Detailed phenotype and long-term follow-up of RAB28-associated cone-rod dystrophy.

PURPOSE: To gain an insight into the pathophysiology of RAB28-associated inherited retinal degeneration through detailed phenotyping and long-term longitudinal follow-up. METHODS: The patient underwent complete ophthalmic examinations. Visual function was assessed with microperimetry, full-field electroretinography (ffERG), imaging with optical coherence tomography (OCT), short-wave (SW), and near-infrared (NIR) fundus autofluorescence (FAF). RESULTS: A healthy Haitian woman with homozygous pathogenic variants (c.68C > T; p.Ser23Phe) in RAB28 presented at 16 years of age with a four-year history of blurred vision. Visual acuities were 20/125 in each eye, which remained relatively stable since. At age 27, cone ffERGs were non-detectable and borderline for rod-mediated responses. Kinetic fields were full to a V-4e target, undetectable to a small I-4e stimulus. Microperimetry showed an absolute central scotoma surrounded by a pericentral relative scotoma. SD-OCT showed an undetectable or barely detectable foveal and parafoveal photoreceptor outer nuclear layer (ONL), photoreceptor outer segment (POS), and retinal pigment epithelium (RPE) signals and loss of the SW- and NIR-FAF signals. This atrophic region was separated from a normally laminated retina by a narrow transition zone (TZ) of hyper SW- and NIR-FAF that co-localized with preserved ONL but abnormally thinned POS and RPE. There was minimal centrifugal (<100 µm) expansion over a six-year period. CONCLUSION: The cone-rod dystrophy phenotype documented herein supports a critical role of RAB28 for cone function and POS maintenance. Severe central photoreceptor and RPE loss with a predilection for POS loss in TZs suggests possible disruptions of complex mechanisms that maintain central cone photoreceptor and RPE homeostasis.

Comparing ventriculoatrial and ventriculopleural shunts in pediatric hydrocephalus: a Hydrocephalus Clinical Research Network study.

OBJECTIVE: When the peritoneal cavity cannot serve as the distal shunt terminus, nonperitoneal shunts, typically terminating in the atrium or pleural space, are used. The comparative effectiveness of these two terminus options has not been evaluated. The authors directly compared shunt survival and complication rates for ventriculoatrial (VA) and ventriculopleural (VPl) shunts in a pediatric cohort. METHODS: The Hydrocephalus Clinical Research Network Core Data Project was used to identify children ≤ 18 years of age who underwent either VA or VPl shunt insertion. The primary outcome was time to shunt failure. Secondary outcomes included distal site complications and frequency of shunt failure at 6, 12, and 24 months. RESULTS: The search criteria yielded 416 children from 14 centers with either a VA (n = 318) or VPl (n = 98) shunt, including those converted from ventriculoperitoneal shunts. Children with VA shunts had a lower median age at insertion (6.1 years vs 12.4 years, p < 0.001). Among those children with VA shunts, a hydrocephalus etiology of intraventricular hemorrhage (IVH) secondary to prematurity comprised a higher proportion (47.0% vs 31.2%) and myelomeningocele comprised a lower proportion (17.8% vs 27.3%) (p = 0.024) compared with those with VPl shunts. At 24 months, there was a higher cumulative number of revisions for VA shunts (48.6% vs 38.9%, p = 0.038). When stratified by patient age at shunt insertion, VA shunts in children < 6 years had the lowest shunt survival rate (p < 0.001, log-rank test). After controlling for age and etiology, multivariable analysis did not find that shunt type (VA vs VPl) was predictive of time to shunt failure. No differences were found in the cumulative frequency of complications (VA 6.0% vs VPl 9.2%, p = 0.257), but there was a higher rate of pneumothorax in the VPl cohort (3.1% vs 0%, p = 0.013). CONCLUSIONS: Shunt survival was similar between VA and VPl shunts, although VA shunts are used more often, particularly in younger patients. Children < 6 years with VA shunts appeared to have the shortest shunt survival, which may be a result of the VA group having more cases of IVH secondary to prematurity; however, when age and etiology were included in a multivariable model, shunt location (atrium vs pleural space) was not associated with time to failure. The baseline differences between children treated with a VA versus a VPl shunt likely explain current practice patterns.

Leveraging GPT-4 for identifying cancer phenotypes in electronic health records: a performance comparison between GPT-4, GPT-3.5-turbo, Flan-T5, Llama-3-8B, and spaCy's rule-based and machine learning-based methods.

Objective: Accurately identifying clinical phenotypes from Electronic Health Records (EHRs) provides additional insights into patients' health, especially when such information is unavailable in structured data. This study evaluates the application of OpenAI's Generative Pre-trained Transformer (GPT)-4 model to identify clinical phenotypes from EHR text in non-small cell lung cancer (NSCLC) patients. The goal was to identify disease stages, treatments and progression utilizing GPT-4, and compare its performance against GPT-3.5-turbo, Flan-T5-xl, Flan-T5-xxl, Llama-3-8B, and 2 rule-based and machine learning-based methods, namely, scispaCy and medspaCy. Materials and Methods: Phenotypes such as initial cancer stage, initial treatment, evidence of cancer recurrence, and affected organs during recurrence were identified from 13 646 clinical notes for 63 NSCLC patients from Washington University in St. Louis, Missouri. The performance of the GPT-4 model is evaluated against GPT-3.5-turbo, Flan-T5-xxl, Flan-T5-xl, Llama-3-8B, medspaCy, and scispaCy by comparing precision, recall, and micro-F1 scores. Results: GPT-4 achieved higher F1 score, precision, and recall compared to Flan-T5-xl, Flan-T5-xxl, Llama-3-8B, medspaCy, and scispaCy's models. GPT-3.5-turbo performed similarly to that of GPT-4. GPT, Flan-T5, and Llama models were not constrained by explicit rule requirements for contextual pattern recognition. spaCy models relied on predefined patterns, leading to their suboptimal performance. Discussion and Conclusion: GPT-4 improves clinical phenotype identification due to its robust pre-training and remarkable pattern recognition capability on the embedded tokens. It demonstrates data-driven effectiveness even with limited context in the input. While rule-based models remain useful for some tasks, GPT models offer improved contextual understanding of the text, and robust clinical phenotype extraction.

Cannabis, Tobacco Use, and COVID-19 Outcomes.

Importance: It is unclear whether cannabis use is associated with adverse health outcomes in patients with COVID-19 when accounting for known risk factors, including tobacco use. Objective: To examine whether cannabis and tobacco use are associated with adverse health outcomes from COVID-19 in the context of other known risk factors. Design, Setting, and Participants: This retrospective cohort study used electronic health record data from February 1, 2020, to January 31, 2022. This study included patients who were identified as having COVID-19 during at least 1 medical visit at a large academic medical center in the Midwest US. Exposures: Current cannabis use and tobacco smoking, as documented in the medical encounter. Main Outcomes and Measures: Health outcomes of hospitalization, intensive care unit (ICU) admission, and all-cause mortality following COVID-19 infection. The association between substance use (cannabis and tobacco) and these COVID-19 outcomes was assessed using multivariable modeling. Results: A total of 72 501 patients with COVID-19 were included (mean [SD] age, 48.9 [19.3] years; 43 315 [59.7%] female; 9710 [13.4%] had current smoking; 17 654 [24.4%] had former smoking; and 7060 [9.7%] had current use of cannabis). Current tobacco smoking was significantly associated with increased risk of hospitalization (odds ratio [OR], 1.72; 95% CI, 1.62-1.82; P < .001), ICU admission (OR, 1.22; 95% CI, 1.10-1.34; P < .001), and all-cause mortality (OR, 1.37, 95% CI, 1.20-1.57; P < .001) after adjusting for other factors. Cannabis use was significantly associated with increased risk of hospitalization (OR, 1.80; 95% CI, 1.68-1.93; P < .001) and ICU admission (OR, 1.27; 95% CI, 1.14-1.41; P < .001) but not with all-cause mortality (OR, 0.97; 95% CI, 0.82-1.14, P = .69) after adjusting for tobacco smoking, vaccination, comorbidity, diagnosis date, and demographic factors. Conclusions and Relevance: The findings of this cohort study suggest that cannabis use may be an independent risk factor for COVID-19-related complications, even after considering cigarette smoking, vaccination status, comorbidities, and other risk factors.

Levels of engagement among office-based opioid treatment (OBOT) patients with concurrent methamphetamine use.

BACKGROUND AND OBJECTIVES: Recent increases in methamphetamine use among people seeking treatment for opioid use disorder (OUD) has created significant demand for effective approaches to support this clinical population. This study assessed the extent to which office-based opioid treatment (OBOT) patients, who were diagnosed with methamphetamine use disorder (MUD), engaged with providers. METHODS: A retrospective analysis was conducted of adult patients (n = 470) seeking treatment for OUD who attended at least one visit between March 2020 and March 2023 at a rural regional OBOT provider. Approximately one quarter (28.7%) of patients were diagnosed with MUD in addition to receiving an OUD diagnosis. Bivariate methods and multivariate negative binomial regression models were estimated to examine the associations between clinical measures and the numbers of office visits, peer visits, and telehealth visits. RESULTS: Regression results indicated patients who met criteria for MUD in addition to OUD attended a higher rate of peer visits (incidence rate ratio [IRR] = 2.63, p = .036) when compared to patients who did not meet criteria for MUD. In contrast, patients with MUD and OUD diagnoses displayed significantly lower (IRR = 0.68, p < .001) engagement rates through fewer office visits relative to those who did not meet MUD criteria. DISCUSSION AND CONCLUSIONS: Patients seeking treatment for OUD who meet criteria for MUD are more likely to engage through peer support specialists rather than office visits. SCIENTIFIC SIGNIFICANCE: This study demonstrates the ways patients who meet criteria for OUD and MUD engage with providers to receive treatment.

Gene Editing for CEP290-Associated Retinal Degeneration.

BACKGROUND: CEP290-associated inherited retinal degeneration causes severe early-onset vision loss due to pathogenic variants in CEP290. EDIT-101 is a clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9) gene-editing complex designed to treat inherited retinal degeneration caused by a specific damaging variant in intron 26 of CEP290 (IVS26 variant). METHODS: We performed a phase 1-2, open-label, single-ascending-dose study in which persons 3 years of age or older with CEP290-associated inherited retinal degeneration caused by a homozygous or compound heterozygous IVS26 variant received a subretinal injection of EDIT-101 in the worse (study) eye. The primary outcome was safety, which included adverse events and dose-limiting toxic effects. Key secondary efficacy outcomes were the change from baseline in the best corrected visual acuity, the retinal sensitivity detected with the use of full-field stimulus testing (FST), the score on the Ora-Visual Navigation Challenge mobility test, and the vision-related quality-of-life score on the National Eye Institute Visual Function Questionnaire-25 (in adults) or the Children's Visual Function Questionnaire (in children). RESULTS: EDIT-101 was injected in 12 adults 17 to 63 years of age (median, 37 years) at a low dose (in 2 participants), an intermediate dose (in 5), or a high dose (in 5) and in 2 children 9 and 14 years of age at the intermediate dose. At baseline, the median best corrected visual acuity in the study eye was 2.4 log10 of the minimum angle of resolution (range, 3.9 to 0.6). No serious adverse events related to the treatment or procedure and no dose-limiting toxic effects were recorded. Six participants had a meaningful improvement from baseline in cone-mediated vision as assessed with the use of FST, of whom 5 had improvement in at least one other key secondary outcome. Nine participants (64%) had a meaningful improvement from baseline in the best corrected visual acuity, the sensitivity to red light as measured with FST, or the score on the mobility test. Six participants had a meaningful improvement from baseline in the vision-related quality-of-life score. CONCLUSIONS: The safety profile and improvements in photoreceptor function after EDIT-101 treatment in this small phase 1-2 study support further research of in vivo CRISPR-Cas9 gene editing to treat inherited retinal degenerations due to the IVS26 variant of CEP290 and other genetic causes. (Funded by Editas Medicine and others; BRILLIANCE ClinicalTrials.gov number, NCT03872479.).

The identification of intact HIV proviral DNA from human cerebrospinal fluid.

We evaluated the HIV-1 DNA reservoir in peripheral blood mononuclear cells (PBMC) and cerebrospinal fluid (CSF) in people with HIV (PWH) and associations to cognitive dysfunction. Using the intact proviral DNA assay (IPDA), an emerging technique to identify provirus that may be the source of viral rebound, we assessed HIV DNA in CSF and PBMC in PWH regardless of antiretroviral therapy (ART). CSF was used as a sampling surrogate for the central nervous system (CNS) as opposed to tissue. IDPA results (3' defective, 5' defective, and intact HIV DNA) were analyzed by compartment (Wilcoxon signed rank; matched and unmatched pairs). Cognitive performance, measured via a battery of nine neuropsychological (NP) tests, were analyzed for correlation to HIV DNA (Spearman's rho). 11 CSF and 8 PBMC samples from PWH were evaluated both unmatched and matched. Total CSF HIV DNA was detectable in all participants and was significantly higher than in matched PBMCs (p â€‹= â€‹0.0039). Intact CSF HIV DNA was detected in 7/11 participants and correlated closely with those in PBMCs but tended to be higher in CSF than in PBMC. CSF HIV DNA did not correlate with global NP performance, but higher values did correlate with worse executive function (p â€‹= â€‹0.0440). Intact HIV DNA is frequently present in the CSF of PWH regardless of ART. This further supports the presence of an HIV CNS reservoir and provides a method to study CNS reservoirs during HIV cure studies. Larger studies are needed to evaluate relationships with CNS clinical outcomes.

Objective monitoring tools for improved management of childhood asthma.

Asthma is a common chronic disease amongst children. Epidemiological studies showed that the mortality rate of asthma in children is still high worldwide. Asthma control is therefore essential to minimize asthma exacerbations, which can be fatal if the condition is poorly controlled. Frequent monitoring could help to detect asthma progression and ensure treatment effectiveness. Although subjective asthma monitoring tools are available, the results vary as they rely on patients' self-perception. Emerging evidence suggests several objective tools could have the potential for monitoring purposes. However, there is no consensus to standardise the use of objective monitoring tools. In this review, we start with the prevalence and severity of childhood asthma worldwide. Then, we detail the latest available objective monitoring tools, focusing on their effectiveness in paediatric asthma management. Publications of spirometry, fractional exhaled nitric oxide (FeNO), hyperresponsiveness tests and electronic monitoring devices (EMDs) between 2016 and 2023 were included. The potential advantages and limitations of each tool were also discussed. Overall, this review provides a summary for researchers dedicated to further improving objective paediatric asthma monitoring and provides insights for clinicians to incorporate different objective monitoring tools in clinical practices.

Molecular Probing of the Microscopic Pressure at Contact Interfaces.

Obtaining insights into friction at the nanoscopic level and being able to translate these into macroscopic friction behavior in real-world systems is of paramount importance in many contexts, ranging from transportation to high-precision technology and seismology. Since friction is controlled by the local pressure at the contact it is important to be able to detect both the real contact area and the nanoscopic local pressure distribution simultaneously. In this paper, we present a method that uses planarizable molecular probes in combination with fluorescence microscopy to achieve this goal. These probes, inherently twisted in their ground states, undergo planarization under the influence of pressure, leading to bathochromic and hyperchromic shifts of their UV-vis absorption band. This allows us to map the local pressure in mechanical contact from fluorescence by exciting the emission in the long-wavelength region of the absorption band. We demonstrate a linear relationship between fluorescence intensity and (simulated) pressure at the submicron scale. This relationship enables us to experimentally depict the pressure distribution in multiasperity contacts. The method presented here offers a new way of bridging friction studies of the nanoscale model systems and practical situations for which surface roughness plays a crucial role.

Detecting DSM-5 Opioid and Methamphetamine Use Disorders With the UNCOPE Screen.

BACKGROUND: The most recent wave of the opioid epidemic has contributed to record number of drug overdoses. Most fatal outcomes are associated with opioids and methamphetamine; two substances that tend to be used at high rates among criminal justice populations. Despite the steady rise in the number of overdoses in local detention centers, many correctional facilities do not conduct routine screens for opioid and methamphetamine use disorders. This study examines the utility of the UNCOPE, a 6-item brief screen, to detect probable Diagnostic and Statistical Manual for Mental Disorders, fifth edition (DSM-5) diagnoses for these 2 specific substance use disorders (SUDs). The study also examines key indicators of these specific SUDs. METHODS: Data were collected from comprehensive substance use assessments conducted with 717 adults who were recently admitted to 4 county jails. RESULTS: Findings indicate that 3 positive UNCOPE responses accurately detected 99.8% of opioid use disorder diagnoses and 98.7% of methamphetamine use disorder diagnoses. Receiver operating characteristic curve results generate an area under the curve at 0.99 for severe opioid use cases and 0.98 for severe methamphetamine use cases. Subsequent analyses indicate 2 of the 6 items on the UNCOPE function to accurately identify 100% of cases classified with opioid use disorder and 99.6% of cases classified with methamphetamine use disorder. CONCLUSIONS: Evidence suggests that UNCOPE is a practical and efficient approach to identifying opioid and methamphetamine use disorders. In addition, 2 items can serve as an ultra-brief method to detecting these conditions at the time of admission to detention centers.

XUV Absorption Spectroscopy and Photoconversion of a Tin-Oxo Cage Photoresist.

Extreme ultraviolet lithography has recently been introduced in high-volume production of integrated circuits for manufacturing the smallest features in high-end computer chips. Hybrid organic/inorganic materials are considered as the next generation of photoresists for this technology, but detailed knowledge about the response of such materials to the ionizing radiation used (13.5 nm, 92 eV) is still scarce. In the present work, we use broadband high-harmonic radiation in the energy range 22-70 eV for absorption spectroscopy and photobleaching (that is, the decrease of absorbance) of thin films of an n-butyltin oxo-cage, a representative of the class of metal-based EUV photoresist. The shape of the absorption spectrum in the range 22-92 eV matches well with the spectrum predicted using tabulated atomic cross sections. The photobleaching results are consistent with loss of the butyl side groups due to the breaking of Sn-C bonds following photoionization. Bleaching is strongest in the low-energy range (<40 eV), where the absorption is largely due to the carbon atoms in the organic groups. At higher energies (42-70 eV), absorption is dominated by the tin atoms, and since these remain in the film after photoconversion, the absorption change in this region is smaller. It is estimated that after prolonged irradiation (up to ∼3 J cm-2 in the range 22-40 eV) about 70% of the hydrocarbon groups are removed from the film. The rate of bleaching is high at the beginning of exposure, but it rapidly decreases with increasing conversion. We rationalize this using density functional theory calculations: the first Sn-C bonds are efficiently cleaved (quantum yield Φ ≈ 0.9), because the highest occupied molecular orbitals (HOMOs) (from which an electron is removed after photoionization) are located on Sn-C sigma bonds. In the photoproducts, the HOMO is localized on tin atoms that have lost their hydrocarbon group (formally reduced to the Sn(II) oxidation state), and holes formed on those tin atoms lead to less efficient cleavage reactions. Our results reveal the primary reaction steps following excitation with ionizing radiation of tin-oxo cages. Our methodology represents a systematic approach of studying and quantitatively assessing the performance of new photoresists and as such enables the development of future EUV photoresists.

Menstrual health and hygiene knowledge among post menarche adolescent school girls in urban and rural Tanzania.

Adolescent girls' capacity to lead healthy lives and perform well in school has been hampered by their lack of awareness about menstruation and the requirements for its hygienic management. Lack of enabling infrastructure, improper menstrual supplies, and limited socioeconomic support for good menstrual health and cleanliness are characteristics of schools in Africa South of the Sahara. We evaluated school-age girls' knowledge of menstrual hygiene and identified bottlenecks that could affect policy and programming for menstrual health and hygiene. A school-based cross-sectional study involved 8,012 adolescent school girls in the age group of 11-18 years (mean age = 14.9 years). The study evaluated students' knowledge of menstrual health and hygiene (MHH) from the viewpoints of schools and communities using a combination of qualitative and quantitative approaches. Data was collected using self-administered surveys, focus group discussions, in-depth interviews, and site observations. Girls' older age (AOR = 1.62, P 0.001), having a female guardian (AOR = 1.39: P = 001), and having a parent in a formal job (AOR = 1.03: P 0.023) were positively associated with Menstrual health and Hygiene Knowledge. MHH knowledge levels varied significantly between girls attending government (53.3) and non-government schools (50.5%, P = 0.0001), although they were comparable for girls attending rural and urban schools. Only 21% of the study's schools had at least one instructor who had received training in MHH instruction for students. We have established that the majority of adolescent girls in schools have inadequate knowledge on menstrual health and hygiene, and that school teachers lack the skills to prepare and support young adolescents as they transition into puberty. Concerted actions aimed at building supportive policy are paramount, for school-aged teenagers to learn about and reap the long-term advantages of good menstrual health practices.

Efficient and reproducible generation of human iPSC-derived cardiomyocytes using a stirred bioreactor.

In the last decade human iPSC-derived cardiomyocytes (hiPSC-CMs) proved to be valuable for cardiac disease modeling and cardiac regeneration, yet challenges with scale, quality, inter-batch consistency, and cryopreservation remain, reducing experimental reproducibility and limiting clinical translation. Here, we report a robust cardiac differentiation protocol that uses Wnt modulation and a stirred suspension bioreactor to produce on average 124 million hiPSC-CMs with >90% purity using a variety of hiPSC lines (19 differentiations; 10 iPSC lines). After controlled freeze and thaw, bioreactor-derived CMs (bCMs) showed high viability (>90%), interbatch reproducibility in cellular morphology, function, drug response and ventricular identity, which was further supported by single cell transcriptomes. bCMs on microcontact printed substrates revealed a higher degree of sarcomere maturation and viability during long-term culture compared to monolayer-derived CMs (mCMs). Moreover, functional investigation of bCMs in 3D engineered heart tissues showed earlier and stronger force production during long-term culture, and robust pacing capture up to 4 Hz when compared to mCMs. bCMs derived from this differentiation protocol will expand the applications of hiPSC-CMs by providing a reproducible, scalable, and resource efficient method to generate cardiac cells with well-characterized structural and functional properties superior to standard mCMs.

The clinical effectiveness of a self-management intervention for patients with persistent depressive disorder and their partners/caregivers: results from a multicenter, pragmatic randomized controlled trial.

BACKGROUND: Persistent depressive disorder (PDD) is prevalent and debilitating. For patients with PDD, psychiatric rehabilitation using self-management interventions is advised as the next therapeutic step after multiple unsuccessful treatment attempts. The "Patient and Partner Education Program for All Chronic Diseases" (PPEP4All) is a brief, structured self-management program that focuses on functional recovery for patients and their partners/caregivers. In chronic somatic disorder populations, PPEP4All has already been shown to be clinically effective. We examined whether PPEP4All adapted for PDD (PPEP4All-PDD, nine weekly group or individual sessions) is also clinically effective for adults/elderly with PDD and their partners/caregivers compared to care-as-usual (CAU) in specialized mental healthcare. METHODS: In this mixed-method multicenter pragmatic randomized controlled trial, 70 patients with PDD and 14 partners/caregivers were allocated to either PPEP4All-PDD (patients, n = 37; partners/caregivers, n = 14) or CAU (patients, n = 33; partners/caregivers, not included) and completed questionnaires at 0, 3, 6, and 12 months regarding depressive symptoms, psychopathology, psychosocial burden, mental resilience, and happiness/well-being. Qualitative data were collected regarding treatment satisfaction. Data were analyzed using mixed model analyses and an intention-to-treat (ITT) approach. RESULTS: There was no statistically significant difference in any outcome regarding clinical effectiveness between PPEP4All-PDD and CAU. Subgroup analysis for depressive symptoms did not show any interaction effect for any subgroup. Although 78% of participants recommended PPEP4All-PDD, there was no difference in treatment satisfaction between PPEP4All-PDD (score = 6.6; SD = 1.7) and CAU (score = 7.6; SD = 1.2), p = 0.06. CONCLUSION: Although depressive symptoms did not improve relative to CAU, this only confirmed that treatment for patients with treatment-resistant PDD should move from symptom reduction to functional recovery. Also, functional recovery may be reflected in other outcomes than psychosocial burden, such as self-empowerment, in patients with treatment-resistant PDD. Future research on PPEP4All-PDD could focus on a longer-term program and/or online program that may also be offered earlier in the treatment process as an empowerment intervention.  TRIAL REGISTRATION: Netherlands Trial Register Identifier NL5818. Registered on 20 July 2016 https://clinicaltrialregister.nl/nl/trial/20302.

Mitochondrial Raf1 Regulates Glutamine Catabolism.

Raf kinases play vital roles in normal mitogenic signaling and cancer, however, the identities of functionally important Raf-proximal proteins throughout the cell are not fully known. Raf1 proximity proteomics/BioID in Raf1-dependent cancer cells unexpectedly identified Raf1-adjacent proteins known to reside in the mitochondrial matrix. Inner-mitochondrial localization of Raf1 was confirmed by mitochondrial purification and super-resolution microscopy. Inside mitochondria, Raf1 associated with glutaminase (GLS) in diverse human cancers and enabled glutaminolysis, an important source of biosynthetic precursors in cancer. These impacts required Raf1 kinase activity and were independent of canonical MAP kinase pathway signaling. Kinase-dead mitochondrial matrix-localized Raf1 impaired glutaminolysis and tumorigenesis in vivo. These data indicate that Raf1 localizes inside mitochondria where it interacts with GLS to engage glutamine catabolism and support tumorigenesis.

Health and environmental effects to wildlife from radio telemetry and tracking devices-state of the science and best management practices.

This paper discusses the potential health risks and benefits to tagged wildlife from the use of radio tracking, radio telemetry, and related microchip and data-logger technologies used to study, monitor and track mostly wildlife in their native habitats. Domestic pets, especially canids, are briefly discussed as radio-tagging devices are also used on/in them. Radio tracking uses very high frequency (VHF), ultra-high frequency (UHF), and global positioning system (GPS) technologies, including via satellites where platform terminal transmitters (PTTs) are used, as well as geo-locating capabilities using satellites, radio-frequency identification (RFID) chips, and passive integrated responder (PIT) tags, among others. Such tracking technologies have resulted in cutting-edge findings worldwide that have served to protect and better understand the behaviors of myriad wildlife species. As a result, scientists, field researchers, technicians, fish and wildlife biologists and managers, plus wildlife and other veterinarian specialists, frequently opt for its use without fully understanding the ramifications to target species and their behaviors. These include negative physiological effects from electromagnetic fields (EMF) to which many nonhuman species are exquisitely sensitive, as well as direct placement/use-attachment impacts from radio collars, transmitters, and implants themselves. This paper provides pertinent studies, suggests best management practices, and compares technologies currently available to those considering and/or using such technologies. The primary focus is on the health and environmental risk/benefit decisions that should come into play, including ethical considerations, along with recommendations for more caution in the wildlife and veterinarian communities before such technologies are used in the first place.

The Impact of Environmental Benzene, Toluene, Ethylbenzene, and Xylene Exposure on Blood-Based DNA Methylation Profiles in Pregnant African American Women from Detroit.

African American women in the United States have a high risk of adverse pregnancy outcomes. DNA methylation is a potential mechanism by which exposure to BTEX (benzene, toluene, ethylbenzene, and xylenes) may cause adverse pregnancy outcomes. Data are from the Maternal Stress Study, which recruited African American women in the second trimester of pregnancy from February 2009 to June 2010. DNA methylation was measured in archived DNA from venous blood collected in the second trimester. Trimester-specific exposure to airshed BTEX was estimated using maternal self-reported addresses and geospatial models of ambient air pollution developed as part of the Geospatial Determinants of Health Outcomes Consortium. Among the 64 women with exposure and outcome data available, 46 differentially methylated regions (DMRs) were associated with BTEX exposure (FDR adjusted p-value < 0.05) using a DMR-based epigenome-wide association study approach. Overall, 89% of DMRs consistently exhibited hypomethylation with increasing BTEX exposure. Biological pathway analysis identified 11 enriched pathways, with the top 3 involving gamma-aminobutyric acid receptor signaling, oxytocin in brain signaling, and the gustation pathway. These findings highlight the potential impact of BTEX on DNA methylation in pregnant women.

Jail Characteristics and Availability of Opioid Treatment Services: Results from a Nationally Representative Survey.

The current wave of the opioid epidemic has contributed to a record number of drug-related overdoses and a significant proportion of people who experience opioid use disorder are admitted to local jails. These correctional facilities serve as the principal entry point to the criminal justice system as nearly every person who is taken into custody is admitted to a local detention center. Although jails are recognized as primary intervention points for people who may require treatment for opioid use disorder, services in these facilities remain deficient. The absence of jail-based treatment has become a pressing concern as the number of drug-related deaths in custody continues to rise and the risk of post-release overdose also remains high. The present study draws on the opioid-related module of the 2019 Bureau of Justice Statistics' Census of Jails to assess the relationships between the characteristics of 2588 local detention centers and the availability of treatment services. These specific approaches included screening for opioid use disorder, providing medication to manage withdrawal symptoms, administering medication for opioid use disorder (MOUD), providing overdose reversal medication at the time of release, and linking people with community-based care following release from the detention center. The results demonstrate facilities located in the Northeast, larger jails, those in urban areas, and detention centers with higher turnover rates are significantly more likely to provide a wider variety of opioid treatment services. These findings have important implications for the prioritization of policies and the allocation of resources to support the adoption of opioid treatment services in local jails.

Cancer immunity by tissue-resident type 1 innate lymphoid cells and killer innate-like T cells.

Cancer progression can be restrained by tumor-infiltrating lymphocytes in a process termed cancer immunosurveillance. Based on how lymphocytes are activated and recruited to the tumor tissue, cancer immunity is either pre-wired, in which innate lymphocytes and innate-like T cells are directly recruited to and activated in tumors following their differentiation in primary lymphoid organs; or priming-dependent, in which conventional adaptive T cells are first primed by cognate antigens in secondary lymphoid organs before homing to and reactivated in tumors. While priming-dependent cancer immunity has been a focus of cancer immunology research for decades, in part due to historical preconception of cancer theory and tumor model choice as well as clinical success of conventional adaptive T cell-directed therapeutic programs, recent studies have revealed that pre-wired cancer immunity mediated by tissue-resident type 1 innate lymphoid cells (ILC1s) and killer innate-like T cells (ILTCKs) is an integral component of the cancer immunosurveillance process. Herein we review the distinct ontogenies and cancer-sensing mechanisms of ILC1s and ILTCKs in murine genetic cancer models as well as the conspicuously conserved responses in human malignancies. How ILC1s and ILTCKs may be targeted to broaden the scope of cancer immunotherapy beyond conventional adaptive T cells is also discussed.

Mitochondrial uncoupler and retinoic acid synergistically induce differentiation and inhibit proliferation in neuroblastoma.

Neuroblastoma is a leading cause of death in childhood cancer cases. Unlike adult malignancies, which typically develop from aged cells through accumulated damage and mutagenesis, neuroblastoma originates from neural crest cells with disrupted differentiation. This distinct feature provides novel therapeutic opportunities beyond conventional cytotoxic methods. Previously, we reported that the mitochondrial uncoupler NEN (niclosamide ethanolamine) activated mitochondria respiration to reprogram the epigenome, promoting neuronal differentiation. In the current study, we further combine NEN with retinoic acid (RA) to promote neural differentiation both in vitro and in vivo. The treatment increased the expression of RA signaling and neuron differentiation-related genes, resulting in a global shift in the transcriptome towards a more favorable prognosis. Overall, these results suggest that the combination of a mitochondrial uncoupler and the differentiation agent RA is a promising therapeutic strategy for neuroblastoma.