Addressing substance abuse and violence in substance use disorder treatment and batterer intervention programs

Background Substance use disorders and perpetration of intimate partner violence (IPV) are interrelated, major public health problems. Methods We surveyed directors of a sample of substance use disorder treatment programs (SUDPs; N=241) and batterer intervention programs (BIPs; N=235) in California (70% response rate) to examine the extent to which SUDPs address IPV, and BIPs address substance abuse. Results Generally, SUDPs were not addressing co-occurring IPV perpetration in a formal and comprehensive way. Few had a policy requiring assessment of potential clients, or monitoring of admitted clients, for violence perpetration; almost one-quarter did not admit potential clients who had perpetrated IPV, and only 20% had a component or track to address violence. About one-third suspended or terminated clients engaging in violence. The most common barriers to SUDPs providing IPV services were that violence prevention was not part of the program’s mission, staff lacked training in violence, and the lack of reimbursement mechanisms for such services. In contrast, BIPs tended to address substance abuse in a more formal and comprehensive way; e.g., one-half had a policy requiring potential clients to be assessed, two-thirds required monitoring of substance abuse among admitted clients, and almost one-half had a component or track to address substance abuse. SUDPs had clients with fewer resources (marriage, employment, income, housing), and more severe problems (both alcohol and drug use disorders, dual substance use and other mental health disorders, HIV + status). We found little evidence that services are centralized for individuals with both substance abuse and violence problems, even though most SUDP and BIP directors agreed that help for both problems should be obtained simultaneously in separate programs. Conclusions SUDPs may have difficulty addressing violence because they have a clientele with relatively few resources and more complex psychological and medical needs. However, policy change can modify barriers to treatment integration and service linkage, such as reimbursement restrictions and lack of staff training

Activation of the innate immune receptor Dectin-1 upon formation of a 'phagocytic synapse'.

Innate immune cells must be able to distinguish between direct binding to microbes and detection of components shed from the surface of microbes located at a distance. Dectin-1 (also known as CLEC7A) is a pattern-recognition receptor expressed by myeloid phagocytes (macrophages, dendritic cells and neutrophils) that detects β-glucans in fungal cell walls and triggers direct cellular antimicrobial activity, including phagocytosis and production of reactive oxygen species (ROS). In contrast to inflammatory responses stimulated upon detection of soluble ligands by other pattern-recognition receptors, such as Toll-like receptors (TLRs), these responses are only useful when a cell comes into direct contact with a microbe and must not be spuriously activated by soluble stimuli. In this study we show that, despite its ability to bind both soluble and particulate β-glucan polymers, Dectin-1 signalling is only activated by particulate β-glucans, which cluster the receptor in synapse-like structures from which regulatory tyrosine phosphatases CD45 and CD148 (also known as PTPRC and PTPRJ, respectively) are excluded (Supplementary Fig. 1). The 'phagocytic synapse' now provides a model mechanism by which innate immune receptors can distinguish direct microbial contact from detection of microbes at a distance, thereby initiating direct cellular antimicrobial responses only when they are required

Impact of vaccination and non-pharmacological interventions on COVID-19: a review of simulation modeling studies in Asia

IntroductionEpidemiological modeling is widely used to offer insights into the COVID-19 pandemic situation in Asia. We reviewed published computational (mathematical/simulation) models conducted in Asia that assessed impacts of pharmacological and non-pharmacological interventions against COVID-19 and their implications for vaccination strategy.MethodsA search of the PubMed database for peer-reviewed, published, and accessible articles in English was performed up to November 2022 to capture studies in Asian populations based on computational modeling of outcomes in the COVID-19 pandemic. Extracted data included model type (mechanistic compartmental/agent-based, statistical, both), intervention type (pharmacological, non-pharmacological), and procedures for parameterizing age. Findings are summarized with descriptive statistics and discussed in terms of the evolving COVID-19 situation.ResultsThe literature search identified 378 results, of which 59 met criteria for data extraction. China, Japan, and South Korea accounted for approximately half of studies, with fewer from South and South-East Asia. Mechanistic models were most common, either compartmental (61.0%), agent-based (1.7%), or combination (18.6%) models. Statistical modeling was applied less frequently (11.9%). Pharmacological interventions were examined in 59.3% of studies, and most considered vaccination, except one study of an antiviral treatment. Non-pharmacological interventions were also considered in 84.7% of studies. Infection, hospitalization, and mortality were outcomes in 91.5%, 30.5%, and 30.5% of studies, respectively. Approximately a third of studies accounted for age, including 10 that also examined mortality. Four of these studies emphasized benefits in terms of mortality from prioritizing older adults for vaccination under conditions of a limited supply; however, one study noted potential benefits to infection rates from early vaccination of younger adults. Few studies (5.1%) considered the impact of vaccination among children.ConclusionEarly in the COVID-19 pandemic, non-pharmacological interventions helped to mitigate the health burden of COVID-19; however, modeling indicates that high population coverage of effective vaccines will complement and reduce reliance on such interventions. Thus, increasing and maintaining immunity levels in populations through regular booster shots, particularly among at-risk and vulnerable groups, including older adults, might help to protect public health. Future modeling efforts should consider new vaccines and alternative therapies alongside an evolving virus in populations with varied vaccination histories

A Single-Arm, Proof-Of-Concept Trial of Lopimune (Lopinavir/Ritonavir) as a Treatment for HPV-Related Pre-Invasive Cervical Disease

BACKGROUND: Cervical cancer is the most common female malignancy in the developing nations and the third most common cancer in women globally. An effective, inexpensive and self-applied topical treatment would be an ideal solution for treatment of screen-detected, pre-invasive cervical disease in low resource settings. METHODS: Between 01/03/2013 and 01/08/2013, women attending Kenyatta National Hospital's Family Planning and Gynaecology Outpatients clinics were tested for HIV, HPV (Cervista®) and liquid based cervical cytology (LBC -ThinPrep®). HIV negative women diagnosed as high-risk HPV positive with high grade squamous intraepithelial lesions (HSIL) were examined by colposcopy and given a 2 week course of 1 capsule of Lopimune (CIPLA) twice daily, to be self-applied as a vaginal pessary. Colposcopy, HPV testing and LBC were repeated at 4 and 12 weeks post-start of treatment with a final punch biopsy at 3 months for histology. Primary outcome measures were acceptability of treatment with efficacy as a secondary consideration. RESULTS: A total of 23 women with HSIL were treated with Lopimune during which time no adverse reactions were reported. A maximum concentration of 10 ng/ml of lopinavir was detected in patient plasma 1 week after starting treatment. HPV was no longer detected in 12/23 (52.2%, 95%CI: 30.6-73.2%). Post-treatment cytology at 12 weeks on women with HSIL, showed 14/22 (63.6%, 95%CI: 40.6-82.8%) had no dysplasia and 4/22 (18.2%, 95%CI: 9.9-65.1%) were now low grade demonstrating a combined positive response in 81.8% of women of which 77.8% was confirmed by histology. These data are supported by colposcopic images, which show regression of cervical lesions. CONCLUSIONS: These results demonstrate the potential of Lopimune as a self-applied therapy for HPV infection and related cervical lesions. Since there were no serious adverse events or detectable post-treatment morbidity, this study indicates that further trials are clearly justified to define optimal regimes and the overall benefit of this therapy. TRIAL REGISTRATION: ISRCTN Registry 48776874

RNA polymerase II stalling promotes nucleosome occlusion and pTEFb recruitment to drive immortalization by Epstein-Barr virus

Epstein-Barr virus (EBV) immortalizes resting B-cells and is a key etiologic agent in the development of numerous cancers. The essential EBV-encoded protein EBNA 2 activates the viral C promoter (Cp) producing a message of ~120 kb that is differentially spliced to encode all EBNAs required for immortalization. We have previously shown that EBNA 2-activated transcription is dependent on the activity of the RNA polymerase II (pol II) C-terminal domain (CTD) kinase pTEFb (CDK9/cyclin T1). We now demonstrate that Cp, in contrast to two shorter EBNA 2-activated viral genes (LMP 1 and 2A), displays high levels of promoter-proximally stalled pol II despite being constitutively active. Consistent with pol II stalling, we detect considerable pausing complex (NELF/DSIF) association with Cp. Significantly, we observe substantial Cp-specific pTEFb recruitment that stimulates high-level pol II CTD serine 2 phosphorylation at distal regions (up to +75 kb), promoting elongation. We reveal that Cp-specific pol II accumulation is directed by DNA sequences unfavourable for nucleosome assembly that increase TBP access and pol II recruitment. Stalled pol II then maintains Cp nucleosome depletion. Our data indicate that pTEFb is recruited to Cp by the bromodomain protein Brd4, with polymerase stalling facilitating stable association of pTEFb. The Brd4 inhibitor JQ1 and the pTEFb inhibitors DRB and Flavopiridol significantly reduce Cp, but not LMP1 transcript production indicating that Brd4 and pTEFb are required for Cp transcription. Taken together our data indicate that pol II stalling at Cp promotes transcription of essential immortalizing genes during EBV infection by (i) preventing promoter-proximal nucleosome assembly and ii) necessitating the recruitment of pTEFb thereby maintaining serine 2 CTD phosphorylation at distal regions

A proposal for a coordinated effort for the determination of brainwide neuroanatomical connectivity in model organisms at a mesoscopic scale

In this era of complete genomes, our knowledge of neuroanatomical circuitry remains surprisingly sparse. Such knowledge is however critical both for basic and clinical research into brain function. Here we advocate for a concerted effort to fill this gap, through systematic, experimental mapping of neural circuits at a mesoscopic scale of resolution suitable for comprehensive, brain-wide coverage, using injections of tracers or viral vectors. We detail the scientific and medical rationale and briefly review existing knowledge and experimental techniques. We define a set of desiderata, including brain-wide coverage; validated and extensible experimental techniques suitable for standardization and automation; centralized, open access data repository; compatibility with existing resources, and tractability with current informatics technology. We discuss a hypothetical but tractable plan for mouse, additional efforts for the macaque, and technique development for human. We estimate that the mouse connectivity project could be completed within five years with a comparatively modest budget.Comment: 41 page

In-shoe plantar shear stress sensor design, calibration and evaluation for the diabetic foot

Plantar shear stress may have an important role in the formation of a Diabetic Foot Ulcer, but its measurement is regarded as challenging and has limited research. This paper highlights the importance of anatomical specific shear sensor calibration and presents a feasibility study of a novel shear sensing system which has measured in-shoe shear stress from gait activity on both healthy and diabetic subjects. The sensing insole was based on a strain gauge array embedded in a silicone insole backed with a commercial normal pressure sensor. Sensor calibration factors were investigated using a custom mechanical test rig with indenter to exert both normal and shear forces. Indenter size and location were varied to investigate the importance of both loading area and position on measurement accuracy. The sensing insole, coupled with the calibration procedure, was tested one participant with diabetes and one healthy participant during two sessions of 15 minutes of treadmill walking. Calibration with different indenter areas (from 78.5 mm2 to 707 mm2) and different positions (up to 40 mm from sensor centre) showed variation in measurements of up to 80% and 90% respectively. Shear sensing results demonstrated high repeatability (>97%) and good accuracy (mean absolute error < ±18 kPa) in bench top mechanical tests and less than 21% variability within walking of 15-minutes duration. The results indicate the importance of mechanical coupling between embedded shear sensors and insole materials. It also highlights the importance of using an appropriate calibration method to ensure accurate shear stress measurement. The novel shear stress measurement system presented in this paper, demonstrates a viable method to measure accurate and repeatable in-shoe shear stress using the calibration procedure described. The validation and calibration methods outlined in this paper could be utilised as a standardised approach for the research community to develop and validate similar measurement technologies

CLO: The cell line ontology

Abstract Background Cell lines have been widely used in biomedical research. The community-based Cell Line Ontology (CLO) is a member of the OBO Foundry library that covers the domain of cell lines. Since its publication two years ago, significant updates have been made, including new groups joining the CLO consortium, new cell line cells, upper level alignment with the Cell Ontology (CL) and the Ontology for Biomedical Investigation, and logical extensions. Construction and content Collaboration among the CLO, CL, and OBI has established consensus definitions of cell line-specific terms such as ‘cell line’, ‘cell line cell’, ‘cell line culturing’, and ‘mortal’ vs. ‘immortal cell line cell’. A cell line is a genetically stable cultured cell population that contains individual cell line cells. The hierarchical structure of the CLO is built based on the hierarchy of the in vivo cell types defined in CL and tissue types (from which cell line cells are derived) defined in the UBERON cross-species anatomy ontology. The new hierarchical structure makes it easier to browse, query, and perform automated classification. We have recently added classes representing more than 2,000 cell line cells from the RIKEN BRC Cell Bank to CLO. Overall, the CLO now contains ~38,000 classes of specific cell line cells derived from over 200 in vivo cell types from various organisms. Utility and discussion The CLO has been applied to different biomedical research studies. Example case studies include annotation and analysis of EBI ArrayExpress data, bioassays, and host-vaccine/pathogen interaction. CLO’s utility goes beyond a catalogue of cell line types. The alignment of the CLO with related ontologies combined with the use of ontological reasoners will support sophisticated inferencing to advance translational informatics development.http://deepblue.lib.umich.edu/bitstream/2027.42/109554/1/13326_2013_Article_185.pd