNA) directly with the potential of permanently disabling this important viral replicative intermediate. Potential off-target cleavage by engineered nucleases leading to toxicity presents a limitation of this technology. To address this, in the context of HBV gene therapy, existing TALENs targeting the viral core and surface open reading frames were modified with second- and third-generation FokI nuclease domains. As obligate heterodimers these TALENs prevent target cleavage as a result of FokI homodimerization. Second-generation obligate heterodimeric TALENs were as effective at silencing viral gene expression as first-generation counterparts and demonstrated an improved specificity in a mouse model of HBV replication.