Adult Pneumococcal Vaccination in Ghana: Current Status and Future Recommendations - Expert Opinion.

Vaccination programs have proven successful in the prevention and control of infectious diseases among children on a global scale, but the majority of adult populations remain unvaccinated. immunocompromised adults as well as older adults aged low-income countries as Streptococcus pneumoniae infections are associated with substantial morbidity and mortality among 65 years and above. Despite the introduction of pneumococcal conjugate vaccines (PCVs), the burden of vaccine-type serotypes remains high in there are no clear policies for adult vaccination. As per the Global Burden of Disease 2019 report, about 120,000 individuals aged 70 years and older died as a result of LRTIs) in sub-Saharan Africa. A medical advisory board meeting was conducted in April 2022 to discuss the burden of pneumococcal diseases in adults, the current status of policies and practices of adult vaccination, unmet needs, and challenges in Ghana. This expert opinion paper outlines the pneumococcal epidemiology and burden of disease in Ghana, as well as the rationale for adult pneumococcal vaccination. It also highlights the potential barriers to adult vaccination and offers recommendations to overcome these obstacles and enhance vaccine acceptance in Ghana.

Les programmes de vaccination ont prouvé leur succès dans la prévention et le contrôle des maladies infectieuses chez les enfants à l'échelle mondiale, mais la majorité des populations adultes restent non vaccinées. Les infections à Streptococcus pneumoniae sont associées à une morbidité et une mortalité substantielles chez les adultes immunodéprimés ainsi que chez les personnes âgées de 65 ans et plus. Malgré l'introduction des vaccins conjugués contre le pneumocoque (VCP), la charge des sérotypes vaccinaux reste élevée dans les pays à faible revenu car il n'existe pas de politiques claires en matière de vaccination des adultes. Selon le rapport sur la charge mondiale de morbidité de 2019, environ 120 000 personnes âgées de 70 ans et plus sont décédées des suites d'infections des voies respiratoires inférieures (IVRI) en Afrique subsaharienne. Une réunion du conseil consultatif médical a eu lieu en avril 2022 pour discuter du fardeau des maladies pneumococciques chez les adultes, de l'état actuel des politiques et pratiques de vaccination des adultes, des besoins non satisfaits et des défis au Ghana. Cet article d'opinion d'experts présente l'épidémiologie pneumococcique et le fardeau de la maladie au Ghana, ainsi que les arguments en faveur de la vaccination pneumococcique des adultes. Il met également en lumière les obstacles potentiels à la vaccination des adultes et propose des recommandations pour surmonter ces obstacles et améliorer l'acceptation des vaccins au Ghana. MOTS-CLÉS: Maladie pneumococcique, Fardeau de la maladie, Vaccin conjugué contre le pneumocoque, Vaccination des adultes, Streptococcus pneumoniae, Ghana, Défis de la vaccination, Immunisation des adultes, VCP-13, Pneumonie acquise en communauté.

Implementation of systematic screening for tuberculosis disease and tuberculosis preventive treatment among people living with HIV attending antiretroviral treatment clinics in Ghana: a national pilot study.

OBJECTIVES: To assess the yield and cost of implementing systematic screening for tuberculosis (TB) disease among people living with HIV (PLHIV) and initiation of TB preventive treatment (TPT) in Ghana. DESIGN: Prospective cohort study from August 2019 to December 2020. SETTING: One hospital from each of Ghana's regions (10 total). PARTICIPANTS: Any PLHIV already receiving or newly initiating antiretroviral treatment were eligible for inclusion. INTERVENTIONS: All participants received TB symptom screening and chest radiography. Those with symptoms and/or an abnormal chest X-ray provided a sputum sample for microbiological testing. All without TB disease were offered TPT. PRIMARY AND SECONDARY OUTCOME MEASURES: We estimated the proportion diagnosed with TB disease and proportion initiating TPT. We used logistic regression to identify factors associated with TB disease diagnosis. We used microcosting to estimate the health system cost per person screened (2020 US$). RESULTS: Of 12 916 PLHIV attending participating clinics, 2639 (20%) were enrolled in the study and screened for TB disease. Overall, 341/2639 (12.9%, 95% CI 11.7% to 14.3%) had TB symptoms and/or an abnormal chest X-ray; 50/2639 (1.9%; 95% CI 1.4% to 2.5%) were diagnosed with TB disease, 20% of which was subclinical. In multivariable analysis, only those newly initiating antiretroviral treatment were at increased odds of TB disease (adjusted OR 4.1, 95% CI 2.0 to 8.2). Among 2589 participants without TB, 2581/2589 (99.7%) initiated TPT. Overall, the average cost per person screened during the study was US$57.32. CONCLUSION: In Ghana, systematic TB disease screening among PLHIV was of high yield and modest cost when combined with TPT. Our findings support WHO recommendations for routine TB disease screening among PLHIV.

Viral reprogramming of host transcription initiation.

Viruses are master remodelers of the host cell environment in support of infection and virus production. For example, viruses typically regulate cell gene expression through modulating canonical cell promoter activity. Here, we show that Epstein Barr virus (EBV) replication causes 'de novo' transcription initiation at 29674 new transcription start sites throughout the cell genome. De novo transcription initiation is facilitated in part by the unique properties of the viral pre-initiation complex (vPIC) that binds a TATT[T/A]AA, TATA box-like sequence and activates transcription with minimal support by additional transcription factors. Other de novo promoters are driven by the viral transcription factors, Zta and Rta and are influenced by directional proximity to existing canonical cell promoters, a configuration that fosters transcription through existing promoters and transcriptional interference. These studies reveal a new way that viruses interact with the host transcriptome to inhibit host gene expression and they shed light on primal features driving eukaryotic promoter function.

Prevention of Equinus Deformity after External Fixation for Open Tibia Fractures: A Comparison between Plaster of Paris Backslab and Passive Ankle Physiotherapy.

Background: Ankle equinus deformity is a common complication of prolonged external fixator use in tibia fractures with an incidence of 15%-16%. It affects gait and may lead to foot, leg, and back problems. Treatment of equinus deformity increases the cost of treatment of open tibia fractures and increases the time spent off work. Several preventive modalities have been suggested in literature with variable success, but no standard protocol exists. Objectives: The aim of this study was to determine the most appropriate method of preventing equinus deformity of the ankle joint during the management of open tibia fractures with unilateral uniplanar external fixators by comparing plaster of paris (POP) backslab application with passive ankle physiotherapy using strips of car tyre inner tubing. Materials and Methods: The study was a prospective randomised study involving patients with open tibia fractures who were managed with external fixators at the Korle Bu Teaching Hospital between April 2020 and February 2021. Patients were randomised into two groups; one group had below knee POP backslab and the other group did passive ankle physiotherapy using a strip of car tyre inner tubing. The passive ankle range of motion was measured at the beginning and after 6 weeks using a goniometer. Results: Fifty-six participants were recruited with 29 in the POP backslab group and 27 in the ankle physiotherapy group. The median age was 35.0 years. Male-to-female ratio was 4.6:1. Motor vehicle crash contributed to over 90% with 42.9% being motorbike riders. Initial and final mean ankle measurements for the POP backslab group were 6.79° and 10.14° for dorsiflexion and 29.93° and 34.52° for plantarflexion, respectively. The ankle physiotherapy group had initial and final dorsiflexion of 7.19° and 12.85° and plantarflexion of 30.44° and 34.52°, respectively. The ankle physiotherapy group had a better range of motion (47.37°) than the POP group (40.66°) with a P value of 0.008. One participant (3.7%) from the ankle physiotherapy group had equinus deformity compared with seven (24%) from the POP backslab group, a difference which gives a P value of 0.029. Conclusions: Passive ankle physiotherapy with car tyre inner tube is a better and cheaper modality of preventing ankle equinus deformity and maintaining ankle range of motion.

Transcriptomic analysis identifies B-lymphocyte kinase as a therapeutic target for desmoplastic small round cell tumor cancer stem cell-like cells.

Desmoplastic small round cell tumor (DSRCT) is an aggressive pediatric cancer caused by the EWSR1-WT1 fusion oncoprotein. The tumor is refractory to treatment with a 5-year survival rate of only 15-25%, necessitating the development of novel therapeutics, especially those able to target chemoresistant subpopulations. Novel in vitro cancer stem cell-like (CSC-like) culture conditions increase the expression of stemness markers (SOX2, NANOG) and reduce DSRCT cell line susceptibility to chemotherapy while maintaining the ability of DSRCT cells to form xenografts. To gain insights into this chemoresistant model, RNA-seq was performed to elucidate transcriptional alterations between DSRCT cells grown in CSC-like spheres and normal 2-dimensional adherent state. Commonly upregulated and downregulated genes were identified and utilized in pathway analysis revealing upregulation of pathways related to chromatin assembly and disassembly and downregulation of pathways including cell junction assembly and extracellular matrix organization. Alterations in chromatin assembly suggest a role for epigenetics in the DSRCT CSC-like state, which was further investigated with ATAC-seq, identifying over 10,000 differentially accessible peaks, including 4444 sphere accessible peaks and 6,120 adherent accessible peaks. Accessible regions were associated with higher gene expression, including increased accessibility of the CSC marker SOX2 in CSC-like culture conditions. These analyses were further utilized to identify potential CSC therapeutic targets, leading to the identification of B-lymphocyte kinase (BLK) as a CSC-enriched, EWSR1-WT1-regulated, druggable target. BLK inhibition and knockdown reduced CSC-like properties, including abrogation of tumorsphere formation and stemness marker expression. Importantly, BLK knockdown reduced DSRCT CSC-like cell chemoresistance, making its inhibition a promising target for future combination therapy.

Loss of feedback regulation between FAM3B and androgen receptor driving prostate cancer progression.

BACKGROUND: Although the fusion of the transmembrane serine protease 2 gene (TMPRSS2) with the erythroblast transformation-specific-related gene (ERG), or TMPRSS2-ERG, occurs frequently in prostate cancer, its impact on clinical outcomes remains controversial. Roughly half of TMPRSS2-ERG fusions occur through intrachromosomal deletion of interstitial genes and the remainder via insertional chromosomal rearrangements. Because prostate cancers with deletion-derived TMPRSS2-ERG fusions are more aggressive than those with insertional fusions, we investigated the impact of interstitial gene loss on prostate cancer progression. METHODS: We conducted an unbiased analysis of transcriptome data from large collections of prostate cancer samples and employed diverse in vitro and in vivo models combined with genetic approaches to characterize the interstitial gene loss that imposes the most important impact on clinical outcome. RESULTS: This analysis identified FAM3B as the top-ranked interstitial gene whose loss is associated with a poor prognosis. The association between FAM3B loss and poor clinical outcome extended to fusion-negative prostate cancers where FAM3B downregulation occurred through epigenetic imprinting. Importantly, FAM3B loss drives disease progression in prostate cancer. FAM3B acts as an intermediator of a self-governing androgen receptor feedback loop. Specifically, androgen receptor upregulates FAM3B expression by binding to an intronic enhancer to induce an enhancer RNA and facilitate enhancer-promoter looping. FAM3B, in turn, attenuates androgen receptor signaling. CONCLUSION: Loss of FAM3B in prostate cancer, whether through the TMPRSS2-ERG translocation or epigenetic imprinting, causes an exit from this autoregulatory loop to unleash androgen receptor activity and prostate cancer progression. These findings establish FAM3B loss as a new driver of prostate cancer progression and support the utility of FAM3B loss as a biomarker to better define aggressive prostate cancer.

Maternal Western diet programs cardiometabolic dysfunction and hypothalamic inflammation via epigenetic mechanisms predominantly in the male offspring.

OBJECTIVE: Maternal exposure during pregnancy is a strong determinant of offspring health outcomes. Such exposure induces changes in the offspring epigenome resulting in gene expression and functional changes. In this study, we investigated the effect of maternal Western hypercaloric diet (HCD) programming during the perinatal period on neuronal plasticity and cardiometabolic health in adult offspring. METHODS: C57BL/6J dams were fed HCD for 1 month prior to mating with regular diet (RD) sires and kept on the same diet throughout pregnancy and lactation. At weaning, offspring were maintained on either HCD or RD for 3 months resulting in 4 treatment groups that underwent cardiometabolic assessments. DNA and RNA were extracted from the hypothalamus to perform whole genome methylation, mRNA, and miRNA sequencing followed by bioinformatic analyses. RESULTS: Maternal programming resulted in male-specific hypertension and hyperglycemia, with both males and females showing increased sympathetic tone to the vasculature. Surprisingly, programmed male offspring fed HCD in adulthood exhibited lower glucose levels, less insulin resistance, and leptin levels compared to non-programmed HCD-fed male mice. Hypothalamic genes involved in inflammation and type 2 diabetes were targeted by differentially expressed miRNA, while genes involved in glial and astrocytic differentiation were differentially methylated in programmed male offspring. These data were supported by our findings of astrogliosis, microgliosis and increased microglial activation in programmed males in the paraventricular nucleus (PVN). Programming induced a protective effect in male mice fed HCD in adulthood, resulting in lower protein levels of hypothalamic TGFß2, NF-κB2, NF-κBp65, Ser-pIRS1, and GLP1R compared to non-programmed HCD-fed males. Although TGFß2 was upregulated in male mice exposed to HCD pre- or post-natally, only blockade of the brain TGFß receptor in RD-HCD mice improved glucose tolerance and a trend to weight loss. CONCLUSIONS: Our study shows that maternal HCD programs neuronal plasticity in the offspring and results in male-specific hypertension and hyperglycemia associated with hypothalamic inflammation in mechanisms and pathways distinct from post-natal HCD exposure. Together, our data unmask a compensatory role of HCD programming, likely via priming of metabolic pathways to handle excess nutrients in a more efficient way.

An exploratory qualitative study of the psychological effects of HIV diagnosis; the need for early involvement of mental health professionals to improve linkage to care.

BACKGROUND: Diagnosing a life-threatening disease like the human immunodeficiency virus (HIV) can be unbearable to the individual, which has implications for their subsequent care-seeking decision-making. However, an essential element of HIV testing is identifying infected individuals and linking them with adequate care services, thus contributing to the UNAIDS 95-95-95 targets. The attainment of these targets has been particularly challenging for lower and middle-income countries (LMIC). This study explored the psychological reactions to a positive HIV status in a hospital treatment centre to provide insight into mental health interventions' role in improving HIV screening and early antiretroviral therapy (ART) initiation to enhance the quality of life. METHODS: An exploratory qualitative study was investigated among adults who were diagnosed as HIV positive. Participants were purposively recruited from an HIV Treatment Centre. Data were collected with semi-structured interviews that explored the interpretations and psychological reactions to their positive HIV status. Overall, 18 participants were interviewed to reach saturation. Data were transcribed verbatim and analysed thematically to produce findings that address the study's objective. RESULTS: Following analysis of participants' interpretations, understanding and implications of their HIV-positive diagnosis, two major themes emerged: (1) anxiety regarding the impact of the disease on self, family and society was overwhelming. Participants were anxious because of the stigma, fear, worry, shock, and shame they faced. (2) Participants expressed hopelessness and could not see meaning or purpose in life. Suicidal ideation, suicide plans and self-harm characterised hopelessness. CONCLUSIONS: The initial reaction to the diagnosis of HIV in this LMIC context has the potential to impact linkage to care negatively and, thus, the attainment of the global 95-95-95 targets. It is, therefore, essential that mental health and psychological support services are integrated with testing services to manage the initial reactions and support individuals to improve early linkage to care and thus improve overall outcomes for the infected individual and society.

Pilot-wave dynamics: Using dynamic mode decomposition to characterize bifurcations, routes to chaos, and emergent statistics.

We develop a data-driven characterization of the pilot-wave hydrodynamic system in which a bouncing droplet self-propels along the surface of a vibrating bath. We consider drop motion in a confined one-dimensional geometry and apply the dynamic mode decomposition (DMD) in order to characterize the evolution of the wave field as the bath's vibrational acceleration is increased progressively. Dynamic mode decomposition provides a regression framework for adaptively learning a best-fit linear dynamics model over snapshots of spatiotemporal data. Thus, DMD reduces the complex nonlinear interactions between pilot waves and droplet to a low-dimensional linear superposition of DMD modes characterizing the wave field. In particular, it provides a low-dimensional characterization of the bifurcation structure of the pilot-wave physics, wherein the excitation and recruitment of additional modes in the linear superposition models the bifurcation sequence. This DMD characterization yields a fresh perspective on the bouncing-droplet problem that forges valuable new links with the mathematical machinery of quantum mechanics. Specifically, the analysis shows that as the vibrational acceleration is increased, the pilot-wave field undergoes a series of Hopf bifurcations that ultimately lead to a chaotic wave field. The established relation between the mean pilot-wave field and the droplet statistics allows us to characterize the evolution of the emergent statistics with increased vibrational forcing from the evolution of the pilot-wave field. We thus develop a numerical framework with the same basic structure as quantum mechanics, specifically a wave theory that predicts particle statistics.

Preoperative Intravenous Dexamethasone and Postoperative Analgesia Following Breast Surgery: A Prospective, Randomized Double-Blind Trial at a Tertiary Healthcare Facility in Ghana.

Introduction: Breast surgery may be associated with significant postoperative pain and if not adequately treated, may lead to the development of chronic post-surgical pain. This necessitates the use of effective management, involving the use a multimodal analgesia regimen for the management of post breast surgery pain. The analgesic effect of perioperative use of dexamethasone has been explored but findings have been inconsistent. Aim: The aim of this study was to determine the postoperative analgesic enhancing effect of a single preoperative dose of dexamethasone on patients undergoing breast surgery at a tertiary hospital in Ghana. Materials and Methods: This was a prospective, double-blind, placebo-controlled study involving 94 consecutively recruited patients. Patients were randomized into two groups: dexamethasone (n = 47) and placebo (n = 47). Patients in the dexamethasone group had 8mg (2 mL of 4 mg/mL) dexamethasone and those in the placebo group had 2 mL of saline administered intravenously just before induction of anaesthesia. All patients received a standard general anaesthesia with endotracheal intubation. The numerical rating score (NRS), time to first analgesic request and the total opioid consumed in the first 24 h were recorded. Results: Patients receiving dexamethasone had lower NRS scores at all measured time points but this was significant only at 8 h post-surgery (P = 0.037). The time to first rescue analgesia was significantly prolonged in the dexamethasone group (339.26 ± 312.90 min vs. 182.10 ± 166.72 min; P = 0.020). However, the mean total opioid (pethidine) consumed in the first 24 h postoperatively was not significantly different between the dexamethasone and control groups (113.75 ± 51.35 mg vs. 100.00 ± 60.93 mg; P = 0.358). Conclusion: A single preoperative dose of 8mg dexamethasone given intravenously, reduces postoperative pain compared to placebo, significantly reduces the time to first analgesia but not the total opioid consumed in the first 24 h post breast surgery.

A novel role of TRIM28 B box domain in L1 retrotransposition and ORF2p-mediated cDNA synthesis.

The long interspersed element 1 (LINE-1 or L1) integration is affected by many cellular factors through various mechanisms. Some of these factors are required for L1 amplification, while others either suppress or enhance specific steps during L1 propagation. Previously, TRIM28 has been identified to suppress transposable elements, including L1 expression via its canonical role in chromatin remodeling. Here, we report that TRIM28 through its B box domain increases L1 retrotransposition and facilitates shorter cDNA and L1 insert generation in cultured cells. Consistent with the latter, we observe that tumor specific L1 inserts are shorter in endometrial, ovarian, and prostate tumors with higher TRIM28 mRNA expression than in those with lower TRIM28 expression. We determine that three amino acids in the B box domain that are involved in TRIM28 multimerization are critical for its effect on both L1 retrotransposition and cDNA synthesis. We provide evidence that B boxes from the other two members in the Class VI TRIM proteins, TRIM24 and TRIM33, also increase L1 retrotransposition. Our findings could lead to a better understanding of the host/L1 evolutionary arms race in the germline and their interplay during tumorigenesis.

SpliceTools, a suite of downstream RNA splicing analysis tools to investigate mechanisms and impact of alternative splicing.

As a fundamental aspect of normal cell signaling and disease states, there is great interest in determining alternative splicing (AS) changes in physiologic, pathologic, and pharmacologic settings. High throughput RNA sequencing and specialized software to detect AS has greatly enhanced our ability to determine transcriptome-wide splicing changes. Despite the richness of this data, deriving meaning from sometimes thousands of AS events is a substantial bottleneck for most investigators. We present SpliceTools, a suite of data processing modules that arms investigators with the ability to quickly produce summary statistics, mechanistic insights, and functional significance of AS changes through command line or through an online user interface. Utilizing RNA-seq datasets for 186 RNA binding protein knockdowns, nonsense mediated RNA decay inhibition, and pharmacologic splicing inhibition, we illustrate the utility of SpliceTools to distinguish splicing disruption from regulated transcript isoform changes, we show the broad transcriptome footprint of the pharmacologic splicing inhibitor, indisulam, we illustrate the utility in uncovering mechanistic underpinnings of splicing inhibition, we identify predicted neo-epitopes in pharmacologic splicing inhibition, and we show the impact of splicing alterations induced by indisulam on cell cycle progression. Together, SpliceTools puts rapid and easy downstream analysis at the fingertips of any investigator studying AS.

Coping with loneliness and stigma associated with HIV in a resource-limited setting, making a case for mental health interventions; a sequential mixed methods study.

BACKGROUND: Challenges such as stigma and loneliness may increase vulnerability to Human Immunodeficiency Virus (HIV) infection and negatively affect the quality of life of people living with HIV (PLHIV) despite the massive investment in access to antiretroviral therapy. This study aims to determine the level of loneliness and stigma and explore the coping resources employed by PLHIV in a resource-constrained setting. METHODS: This was a sequential mixed methods study conducted at the Cape Coast Teaching Hospital (CCTH) in Ghana between May and December 2021. A total of 395 adults were selected using a simple random sampling technique. HIV Stigma Scale and UCLA Loneliness Scale were used to collect quantitative data. A purposive sampling technique was applied to recruit 18 participants to saturation using a semi-structured interview guide. SPSS version 21 was used for the statistical analysis of the quantitative data. HIV-related loneliness and stigma levels were estimated, and bivariate and multivariable logistic regression were used to evaluate associated factors using a statistical significance of p-value (p < .05). In general, the thematic analysis approach by Braun and Clark was employed to analyse the qualitative data. Findings were then triangulated. RESULTS: The mean age was 46.79 years (± 12.53), 75.4% of the participants were female, with a prevalence of stigma of 99.0% (95%CI = 97.4-99.7) and loneliness of 30.1% (95%CI = 25.6-34.9). Tertiary-level education and instrumental support were associated with lower levels of loneliness. In contrast, comorbidity, personalised stigma, negative self-image, and self-blame were positively related to loneliness. Thematic analyses of the qualitative data produced a range of themes that showed that people living with HIV rely on personal resources, social support networks, and behaviour modification strategies to manage their condition. In particular, some of these strategies include; religiosity and spirituality, family and friends, medication and professional support systems. CONCLUSION: The results suggest that PLHIV in the developing world face enormous challenges, socially, psychologically and financially. Although there have been global efforts to make HIV services accessible, the findings suggest a need for integrating mental health services contextually to reduce loneliness and HIV-related stigma to improve quality of life.

Metabolic pathways enriched according to ERG status are associated with biochemical recurrence in Hispanic/Latino patients with prostate cancer.

BACKGROUND: The role of ERG-status molecular subtyping in prognosis of prostate cancer (PCa) is still under debate. In this study, we identified differentially expressed genes (DEGs) according to ERG-status to explore their enriched pathways and implications in prognosis in Hispanic/Latino PCa patients. METHODS: RNA from 78 Hispanic PCa tissues from radical prostatectomies (RP) were used for RNA-sequencing. ERGhigh /ERGlow tumor groups were determined based on the 1.5-fold change median expression in non-tumor samples. DEGs with a False Discovery Rate (FDR) < 0.01 and a fold change >2 were identified between ERGhigh and ERGlow tumors and submitted to enrichment analysis in MetaCore. Survival and association analyses were performed to evaluate biochemical recurrence (BCR)-free survival. RESULTS: The identification of 150 DEGs between ERGhigh and ERGlow tumors revealed clustering of most of the non-BCR cases (60%) into de ERGhigh group and most of the BCR cases (60.8%) in ERGlow group. Kaplan-Meier survival curves showed a worst BCR-free survival for ERGlow patients, and a significant reduced risk of BCR was observed for ERGhigh cases (OR = 0.29 (95%CI, 0.10-0.8)). Enrichment pathway analysis identified metabolic-related pathways, such as the renin-angiotensin system and angiotensin maturation system, the linoleic acid metabolism, and polyamines metabolism in these ERG groups. CONCLUSIONS: ERGlow tumor cases were associated with poor BCR-free survival in our Hispanic/Latino patients, with metabolism-related pathways altered in the BCR progression. IMPACT: Our findings suggest the need to dissect the role of diet, metabolism, and lifestyle as risk factors for more aggressive PCa subtypes.

Apremilast in Recalcitrant Cutaneous Dermatomyositis: A Nonrandomized Controlled Trial.

Importance: Cutaneous disease in dermatomyositis has no standardized treatment approach and so presents a challenging task for patients and clinicians. Objective: To study the efficacy and safety of apremilast as an add-on therapy in patients with recalcitrant cutaneous dermatomyositis. Design, Setting, and Participants: This phase 2a, open-label, single-arm nonrandomized controlled trial was conducted at a single center from June 2018 to June 2021. Participants were 8 patients with recalcitrant cutaneous dermatomyositis, defined by a cutaneous disease activity severity index (CDASI) score greater than 5 despite treatment with steroids, steroid-sparing agents, or both. Data were analyzed from June 2018 to June 2021. Interventions: Apremilast 30 mg orally twice daily was added to ongoing treatment regimens. Main Outcomes and Measures: The primary outcome was the overall response rate (ORR) at 3 months. Key secondary outcomes were the safety and toxicity of apremilast and the durability of response at 6 months. The CDASI, muscle score, dermatology life quality index (DLQI), and depression assessments were performed at baseline and regularly until month 7. Skin biopsies were performed at baseline and 3 months after apremilast (defined as 3 months into active apremilast therapy) and tested for gene expression profiling and immunohistochemical stains. Adverse events were assessed using the Common Terminology Criteria for Adverse Events version 5.0. Results: Among 8 patients with recalcitrant cutaneous dermatomyositis (all women; mean [SD] age, 54 [15.9] years), a response was found at 3 months after apremilast among 7 patients (ORR, 87.5%). The mean (SD) decrease in CDASI was 12.9 (6.3) points at 3 months (P < .001). Apremilast was well tolerated, with no grade 3 or higher adverse events. Sequencing of RNA was performed on skin biopsies taken from 7 patients at baseline and at 3 months after therapy. Appropriate negative (ie, no primary antibody) and positive (ie, tonsil and spleen) controls were stained in parallel with each set of slides studied. Of 39 076 expressed genes, there were 195 whose expression changed 2-fold or more at P < .01 (123 downregulated and 72 upregulated genes). Gene set enrichment analysis identified 13 pathways in which apremilast was associated with downregulated expression, notably signal transducers and activators of transcription 1 (STAT1), STAT3, interleukin 4 (IL-4), IL-6, IL-12, IL-23, interferon γ (IFNγ), and tumor necrosis factor α (TNFα) pathways. In immunohistochemical staining, there was a mean (SD) decrease in phosphorylation levels STAT1 (22.3% [28.3%] positive cells) and STAT3 (13.4% [11.6%] positive cells) at the protein level, a downstream signaling pathway for the downregulated cytokines. Conclusions and Relevance: These findings suggest that apremilast was a safe and efficacious add-on treatment in recalcitrant dermatomyositis, with an overall response rate of 87.5% and associations with downregulation of multiple inflammatory pathways. Trial Registration: ClinicalTrials.gov Identifier: NCT03529955.

SCIFER: approach for analysis of LINE-1 mRNA expression in single cells at a single locus resolution.

BACKGROUND: Endogenous expression of L1 mRNA is the first step in an L1-initiated mutagenesis event. However, the contribution of individual cell types to patterns of organ-specific L1 mRNA expression remains poorly understood, especially at single-locus resolution. We introduce a method to quantify expression of mobile elements at the single-locus resolution in scRNA-Seq datasets called Single Cell Implementation to Find Expressed Retrotransposons (SCIFER). SCIFER aligns scRNA-Seq reads uniquely to the genome and extracts alignments from single cells by cell-specific barcodes. In contrast to the alignment performed using default parameters, this alignment strategy increases accuracy of L1 locus identification by retaining only reads that are uniquely mapped to individual L1 loci. L1 loci expressed in single cells are unambiguously identified using a list of L1 loci manually validated to be expressed in bulk RNA-Seq datasets generated from the same cell line or organ. RESULTS: Validation of SCIFER using MCF7 cells determined technical parameters needed for optimal detection of L1 expression in single cells. We show that unsupervised analysis of L1 expression in single cells exponentially inflates both the levels of L1 expression and the number of expressed L1 loci. Application of SCIFER to analysis of scRNA-Seq datasets generated from mouse and human testes identified that mouse Round Spermatids and human Spermatogonia, Spermatocytes, and Round Spermatids express the highest levels of L1 mRNA. Our analysis also determined that similar to mice, human testes from unrelated individuals share as much as 80% of expressed L1 loci. Additionally, SCIFER determined that individual mouse cells co-express different L1 sub-families and different families of transposable elements, experimentally validating their co-existence in the same cell. CONCLUSIONS: SCIFER detects mRNA expression of individual L1 loci in single cells. It is compatible with scRNA-Seq datasets prepared using traditional sequencing methods. Validated using a human cancer cell line, SCIFER analysis of mouse and human testes identified key cell types supporting L1 expression in these species. This will further our understanding of differences and similarities in endogenous L1 mRNA expression patterns in mice and humans.

Prevalence and associations of depression, anxiety, and stress among people living with HIV: A hospital-based analytical cross-sectional study.

Background and Aims: An important but much less researched burden of human immunodeficiency virus (HIV) in Sub-Saharan Africa includes the associated mental health outcomes of living with the virus. This study aimed to estimate the prevalence of depression, anxiety, and stress, and describe some of the socio-demographic associations among people living with HIV (PLHIV) in Ghana. Methods: A cross-sectional study was conducted at the Cape Coast Teaching Hospital, Ghana. Simple random sampling was used to recruit 395 PLHIV who access HIV-related services at the antiretroviral therapy clinic. The Depression, Anxiety, and Stress Scale-21 was used to assess prevalence of depression, anxiety, and stress. Frequencies and percentages were used to estimate the prevalence and multivariable logistic regression was used to evaluate sociodemographic factors associated with depression, anxiety, and stress. Results: The prevalence estimates of depression, anxiety, and stress among PLHIV were 28.6% (95% confidence interval [CI] 24.4-33.3), 40.8% (95% CI = 36.0-45.8), and 10.6% (95% CI = 7.9-14.1), respectively. Females reported higher prevalence of depression (32.2%; 95% CI = 27.2-37.7), anxiety (44.0%; 95% CI = 38.4-49.6), and stress (12.6%; 95% CI = 9.4-17.0) compared to depression (17.5%; 95% CI = 11.1-26.4), anxiety (30.9%; 95% CI = 22.5-40.7), and stress (4.1%; 95% CI = 1.2-10.4) among males. PLHIV without a regular partner were about 0.63 increased odds of experiencing anxiety compared to those with a regular partner (AOR = 0.63, 95% CI = 0.40-1.00: p = 0.049). PLHIV without formal education were about 0.49 and 0.44 increased odds to experience anxiety and stress, respectively compared to those with tertiary education. Conclusions: Generally, the levels of stress, anxiety, and depression are high among PLHIV, but disproportionately higher among females. Mental health assessment and management should be integrated into the HIV care services. There should be capacity building for health care workers to offer differentiated service delivery based on mental health care needs of PLHIV.

SDHx mutations and temozolomide in malignant pheochromocytoma and paraganglioma.

Malignant pheochromocytomas (PHEOs)/paragangliomas (PGLs) are rare tumors for which clinical outcomes remain poorly defined and therapeutic options are limited. Approximately 27% carry pathogenic germline succinate dehydrogenase (SDHx) mutations; the presence of such mutations has been correlated with response to temozolomide (TMZ). We aimed to investigate the association between germline mutations in SDHx and response to TMZ. We retrospectively identified patients with metastatic malignant PHEO/PGLs treated with TMZ- based chemotherapy at Dana-Farber Cancer Institute between 2003 and 2020. The correlation between response by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and PET Response Criteria in Solid Tumors (PERCIST) and the presence of SDHx mutations in the germline and tumor was evaluated. Nineteen patients received TMZ. Seventeen underwent germline assessment: 9 (53%) carried a pathogenic SDHx germline mutation. Fifteen patients were evaluable for response by RECIST 1.1: 6 (40%) partial response, 4 (27%) stable disease, and 5 (33%) progressive disease. Overall median progression-free survival was 2.2 years. Three-year overall survival (OS) was 58%. Median PFS was 1.3 years and 5.5 years for carriers and non-carriers, respectively and OS was 1.5 years and not estimable for carriers and non-carriers, respectively. The response by PERCIST criteria in nine patients correlated with the RECIST 1.1 assessment. Our series represents one of the largest analyses of patients with malignant PHEOs/PGLs treated with TMZ who have available germline data. The incidence of pathogenic germline SDHx mutations was similar to what has been previously published, though our analysis suggests that there may be a limited association between response to TMZ and pathogenic germline SDHx mutations.

Kernel learning for robust dynamic mode decomposition: linear and nonlinear disambiguation optimization.

Research in modern data-driven dynamical systems is typically focused on the three key challenges of high dimensionality, unknown dynamics and nonlinearity. The dynamic mode decomposition (DMD) has emerged as a cornerstone for modelling high-dimensional systems from data. However, the quality of the linear DMD model is known to be fragile with respect to strong nonlinearity, which contaminates the model estimate. By contrast, sparse identification of nonlinear dynamics learns fully nonlinear models, disambiguating the linear and nonlinear effects, but is restricted to low-dimensional systems. In this work, we present a kernel method that learns interpretable data-driven models for high-dimensional, nonlinear systems. Our method performs kernel regression on a sparse dictionary of samples that appreciably contribute to the dynamics. We show that this kernel method efficiently handles high-dimensional data and is flexible enough to incorporate partial knowledge of system physics. It is possible to recover the linear model contribution with this approach, thus separating the effects of the implicitly defined nonlinear terms. We demonstrate our approach on data from a range of nonlinear ordinary and partial differential equations. This framework can be used for many practical engineering tasks such as model order reduction, diagnostics, prediction, control and discovery of governing laws.