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PURPOSE Cancer genetic risk assessment (CGRA) is recommended for women with ovarian cancer or high-risk breast cancer, yet fewer than 30% receive recommended genetic services, with the lowest rates among underserved populations. We hypothesized that compared with usual care (UC) and mailed targeted print (TP) education, CGRA uptake would be highest among women receiving a phone-based tailored risk counseling and navigation intervention (TCN). METHODS In this three-arm randomized trial, women with ovarian or high-risk breast cancer were recruited from statewide cancer registries in Colorado, New Jersey, and New Mexico. Participants assigned to TP received a mailed educational brochure. Participants assigned to TCN received the mailed educational brochure, an initial phone-based psychoeducational session with a health coach, a follow-up letter, and a follow-up navigation phone call. RESULTS Participants' average age was 61 years, 25.4% identified as Hispanic, 5.9% identified as non-Hispanic Black, and 17.5% lived in rural areas. At 6 months, more women in TCN received CGRA (18.7%) than those in TP (3%; odds ratio, 7.4; 95% CI, 3.0 to 18.3; P < .0001) or UC (2.5%; odds ratio, 8.9; 95% CI, 3.4 to 23.5; P < .0001). There were no significant differences in CGRA uptake between TP and UC. Commonly cited barriers to genetic counseling were lack of provider referral (33.7%) and cost (26.5%), whereas anticipated difficulty coping with test results (14.0%) and cost (41.2%) were barriers for genetic testing. CONCLUSION TCN increased CGRA uptake in a group of geographically and ethnically diverse high-risk breast and ovarian cancer survivors. Remote personalized interventions that incorporate evidence-based health communication and behavior change strategies may increase CGRA among women recruited from statewide cancer registries.

Prurigo nodularis (PN) is a chronic inflammatory skin disease with intensely pruritic nodules. The LIBERTY-PN PRIME and PRIME2 phase 3 trials enrolled adults with PN with ≥20 nodules and severe itch uncontrolled with topical therapies. Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin (IL)-4 and IL-13. Patients were randomized 1:1 to 300 mg dupilumab or placebo subcutaneously every 2 weeks for 24 weeks. The primary endpoint was pruritus improvement, measured by proportion of patients with a ≥4-point reduction in Worst Itch Numeric Rating Scale (WI-NRS) from baseline at week 24 (PRIME) or week 12 (PRIME2). Key secondary endpoints included nodule number reduction to ≤5 at week 24. PRIME and PRIME2 enrolled 151 and 160 patients, respectively. Both trials met all the pre-specified primary and key secondary endpoints. A ≥4-point WI-NRS reduction at week 24 in the dupilumab and placebo arms was achieved by 60.0% and 18.4% of patients, respectively, in PRIME (95% confidence interval (CI), 27.8–57.7 for the difference, P P = 0.022). Dupilumab demonstrated clinically meaningful and statistically significant improvements in itch and skin lesions versus placebo in PN. Safety was consistent with the known dupilumab safety profile.ClinicalTrials.gov identifiers: NCT04183335 and NCT04202679.

Objectives: The COVID-19 pandemic affected consumers’ access to oral health care. This study evaluated factors associated with teledentistry use among US adults from June 2019 through June 2020. Methods: We used data from a nationally representative survey of 3500 consumers. We estimated teledentistry use and adjusted associations with respondents’ concerns about the impacts of the pandemic on health and welfare and with their sociodemographic characteristics using Poisson regression models. We also analyzed teledentistry use across 5 teledentistry modalities (email, telephone, text, video conferencing, and mobile application). Results: Overall, 29% of respondents used teledentistry, and 68% of teledentistry users reported doing so for the first time because of the COVID-19 pandemic. First-time teledentistry use was positively associated with a high level of pandemic concerns (relative risk [RR] = 5.02; 95% CI, 3.49-7.20), age 35-44 years (RR = 4.22; 95% CI, 2.89-6.17), and annual household income $100 000-$124 999 (RR = 2.10; 95% CI, 1.55-2.84) and negatively associated with rural residence (RR = 0.68; 95% CI, 0.50-0.94). Having a high level of pandemic concerns (RR = 3.42; 95% CI, 2.30-5.08), young age (age 25-34 years: RR = 5.05; 95% CI, 3.23-7.90), and higher level of education (some college: RR = 1.59; 95% CI, 1.22-2.07) were strongly associated with teledentistry use for all “other” users (ie, existing or first-time use because of reasons unrelated to the pandemic). Most first-time teledentistry users used email (74.2%) and mobile applications (73.9%), whereas “other” teledentistry users used telephone communication (41.3%). Conclusions: Teledentistry use during the pandemic was higher in the general population than among those for whom teledentistry programs were originally designed (eg, low-income, rural populations). Favorable regulatory changes to teledentistry should be expanded to meet patient needs beyond the pandemic.

Background: The PRIMA/ENGOT-OV26/GOG-3012 (NCT02655016) trial was amended to prospectively evaluate the safety and efficacy of an individualized starting dose (ISD) regimen of niraparib for first-line maintenance therapy in patients with newly diagnosed advanced ovarian cancer. Methods: In the phase 3 PRIMA trial, patients with newly diagnosed advanced ovarian cancer with a complete/partial response to first-line platinum-based chemotherapy (N = 733) were initially treated with a fixed starting dose (FSD) regimen of 300 mg every day. Subsequently, the protocol was amended so newly enrolled patients received an ISD: 200 mg every day in patients with baseline body weight < 77 kg or baseline platelet count < 150,000/mu L, and 300 mg every day in all other patients. Efficacy and safety outcomes were assessed by starting dose. Results: Overall, 475 (64.8%) patients were assigned to an FSD (niraparib, n = 317; placebo, n = 158) and 258 (35.2%) were assigned to an ISD (niraparib, n = 170; placebo, n = 88). Efficacy in patients who received FSD or ISD was similar for the overall (FSD hazard ratio [HR], 0.59 [95% CI, 0.46-0.76] vs. ISD HR, 0.69 [95% CI, 0.48-0.98]) and the homologous recombination-deficient (FSD HR, 0.44 [95% CI, 0.30-0.64] vs. ISD HR, 0.39 [95% CI, 0.22-0.72]) populations. In patients with low body weight/platelet count, rates of grades =3 and 4 hematologic treatment-emergent adverse events, dose interruptions, and dose reductions were lower for those who received ISD than for those who received FSD. Conclusions: In PRIMA, similar dose intensity, similar efficacy, and improved safety were observed with the ISD compared with the FSD regimen.

The recent Covid-19 pandemic highlighted stark social inequalities, notably around access to food, nutrition and to green or blue space (i.e. outdoor spaces with vegetation and water). Consequently, obesity is socio-economically patterned by this inequality; and while the environmental drivers of obesity are widely acknowledged, there is currently little upstream intervention. We know that living with obesity contributes to increasing health inequalities, and places healthcare systems under huge strain. Our environment could broadly be described obesogenic, in the sense of supporting unhealthful eating patterns and sedentary behaviour. Evidence points to the existence of nearly 700 UK obesity policies, all of which have had little success. Obesity prevention and treatment has focused on educational and behavioural interventions targeted at individual consumers. A more sustainable approach would be to try and change the environments that promote less healthy eating and high energy intake as well as sedentary behaviour. Approaches which modify the environment have the potential to assist in the prevention of this complex condition. This review paper focuses on the role of wider food environments or foodscapes. While there is an imperfect evidence base relating to the role of the foodscape in terms of the obesity crisis, policy, practice, civic society and industry must work together and take action now, in areas where current evidence suggests change is required. Despite the current cost-of-living crisis, shaping the foodscape to better support healthful eating decisions has the potential to be a key aspect of a successful obesity prevention intervention.

In this paper, we present the results of a study that examines the role of data in nonprofit advocacy work. We conducted semi-structured interviews with 25 individuals who play critical roles in the data work of 18 different advocacy organizations. Our analysis reveals five key stakeholders in advocacy data work-beneficiaries, policymakers, funding and partner organizations, gatekeepers, and local publics. It also contributes a framework of four functions of data work in nonprofit organizations-data as amplifier, activator, legitimizer, and incubator. We characterize the challenges in data work that exist, particularly in widespread attempts to reappropriate data work across functions. These challenges in reappropriation are often rooted in participants' effects to enact data feminist principles from the margins of the data economy. Finally, we discuss how nonprofit institutions operate outside of the dominant data work goals known as the three Ss (surveillance, selling, and science) and propose a fourth S, social good, that is working to challenge the norms of the data economy and should be considered in research regarding the data economy moving forward.

Non-uniform shell growth commonly caused by the peritectic transformation in low carbon and low alloy steels has been directly correlated with mold thermal maps using a mold immersion test into a molten steel alloy. Mold thermal maps were obtained by performing real-time temperature measurements with optical fibers embedded 1 mm from the mold working surface. Shell growth measurements were obtained by 3D optical scanning of the recovered steel shell following immersion testing. The effects of silicon and manganese on the shell growth and mold temperature maps have been examined in relation to the peritectic transformation for varying carbon contents. Results of thermodynamic and kinetic simulations using ThermoCalc and its kinetic module—DICTRA predicted that silicon expands the carbon content range to values between (0.12 pct C to 0.21 pct C) where peritectic behavior occurs and that manganese shrinks the carbon content range and shifts the range to lower carbon contents (0.06 pct C to 0.12 pct C). The results of these simulations were used to guide the selection of chemistries examined in the dip test experiments with the aim of validating the software predictions. Dip tests were performed at similar steel making temperatures that were used for the software simulations between 1600 °C and 1650 °C. Both software results and experimental observation showed relatively good agreement for the compositions examined.

This article contains a short update on the work of the sigma Accessibility Special Interest Group. We announce the release of resources to assist mathematics tutors and coordinators with the support of mature students and those with dyslexia, dyscalculia and dyspraxia. We provide a brief background to the development of these resources and describe their pilot in two institutions, one in England and the other in Ireland. We close with a description of the next stages of work for the special interest group and a call for additional people to get involved.

Research organizations should be proactive in regularly evaluating and refining their animal care and use programs in order to advance animal welfare and minimize distress. Pigs are often used in research, but few empirical studies have examined optimal husbandry and research use practices for pigs in a research environment. We developed the Pig Welfare Working Group (PWWG) to address the need for more formal guidelines on the management and use of pigs in research. The PWWG was a stakeholder focus group whose goal was to identify challenges and opportunities relevant to improving animal welfare through collaboration, knowledge sharing, and inclusive decision-making. Through consensus building, the PWWG developed 12 recommendations for behavioral management, housing, research procedures, transportation, and rehoming programs. The recommendations were rolled out across the contract research organization, business units, sites, and countries. Follow up will be conducted regularly to assess welfare, monitor progress toward implementing the recommendations, and recognize and reward participants making changes at their site.

Introduction Isolated volar dislocations of the distal radioulnar joint are reported as rare. We observed three such cases over a 12-month period. Literature to date consists of multiple case reports and case series with no structured reviews. There is debate as to incidence, mechanism, investigation, treatment and prognosis. Methods A case series and formal systematic review was performed. This included an analysis of the demographics, mechanism, presentation, investigation, treatment and outcome of the cases identified from the wider published series. Findings In total 99 cases of this injury were identified from 59 papers, with a further 9 cases having an associated ulna styloid fracture. Conclusions This is a rare injury, representing up to 0.02% of all bony injuries, which is diagnosed late in 36% of cases. Inability to obtain a true lateral radiograph may contribute to the diagnosis being missed. Computed tomography scans are useful in suspected cases without radiographic confirmation. Acute cases are successfully treated with closed reduction in 78% of cases; however associated soft tissue injuries may need to be surgically addressed. Delayed presentation is more likely to require open surgery and preoperative MRI scans are indicated to aid surgical planning. Chronic instability rarely occurs and may need treatment with reconstruction or salvage. A good, subjective, result is reported in the majority of patients.

Background Outcomes for patients with metastatic renal cell carcinoma (mRCC) and tumour thrombus remain poor. Recent data suggest limited role for cytoreductive nephrectomy (CN) and data on thrombus response to systemic therapy (ST) is scarce. Here, we describe response and survival of patients with de novo mRCC and thrombi treated with ST with or without CN. Methods Demographics, disease characteristics and survival of patients with de novo mRCC were collected. Progression-free survival (PFS) and overall survival (OS) in months (m) was calculated using the Kaplan–Meier method (log-rank). Results Between 2002 and 2019, 226 patients with mRCC were identified, 64 (28.3%) had tumour thrombus out of which 18 (28.1%) received only ST. Among 12 evaluable patients, thrombus response, stability and progression were seen in 3 (25%), 6 (50%) and 3 (25%) patients, respectively. Median OS was similar for patients with and without tumour thrombus treated with systemic therapy alone [OS: 12.1 m (8.8–27.7) vs. 13.9 m (7.9–21.5), p = 0.87]. CN predicted for better OS in patients with tumour thrombus [OS: 29.4 m (17.4–48.9) vs. 12.1 m (8.8–27.7), p = 0.01]. Conclusion In this retrospective series of patients with mRCC and tumour thrombus, addition of CN to ST improved outcomes. Validation of these findings with contemporary regimens is needed.

End-stage kidney disease, the most advanced stage of chronic kidney disease (CKD), requires renal replacement therapy or kidney transplant to sustain life. To accomplish durable dialysis access, the creation of an arteriovenous fistula (AVF) has emerged as a preferred approach. Unfortunately, a significant proportion of patients that receive an AVF experience some form of hand dysfunction; however, the mechanisms underlying these side effects are not understood. In this study, we used nuclear magnetic resonance spectroscopy to investigate the muscle metabolome following iliac AVF placement in mice with CKD. To induce CKD, C57BL6J mice were fed an adenine-supplemented diet for 3 wk and then randomized to receive AVF or sham surgery. Two weeks following surgery, the quadriceps muscles were rapidly dissected and snap frozen for metabolite extraction and subsequent nuclear magnetic resonance analysis. Principal component analysis demonstrated clear separation between groups, confirming a unique metabolome in mice that received an AVF. AVF creation resulted in reduced levels of creatine, ATP, and AMP as well as increased levels of IMP and several tricarboxylic acid cycle metabolites suggesting profound energetic stress. Pearson correlation and multiple linear regression analyses identified several metabolites that were strongly linked to measures of limb function (grip strength, gait speed, and mitochondrial respiration). In summary, AVF creation generates a unique metabolome profile in the distal skeletal muscle indicative of an energetic crisis and myosteatosis.

To report speech outcomes after cochlear implantation (CI) for asymmetric hearing loss (AHL) and assess the influence of contralateral hearing.Retrospective review.Tertiary referral center.One hundred eighty-eight adults (mean age, 70 yr) undergoing CI for AHL from 2015 to 2020. Candidacy included pure-tone average (PTA) at least 70 dB hearing level and AzBio in quiet 60% or less in the implanted ear and AzBio in quiet greater than 40% in the contralateral ear.PTA; Consonant-Nucleus-Consonant (CNC) word, AzBio sentences scores; Speech, Spatial, and Qualities of Hearing Scale (SSQ).Mean preoperative PTA and AzBio in the implanted and contralateral ears were 85.2 and 68.1 dB hearing level and 24.7% and 69.2%, respectively. Mean CNC in the implanted ear increased from 18.3% preoperatively to 44.4% ( p0.0001) at 6 months and 49.3% ( p0.0001) at 12 months. Mean AzBio in the implanted ear improved from 24.7% preoperatively to 60.3% ( p0.0001) at 6 months and 64.3% ( p0.0001) at 12 months. Patients demonstrated significant improvement in all SSQ domains at 6 and 12 months. When comparing patients with preoperative contralateral AzBio greater than 60% versus 41% to 60%, no significant differences existed in postoperative CNC scores (6-mo: 47% versus 41%, p = 0.276; 12-mo: 51% versus 47%, p = 0.543). There were no significant differences in 6-month ( p = 0.936) or 12-month ( p = 0.792) CNC scores between patients with AHL (contralateral ear AzBio40%) and 169 unilateral CI patients meeting the traditional Medicare criteria (contralateral ear AzBio ≤40%).CI recipients with AHL derive significant speech improvements, supporting individual ear consideration for CI candidacy and patient benefit outside of current Medicare criteria.

Objectives: To examine and compare rates and methods of self-harm presenting to a tertiary referral hospital during an 18-month period since the onset of the COVID-19 pandemic with a similar period immediately prior to the pandemic onset. Methods: Data from an anonymized database compared rates of self-harm presentations and methods employed between 1st March 2020 and 31st August 2021 to a similar time-frame prior to the onset of the COVID-19 pandemic. Results: A 9.1% increase in presentations with self-harm was noted since the onset of the COVID-19 pandemic. Periods of more stringent restrictions were associated with higher levels of self-harm (daily rate of 2.10 v 0.77). A higher lethality of attempt was demonstrated post-COVID-19 onset (χ2 = 15.38, p < 0.001). Fewer individuals presenting with self-harm were diagnosed with an adjustment disorder since the onset of the COVID-19 pandemic (n = 84, 11.1%, v. n = 112, 16.2%, χ2 = 7.898, p = 0.005), with no other differences pertaining to psychiatric diagnosis noted. More patients actively engaged with mental health services (MHS) presented with self-harm (n = 239 (31.7%) v. n = 137, (19.8%), χ2 = 40.798, p ≤ 0.001) since the onset of the COVID-19 pandemic. Conclusions: Despite an initial reduction, an increase in rates of self-harm has occurred since the onset of the COVID-19 pandemic with higher rates evident during periods of higher government mandated restrictions. An increase in active patients of MHS presenting with self-harm potentially relates to reduced availability of supports and particularly group activities. The recommencement of group therapeutic interventions for individuals attending MHS in particular is warranted.

Background: The comparative real-world outcomes of older patients with atrial fibrillation (AF) treated with anticoagulation compared with left atrial appendage occlusion (LAAO) may be different from those in clinical trials because of differences in anticoagulation strategies and patient demographics, including a greater proportion of women. We sought to compare real-world outcomes between older patients with AF treated with anticoagulation and those treated with LAAO by sex. Methods: Using Medicare claims data from 2015 to 2019, we identified LAAO-eligible beneficiaries and divided them into sex subgroups. Patients receiving LAAO were matched 1:1 to those receiving anticoagulation alone through propensity score matching. The risks of mortality, stroke or systemic embolism, and bleeding were compared between matched groups with adjustment for potential confounding characteristics in Cox proportional hazards models. Results: Among women, 4085 LAAO recipients were matched 1:1 to those receiving anticoagulation; among men, 5378 LAAO recipients were similarly matched. LAAO was associated with a significant reduction in the risk of mortality for women and men (hazard ratio [HR], 0.509 [95% CI, 0.447–0.580]; and HR, 0.541 [95% CI, 0.487–0.601], respectively; P P P Conclusions: In a real-world population of older Medicare beneficiaries with AF, compared with anticoagulation, LAAO was associated with a reduction in the risk of death, stroke, and long-term bleeding among women and men. These findings should be incorporated into shared decision-making with patients considering strategies for reduction in AF-related stroke.

Tumor-associated macrophages (TAM) play an important role in maintaining the immunosuppressive state of the tumor microenvironment (TME). High levels of CD163+ TAMs specifically are associated with poor prognosis in many solid tumor types. Targeting TAMs may represent a key approach in development of the next generation of cancer immune therapeutics. Members of the leukocyte immunoglobulin-like receptor B (LILRB) family, including LILRB2 (ILT4), are known to transmit inhibitory signals in macrophages and other myeloid cells. Leveraging bulk and single cell RNA-sequencing datasets, as well as extensive immunophenotyping of human tumors, we found that LILRB2 is highly expressed on CD163+ CD11b+ cells in the TME and that LILRB2 expression correlates with CD163 expression across many tumor types. To target LILRB2, we have developed JTX-8064, a highly potent and selective antagonistic mAb. JTX-8064 blocks LILRB2 binding to its cognate ligands, including classical and nonclassical MHC molecules. In vitro, JTX-8064 drives the polarization of human macrophages and dendritic cells toward an immunostimulatory phenotype. As a result, human macrophages treated with a LILRB2 blocker are reprogrammed to increase the activation of autologous T cells in co-culture systems. Furthermore, JTX-8064 significantly potentiates the activity of anti-PD-1 in allogeneic mixed lymphocyte reaction. In a human tumor explant culture, pharmacodynamic activity of JTX-8064 was observed in monotherapy and in combination with anti-PD-1. Collectively, our work provides strong translational and preclinical rationale to target LILRB2 in cancer.

Evidence on post-diagnostic support for people with young onset dementia is scarce. Previous studies have employed a problem-focused approach; however, evidence on ‘what works’ in real-life practice is essential to develop recommendations for service design and delivery. This study aimed to provide insight into ‘what works’ from the perspectives of people with young onset dementia and their supporters. We gathered free-text responses on positive service experiences via a UK cross-sectional survey. Inductive thematic analysis was used to identify the objectives of positive services and the needs these met. Follow-up interviews enabled in-depth insights from people with diverse diagnoses, ages and social situations. These were analysed using a template drawn from the survey. The 233 survey respondents gave 856 examples of positive support. Analysis of 24 follow-up interviews led to 16 themes clustered under three superordinate themes: ‘maintaining autonomy’, ‘being myself’ and ‘togetherness’. We found that positive services address the disruptions to sense of agency, selfhood and meaningful relationships that are experienced by those with young onset dementia. The study provides an in-depth understanding of the needs met by positive services for younger people with dementia. Our nuanced findings on good practice can inform age-specific guidelines for young onset dementia and indicate how personalisation can work in practice to help people with young onset dementia to maintain identity, autonomy and connections.

The functional properties of proteorhodopsin (PR) have been found to be strongly modulated by oligomeric distributions and lipid membrane mimetics. This study aims to distinguish and explain their effects by investigating how oligomer formation impacts PR's function of proton transport in lipid-based membrane mimetic environments. We find that PR forms stable hexamers and pentamers in both E. coli membranes and synthetic liposomes. Compared with the monomers, the photocycle kinetics of PR oligomers is ∼2 and ∼4.5 times slower for transitions between the K and M and the M and N photointermediates, respectively, indicating that oligomerization significantly slows PR's rate of proton transport in liposomes. In contrast, the apparent pKa of the key proton acceptor residue D97 (pKa

BACKGROUND: Urinary tract infection (UTI) symptoms are common in primary care, but antibiotics are appropriate only when an infection is present. Urine culture is the reference standard test for infection, but results take >1 day. A machine learning predictor of urine cultures showed high accuracy for an emergency department (ED) population but required urine microscopy features that are not routinely available in primary care (the NeedMicro classifier). METHODS: We redesigned a classifier (NoMicro) that does not depend on urine microscopy and retrospectively validated it internally (ED data set) and externally (on a newly curated primary care [PC] data set) using a multicenter approach including 80,387 (ED) and 472 (PC) adults. We constructed machine learning models using extreme gradient boosting (XGBoost), artificial neural networks, and random forests (RFs). The primary outcome was pathogenic urine culture growing ≥100,000 colony forming units. Predictor variables included age; gender; dipstick urinalysis nitrites, leukocytes, clarity, glucose, protein, and blood; dysuria; abdominal pain; and history of UTI. RESULTS: Removal of microscopy features did not severely compromise performance under internal validation: NoMicro/XGBoost receiver operating characteristic area under the curve (ROC-AUC) 0.86 (95% CI, 0.86-0.87) vs NeedMicro 0.88 (95% CI, 0.87-0.88). Excellent performance in external (PC) validation was also observed: NoMicro/RF ROC-AUC 0.85 (95% CI, 0.81-0.89). Retrospective simulation suggested that NoMicro/RF can be used to safely withhold antibiotics for low-risk patients, thereby avoiding antibiotic overuse. CONCLUSIONS: The NoMicro classifier appears appropriate for PC. Prospective trials to adjudicate the balance of benefits and harms of using the NoMicro classifier are appropriate.

Community detection in networks is the process by which unusually well-connected sub-networks are identified–a central component of many applied network analyses. The paradigm of modularity quality function optimization stipulates a partition of the network’s vertexes that maximizes the difference between the fraction of edges within communities and the corresponding expected fraction if edges were randomly allocated among all vertex pairs while conserving the degree distribution. The modularity quality function incorporates exclusively the network’s topology and has been extensively studied whereas the integration of constraints or external information on community composition has largely remained unexplored. We define a greedy, recursive-backtracking search procedure to identify the constitution of high-quality network communities that satisfy the global constraint that each community be comprised of at least one vertex among a set of so-called special vertexes and apply our methodology to identifying health care communities (HCCs) within a network of hospitals such that each HCC consists of at least one hospital wherein at least a minimum number of cardiac defibrillator surgeries were performed. This restriction permits meaningful comparisons in cardiac care among the resulting health care communities by standardizing the distribution of cardiac care across the hospital network.