A RIPK1-specific PROTAC degrader achieves potent antitumor activity by enhancing immunogenic cell death.

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) functions as a critical stress sentinel that coordinates cell survival, inflammation, and immunogenic cell death (ICD). Although the catalytic function of RIPK1 is required to trigger cell death, its non-catalytic scaffold function mediates strong pro-survival signaling. Accordingly, cancer cells can hijack RIPK1 to block necroptosis and evade immune detection. We generated a small-molecule proteolysis-targeting chimera (PROTAC) that selectively degraded human and murine RIPK1. PROTAC-mediated depletion of RIPK1 deregulated TNFR1 and TLR3/4 signaling hubs, accentuating the output of NF-κB, MAPK, and IFN signaling. Additionally, RIPK1 degradation simultaneously promoted RIPK3 activation and necroptosis induction. We further demonstrated that RIPK1 degradation enhanced the immunostimulatory effects of radio- and immunotherapy by sensitizing cancer cells to treatment-induced TNF and interferons. This promoted ICD, antitumor immunity, and durable treatment responses. Consequently, targeting RIPK1 by PROTACs emerges as a promising approach to overcome radio- or immunotherapy resistance and enhance anticancer therapies.

Development of the next-generation functional neuro-cognitive imaging protocol - Part 1: A 3D sliding-window convolutional neural net for automated brain parcellation.

Functional MRI has emerged as a powerful tool to assess the severity of Post-concussion syndrome (PCS) and to provide guidance for neuro-cognitive therapists during treatment. The next-generation functional neuro-cognitive imaging protocol (fNCI2) has been developed to provide this assessment. This paper covers the first step in the analysis process, the development of a rapidly re-trainable, machine-learning, brain parcellation tool. The use of a sufficiently deep U-Net architecture encompassing a small (39 × 39 × 39 voxel input, 27 × 27 × 27 voxel output) sliding window to sample the entirety of the 3D image allows for the prediction of the entire image using only a single trained network. A large number of training, validating, and testing windows are thus generated from the 101 manually-labeled Mindboggle images, and full-image prediction is provided via a voxel-vote method using overlapping windows. Our method produces parcellated images that are highly consistent with standard atlas-based methods in under 3 min on a modern GPU, and the single network architecture allows for rapid retraining (<36 hr) as needed.

A national evaluation of QbTest to support ADHD assessment: a real-world, mixed methods approach.

BACKGROUND: QbTest is a commercially available, computerised test of attention, impulsivity, and activity designed to assist with the diagnosis of attention deficit hyperactivity disorder (ADHD). Health Innovation East Midlands (formerly East Midlands AHSN), led the implementation of the QbTest on behalf of the 15 Health Innovation Networks across Child and Adolescent Mental Health services (CAMHS) and Paediatric sites in England between April 2020 and March 2023. We evaluate the impact of this programme on diagnostic assessment at participating sites. METHODS: A mixed-methods approach was used including: case-note data collected on 10-30 cases per site pre and post QbTest implementation; interviews with healthcare staff working with QbTest; and surveys to explore perspectives of healthcare staff and patients/carers. Case-note data was descriptively analysed to compare time to diagnosis (number of appointments and days) pre/post QbTest implementation. Survey data was analysed descriptively. Qualitative interview data was explored using thematic analysis. RESULTS: Case-note data was provided by 20 sites across England. Comparison of mean values pre- and post-QbTest implementation identified a decrease of 0.37 (11.5%) in number of appointments to reach a diagnostic decision, a 55-day (12.5%) increase in days from initial referral to diagnosis, and a 12-day (10.3%) increase in days to reach a diagnostic decision. Exploratory analyses indicated greater benefit for Paediatric services over CAMHS, in terms of a decrease in days from referral to diagnosis and number of appointments to diagnosis. Interviews with healthcare staff (n=21) revealed that the QbTest was perceived to support a faster, more efficient diagnostic process. Survey data (n=65 healthcare staff, n=22 patients/carers) identified that the QbTest helped patients understand their symptoms and the diagnostic decision.  Although some logistical issues (e.g., room requirements) and patient issues (e.g., sensory sensitivity) were identified, healthcare staff considered that QbTest was easily incorporated into the ADHD assessment pathway. CONCLUSION: The national implementation of QbTest in ADHD clinics resulted in a small reduction in the number of clinical appointments needed to reach a diagnostic decision, with greatest benefit demonstrated in Paediatric sites. Data were impacted by COVID-19 therefore, further evaluation is warranted.

Characterization and engineering of a two-enzyme system for plastics depolymerization.

Plastics pollution represents a global environmental crisis. In response, microbes are evolving the capacity to utilize synthetic polymers as carbon and energy sources. Recently, Ideonella sakaiensis was reported to secrete a two-enzyme system to deconstruct polyethylene terephthalate (PET) to its constituent monomers. Specifically, the I. sakaiensis PETase depolymerizes PET, liberating soluble products, including mono(2-hydroxyethyl) terephthalate (MHET), which is cleaved to terephthalic acid and ethylene glycol by MHETase. Here, we report a 1.6 Å resolution MHETase structure, illustrating that the MHETase core domain is similar to PETase, capped by a lid domain. Simulations of the catalytic itinerary predict that MHETase follows the canonical two-step serine hydrolase mechanism. Bioinformatics analysis suggests that MHETase evolved from ferulic acid esterases, and two homologous enzymes are shown to exhibit MHET turnover. Analysis of the two homologous enzymes and the MHETase S131G mutant demonstrates the importance of this residue for accommodation of MHET in the active site. We also demonstrate that the MHETase lid is crucial for hydrolysis of MHET and, furthermore, that MHETase does not turnover mono(2-hydroxyethyl)-furanoate or mono(2-hydroxyethyl)-isophthalate. A highly synergistic relationship between PETase and MHETase was observed for the conversion of amorphous PET film to monomers across all nonzero MHETase concentrations tested. Finally, we compare the performance of MHETase:PETase chimeric proteins of varying linker lengths, which all exhibit improved PET and MHET turnover relative to the free enzymes. Together, these results offer insights into the two-enzyme PET depolymerization system and will inform future efforts in the biological deconstruction and upcycling of mixed plastics.

Parent personality traits and problem behavior in adolescence: The mediating role of adolescent personality.

INTRODUCTION: Parental personality traits are predicted to influence offspring outcomes through parenting behavior and offspring personality traits. This study explored whether mother and father personality traits relate to offspring behavior problems in mid-late adolescence METHOD: In total, 3089 Australian adolescents (1576 boys, 1513 girls; Mage = 16.46 ± 0.50 years) and their parents completed questionnaires assessing personality, conduct problems, emotional and social functioning, antisocial and criminal behavior, cigarette smoking and drug use, at a single time-point. RESULTS: After controlling for sociodemographic factors, results showed that problem behaviors in adolescence were most consistently related to mothers' scores on neuroticism and conscientiousness, and fathers' scores on neuroticism. Father personality traits were most important for antisocial and criminal behavior, whereas mother personality traits were most important for social and emotional functioning. Moderation analysis showed that associations between fathers' personality traits and some adolescent outcomes (cigarette smoking and drug use) were stronger for adolescent boys than for adolescent girls. Mediation models further demonstrated that adolescent personality traits mediated associations between parent personality and adolescent outcomes in almost all cases. Indirect effects expressed as a percentage showed that between 1.4% and 33.3% of the variance in the association between parent personality and adolescent outcomes was shared with the corresponding adolescent personality trait. CONCLUSIONS: Overall, the findings of this study provide evidence that traits inherited (directly or indirectly) from parents might have an important role in shaping problem behavior in adolescence.

Neratinib in advanced HER2-positive breast cancer: experience from the royal Marsden hospital.

PURPOSE: To describe the tolerability and efficacy of neratinib as a monotherapy and in combination with capecitabine in advanced HER2-positive breast cancer in a real-world setting. METHODS: Patients who received neratinib for advanced HER2-positive at the Royal Marsden Hospital NHS Trust between August 2016 and May 2020 were identified from electronic patient records and baseline characteristics, previous treatment and response to treatment were recorded. The primary endpoint of the study was progression-free survival (PFS). Secondary endpoints included overall survival (OS) and safety. RESULTS: Seventy-two patients were eligible for the analysis. Forty-five patients received neratinib in combination with capecitabine and 27 patients received monotherapy. After a median duration of follow-up of 38.5 months, the median PFS for all patients was 5.9 months (95% confidence interval (CI) 4.9-7.4 months) and median OS was 15.0 months (95% Cl 10.4-22.2 months). Amongst the 52.7% (38/72) patients with confirmed brain metastases at baseline, median PFS was 5.7 months (95% CI 2.9-7.4 months) and median OS was 12.5 months (95% CI 7.7-21.4 months). Despite anti-diarrhoeal prophylaxis, diarrhoea was the most frequent adverse event, reported in 64% of patients which was grade 3 in 10%. There were no grade 4 or 5 toxicities. Seven patients discontinued neratinib due to toxicity. CONCLUSIONS: Neratinib monotherapy or in combination with capecitabine is a useful treatment for patients with and without brain metastases. PFS and OS were found to be similar as previous trial data. Routine anti-diarrhoeal prophylaxis allows this combination to be safely delivered to patients in a real-world setting.

Incidence of cardiotoxicity and validation of the Heart Failure Association-International Cardio-Oncology Society risk stratification tool in patients treated with trastuzumab for HER2-positive early breast cancer.

PURPOSE: Trastuzumab improves survival in patients with HER2+ early breast cancer. However, cardiotoxicity remains a concern, particularly in the curative setting, and there are limited data on its incidence outside of clinical trials. We retrospectively evaluated the cardiotoxicity rates [left ventricular ejection fraction (LVEF) decline, congestive heart failure (CHF), cardiac death or trastuzumab discontinuation] and assessed the performance of a proposed model to predict cardiotoxicity in routine clinical practice. METHODS: Patients receiving curative trastuzumab between 2011 and 2018 were identified. Demographics, treatments, assessments and toxicities were recorded. Fisher's exact test, Chi-squared and logistic regression were used. RESULTS: 931 patients were included in the analysis. Median age was 54 years (range 24-83) and Charlson comorbidity index 0 (0-6), with 195 patients (20.9%) aged 65 or older. 228 (24.5%) were smokers. Anthracyclines were given in 608 (65.3%). Median number of trastuzumab doses was 18 (1-18). The HFA-ICOS cardiovascular risk was low in 401 patients (43.1%), medium in 454 (48.8%), high in 70 (7.5%) and very high in 6 (0.6%). Overall, 155 (16.6%) patients experienced cardiotoxicity: LVEF decline ≥ 10% in 141 (15.1%), falling below 50% in 55 (5.9%), CHF NYHA class II in 42 (4.5%) and class III-IV in 5 (0.5%) and discontinuation due to cardiac reasons in 35 (3.8%). No deaths were observed. Cardiotoxicity rates increased with HFA-ICOS score (14.0% low, 16.7% medium, 30.3% high/very high; p = 0.002). CONCLUSIONS: Cardiotoxicity was relatively common (16.6%), but symptomatic heart failure on trastuzumab was rare in our cohort. The HFA-ICOS score identifies patients at high risk of cardiotoxicity.

Expanding the Tool Kit of Automated Flow Synthesis: Development of In-line Flash Chromatography Purification.

Recent advancements in in-line extraction and purification technology have enabled complex multistep synthesis in continuous flow reactor systems. However, for the large scope of chemical reactions that yield mixtures of products or residual starting materials, off-line purification is still required to isolate the desired compound. We present the in-line integration of a commercial automated flash chromatography system with a flow reactor for the continuous synthesis and isolation of product(s). A proof-of-principle study was performed to validate the system and test the durability of the column cartridges, performing an automated sequence of 100 runs over 2 days. Three diverse reaction systems that highlight the advantages of flow synthesis were successfully applied with in-line normal- or reversed-phase flash chromatography, continuously isolating products with 97-99% purity. Productivity of up to 9.9 mmol/h was achieved, isolating gram quantities of pure product from a feed of crude reaction mixture. Herein, we describe the development and optimization of the systems and suggest guidelines for selecting reactions well suited to in-line flash chromatography.

Characterization and engineering of a plastic-degrading aromatic polyesterase.

Poly(ethylene terephthalate) (PET) is one of the most abundantly produced synthetic polymers and is accumulating in the environment at a staggering rate as discarded packaging and textiles. The properties that make PET so useful also endow it with an alarming resistance to biodegradation, likely lasting centuries in the environment. Our collective reliance on PET and other plastics means that this buildup will continue unless solutions are found. Recently, a newly discovered bacterium, Ideonella sakaiensis 201-F6, was shown to exhibit the rare ability to grow on PET as a major carbon and energy source. Central to its PET biodegradation capability is a secreted PETase (PET-digesting enzyme). Here, we present a 0.92 Å resolution X-ray crystal structure of PETase, which reveals features common to both cutinases and lipases. PETase retains the ancestral α/ß-hydrolase fold but exhibits a more open active-site cleft than homologous cutinases. By narrowing the binding cleft via mutation of two active-site residues to conserved amino acids in cutinases, we surprisingly observe improved PET degradation, suggesting that PETase is not fully optimized for crystalline PET degradation, despite presumably evolving in a PET-rich environment. Additionally, we show that PETase degrades another semiaromatic polyester, polyethylene-2,5-furandicarboxylate (PEF), which is an emerging, bioderived PET replacement with improved barrier properties. In contrast, PETase does not degrade aliphatic polyesters, suggesting that it is generally an aromatic polyesterase. These findings suggest that additional protein engineering to increase PETase performance is realistic and highlight the need for further developments of structure/activity relationships for biodegradation of synthetic polyesters.

Prophylactic Bronchial Stump Support With Intrathoracic Muscle Flap Transposition.

BACKGROUND: Bronchopleural fistula (BPF) is a dreaded complication of pulmonary resection. For high-risk patients, bronchial stump coverage with vascularized tissue has been recommended. The goal of this study was to report our experience with intrathoracic muscle transposition for bronchial stump coverage. METHODS: A retrospective review of all patients who underwent intrathoracic muscle flap transposition as a prophylactic measure at our institution between 1990 and 2010 was conducted. Demographics, surgical characteristics, and complication rates were abstracted and analyzed. RESULTS: A total of 160 patients were identified. The most common lung resections performed were pneumonectomy (n = 69, 43%) and lobectomy (n = 60, 38%). A total of 168 flaps were used where serratus anterior was the most common flap (n = 136, 81%), followed by intercostal (n = 14, 8%), and latissimus dorsi (n = 12, 7%). Ten patients (6%) developed BPF, and empyema occurred in 13 patients (8%). Median survival was 20 months, and operative mortality occurred in 7 patients (4%). CONCLUSIONS: Reinforcement of the bronchial closure with vascularized muscle is a viable option for potentially decreasing the incidence of BPF in high-risk patients. Further randomized studies are needed to determine the efficacy of this technique for BPF prevention.

Extraversion development in childhood, adolescence and adulthood: Testing the role of sport participation in three nationally-representative samples.

This research sought to test whether sport participation relates to the development of trait extraversion across three life phases. Sport participation and extraversion were measured in children aged 10.5 ± 0.5 years (n = 3600), in adolescents aged 14.5 ± 0.5 years (n = 3463), and in adults with a mean age of 49.4 ± 18.0 years (n = 12,280), with corresponding data collected four years earlier. There were small mean-level decreases in extraversion during childhood and adulthood, and a large decrease in extraversion during adolescence. Four-year rank-order stability in extraversion was .58 in childhood, .61 in adolescence and .76 in adulthood. Sport participation was associated with higher extraversion in all three samples. After controlling for sociodemographic factors, children and adolescents who dropped out of sport showed greater decreases in extraversion than those who continued participation in sport. Sport participation was unrelated to mean-level change in extraversion during adulthood. Sport participation was also associated with greater intra-individual stability in extraversion for children, adolescents and adults. There were no significant sex moderation effects for mean-level change or individual-level stability. These findings provide evidence that sport participation might have an important role in trait extraversion stability and change across the lifespan.

A Matched Control Trial of a Mental Health Literacy Intervention for Parents in Community Sports Clubs.

This controlled trial evaluated the effectiveness of a mental health literacy intervention for parents delivered through community sport clubs. In total, 540 parents (321 females, 219 males) of adolescent athletes participated in a brief educational workshop on youth mental health (n = 352) or a community-matched control group (n = 188). Generalised linear mixed models revealed no significant improvements in the intervention group compared to control in the primary mental health literacy outcomes, at 1 month follow-up. However, parents in the intervention group were more likely to seek formal help for themselves, had increased confidence and knowledge to help someone experiencing a mental health disorder, experienced reduced psychological distress, and perceived more support from other parents in their sport club, relative to the control group. Overall, the findings suggest that a brief educational intervention delivered through community sports clubs can positively affect some components of parents' mental health literacy.

Recruitment of TBK1 to cytosol-invading Salmonella induces WIPI2-dependent antibacterial autophagy.

Mammalian cells deploy autophagy to defend their cytosol against bacterial invaders. Anti-bacterial autophagy relies on the core autophagy machinery, cargo receptors, and "eat-me" signals such as galectin-8 and ubiquitin that label bacteria as autophagy cargo. Anti-bacterial autophagy also requires the kinase TBK1, whose role in autophagy has remained enigmatic. Here we show that recruitment of WIPI2, itself essential for anti-bacterial autophagy, is dependent on the localization of catalytically active TBK1 to the vicinity of cytosolic bacteria. Experimental manipulation of TBK1 recruitment revealed that engagement of TBK1 with any of a variety of Salmonella-associated "eat-me" signals, including host-derived glycans and K48- and K63-linked ubiquitin chains, suffices to restrict bacterial proliferation. Promiscuity in recruiting TBK1 via independent signals may buffer TBK1 functionality from potential bacterial antagonism and thus be of evolutionary advantage to the host.

Pathological complete response to neoadjuvant systemic therapy in 789 early and locally advanced breast cancer patients: The Royal Marsden experience.

PURPOSE: Pathological complete response (pCR) after neoadjuvant chemotherapy (NACT) for breast cancer predicts the risk of recurrence and increasingly may indicate the need for additional therapy postoperatively. METHODS: We identified non-metastatic breast cancer patients receiving NACT during 2013-2017. Patients' and disease characteristics, rates of pCR (ypT0-is ypN0), toxicities, dose delays and reductions, and survival outcomes were recorded. RESULTS: 789 patients had median age of 50 years. 67.8% had stage II disease, 71.1% had grade 3 , and 91.8% had ductal histopathology. 32.8% had estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative, 25.5% had triple-negative (TN), and 38.0% HER2-positive disease. 6.8% received platinum. 48.2% of the HER2-positive patients received trastuzumab and pertuzumab and 51.8% received trastuzumab. Overall pCR rate was 33.5% and differed according to disease subtype, receptor status, grade, histology, and early discontinuation, but not according to age, dose reductions/delays, or year of treatment. The addition of pertuzumab to trastuzumab marginally improved the pCR rates. Survival outcomes were better following pCR. CONCLUSIONS: In our analysis, pCR rates are consistent with the published data. Even with contemporary therapies, many patients have residual disease following NACT, suggesting a significant risk of recurrence, and may benefit from additional postoperative systemic therapy.

A ten-minute, single step, label-free, sample-to-answer assay for qualitative detection of cytokines in serum at femtomolar levels.

Label-free electronic affinity based immuno-sensing is an attractive candidate as a platform technology for analyzing biomarkers due to the ease of miniaturization and minimal use of reagents. Electronic based sensing approaches, however, have lagged behind their optical counterparts in terms of detection limit, selectivity, and reliability. Also, the matrix dependent nature of electronic sensing modalities makes difficult the analysis of biomarkers in high salt concentration samples such as serum due to charge screening. We present a novel sensing platform, the micro-well sensor, that works by functionalizing nanoscale volume wells with antibodies and monitoring the impedance change inside the wells due binding of target protein. This detection modality is advantageous to many label-free electronic sensors in that signal power scales with increase in salt concentration, thus improving the sensitivity of the platform. We demonstrate rapid label-free qualitative detection of cytokines within ten minutes at femtoMolar concentrations and a dynamic range of 3 orders of magnitude in serum samples. We describe the design, fabrication, and characterization of the micro-well sensor in serum samples using inflammatory protein biomarkers.

A Systematic Review of Parent and Caregiver Mental Health Literacy.

This study aimed to systematically review the current body of research on parent and caregiver mental health literacy. Electronic databases were searched in January 2018 with 21 studies meeting inclusion criteria. A narrative synthesis of quantitative and qualitative studies was conducted. Findings across studies suggest that parents and caregivers had limited mental health knowledge. Factors associated with help-seeking included cultural and religious beliefs, financial and knowledge barriers, fear and mistrust of treatment services, and stigma. Notable limitations include non-representative samples, cross-sectional research designs, and use of inconsistent and non-validated study measures. Research would benefit from more diverse samples, an increased focus on prevention, and controlled trials of educational programmes targeting mental health literacy.

Crystal Structures and Nuclear Magnetic Resonance Studies of the Apo Form of the c-MYC:MAX bHLHZip Complex Reveal a Helical Basic Region in the Absence of DNA.

The c-MYC transcription factor is a master regulator of cell growth and proliferation and is an established target for cancer therapy. This basic helix-loop-helix Zip protein forms a heterodimer with its obligatory partner MAX, which binds to DNA via the basic region. Considerable research efforts are focused on targeting the heterodimerization interface and the interaction of the complex with DNA. The only available crystal structure is that of a c-MYC:MAX complex artificially tethered by an engineered disulfide linker and prebound to DNA. We have carried out a detailed structural analysis of the apo form of the c-MYC:MAX complex, with no artificial linker, both in solution using nuclear magnetic resonance (NMR) spectroscopy and by X-ray crystallography. We have obtained crystal structures in three different crystal forms, with resolutions between 1.35 and 2.2 Å, that show extensive helical structure in the basic region. Determination of the α-helical propensity using NMR chemical shift analysis shows that the basic region of c-MYC and, to a lesser extent, that of MAX populate helical conformations. We have also assigned the NMR spectra of the c-MYC basic helix-loop-helix Zip motif in the absence of MAX and showed that the basic region has an intrinsic helical propensity even in the absence of its dimerization partner. The presence of helical structure in the basic regions in the absence of DNA suggests that the molecular recognition occurs via a conformational selection rather than an induced fit. Our work provides both insight into the mechanism of DNA binding and structural information to aid in the development of MYC inhibitors.

Biodegradable batteries with immobilized electrolyte for transient MEMS.

Biodegradable batteries play an important role in fully degradable biomedical or environmental systems. The development of biodegradable batteries faces many challenges including power content, device compactness, performance stability, shelf and functional lifetime. In particular, a key driver in the lifetime and overall size of microfabricated biodegradable batteries is the liquid electrolyte volume. Harnessing liquid from the environment to serve as the battery electrolyte may, therefore, be desirable; however, for stable operation, maintaining a constant electrochemical environment inside the cell is required even in the presence of changing body or environmental conditions. We report a biodegradable battery featuring a solid electrolyte of sodium chloride and polycaprolactone. This approach harnesses the body fluid that diffuses into the cell as an element of the electrolyte; however, the large excess of sodium chloride suspended in the polycaprolactone holds intracell ionic conditions constant. A constant discharge profile can then be achieved even in the presence of varying external aqueous conditions, enabling compact, stable-performing cells. This design also features easy integration and automatic activation, providing a simplified strategy to fabricate batteries with long shelf life and desirable functional life span. In addition, the polymeric skeleton of the solid electrolyte system acts as an insulating layer between electrodes, preventing the metallic structure from short-circuit during discharge.

Erectile Dysfunction: An Umbrella Review of Meta-Analyses of Risk-Factors, Treatment, and Prevalence Outcomes.

INTRODUCTION: Erectile dysfunction (ED) is a major health care problem that has implications for quality of life. AIM: This umbrella review sought to synthesize all meta-analytic research on risk factors, treatment, and prevalence of ED. METHODS: 8 electronic databases were searched for relevant meta-analyses in June 2018. The evidence was graded with 2 measures that use quantitative criteria to establish the quality of report writing and confidence in the effect size reported. MAIN OUTCOME MEASURES: Lifestyle factors, genetic markers, medical conditions, treatments. RESULTS: In total, 98 meta-analyses were identified that included 421 meta-analytic effects, 4,188 primary-effects, and 3,971,122 participants. Pooled estimates showed that an unhealthy lifestyle, genetic markers, and medical conditions were associated with an increased risk of ED. Testosterone therapy and phosphodiesterase type 5 inhibitors showed the greatest treatment efficacy, with mild adverse events observed across treatments. Psychological and behavior change interventions produced effect sizes that were comparable to medication but had greater imprecision in effect sizes. There was little evidence that combined treatments were more efficacious than single treatments. Meta-analyses of prevalence estimates showed consistent age trends but were limited to particular regions or clinical samples, meaning that global estimates of ED are difficult to determine. CLINICAL IMPLICATIONS: The umbrella review synthesized findings for many treatment options that might aid evidence-based clinical decision-making. Based on prevalence estimates, we recommend that primary care physicians take a proactive approach and enquire about erectile problems in all men over age 40 displaying any health-related issue (eg, overweight, cigarette smoking). STRENGTHS & LIMITATIONS: Strengths include the calculation and comparison of summary estimates across multiple meta-analyses. Limitations include heterogeneity in research quality across research themes limiting effect size comparisons. CONCLUSION: The review provides summary estimates for 37 risk factors and 28 treatments. Meta-analyses of risk factors often did not control for important confounders, and meta-analyses of randomized trials were not exclusive to double-blinded trials, active placebo controls, or tests of long-term effects. We recommend further meta-analyses that eliminate lower quality studies and further primary research on behavioral and combined treatments. Allen MS, Walter EE. Erectile Dysfunction: An Umbrella Review of Meta-Analyses of Risk-Factors, Treatment, and Prevalence Outcomes. J Sex Med 2019;16:531-541.

Resource scarcity drives lethal aggression among prehistoric hunter-gatherers in central California.

The origin of human violence and warfare is controversial, and some scholars contend that intergroup conflict was rare until the emergence of sedentary foraging and complex sociopolitical organization, whereas others assert that violence was common and of considerable antiquity among small-scale societies. Here we consider two alternative explanations for the evolution of human violence: (i) individuals resort to violence when benefits outweigh potential costs, which is likely in resource poor environments, or (ii) participation in violence increases when there is coercion from leaders in complex societies leading to group level benefits. To test these hypotheses, we evaluate the relative importance of resource scarcity vs. sociopolitical complexity by evaluating spatial variation in three macro datasets from central California: (i) an extensive bioarchaeological record dating from 1,530 to 230 cal BP recording rates of blunt and sharp force skeletal trauma on thousands of burials, (ii) quantitative scores of sociopolitical complexity recorded ethnographically, and (iii) mean net primary productivity (NPP) from a remotely sensed global dataset. Results reveal that sharp force trauma, the most common form of violence in the record, is better predicted by resource scarcity than relative sociopolitical complexity. Blunt force cranial trauma shows no correlation with NPP or political complexity and may reflect a different form of close contact violence. This study provides no support for the position that violence originated with the development of more complex hunter-gatherer adaptations in the fairly recent past. Instead, findings show that individuals are prone to violence in times and places of resource scarcity.