Development of Allosteric Small Molecule APOBEC3B Inhibitors from In Silico Screening.

APOBEC3B cytosine deaminase contributes to the mutational burdens of tumors, resulting in tumor progression and therapy resistance. Small molecule APOBEC3B inhibitors have potential to slow or mitigate these detrimental outcomes. Through molecular dynamics (MD) simulations and computational solvent mapping analysis, we identified a novel putative allosteric pocket on the C-terminal domain of APOBEC3B (A3Bctd), and virtually screened the ChemBridge Diversity Set (N~110,000) against both the active and potential allosteric sites. Selected high-scoring compounds were subsequently purchased, characterized for purity and composition, and tested in biochemical assays, which yielded 13 hit compounds. Orthogonal NMR assays verified binding to the target protein. Initial selectivity studies suggest these compounds preferentially target A3Bctd over related deaminase APOBEC3A (A3A), and MD simulations indicate this selectivity may be due to the steric repulsion from H56 that is unique to A3A. Taken together, our studies represent the first virtual screening effort against A3Bctd that has yielded candidate inhibitors suitable for further development.

Brain vital sign monitoring of sleep deprivation detects situational cognitive impairment.

Objective, rapid evaluation of cognitive function is critical for identifying situational impairment due to sleep deprivation. The present study used brain vital sign monitoring to evaluate acute changes in cognitive function for healthy adults. Thirty (30) participants were scanned using portable electroencephalography before and after either a night of regular sleep or a night of total sleep deprivation. Brain vital signs were extracted from three established event-related potential components: (1) the N100 (Auditory sensation); (2) the P300 (Basic attention); and (3) the N400 (Cognitive processing) for all time points. As predicted, the P300 amplitude was significantly reduced in the sleep deprivation group. The findings indicate that it is possible to detect situational cognitive impairment due to sleep deprivation using objective, rapid brain vital sign monitoring.

Th17-inducing dendritic cell vaccines stimulate effective CD4 T cell-dependent antitumor immunity in ovarian cancer that overcomes resistance to immune checkpoint blockade.

BACKGROUND: Ovarian cancer (OC), a highly lethal cancer in women, has a 48% 5-year overall survival rate. Prior studies link the presence of IL-17 and Th17 T cells in the tumor microenvironment to improved survival in OC patients. To determine if Th17-inducing vaccines are therapeutically effective in OC, we created a murine model of Th17-inducing dendritic cell (DC) (Th17-DC) vaccination generated by stimulating IL-15 while blocking p38 MAPK in bone marrow-derived DCs, followed by antigen pulsing. METHODS: ID8 tumor cells were injected intraperitoneally into mice. Mice were treated with Th17-DC or conventional DC (cDC) vaccine alone or with immune checkpoint blockade (ICB). Systemic immunity, tumor associated immunity, tumor size and survival were examined using a variety of experimental strategies. RESULTS: Th17-DC vaccines increased Th17 T cells in the tumor microenvironment, reshaped the myeloid microenvironment, and improved mouse survival compared with cDC vaccines. ICB had limited efficacy in OC, but Th17-inducing DC vaccination sensitized it to anti-PD-1 ICB, resulting in durable progression-free survival by overcoming IL-10-mediated resistance. Th17-DC vaccine efficacy, alone or with ICB, was mediated by CD4 T cells, but not CD8 T cells. CONCLUSIONS: These findings emphasize using biologically relevant immune modifiers, like Th17-DC vaccines, in OC treatment to reshape the tumor microenvironment and enhance clinical responses to ICB therapy.

Nurses' Experience Implementing an Automated Video Monitoring System to Decrease the Risk of Patient Falls during a Global Pandemic.

Healthcare is a complex sociotechnical system where information systems (IS) and information technology (IT) intersect to solve problems experienced by patients and providers alike. One example of IS/IT in hospitals is the Ocuvera automated video monitoring system (AVMS), which has been implemented in more than 30 hospitals. The purpose of this study was to evaluate nurses' attitudes toward AVMS implementation over time as they received the training program developed for this intervention. Consistent with the job demands-resources (JDR) model, we found that perceptions of AVMS usefulness increased over time and were positively associated with perceptions of social influence and behavioral control. These results were consistent with our finding that there was a significant decrease in the risk of unassisted falls from the bed from baseline to intervention. Leaders in hospital systems and healthcare organizations may want to consider implementing an AVMS as researchers continue to test, verify, and demonstrate the effectiveness of these interventions for improving patient well-being.

Patient and primary care practitioners' perspectives on consultations for fibromyalgia: a qualitative evidence synthesis.

BACKGROUND: Fibromyalgia presents a challenge to both the patients experiencing symptoms and the staff aiming to treat them. This qualitative review aimed to synthesise how patients and practitioners experience primary care consultations, develop a rounded picture of how they perceive each other, the challenges to primary care consultation and how they might be tackled. METHODS: CINAHL, Embase, CENTRAL and Medline were searched from inception to November 2021. Qualitative studies were included if they explored the perspectives and experiences of either fibromyalgia patients or primary care practitioners. Quantitative data, studies not published in English, not set in primary care or that did not distinguish the type of patient or clinician were excluded. Included studies were analysed using thematic synthesis and their quality assessed. RESULTS: In total, 30 studies met the inclusion criteria. Thematic synthesis identified three overarching themes: (1) life turned upside down - exploring the chaos experienced by patients as they seek help; (2) negative cycle - highlighting how patient and practitioner factors can create a detrimental cycle; and (3) breaking the cycle - validating patient-doctor relationships underpinned by clear communication can help break the negative cycle. CONCLUSIONS: Fibromyalgia patients experience uncertainty and chaos that can clash with the attitudes of GPs and the help they can feasibly provide. Difficult consultations in which neither the GP nor patient are satisfied can easily occur. Promoting supportive, reciprocal and open patient-doctor relationships is essential. Future research is required to further explore GP attitudes and to develop an intervention that could improve consultations, patient outcomes and GP satisfaction.

Racial and Ethnic Differences Among Active-Duty Service Members in Use of Mental Health Care and Perceived Mental Health Stigma: Results From the 2018 Health Related Behaviors Survey.

INTRODUCTION: The prevalence of mental health disorders is rising among US service members; however, research is limited on their use of mental health care. The objective of our study was to determine whether racial and ethnic disparities exist in the use of mental health care and perceived mental health stigma among active-duty service members. METHODS: We obtained data from a sample of 17,166 active-duty service members who participated in the 2018 Department of Defense Health Related Behavior Survey (HRBS). Racial and ethnic groups included Black, Hispanic, White, and other. Yes-no questions about use of mental health care and perceived mental health stigma were our outcome variables. We used multiple logistic regression to assess racial and ethnic differences in mental health care use and perceived mental health stigma by service members. Significance was set at P <.05. RESULTS: In 2018, approximately 25.5% of service members self-reported using mental health services, and 34.2% self-reported perceived mental health stigma. Hispanic service members (AOR = 0.78) and service members in the "other" racial and ethnic group (AOR = 0.81) were less likely than their White counterparts to have used mental health care. Black (AOR = 0.68) and Hispanic (AOR = 0.86) service members were less likely than their White counterparts to self-report perceived mental health stigma. CONCLUSION: The 2018 HRBS showed racial and ethnic differences in mental health care use and perceived stigma among US active-duty service members. Perceived stigma was a barrier to use of mental health care among service members with a mental health condition. Culture-sensitive programs customized for different racial and ethnic groups are needed to promote mental health care and reduce perceptions of stigma associated with its use.

A systematic review and meta-analysis of randomised controlled trials of surgical treatments for ingrown toenails part II: healing time, post-operative complications, pain, and participant satisfaction.

BACKGROUND: When performing nail surgery, clinicians must choose from a multitude of procedures and variations within each procedure. Much has been published to guide this decision making, but there are a lack of up to date robust systematic reviews to assess the totality of this evidence. METHODS: Five databases (MEDLINE, Embase, CINAHL, Web of Science and CENTRAL) and two registers (Clinicaltrials.gov and ISRCTN) were searched to January 2022 for randomised trials evaluating the effects of a surgical intervention(s) for ingrown toenails. Two independent reviewers screened records, extracted data, assessed risk of bias and certainty of evidence. Data on co-primary outcomes of symptom relief and symptomatic regrowth were presented in our first paper. This paper presents data for the secondary outcomes and further discussion. RESULTS: Of 3,928 records identified, 36 randomised trials were included in the systematic review. Healing time appears to be reduced with shorter application of phenol. A reduced healing time was also apparent was with the addition of curettage, although this may also increase the risk of post-operative bleeding and pain. Post operative bleeding was also reportedly lower in people who received local anaesthetic with epinephrine but no tourniquet. Use of phenol with nail bed excision may decrease the risk of infection. Lower pain scores were reported when using partial matrixectomy and surgical interventions with phenol. Shorter duration of pain was reported with phenolisation and wedge resection. Participant satisfaction was high overall. CONCLUSION: This second paper reports secondary outcomes from a robust systematic review of randomised trials on surgical treatment of ingrown toenails. Despite the large volume of clinical trials conducted on the topic, few clinical conclusions can be drawn due to the poor quality of these studies. Further high-quality clinical trials are needed to answer fundamental questions in the surgical treatment of ingrown toenails.

TIGIT can inhibit T cell activation via ligation-induced nanoclusters, independent of CD226 co-stimulation.

TIGIT is an inhibitory receptor expressed on lymphocytes and can inhibit T cells by preventing CD226 co-stimulation through interactions in cis or through competition of shared ligands. Whether TIGIT directly delivers cell-intrinsic inhibitory signals in T cells remains unclear. Here we show, by analysing lymphocytes from matched human tumour and peripheral blood samples, that TIGIT and CD226 co-expression is rare on tumour-infiltrating lymphocytes. Using super-resolution microscopy and other techniques, we demonstrate that ligation with CD155 causes TIGIT to reorganise into dense nanoclusters, which coalesce with T cell receptor (TCR)-rich clusters at immune synapses. Functionally, this reduces cytokine secretion in a manner dependent on TIGIT's intracellular ITT-like signalling motif. Thus, we provide evidence that TIGIT directly inhibits lymphocyte activation, acting independently of CD226, requiring intracellular signalling that is proximal to the TCR. Within the subset of tumours where TIGIT-expressing cells do not commonly co-express CD226, this will likely be the dominant mechanism of action.

Global assessment of marine plastic exposure risk for oceanic birds.

Plastic pollution is distributed patchily around the world's oceans. Likewise, marine organisms that are vulnerable to plastic ingestion or entanglement have uneven distributions. Understanding where wildlife encounters plastic is crucial for targeting research and mitigation. Oceanic seabirds, particularly petrels, frequently ingest plastic, are highly threatened, and cover vast distances during foraging and migration. However, the spatial overlap between petrels and plastics is poorly understood. Here we combine marine plastic density estimates with individual movement data for 7137 birds of 77 petrel species to estimate relative exposure risk. We identify high exposure risk areas in the Mediterranean and Black seas, and the northeast Pacific, northwest Pacific, South Atlantic and southwest Indian oceans. Plastic exposure risk varies greatly among species and populations, and between breeding and non-breeding seasons. Exposure risk is disproportionately high for Threatened species. Outside the Mediterranean and Black seas, exposure risk is highest in the high seas and Exclusive Economic Zones (EEZs) of the USA, Japan, and the UK. Birds generally had higher plastic exposure risk outside the EEZ of the country where they breed. We identify conservation and research priorities, and highlight that international collaboration is key to addressing the impacts of marine plastic on wide-ranging species.

A systematic review and meta-analysis of randomised controlled trials on surgical treatments for ingrown toenails part I: recurrence and relief of symptoms.

BACKGROUND: Ingrown toenails are a common nail pathology. When conservative treatments are ineffective, a surgical approach is often utilised. Despite recent narrative reviews, there is a need for an up-to-date and rigorous systematic review of surgical methods for treating ingrown toenails. METHODS: Five databases (MEDLINE, Embase, CINAHL, Web of Science and CENTRAL) and two registers (Clinicaltrials.gov and ISRCTN) were searched to January 2022 for randomised trials evaluating the effects of a surgical intervention(s) for ingrown toenails with a follow-up of at least 1 month. Two independent reviewers screened records, extracted data, assessed risk of bias and certainty of evidence. RESULTS: Of 3,928 records identified, 36 (3,756 participants; 62.7% males) surgical interventions were included in the systematic review and 31 studies in the meta-analysis. There was very low quality evidence that using phenol with nail avulsion vs nail avulsion without phenol reduces the risk of recurrence (risk ratio [RR] 0.13 [95% CI 0.06 to 0.27], p < 0.001). No favourable effect was observed between chemical or surgical vs conservative management (0.55 [0.19 to 1.61], p = 0.280; 0.72 [0.33 to 1.56], p = 0.410), chemical or surgical vs other (e.g., CO2 laser, electrocautery) (1.61 [0.88 to 2.95], p = 0.120; 0.58 [0.25 to 1.37], p = 0.220), chemical vs surgical (0.75 [0.46 to 1.21], p = 0.230), surgical vs surgical (0.42 [0.21 to 0.85]), chemical vs chemical (0.19 [0.01 to 3.80], p = 0.280), surgical vs surgical + chemical (3.68 [0.20 to 67.35], p = 0.380), chemical vs surgical + chemical (1.92 [0.06 to 62.30], p = 0.710), local anaesthetic vs local anaesthetic + adrenaline (1.03 [0.22 to 4.86], p = 0.970), chemical timings 30 s vs 60 s (2.00 [0.19 to 21.41]) or antibiotics vs no antibiotics (0.54 [0.12 to 2.52], p = 0.430). Central toenail resection was the only procedure to significantly relieve symptoms (p = 0.001) but data were only available up to 8 weeks post-surgery. CONCLUSION: Despite the high number of publications, the quality of research was poor and the conclusions that can be inferred from existing trials is limited. Phenolisation of the nail matrix appears to reduce the risk of recurrence following nail ablation, and with less certainty 1 min appears to be the optimum time for application. Despite this being a widely performed procedure there remains a lack of good quality evidence to guide practice.

Why do people take part in vaccine trials? A mixed methods narrative synthesis.

OBJECTIVES: To understand why individuals do or do not take part in vaccine trials, exploring the motivators and barriers to identify effective strategies to optimise recruitment in vaccine research. METHODS: Qualitative studies and quantitative surveys capturing data on reasons for trial participation/decline were included. Six databases were searched from 1996 to October 2021. Two reviewers independently screened and assessed risk of bias. Results were reported narratively and analysed using thematic analysis. RESULTS: We included 32 studies (17 qualitative; 12 quantitative; 3 mixed-methods) that covered a wide range of populations, geographical areas and disease types. Eight themes were identified 1) altruism; 2) potential for personal benefit; 3) perceived risks; 4) trust or distrust; 5) social networks; 6) stigma; 7) practical implications; 8) research vanguard. CONCLUSION: Our findings provide a detailed description of how potential participants weigh up their decisions to participate in vaccine trials, which could inform the planning and implementation of studies to enhance recruitment. PRACTICE IMPLICATIONS: Clinical trial researchers should consider a patient-centered approach to recruitment, tailoring promoting material and attempt to understand fears, stigma and perceived risks. In addition, recognising the importance of trust and the key role friends, communities, family, and those in supervisory positions play in decisions.

Does self-compassion explain variance in sleep quality in women experiencing hot flushes?

OBJECTIVES: With poor sleep highly prevalent during the menopause transition, there is a need to better understand modifiable psychological resources that may be associated with improved sleep. Hence, we investigated whether self-compassion can explain variance in self-reported sleep quality in midlife women, over and above vasomotor symptoms. METHODS: This cross-sectional study (N = 274) used questionnaire data from self-report measures of sleep, hot flushes and night sweats, hot flush interference, and self-compassion, with analyses conducted using sequential (hierarchical) regression. RESULTS: Poor sleep, as measured by the Pittsburgh Sleep Quality Index, was prevalent and significantly worse in the subsample of women with hot flushes and night sweats, g = 0.28, 95 % CI [0.04, 0.53]. The interference of hot flushes in everyday life (ß = 0.35, p < .01), but not their frequency, predicted self-reported sleep quality. Once self-compassion was added to the model it was the only predictor of poor sleep (ß = -0.32, p < .01). When positive self-compassion and self-coldness were considered separately, the effect on sleep quality appeared to be attributable to self-coldness scores alone (ß = 0.29, p < .05). CONCLUSIONS: Self-compassion may have a stronger relationship with self-reported sleep quality in midlife women than vasomotor symptoms. Future intervention-based research could test the efficacy of self-compassion training for midlife women experiencing sleep disturbances, as this may be an important and modifiable psychological resilience factor.

A scoping review of the outcome reporting following surgery for chronic osteomyelitis of the lower limb.

Chronic osteomyelitis (COM) of the lower limb in adults can be surgically managed by either limb reconstruction or amputation. This scoping review aims to map the outcomes used in studies surgically managing COM in order to aid future development of a core outcome set. A total of 11 databases were searched. A subset of studies published between 1 October 2020 and 1 January 2011 from a larger review mapping research on limb reconstruction and limb amputation for the management of lower limb COM were eligible. All outcomes were extracted and recorded verbatim. Outcomes were grouped and categorized as per the revised Williamson and Clarke taxonomy. A total of 3,303 records were screened, of which 99 studies were included. Most studies were case series (77/99; 78%) and assessed one method of reconstruction (68/99; 69%). A total of 511 outcomes were reported, which were grouped into 58 distinct outcomes. Overall, 143/511 of all outcomes (28%) were provided with a clear, in-text definition, and 231 outcomes (45%) had details reported of how and when they were measured. The most commonly reported outcome was 'recurrence of osteomyelitis' (62; 12%). The single-most patient-reported outcome measure was 'pain'. This study has highlighted significant inconsistencies in the defining, reporting, and measuring of outcomes across studies investigating surgical management for chronic osteomyelitis of the lower limb in adults. Future studies should clearly report complete details of how outcomes are defined and measured, including timing. The development of a standardized core outcome set would be of significant benefit in order to allow evidence synthesis and comparison across studies.

Exercise Perceptions and Experiences in Adults With Crohn's Disease Following a Combined Impact and Resistance Training Program: A Qualitative Study.

Background: Exercise is increasingly being recognized to counteract specific complications of Crohn's disease (CD). The aim of this study was to explore exercise experiences and perceptions after engaging in a combined impact and resistance training program, involving both intervention and control group viewpoints. Methods: Semistructured telephone interviews, involving a convenience sample of participants with CD (n = 41; aged 49.1 ± 12 years) were undertaken up to 6 weeks following completion of the program. Data were analyzed using thematic analysis. Results: Four overarching themes emerged, along with 11 subthemes: (1) Lack of confidence and knowledge, fears surrounding physical ability and symptoms, coupled with issues not addressed as part of the healthcare pathway played a part in transitioning to inactivity; (2) Improvements in strength, mental well-being, physical fitness, fatigue, abdominal and joint pain, comorbidities, and self-management strategies were among the reported benefits of exercise participation; (3) Seeing progress, goal setting, enjoyment, and a peer-led program receiving support and advice increased motivation. Whereas work-related tiredness, other commitments, and self-directed exercise were reported as exercise barriers; (4) The intervention design was well received and the journey from start to finish was positively discussed, important considerations for future interventions and implementation strategies. Conclusions: The study yielded novel perceptions on the transition to inactivity following receiving a diagnosis, physical and psychological benefits accruing from the intervention, and views on program design. Information that will provide an essential step in the development of implementing exercise guidelines into the clinical pathway and supporting individuals with self-management options.

Structure-Based Design of Bisubstrate Tetracycline Destructase Inhibitors That Block Flavin Redox Cycling.

Tetracyclines (TCs) are an important class of antibiotics threatened by an emerging new resistance mechanism─enzymatic inactivation. These TC-inactivating enzymes, also known as tetracycline destructases (TDases), inactivate all known TC antibiotics, including drugs of last resort. Combination therapies consisting of a TDase inhibitor and a TC antibiotic represent an attractive strategy for overcoming this type of antibiotic resistance. Here, we report the structure-based design, synthesis, and evaluation of bifunctional TDase inhibitors derived from anhydrotetracycline (aTC). By appending a nicotinamide isostere to the C9 position of the aTC D-ring, we generated bisubstrate TDase inhibitors. The bisubstrate inhibitors have extended interactions with TDases by spanning both the TC and presumed NADPH binding pockets. This simultaneously blocks TC binding and the reduction of FAD by NADPH while "locking" TDases in an unproductive FAD "out" conformation.

APOBEC3A Catalytic Inactivity Mutation Induces Tertiary Structure Destabilization.

APOBEC3A (A3A)-catalyzed DNA cytosine deamination is implicated in virus and cancer mutagenesis, and A3A is a target for small molecule drug discovery. The catalytic glutamic acid (E72) is frequently mutated in biochemical studies to characterize deamination-dependent versus deamination-independent A3A functions. Additionally, catalytically active A3A is toxic in bacterial expression systems, which adversely affects yield during recombinant A3A expression. Here, we demonstrate that mutating the catalytic glutamic acid to an isosteric glutamine (E72Q) significantly decreases the thermal stability of the protein, compared to the alanine-inactivating mutation (E72A). Differential scanning fluorimetry and mass spectrometry reveal that A3A E72Q is less thermally stable than A3A E72A or wild-type A3A. Strikingly, A3A E72Q is partially denatured at 37 °C and binds single-stranded DNA with significantly poorer affinity compared to A3A E72A. This study constitutes an important cautionary note on A3A protein design and informs that A3A E72A is the preferred catalytic inactivation mutation for most applications.