Targeting Unique Ligand Binding Domain Structural Features Downregulates DKK1 in Y537S ESR1 Mutant Breast Cancer Cells.

Resistance to endocrine therapies remains a major clinical hurdle in breast cancer. Mutations to estrogen receptor alpha (ERα) arise after continued therapeutic pressure. Next generation selective estrogen receptor modulators and degraders/downregulators (SERMs and SERDs) show clinical efficacy, but responses are often non-durable. A tyrosine to serine point mutation at position 537 in the ERα ligand binding domain (LBD) is among the most common and most pathogenic alteration in this setting. It enables endocrine therapy resistance by superceding intrinsic structural-energetic gatekeepers of ER hormone-dependence, it enhances metastatic burden by enabling neomorphic ER-dependent transcriptional programs, and it resists SERM and SERD inhibiton by reducing their binding affinities and abilities to antagonize transcriptional coregulator binding. However, a subset of SERMs and SERDs can achieve efficacy by adopting poses that force the mutation to engage in a new interaction that favors the therapeutic receptor antagonist conformation. We previously described a chemically unconventional SERM, T6I-29, that demonstrates significant anti-proliferative activities in Y537S ERα breast cancer cells. Here, we use a comprehensive suite of structural-biochemical, in vitro, and in vivo approaches to better T6I-29's activities in breast cancer cells harboring Y537S ERα. RNA sequencing in cells treated with T6I-29 reveals a neomorphic downregulation of DKK1, a secreted glycoprotein known to play oncogenic roles in other cancers. Importantly, we find that DKK1 is significantly enriched in ER+ breast cancer plasma compared to healthy controls. This study shows how new SERMs and SERDs can identify new therapeutic pathways in endocrine-resistant ER+ breast cancers.

Using Bulky Dodecaborane-Based Dopants to Produce Mobile Charge Carriers in Amorphous Semiconducting Polymers.

Conjugated polymers are a versatile class of electronic materials featured in a variety of next-generation electronic devices. The utility of such polymers is contingent in large part on their electrical conductivity, which depends both on the density of charge carriers (polarons) and on the carrier mobility. Carrier mobility, in turn, is largely controlled by the separation between the polarons and dopant counterions, as counterions can produce Coulombic traps. In previous work, we showed that large dopants based on dodecaborane (DDB) clusters were able to reduce Coulombic binding and thus increase carrier mobility in regioregular (RR) poly(3-hexylthiophene-2,5-diyl) (P3HT). Here, we use a DDB-based dopant to study the effects of polaron-counterion separation in chemically doped regiorandom (RRa) P3HT, which is highly amorphous. X-ray scattering shows that the DDB dopants, despite their large size, can partially order the RRa P3HT during doping and produce a doped polymer crystal structure similar to that of DDB-doped RR P3HT; Alternating Field (AC) Hall measurements also confirm a similar hole mobility. We also show that use of the large DDB dopants successfully reduces Coulombic binding of polarons and counterions in amorphous polymer regions, resulting in a 77% doping efficiency in RRa P3HT films. The DDB dopants are able to produce RRa P3HT films with a 4.92 S/cm conductivity, a value that is ∼200× higher than that achieved with 3,5,6-tetrafluoro-7,7,8,8-tetracyanoquinodimethane (F4TCNQ), the traditional dopant molecule. These results show that tailoring dopants to produce mobile carriers in both the amorphous and semicrystalline regions of conjugated polymers is an effective strategy for increasing achievable polymer conductivities, particularly in low-cost polymers with random regiochemistry. The results also emphasize the importance of dopant size and shape for producing Coulombically unbound, mobile polarons capable of electrical conduction in less-ordered materials.

Evaluating compliance with the care standard of proactively assessing bone health in patients with diabetes: a pilot audit of practice across Asia by the Asia Pacific Consortium on Osteoporosis (APCO).

This pilot audit explored how bone health is assessed patients with diabetes in diverse centres across Asia. Only 343 of 1092 (31%) audited patients had a bone health assessment, 27% of whom were diagnosed with osteoporosis. Quality improvement strategies are needed to address gaps in patient care in this area. PURPOSE: The Asia Pacific Consortium on Osteoporosis (APCO) Framework outlines clinical standards for assessing and managing osteoporosis. A pilot audit evaluated adherence to clinical standard 4, which states that bone health should be assessed in patients with conditions associated with bone loss and/or increased fracture risk; this report summarises the audit findings in patients with diabetes. A secondary aim was to assess the practicality and real-world use of the APCO bone health audit tool kit. METHODS: Eight centres across Asia participated in the pilot audit, selecting diabetes as the target group. Participants reviewed their practice records for at least 20 consecutively treated patients with the target condition. Questions covered routine investigations, bone health assessment, osteoporosis diagnosis, and patient referral pathways. Data were summarised descriptively. RESULTS: The participants represented public hospitals, university medical centres, and private clinics from India, Malaysia, Pakistan, Singapore, Taiwan, and Vietnam that see an estimated total of 95,000 patients with diabetes per year. Overall, only 343 of 1092 audited patients (31%) had a bone health assessment. Osteoporosis was subsequently diagnosed in 92 of 343 (27%) patients. CONCLUSION: Bone health was not assessed in most patients with diabetes. The results provide insight into current practices across diverse Asian centres and demonstrate the practical value of the audit tool kit. Participant feedback has been used to improve the tool kit. Results of this pilot audit are being used in the respective centres to inform quality improvement projects needed to overcome the gap in patient care.

Targeting Unique Ligand Binding Domain Structural Features Downregulates DKK1 in Y537S ESR1 Mutant Breast Cancer Cells.

Resistance to endocrine therapies remains a major clinical hurdle in breast cancer. Mutations to estrogen receptor alpha (ERα) arise after continued therapeutic pressure. Next generation selective estrogen receptor modulators and degraders/downregulators (SERMs and SERDs) show clinical efficacy, but responses are often non-durable. A tyrosine to serine point mutation at position 537 in the ERα ligand binding domain (LBD) is among the most common and most pathogenic alteration in this setting. It enables endocrine therapy resistance by superceding intrinsic structural-energetic gatekeepers of ER hormone-dependence, it enhances metastatic burden by enabling neomorphic ER-dependent transcriptional programs, and it resists SERM and SERD inhibiton by reducing their binding affinities and abilities to antagonize transcriptional coregulator binding. However, a subset of SERMs and SERDs can achieve efficacy by adopting poses that force the mutation to engage in a new interaction that favors the therapeutic receptor antagonist conformation. We previously described a chemically unconventional SERM, T6I-29, that demonstrates significant anti-proliferative activities in Y537S ERα breast cancer cells. Here, we use a comprehensive suite of structural-biochemical, in vitro, and in vivo approaches to better T6I-29's activities in breast cancer cells harboring Y537S ERα. RNA sequencing in cells treated with T6I-29 reveals a neomorphic downregulation of DKK1, a secreted glycoprotein known to play oncogenic roles in other cancers. Importantly, we find that DKK1 is significantly enriched in ER+ breast cancer plasma compared to healthy controls. This study shows how new SERMs and SERDs can identify new therapeutic pathways in endocrine-resistant ER+ breast cancers.

Modifiable Lifestyle Risk Factors in Adult Survivors of Childhood Cancer: A Nationally Representative Study.

OBJECTIVE: Given the vulnerable health condition of adult childhood cancer survivors, it is essential that they develop positive health behaviors to minimize controllable health risks. Therefore, we evaluated if adult survivors of non-childhood cancer and childhood cancer differ in the odds of each modifiable risk factor compared with each other and compared with the general population. METHODS: This nationally representative study leveraged the National Health Interview Survey (NHIS) sample from 2000 to 2018 and the Behavioral Risk Factor Surveillance System (BRFSS) sample from 2016 to 2021. Our study population included adults diagnosed with cancer when they were ≤14 years of age. Outcomes included physical activity, body mass index (BMI), current smoking, ever-smoking, alcohol use, and binge drinking. RESULTS: Insufficient physical activity was not statistically significant in the BRFSS, but in the NHIS, childhood cancer survivors had significantly more insufficient physical activity compared with non-childhood cancer survivors (aOR 1.29, P=0.038) and the general population (aOR 1.40, P=0.006). Childhood cancer survivors also had a higher likelihood of being significantly underweight (aOR 1.84, P=0.018) and having ever-smoked (aOR 1.42, P=0.001) compared with the general population in the NHIS. There was a significantly higher likelihood of smoking among childhood cancer survivors in the BRFSS (aOR 2.02, P=0.004). CONCLUSIONS: The likelihoods of many risky behaviors between adult childhood cancer survivors and general population controls were comparable, although rates of physical activity may be decreased, and rates of smoking may be increased among childhood cancer survivors. Targeted interventions are needed to promote healthy behaviors in this vulnerable population.

Correction: Blair et al. Molecular Phylogenetic Relationships and Unveiling Novel Genetic Diversity among Slow and Pygmy Lorises, including Resurrection of Xanthonycticebus intermedius. Genes 2023, 14, 643.

In the original publication [...].

Toward Design Rules for Multilayer Ferroelectric Energy Storage Capacitors - A Study Based on Lead-Free and Relaxor-Ferroelectric/Paraelectric Multilayer Devices.

Future pulsed-power electronic systems based on dielectric capacitors require the use of environment-friendly materials with high energy-storage performance that can operate efficiently and reliably in harsh environments. Here, a study of multilayer structures, combining paraelectric-like Ba0.6Sr0.4TiO3 (BST) with relaxor-ferroelectric BaZr0.4Ti0.6O3 (BZT) layers on SrTiO3-buffered Si substrates, with the goal to optimize the high energy-storage performance is presented. The energy-storage properties of various stackings are investigated and an extremely large maximum recoverable energy storage density of ≈165.6 J cm-3 (energy efficiency ≈ 93%) is achieved for unipolar charging-discharging of a 25-nm-BZT/20-nm-BST/910-nm-BZT/20-nm-BST/25-nm-BZT multilayer structure, due to the extremely large breakdown field of 7.5 MV cm-1 and the lack of polarization saturation at high fields in this device. Strong indications are found that the breakdown field of the devices is determined by the outer layers of the multilayer stack and can be increased by improving the quality of these layers. Authors are also able to deduce design optimization rules for this material combination, which can be to a large extend justify by structural analysis. These rules are expected also to be useful for optimizing other multilayer systems and are therefore very relevant for further increasing the energy storage density of capacitors.

Intramedullary nailing of femoral shaft fractures: an analysis of rotational malunions using 3D EOS.

PURPOSE: Rotational malalignment and leg length discrepancy after intramedullary nailing of femoral shaft are frequent. This study has three objectives: evaluate the rate of femoral rotational malalignment and leg length discrepancy using EOS imaging after antegrade intramedullary nailing of femoral shaft fracture, find a relevant clinical examination to detect malrotation and identified risk factors. METHODS: We performed a retrospective single-centre study between January 2014 and January 2022. Fifty-eight patients were clinically and radiographically assessed at a minimum of three months. RESULTS: The femoral rotation of the operated side was significantly greater by a mean of 15.4° in internal rotation compared to the healthy side. There was no statically significant difference for the femoral length (p = 0.08). CONCLUSION: When using EOS stereography following antegrade intramedullary nailing of post-traumatic diaphyseal femur fractures, a statistically significant difference of more than 15.4° in internal rotation was found for femoral rotation on the operated side compared to the healthy side.Please confirm if the author names are presented accurately and in the correct sequence (given name, middle name/initial, family name). Author 1 Given name: [B. Poirot] Last name [Seynaeve]. Also, kindly confirm the details in the metadata are correct.The last name of the first author was corrected : Given name = B. and last name = Poirot Seynaeve The details in matadata are correct LEVEL OF EVIDENCE: III.

Effectiveness of care bundles for prevention and treatment of postpartum hemorrhage: a systematic review.

OBJECTIVE: Care bundles are a promising approach to reducing postpartum hemorrhage-related morbidity and mortality. We assessed the effectiveness and safety of care bundles for postpartum hemorrhage prevention and/or treatment. DATA SOURCES: We searched MEDLINE, Embase, Cochrane CENTRAL, Maternity and Infant Care Database, and Global Index Medicus (inception to June 9, 2023) and ClinicalTrials.gov and the International Clinical Trials Registry Platform (last 5 years) using a phased search strategy, combining terms for postpartum hemorrhage and care bundles. STUDY ELIGIBILITY CRITERIA: Peer-reviewed studies evaluating postpartum hemorrhage-related care bundles were included. Care bundles were defined as interventions comprising ≥3 components implemented collectively, concurrently, or in rapid succession. Randomized and nonrandomized controlled trials, interrupted time series, and before-after studies (controlled or uncontrolled) were eligible. METHODS: Risk of bias was assessed using RoB 2 (randomized trials) and ROBINS-I (nonrandomized studies). For controlled studies, we reported risk ratios for dichotomous outcomes and mean differences for continuous outcomes, with certainty of evidence determined using GRADE. For uncontrolled studies, we used effect direction tables and summarized results narratively. RESULTS: Twenty-two studies were included for analysis. For prevention-only bundles (2 studies), low-certainty evidence suggests possible benefits in reducing blood loss, duration of hospitalization, and intensive care unit stay, and maternal well-being. For treatment-only bundles (9 studies), high-certainty evidence shows that the E-MOTIVE intervention reduced risks of composite severe morbidity (risk ratio, 0.40; 95% confidence interval, 0.32-0.50) and blood transfusion for bleeding, postpartum hemorrhage, severe postpartum hemorrhage, and mean blood loss. One nonrandomized trial and 7 uncontrolled studies suggest that other postpartum hemorrhage treatment bundles might reduce blood loss and severe postpartum hemorrhage, but this is uncertain. For combined prevention/treatment bundles (11 studies), low-certainty evidence shows that the California Maternal Quality Care Collaborative care bundle may reduce severe maternal morbidity (risk ratio, 0.64; 95% confidence interval, 0.57-0.72). Ten uncontrolled studies variably showed possible benefits, no effects, or harms for other bundle types. Nearly all uncontrolled studies did not use suitable statistical methods for single-group pretest-posttest comparisons and should thus be interpreted with caution. CONCLUSION: The E-MOTIVE intervention improves postpartum hemorrhage-related outcomes among women delivering vaginally, and the California Maternal Quality Care Collaborative bundle may reduce severe maternal morbidity. Other bundle designs warrant further effectiveness research before implementation is contemplated.

Caregiver-reported outcomes with real-world use of cannabidiol in Lennox-Gastaut syndrome and Dravet syndrome from the BECOME survey.

PURPOSE: Plant-derived highly purified cannabidiol (CBD) reduced the frequency of seizures associated with Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS) and improved the overall condition of patients in placebo-controlled phase 3 clinical trials. Anecdotal reports also suggest a positive effect on nonseizure outcomes. In this study, we aimed to identify, through a caregiver survey which nonseizure outcomes were most likely to change in these patients. METHODS: The BEhavior, COgnition, and More with Epidiolex® (BECOME) was a 20-minute, cross-sectional, online survey that was developed with extensive input from caregivers, healthcare professionals, and epilepsy researchers, and was based on questions from validated measures and previously published caregiver reports. US-based caregivers (from Jazz Pharmaceuticals patient/caregiver database) of people with LGS or DS who were treated with CBD (Epidiolex®, 100 mg/mL oral solution) for ≥3 months were asked to compare the past month to the period before CBD initiation and rate their impression of changes using symmetrical Likert scales. RESULTS: A total of 498 caregivers (97% parents) of patients with LGS (80%) or DS (20%) completed the survey. Mean (range) age of patients was 16 (1-73) years, and 52% were male. Patients were taking a median CBD dose of 14 mg/kg/d and median 4 concomitant antiseizure medications. A large proportion of respondents reported improvements in ≥1 survey question for all nonseizure-related domains: alertness, cognition, and executive function (85%); emotional functioning (82%); language and communication (79% in nonverbal patients and 74% in verbal); activities of daily living (51%); sleep (51%); and physical functioning (46%). Respondents reported improvements in seizure-related domains, including overall seizure frequency (85%), overall seizure severity (76%), seizure-free days per week for ≥1 seizure type (67%), and seizure freedom during the past month (16%). The majority of respondents who reported reduction in seizure frequency also reported improvements in nonseizure outcomes domains (51-80%). However, improvements in nonseizure outcomes (18-56%) were also reported in patients who either had no change or worsening of seizure frequency. CONCLUSIONS: This survey characterized and quantified caregiver impression of changes in the seizure and nonseizure outcomes in patients taking add-on CBD treatment. Overall, 93% of caregivers reported planning to continue CBD treatment, primarily because of reduced seizure burden but also because of improvements in nonseizure-related outcomes. Despite the limitations that are associated with a retrospective survey-based study design, these results support further evaluation of the effect of CBD treatment on nonseizure outcomes among patients with LGS or DS.

Unravelling the signaling power of pollutants.

Exposure to environmental pollutants contributes to diverse pathologies, including pulmonary disease, lower respiratory infections, cancer, and stroke. Pollutants' entry can occur through inhalation, traversing endothelial and epithelial barriers, and crossing the blood-brain barrier, leading to a wide distribution throughout the human body via systemic circulation. Pollutants cause cellular damage by multiple mechanisms encompassing oxidative stress, mitochondrial dysfunction, (neuro)inflammation, and protein instability/proteotoxicity. Sensing pollutants has added a new dimension to disease progression and drug failure. Understanding the molecular pathways and potential receptor binding/signaling that underpin 'sensing' could contribute to ways to combat the detrimental effects of pollutants. We highlight key points of pollutant signaling, crosstalk with receptors acting as drug targets for chronic diseases, and discuss the potential for future therapeutics.

Patient Perspective on the Role of Substance-Free Activities During Alcohol Use Disorder Treatment: A Mixed-Method Study.

Behavioral economic theory of addiction proposes that substance use often takes place in environments with limited substance-free reinforcement. While increasing substance-free reinforcement is known to reduce substance use, systematic efforts to boost substance-free reinforcement is not often a focus of most alcohol treatment programs. Participants (N=21) with alcohol use disorder participated in virtual focus group sessions. Qualitative content analysis was conducted on participants' verbatim responses. Substance-free activities were also assessed with a 66-item modified pleasant activity list specifying activity engagement frequency and enjoyment. All participants reported introduction to substance-free activity engagement as part of their treatment, although those in group therapy (relative to individual) reported less consistent support. While motives for initial activity engagement were reported as stemming from external sources (i.e., therapist), activity maintenance was linked to intrinsic motives (i.e., personal interest). All participants identified substance-free activities as a key aid to successful recovery. Types of most helpful activities were ones related to self-care, social connections, acts of service, and creative outlets. Findings are consistent with theories of behavior change and suggest participants believe substance-free activity engagement is an important component of their recovery, however they are not receiving consistent support during the pivotal early recovery period.

The old second messenger cAMP teams up with novel cell death mechanisms: potential translational therapeutical benefit for Alzheimer's disease and Parkinson's disease.

Alzheimer's disease (AD) and Parkinson's disease (PD) represent the most prevalent neurodegenerative disorders severely impacting life expectancy and quality of life of millions of people worldwide. AD and PD exhibit both a very distinct pathophysiological disease pattern. Intriguingly, recent researches, however, implicate that overlapping mechanisms may underlie AD and PD. In AD and PD, novel cell death mechanisms, encompassing parthanatos, netosis, lysosome-dependent cell death, senescence and ferroptosis, apparently rely on the production of reactive oxygen species, and seem to be modulated by the well-known, "old" second messenger cAMP. Signaling of cAMP via PKA and Epac promotes parthanatos and induces lysosomal cell death, while signaling of cAMP via PKA inhibits netosis and cellular senescence. Additionally, PKA protects against ferroptosis, whereas Epac1 promotes ferroptosis. Here we review the most recent insights into the overlapping mechanisms between AD and PD, with a special focus on cAMP signaling and the pharmacology of cAMP signaling pathways.

Foregone health care in adolescents from school and community settings in Indonesia: a cross-sectional study.

Background: Adolescence is a development period marked by the onset of a new set of health needs. The present study sought to quantify the prevalence of foregone care (not seeking medical care when needed) and identify which adolescents are at greater risk of having unmet healthcare needs. Methods: A multi-stage random sampling strategy was used to recruit school participants (grade 10-12) in two provinces in Indonesia. Respondent driven sampling was used to recruit out-of-school adolescents in the community. All participants completed a self-reported questionnaire which measured healthcare seeking behaviours, psychosocial wellbeing, use of healthcare services, and perceived barriers to accessing healthcare. Multivariable regression analysis was performed to examine factors associated with foregone care. Findings: A total of 2161 adolescents participated in the present study and nearly one in four adolescents reported foregone care in the past year. Experiences of poly-victimisation and seeking care for mental health needs increased the risk of foregone care. In-school adolescents who reported psychological distress [adjusted risk ratio (aRR) = 1.88, 95%CI = 1.48-2.38] or had high body mass index (aRR = 1.25, 95%CI = 1.00-1.57) were at greater risk of foregone care. The leading reason for foregone care was lack of knowledge of available services. In-school adolescents predominantly reported non-access barriers to care (e.g., perception of the health concern or anxiety about accessing care) whereas most out-of-school adolescents reported access barriers (e.g., did not know where to get care or could not pay). Interpretation: Foregone care is common among Indonesian adolescents, especially in adolescents with mental and physical health risks. Differences between in-school and out-of-school adolescents suggest that interventions to promote appropriate healthcare use will need tailoring. Further research is needed to determine causal relationships around barriers in access to healthcare. Funding: Australia-Indonesia Centre.

Digital Healthy Diet Literacy and Fear of COVID-19 as Associated with Treatment Adherence and Its Subscales among Hemodialysis Patients: A Multi-Hospital Study.

Treatment adherence (TA) is a critical issue and is under-investigated in hemodialysis patients. A multi-center study was conducted from July 2020 to March 2021 on 972 hemodialysis patients in eight hospitals in Vietnam to explore the factors associated with TA during the COVID-19 pandemic. Data were collected, including socio-demographics, an End-Stage Renal Disease Adherence Questionnaire (ESRD-AQ), 12-item short-form health literacy questionnaire (HLS-SF12), 4-item digital healthy diet literacy scale (DDL), 10-item hemodialysis dietary knowledge scale (HDK), 7-item fear of COVID-19 scale (FCoV-19S), and suspected COVID-19 symptoms (S-COVID19-S). Bivariate and multivariate linear regression models were used to explore the associations. Higher DDL scores were associated with higher TA scores (regression coefficient, B, 1.35; 95% confidence interval, 95%CI, 0.59, 2.12; p = 0.001). Higher FCoV-19S scores were associated with lower TA scores (B, -1.78; 95%CI, -3.33, -0.24; p = 0.023). In addition, patients aged 60-85 (B, 24.85; 95%CI, 6.61, 43.11; p = 0.008) with "very or fairly easy" medication payment ability (B, 27.92; 95%CI, 5.89, 44.95; p = 0.013) had higher TA scores. Patients who underwent hemodialysis for ≥5 years had a lower TA score than those who received <5 years of hemodialysis (B, -52.87; 95%CI, -70.46, -35.28; p < 0.001). These findings suggested that DDL and FCoV-19S, among other factors, should be considered in future interventions to improve TA in hemodialysis patients.

Using social practice theory in measuring perceived stigma among female sex workers in Mombasa, Kenya.

BACKGROUND: Perceived stigma is a complex societal phenomenon that is harboured especially by female sex workers because of the interplay of a myriad of factors. As such, a precise measure of the contribution of different social practices and characteristics is necessary for both understanding and intervening in matters related to perceived stigma. We developed a Perceived Stigma Index that measures the factors that greatly contribute to the stigma among sex workers in Kenya, and thereby inform a framework for future interventions. METHODS: Social Practice Theory was adopted in the development of the Perceived Stigma Index in which three social domains were extracted from data collected in the WHISPER or SHOUT study conducted among female sex workers (FSW), aged 16-35 years in Mombasa, Kenya. The three domains included: Social demographics, Relationship Control and Sexual and Gender-based Violence, and Society awareness of sexual and reproductive history. The factor assessment entailed Exploratory Factor Analysis (EFA), Confirmatory Factor Analysis (CFA), and the internal consistency of the index was measured using Cronbach's alpha coefficient. RESULTS: We developed a perceived stigma index to measure perceived stigma among 882 FSWs with a median age of 26 years. A Cronbach's alpha coefficient of 0.86 (95% confidence interval (CI) 0.85-0.88) was obtained as a measure of the internal consistency of our index using the Social Practice Theory. In regression analysis, we identified three major factors that contribute to the perceived stigma and consists of : (i) income and family support (ß = 1.69; 95% CI); (ii) society's awareness of the sex workers' sexual and reproductive history (ß = 3.54; 95% CI); and (iii) different forms of relationship control e.g. physical abuse (ß = 1.48; 95%CI that propagate the perceived stigma among the FSWs. CONCLUSION: Social practice theory has solid properties that support and capture the multi-dimensional nature of perceived stigma. The findings support the fact that social practices contribute or provoke this fear of being discriminated against. Thus, in offering interventions to curb perceived stigma, focus should fall on the education of the society on the importance of acceptance and integration of the FSWs as part of the society and the eradication of sexual and gender based violence meted out on them. TRIAL REGISTRATION: The trial was registered in the Australian New Zealand Clinical Trials Registry, ACTRN12616000852459.

Timing and duration of bevacizumab treatment and survival in patients with recurrent ovarian, fallopian tube, and peritoneal cancer: a multi-institution study.

Bevacizumab has demonstrated significant benefit in recurrent ovarian, fallopian tube and peritoneal cancer (OC), but its optimal position within the sequence of systemic therapies remains controversial. Since rebound progression after bevacizumab has been observed in other cancers, and because bevacizumab is incorporated in several regimens used in the recurrent setting, the duration of treatment may impact survival. We sought to identify whether earlier bevacizumab exposure is associated with prolonged bevacizumab therapy and survival by conducting a multi-institution retrospective study of recurrent OC patients treated with bevacizumab from 2004-2014. Multivariate logistic regression identified factors associated with receiving more than six bevacizumab cycles. Overall survival by duration and ordinal sequence of bevacizumab therapy were evaluated using logrank testing and Cox regression. In total, 318 patients were identified. 89.1% had stage III or IV disease; 36% had primary platinum resistance; 40.5% received two or fewer prior chemotherapy regimens. Multivariate logistic regression demonstrated that primary platinum sensitivity (Odds Ratio (OR) 2.34, p = 0.001) or initiating bevacizumab at the first or second recurrence (OR 2.73, p < 0.001) were independently associated with receiving more than six cycles of bevacizumab. Receiving more cycles of bevacizumab was associated with improved overall survival whether measured from time of diagnosis (logrank p < 0.001), bevacizumab initiation (logrank p < 0.001), or bevacizumab discontinuation (logrank p = 0.017). Waiting one additional recurrence to initiate bevacizumab resulted in a 27% increased hazard of death (Hazard Ratio (HR) 1.27, p < 0.001) by multivariate analysis. In conclusion, patients with primary platinum sensitive disease who received fewer prior lines of chemotherapy were able to receive more cycles of bevacizumab, which was associated with improved overall survival. Survival worsened when bevacizumab was initiated later in the ordinal sequence of therapies.

Molecular Phylogenetic Relationships and Unveiling Novel Genetic Diversity among Slow and Pygmy Lorises, including Resurrection of Xanthonycticebus intermedius.

Genetic analysis of historical museum collections presents an opportunity to clarify the evolutionary history of understudied primate groups, improve taxonomic inferences, and inform conservation efforts. Among the most understudied primate groups, slow and pygmy lorises (genera Nycticebus and Xanthonycticebus) are nocturnal strepsirrhines found in South and Southeast Asia. Previous molecular studies have supported five species, but studies using morphological data suggest the existence of at least nine species. We sequenced four mitochondrial loci, CO1, cytb, d-loop, and ND4, for a total of 3324 aligned characters per sample from 41 historical museum specimens for the most comprehensive geographic coverage to date for these genera. We then combined these sequences with a larger dataset composed of samples collected in Vietnam as well as previously published sequences (total sample size N = 62). We inferred phylogenetic relationships using Bayesian inference and maximum likelihood methods based on data from each locus and on concatenated sequences. We also inferred divergence dates for the most recent common ancestors of major lineages using a BEAST analysis. Consistent with previous studies, we found support for Xanthonycticebus pygmaeus as a basal taxon to the others in the group. We also confirmed the separation between lineages of X. pygmaeus from northern Vietnam/Laos/China and southern Vietnam/Cambodia and included a taxonomic revision recognizing a second taxon of pygmy loris, X. intermedius. Our results found support for multiple reciprocally monophyletic taxa within Borneo and possibly Java. The study will help inform conservation management of these trade-targeted animals as part of a genetic reference database for determining the taxonomic unit and provenance of slow and pygmy lorises confiscated from illegal wildlife trade activities.

A novel point-of-care test for cirrhosis based on dimeric to monomeric IgA ratio in blood: a pilot cohort study.

BACKGROUND AND AIMS: Dimeric IgA to monomeric IgA ratio (dIgA ratio) is a biomarker of gut mucosal leakage in liver cirrhosis. We evaluated the diagnostic performance of a novel point-of-care (POC) dIgA ratio test for cirrhosis. METHODS: Plasma samples from people with chronic liver disease were analyzed using the BioPoint POC dIgA ratio antigen immunoassay lateral flow test. Cirrhosis was defined by Fibroscan>12.5 kPa, clinical evidence of cirrhosis or liver histopathology. POC dIgA test diagnostic accuracy was determined in a test cohort using receiver operating characteristic curve analysis; optimal cutoffs for sensitivity and specificity were then applied to a validation cohort. RESULTS: A total of 1478 plasma samples from 866 patients with chronic liver disease were included (test cohort n = 260, validation cohort n = 606). In all, 32% had cirrhosis; 44% Child-Pugh A, 26% Child-Pugh B, and 29% Child-Pugh C. Median POC dIgA ratio was higher in cirrhosis (0.9) compared with no cirrhosis (0.4, p < 0.001), and in Child-Pugh class B/C compared with A cirrhosis (1.4 Child-Pugh B/C vs. 0.6 Child-Pugh A, p < 0.001). POC dIgA ratio test had good diagnostic accuracy for liver cirrhosis in the test cohort (area under the receiver operating characteristic curve=0.80); a dIgA ratio cutoff of 0.6 had a sensitivity of 74% and specificity of 86%. POC dIgA test accuracy was moderate in the validation cohort (area under the receiver operating characteristic curve=0.75; positive predictive value 64%, negative predictive value 83%). Using a dual cutoff approach, 79% of cirrhosis cases were correctly diagnosed and further testing was avoided in 57%. CONCLUSIONS: POC dIgA ratio test had moderate accuracy for cirrhosis. Further studies evaluating the accuracy of POC dIgA ratio testing for cirrhosis screening are warranted.

Passive and reversible area regulation of supported lipid bilayers in response to fluid flow.

Biological and model membranes are frequently subjected to fluid shear stress. However, membrane mechanical responses to flow remain incompletely described. This is particularly true of membranes supported on a solid substrate, and the influences of membrane composition and substrate roughness on membrane flow responses remain poorly understood. Here, we combine microfluidics, fluorescence microscopy, and neutron reflectivity to explore how supported lipid bilayer patches respond to controlled shear stress. We demonstrate that lipid membranes undergo a significant, passive, and partially reversible increase in membrane area due to flow. We show that these fluctuations in membrane area can be constrained, but not prevented, by increasing substrate roughness. Similar flow-induced changes to membrane structure may contribute to the ability of living cells to sense and respond to flow.