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Introduction Men who have sex with men continue to account for the majority of new HIV infections in the United States. Many of those with new infections are unaware that they have HIV. Preventative measures continue to be essential in reducing new infections, with pre‐exposure prophylaxis (PrEP) being widely recommended. Objectives The overall aim of this qualitative study is to explore the impact of stigma, patient–provider dynamics and patient perception of PrEP on men's engagement with PrEP in a primary care setting. Methods The Consensual Qualitative Research Methodology (Hill, 2012) was used to explore the experiences of 14 men receiving care for PrEP at a Family Medicine clinic in the Midwest. Semistructured interviews were conducted to allow for depth of understanding of individuals' experience. Results Four major domains were identified: motivation to pursue PrEP, barriers and adherence to care, beliefs about how PrEP is perceived by others and experiences discussing sexual health and PrEP with providers. Conclusion It is important to better understand factors contributing to the pursuit of and adherence to HIV prevention measures and HIV care. Further, health systems and providers are encouraged to consider opportunities in terms of how their practice can destigmatize PrEP use and offer a welcoming environment for those pursuing HIV prevention. Patient or Public Contribution Patients were involved in the study through their participation in semistructured interviews, which provided the data analysed for this study. There was no additional participation beyond the one‐time interview or follow‐up poststudy. Their interviews helped contribute to our better understanding of the needs and experiences of those receiving PrEP‐related care.

Background: Emotion dysregulation is a hallmark characteristic of psychopathology following trauma. Yet, emotion dysregulation is multifaceted, and little is known about which aspects of emotion dysregulation predict depression and posttraumatic stress disorder (PTSD) symptom severity following traumatic injury. Objective: The aim of this longitudinal study was to evaluate how facets of dysregulation differentially predicted the severity of PTSD symptom clusters and depressive symptoms six months after a traumatic injury requiring medical treatment. Methods: Traumatically injured adults (N = 99) presenting to a Level 1 trauma centre completed a measure of emotion dysregulation 2 weeks post-injury, and PTSD and depression were assessed at 2-weeks and 6 months later. Results: Using stepwise regressions controlling for baseline symptoms, age, gender, race, and injury severity, results showed baseline emotion dysregulation significantly predicted the four symptom clusters of PTSD 6 months post-injury. Notably, hyperarousal symptoms and negative alterations in mood and cognition were predicted by a lack of clarity. On the other hand, depressive symptoms were significantly predicted by difficulty accessing emotion regulation strategies. Conclusion: Results highlight that specific facets of emotion dysregulation predict PTSD and depression symptom severity differentially after injury. Indeed, lack of emotional clarity appears to predict PTSD symptomatology, suggesting a potential mechanism driving worsening symptoms. Lack of clarity could also be detrimental to engagement in PTSD treatment. Conversely, lack of regulation strategies may represent a sense of helplessness in managing depression after trauma. As such, future research should elucidate whether interventions targeting aspects of emotion dysregulation based on symptom presentations are useful in treating PTSD and depression following injury. Specific facets of emotion dysregulation are differentially associated with PTSD symptom clusters and depression symptom severity after injury. Findings suggest that targeting lack of emotional clarity may be critical for patients with prominent hyperarousal and trauma-related changes in mood and cognitions (i.e. two PTSD symptom clusters). Patients with depressive symptoms following trauma may especially benefit from the development of emotion regulation strategies.

ObjectivesAnnually, approximately 27 million individuals in the United States are admitted to hospitals for emergency general surgery (EGS). Approximately 50% develop postoperative complications and 22% require unplanned readmission within 90 days, highlighting a need to understand factors impacting well-being and recovery. Psychiatric comorbidity can impact medical treatment adherence, cost, and premature mortality risk. Despite the severity of illness in EGS, there is limited research on psychiatric comorbidity in EGS patients. Thus, the purpose of the current study was to characterize EGS patient mental health and to assess its relationship with pain, social support, and healthcare utilization (ie, length of stay, readmission).MethodsAdult EGS patients were screened for participation during hospitalization. Inclusion criteria included: (1) 18 years or older, (2) communicate fluently in English, and (3) assessed within 7 days of admission. Participants (n=95) completed assessment, which included a structured clinical diagnostic interview. Record review captured medical variables, including length of stay, discharge disposition, narcotic prescription, and 90-day readmission rates.ResultsNinety-five patients completed the assessment, and 31.6% met criteria for at least one current psychiatric diagnosis; 21.3% with a major depressive episode, 9.6% with a substance use disorder, and 7.5% with post-traumatic stress disorder (PTSD). Lower perceived social support and greater pain severity and interference were significantly related to more severe depression and anxiety. Depression was associated with longer length of stay, and those with PTSD were more likely to be re-admitted.ConclusionThe EGS patient sample exhibited psychiatric disorder rates greater than the general public, particularly regarding depression and anxiety. Screening protocols and incorporation of psychological and social interventions may assist in recovery following EGS.Level of evidenceLevel II, prognostic.

BackgroundIntimate partner violence (IPV) is a serious public health issue with a substantial burden on society. Screening and intervention practices vary widely and there are no standard guidelines. Our objective was to review research on current practices for IPV prevention in emergency departments and trauma centers in the USA and provide evidenced-based recommendations.MethodsAn evidence-based systematic review of the literature was conducted to address screening and intervention for IPV in adult trauma and emergency department patients. The Grading of Recommendations, Assessment, Development and Evaluations methodology was used to determine the quality of evidence. Studies were included if they addressed our prespecified population, intervention, control, and outcomes questions. Case reports, editorials, and abstracts were excluded from review.ResultsSeven studies met inclusion criteria. All seven were centered around screening for IPV; none addressed interventions when abuse was identified. Screening instruments varied across studies. Although it is unclear if one tool is more accurate than others, significantly more victims were identified when screening protocols were implemented compared with non-standardized approaches to identifying IPV victims.ConclusionOverall, there were very limited data addressing the topic of IPV screening and intervention in emergency medical settings, and the quality of the evidence was low. With likely low risk and a significant potential benefit, we conditionally recommend implementation of a screening protocol to identify victims of IPV in adults treated in the emergency department and trauma centers. Although the purpose of screening would ultimately be to provide resources for victims, no studies that assessed distinct interventions met our inclusion criteria. Therefore, we cannot make specific recommendations related to IPV interventions.PROSPERO registration numberCRD42020219517.

Recent estimates indicate that 18.5% of heterosexual college students and 30.3% of sexual minority college students are victims of physical intimate partner violence (IPV; Edwards, Sylaska, Barry, et al., 2015). Research among adult women in opposite- sex relationships has shown that once an individual is victimized by IPV she is subsequently at high risk for future IPV victimization. Re-victimization is associated with more severe physical and mental health consequences of IPV. No prior study has assessed the rate of re-victimization among sexual minority adults. Help-seeking behavior, which refers to accessing a range of sources of support (e.g., family and friends, law enforcement, mental health professionals), may mitigate many of the consequences of IPV, including re-victimization. However, no prior study has explored the effect of help-seeking on the re-victimization of sexual minorities. Results from this longitudinal study show that sexual minorities were approximately two times more likely than their heterosexual counterparts to be victims of IPV. Sexual minority victims at the first study time point (T1) were, as compared to heterosexual victims, also at heightened risk for re-victimization one year later while controlling for severity of the violence at T1. Contrary to my expectations, sexual minority victims more often sought help than heterosexual ones. This may be due to the more severe IPV reported by sexual minorities. Help-seeking did not influence risk for re-victimization. Continued research on IPV and the help-seeking behavior of sexual minority victims of IPV is needed to better understand this phenomenon, which has substantial public health implications.

Members of the cofilin/ADF family of proteins sever actin filaments, increasing the number of filament ends available for polymerization or depolymerization. Cofilin binds actin filaments with positive cooperativity, forming clusters of contiguously bound cofilin along the filament lattice. Filament severing occurs preferentially at boundaries between bare and cofilin-decorated (cofilactin) segments and is biased at 1 side of a cluster. A molecular understanding of cooperative binding and filament severing has been impeded by a lack of structural data describing boundaries. Here, we apply methods for analyzing filament cryo-electron microscopy (cryo-EM) data at the single subunit level to directly investigate the structure of boundaries within partially decorated cofilactin filaments. Subnanometer resolution maps of isolated, bound cofilin molecules and an actin-cofilactin boundary indicate that cofilin-induced actin conformational changes are local and limited to subunits directly contacting bound cofilin. An isolated, bound cofilin compromises longitudinal filament contacts of 1 protofilament, consistent with a single cofilin having filament-severing activity. An individual, bound phosphomimetic (S3D) cofilin with weak severing activity adopts a unique binding mode that does not perturb actin structure. Cofilin clusters disrupt both protofilaments, consistent with a higher severing activity at boundaries compared to single cofilin. Comparison of these structures indicates that this disruption is substantially greater at pointed end sides of cofilactin clusters than at the barbed end. These structures, with the distribution of bound cofilin clusters, suggest that maximum binding cooperativity is achieved when 2 cofilins occupy adjacent sites. These results reveal the structural origins of cooperative cofilin binding and actin filament severing.

Contributions of fast (femtosecond) dynamic motion to barrier crossing at enzyme catalytic sites is in dispute. Human purine nucleoside phosphorylase (PNP) forms a ribocation-like transition state in the phosphorolysis of purine nucleosides and fast protein motions have been proposed to participate in barrier crossing. In the present study, 13C-, 15N-, 2H-labeled human PNP (heavy PNP) was expressed, purified to homogeneity, and shown to exhibit a 9.9% increase in molecular mass relative to its unlabeled counterpart (light PNP). Kinetic isotope effects and steady-state kinetic parameters were indistinguishable for both enzymes, indicating that transition-state structure, equilibrium binding steps, and the rate of product release were not affected by increased protein mass. Single-turnover rate constants were slowed for heavy PNP, demonstrating reduced probability of chemical barrier crossing from enzyme-bound substrates to enzyme-bound products. In a second, independent method to probe barrier crossing, heavy PNP exhibited decreased forward commitment factors, also revealing mass-dependent decreased probability for barrier crossing. Increased atomic mass in human PNP alters bond vibrational modes on the femtosecond time scale and reduces on-enzyme chemical barrier crossing. This study demonstrates coupling of enzymatic bond vibrations on the femtosecond time scale to barrier crossing.

Miscellaneous crenarchaeotal group (MCG) and marine benthic group-D (MBG-D) are among the most numerous archaea in sea-floor sediments; single-cell genomics reveals that these archaea belong to new branches of the archaeal tree and probably have a role in protein remineralization in anoxic marine sediments. Marine archaeans as protein recyclers Sediments on the sea floor are home to almost half of the microorganisms in the ocean, including a large number of Archaea that have not been cultured in the laboratory. Here Karen Lloyd et al . identify uncultured miscellaneous crenarchaeotal group (MCG) and marine benthic group-D (MBG-D) organisms as the predominant archaeans in sediments. Single-cell genomic analysis of four different cell types indicates that they belong to new branches of the archaeal tree. All cells tested encode extracellular protein-degrading enzymes, pointing to a possible role in protein remineralization in anoxic marine sediments. Half of the microbial cells in the Earth’s oceans are found in sediments 1 . Many of these cells are members of the Archaea 2 , single-celled prokaryotes in a domain of life separate from Bacteria and Eukaryota. However, most of these archaea lack cultured representatives, leaving their physiologies and placement on the tree of life uncertain. Here we show that the uncultured miscellaneous crenarchaeotal group (MCG) and marine benthic group-D (MBG-D) are among the most numerous archaea in the marine sub-sea floor. Single-cell genomic sequencing of one cell of MCG and three cells of MBG-D indicated that they form new branches basal to the archaeal phyla Thaumarchaeota 3 and Aigarchaeota 4 , for MCG, and the order Thermoplasmatales, for MBG-D. All four cells encoded extracellular protein-degrading enzymes such as gingipain and clostripain that are known to be effective in environments chemically similar to marine sediments. Furthermore, we found these two types of peptidase to be abundant and active in marine sediments, indicating that uncultured archaea may have a previously undiscovered role in protein remineralization in anoxic marine sediments.

In contrast to previously reported findings, M2-like polarized macrophages are not a source of catecholamines and do not contribute to browning of the fat. Adaptive thermogenesis is the process of heat generation in response to cold stimulation. It is under the control of the sympathetic nervous system, whose chief effector is the catecholamine norepinephrine (NE). NE enhances thermogenesis through β3-adrenergic receptors to activate brown adipose tissue and by 'browning' white adipose tissue. Recent studies have reported that alternative activation of macrophages in response to interleukin (IL)-4 stimulation induces the expression of tyrosine hydroxylase (TH), a key enzyme in the catecholamine synthesis pathway, and that this activation provides an alternative source of locally produced catecholamines during the thermogenic process. Here we report that the deletion of Th in hematopoietic cells of adult mice neither alters energy expenditure upon cold exposure nor reduces browning in inguinal adipose tissue. Bone marrow–derived macrophages did not release NE in response to stimulation with IL-4, and conditioned media from IL-4-stimulated macrophages failed to induce expression of thermogenic genes, such as uncoupling protein 1 ( Ucp1 ), in adipocytes cultured with the conditioned media. Furthermore, chronic treatment with IL-4 failed to increase energy expenditure in wild-type, Ucp1 −/− and interleukin-4 receptor-α double-negative ( Il4ra −/− ) mice. In agreement with these findings, adipose-tissue-resident macrophages did not express TH. Thus, we conclude that alternatively activated macrophages do not synthesize relevant amounts of catecholamines, and hence, are not likely to have a direct role in adipocyte metabolism or adaptive thermogenesis.

Methylthioadenosine-DADMe immucillin-A (MTDIA) is a transition-state analog that potently inhibits the human protein 5′-methylthioadenosine phosphorylase (MTAP) at picomolar concentrations and elicits anti-tumor activity against lung, prostate, colon, cervical, head and neck, and triple-negative breast cancers in cell and animal models. The anti-cancer mechanisms of MTDIA involve elevated methylthioadenosine levels but are not fully understood. The yeast protein MEU1 is functionally equivalent to human MTAP. To gain further understanding, we performed chemical genetic analyses via gene deletion and GFP-tagged protein libraries in yeast that express a member of the human equilibrative nucleoside transporter (ENT) family to permit MTDIA uptake. Genomic and proteomic analyses identified genes and proteins critical to MTDIA bioactivity. Network analysis of these genes and proteins revealed an important link to ribosomal function, which was confirmed by observing reduced levels of ribosomal subunit proteins. Network analysis also implicated autophagy, which was confirmed by analyzing intracellular trafficking of GFP-Atg8 and Phloxine B viability. In yeast, a comparable effect occurred after deletion of MEU1, indicating a single target for MTDIA in yeast. Overall, our yeast model reveals specific components of the ribosome as well as induction of autophagy as integral mechanisms that mediate the bioactivity of MTDIA.