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Gender diversity in policing has never been more important than it is today. However, women in state law enforcement are the least noticeable and most underrepresented of all women in policing. Using data from the Law Enforcement Management and Administrative Statistics (LEMAS) surveys, this study examines gender diversity across the 49 primary state law enforcement agencies in the United States between 2000 and 2016. Although representation varies broadly across the states, the findings are mostly negative and suggest that women in state law enforcement have remained stagnant over the past two decades with very little improvement. This is important because scholarship must continue to bring attention to the underrepresentation of women in law enforcement, regardless of intergovernmental level, and monitor its progress.

PurposeThis study aims to examine minority representation amid the largest police departments in the USA that employ at least 500 sworn officers to determine whether the passage of Executive Order 13684 (2014)—a comprehensive criminal justice reform initiative to identify policing best practices and offer recommendations on how those practices can promote effective crime reduction while (re)building public trust—had any policy impact for increasing racial diversity in policing.Design/methodology/approachSurvey responses on race and ethnicity are collected from 83 police departments across three cross-sectional points in time (2007–2013 and 2013–2016) to examine changes in racial diversity.FindingsThe findings suggest that nearly 20% of the police departments in this study had increases in racial diversity that could be attributed to Executive Order 13684 (2014).Research limitations/implicationsInsufficient time may have lapsed between the passage of Executive Order 13684 (2014) and the last survey collection period to generate meaningful change.Practical implicationsThis study responds to the call by the President’s Task Force on 21st Century Policing (2015) to highlight those successful police departments, as well as those less successful police departments, for improving diversity in the police force.Originality/valueTo the best of the author’s knowledge, the findings from this study provide one of the first attempts to examine how federal recommendations impact local policing practices.

The rising nationwide concerns about violence targeting Asians have highlighted the scant research on Asian American police officers. This article aims to (re)introduce this important dialogue and calls for a commitment from other race and social equity scholars to extend the discourse on racial diversity in policing. Using data on race and ethnicity compiled by the Law Enforcement Management and Administrative Statistics survey, this article compares data from the largest 100 cities ranked by their respective Asian population percentage with the percentage of Asian police officers from those same cities to examine Asian diversity in policing. Analysis reveals that all the cities with the exception of five were underrepresented by Asian police officers, and that more work needs to be done by these police departments if they hope to reflect the diversity of the communities they serve.

The functionality of digital health technologies (DHTs), such as wearable devices and virtual assistants, is being promoted as essential tools to empower people to take control and responsibility of their own health and wellness. Examples of wearable devices referred to in this article include devices that track health-related and fitness-related data such as heart rate, activity level, sleep cycles and caloric intake. An example of a virtual assistant includes Amazon Echo with its technology to analyse the user’s voice to detect and determine ‘physical or emotional abnormality’ and provide targeted content related to a particular medicine sold by a particular retailer to address the detected problem.1 There is significant literature on the potential benefits of DHTs in reducing costs and the burden on the healthcare system, for example, by offering the public ways to self-manage health from home.2 DHTs are also attributed with the ability to help detect early warning signs of potentially serious health conditions that may otherwise go unnoticed.3 While healthcare providers generally recognise DHTs as useful tools, there is evidence that these technologies are increasingly being used by the public in a manner that potentially increases healthcare costs in the long run.4 5 One study reported an increase in physician–‘digital chondriac’ interaction where patients demand immediate attention from medical professionals based on troubling health indicators detected by wearable devices, which may or may not be accurate.6 On the other end of the spectrum, some patients elect to bypass traditional health service structures and take medical and health decision into their own hands at great risk to themselves instead of consulting a medical professional.7 8 The medical literature also echoes concerns regarding the accuracy and unsubstantiated scientific claims of DHTs which may mislead consumers about their health and lead to potentially harmful …

Failure to share and make use of existing knowledge, particularly negative research outcomes, has been recognized as one of the key sources of waste and inefficiency in the drug discovery and development process. In the field of antibiotic research, providing a platform where negative outcomes could be shared to prevent the vicious cycle of duplicating costly studies that produce the same negative results would greatly de-risk and accelerate the development of new antibiotics. Providing a legally supported framework that recognizes negative outcomes as intellectual contributions, which can subsequently be translated into a revenue-sharing model, may lead to more openness and value creation in support of a sustainable and responsible transformation of research into socially and economically beneficial innovations.

Oral antiretroviral agents provide life-saving treatments for millions of people living with HIV, and can prevent new infections via pre-exposure prophylaxis1–5. However, some people living with HIV who are heavily treatment-experienced have limited or no treatment options, owing to multidrug resistance6. In addition, suboptimal adherence to oral daily regimens can negatively affect the outcome of treatment—which contributes to virologic failure, resistance generation and viral transmission—as well as of pre-exposure prophylaxis, leading to new infections1,2,4,7–9. Long-acting agents from new antiretroviral classes can provide much-needed treatment options for people living with HIV who are heavily treatment-experienced, and additionally can improve adherence10. Here we describe GS-6207, a small molecule that disrupts the functions of HIV capsid protein and is amenable to long-acting therapy owing to its high potency, low in vivo systemic clearance and slow release kinetics from the subcutaneous injection site. Drawing on X-ray crystallographic information, we designed GS-6207 to bind tightly at a conserved interface between capsid protein monomers, where it interferes with capsid-protein-mediated interactions between proteins that are essential for multiple phases of the viral replication cycle. GS-6207 exhibits antiviral activity at picomolar concentrations against all subtypes of HIV-1 that we tested, and shows high synergy and no cross-resistance with approved antiretroviral drugs. In phase-1 clinical studies, monotherapy with a single subcutaneous dose of GS-6207 (450 mg) resulted in a mean log10-transformed reduction of plasma viral load of 2.2 after 9 days, and showed sustained plasma exposure at antivirally active concentrations for more than 6 months. These results provide clinical validation for therapies that target the functions of HIV capsid protein, and demonstrate the potential of GS-6207 as a long-acting agent to treat or prevent infection with HIV. The small molecule GS-6207, which disrupts the function of the HIV capsid protein, shows potential as a long-acting therapeutic agent for the treatment and prevention of HIV infection.

BACKGROUND Cervical screening programs have had an important effect on the reduction of cervical cancer rates. Comprehensive programs require access to pathological review to improve the sensitivity of screening cytology and the specificity of diagnostic histology. AIMS To determine the number of cases where cervical cytology or histology was amended at cytopathological review; whether amendments were 'upgrades' or 'downgrades', and how amendments aligned with follow-up results for these patients. MATERIALS AND METHODS A retrospective cohort study was performed of all patients reviewed from January 2016 to December 2017 (n = 287 cases, from 254 patients) at colposcopy multidisciplinary meetings at Wellington Hospital, a tertiary referral hospital. Where amendments to cytology or histology were made, follow-up results were retrieved where available (85.7% and 84.2% respectively). RESULTS Cytology or histology was amended in 24.7% of cases. Smear cytology was amended in 16.7%. Where cytology was upgraded (n = 9), 44% had subsequent results of equal or higher grade including one case of adenocarcinoma. Where cytology was downgraded (n = 19), 93.8% (81.9-100%) had follow-up studies showing equal or lower results. Cervical biopsy histology was amended in 12.2% of cases (upgraded n = 19, downgraded n = 6). Large loop excision of the transformation zone or cone biopsy histology was amended in three cases (7.9%). CONCLUSIONS Cytopathological review appears to improve the specificity of the comprehensive cervical screening program, leading to a reduction in unnecessary treatment. Additionally, a small number of cases of malignant or premalignant disease were detected.

Since the adaptation of medical imaging as a standard clinical diagnostic tool, an ever-growing number of images has been taken. Radiomics took the big-data approach to extract quantitative features from medical images invisible to the naked eye to support clinical decision making, known as biomarkers. Over 440 radiomics features are available including size and shape based features, features derived from intensity histogram and texture features that describes the relationship between voxels. To date, there are no widely accepted biomarkers like tumour, nodes and metastases (TNM) staging in oncology due to concerns on the robustness of features., This thesis presents a detailed robustness study of 43 commonly used radiomics mainly 3-dimensional texture features extracted from the CT part of PET/CT images of patients diagnosed with non-small cell lung cancer (NSCLC) in two aspects: repeatability and reproducibility. Repeatability of features were studied using an open source dataset with 31 sets of repeat scans taken 15 minutes apart on quantisation parameters including quantisation method; levels of quantisation and the use of an intensity threshold. Reproducibility of features were studied using a locally acquired dataset of 50 scans on acquisition parameters including scanner model/make and the embedded reconstruction method; variation in tumour delineation and the afore mentioned quantisation parameters. The robust features were validated using the two independent dataset before highly correlated features were identified to reduce type one error caused by over-fitting. The robust texture features were applied to clinical applications from patient stratification to tumour delineation., Features were extremely sensitive to changes in the quantisation parameters. Stability of features were improved by quantising with an intensity threshold and at high levels of quantisation such as 128. The group uniform quantiser (GUQ) produced the most stable results among the four quantisers tested. Using the same quantisation parameters, radiomics features were highly repeatable, 31/43 features had a Spearman's rank correlation (rs) greater than 0.9 across all quantisers. Features were highly reproducible to scanner make/model and variation in tumour delineation under the same quantisation parameters. Features were not reproducible to different quantisation methods, using features quantised with GUQ at 128 intensity levels as a reference, 32 features correlated (rs > 0.8) when quantised using other quantisers with a threshold, 26 features correlated when quantised using other quantisers without a threshold. 7 features correlated with tumour volume (rs > 0.8). All features expect GLSZM GLN and ZSN features were successfully validated. The robust features were able to stratify patients and improve delineation accuracy in clinical applications., Robustness and validation of 43 commonly used radiomics features were investigated from CT scans of patients with NSCLC. Features were extremely sensitive to quantisation parameters. Features were repeatable, reproducible and validated successfully using the same quantisation parameters. Based on the results of this study, it is suggested to quantise using GUQ at 128 intensity levels with a threshold.

Tirabrutinib is an irreversible, small-molecule Bruton's tyrosine kinase (BTK) inhibitor, which was approved in Japan (VELEXBRU) to treat B-cell malignancies and is in clinical development for inflammatory diseases. As an application of model-informed drug development, a semimechanistic pharmacokinetic/pharmacodynamic (PK/PD) model for irreversible BTK inhibition of tirabrutinib was developed to support dose selection in clinical development, based on clinical PK and BTK occupancy data from two phase I studies with a wide range of PK exposures in healthy volunteers and in subjects with rheumatoid arthritis. The developed model adequately described and predicted the PK and PD data. Overall, the model-based simulation supported a total daily dose of at least 40 mg, either q.d. or b.i.d., with adequate BTK occupancy (> 90%) for further development in inflammatory diseases. Following the PK/PD modeling and simulation, the relationship between model-predicted BTK occupancy and preliminary clinical efficacy data was also explored and a positive trend was identified between the increasing time above adequate BTK occupancy and better efficacy in treatment for RA by linear regression.

People living with HIV (PLWH) have expressed concern about the life-long burden and stigma associated with taking pills daily and can experience medication fatigue that might lead to suboptimal treatment adherence and the emergence of drug-resistant viral variants, thereby limiting future treatment options1–3. As such, there is strong interest in long-acting antiretroviral (ARV) agents that can be administered less frequently4. Herein, we report GS-CA1, a new archetypal small-molecule HIV capsid inhibitor with exceptional potency against HIV-2 and all major HIV-1 types, including viral variants resistant to the ARVs currently in clinical use. Mechanism-of-action studies indicate that GS-CA1 binds directly to the HIV-1 capsid and interferes with capsid-mediated nuclear import of viral DNA, HIV particle production and ordered capsid assembly. GS-CA1 selects in vitro for unfit GS-CA1-resistant capsid variants that remain fully susceptible to other classes of ARVs. Its high metabolic stability and low solubility enabled sustained drug release in mice following a single subcutaneous dosing. GS-CA1 showed high antiviral efficacy as a long-acting injectable monotherapy in a humanized mouse model of HIV-1 infection, outperforming long-acting rilpivirine. Collectively, these results demonstrate the potential of ultrapotent capsid inhibitors as new long-acting agents for the treatment of HIV-1 infection. A new compound that inhibits HIV capsid assembly and nuclear transport functions offers potential as a long-acting antiretroviral.

Ingestible electronic sensors are a promising technology for improving health outcomes that may, for example, be useful in monitoring and promoting the taking of medication. However, these sensors also raise ethical and legal challenges that need to be considered by all stakeholders—notably, the creators of such products—at the earliest stages of the development process. Here, we examine selected ethical and legal issues related to ingestible electronic sensors. We first briefly describe sensors that are already available on the US and European markets as well as potential future sensor combinations. We then focus on ethical aspects, discussing patient, provider, and social issues. Finally, we provide a comparative analysis of legal regulation of ingestible electronic sensors in the US and Europe. This Perspective examines key ethical challenges of ingestible electronic sensors, which are related to patients, physicians, and society more generally, and provides a comparative analysis of legal regulation of the sensors in the US and Europe.

ObjectiveOne of the features of ulcerative colitis (UC) is a defect in the protective mucus layer. This has been attributed to a reduced number of goblet cells (GC). However, it is not known whether abnormal GC mucus secretion also contributes to the reduced mucus layer. Our aims were to test the hypothesis that GC secretion was abnormal in UC with the changes persistent in colonoids even in the absence of immune cells.DesignColonoids were established from intestinal stem cells of healthy subjects (HS) and from patients with UC (inactive and active sites). Colonoids were maintained as undifferentiated (UD) or induced to differentiate (DF) and studied as 3D or monolayers on Transwell filters. Total RNA was extracted for quantitative real-time PCR analysis. Carbachol and PGE2 mediated stimulation followed by examination of mucus layer by MUC2 IF/confocal microscopy and TEM were performed.ResultsColonoids derived from patients with UC can be propagated over many passages; however, they exhibit a reduced rate of growth and TEER compared with colonoids from HS. Differentiated UC colonoid monolayers form a thin and non-continuous mucus layer. UC colonoids have increased expression of secretory lineage markers: ATOH1 and SPDEF, including MUC2 positive GCs and ChgA positive enteroendocrine cells but failed to secrete mucin when exposed to the cholinergic agonist carbachol and PGE2, which caused increased secretion in HS. Exposure to TNF-α (5days), reduced the number of GC with a greater percentage decrease in UC colonoids compared to HS.ConclusionsAbnormal mucus layer in UC is due to long term changes in epithelial cells that lead to abnormal mucus secretion as well as effects of the inflammatory environment to reduce the number of GC. This continued defect in GC mucus secretion may be involved in UC recurrence.

This chapter focuses on the development of therapeutics that work to induce the degradation of nuclear receptors. These therapeutics, unlike traditional small molecule inhibitors, work by redirecting the cellular waste disposal machinery to remove a therapeutic target. They are advantageous because they work through a catalytic mechanism, raising the possibility of drugs with enhanced potency. Current work in the field is toward identifying novel molecular “glues,” in the hopes of bringing proteolysis targeting chimeras (PROTACs) to the clinic. However, translating it from a concept dreamed up in a laboratory to a clinically viable tool took almost 20 years of basic research.

Yanzhi Zeng,1 Chin Wen Tan,1,2 Rehena Sultana,3 Tze-Ern Chua,4,5 Helen Yu Chen,4,5 Alex Tiong Heng Sia,1,2 Ban Leong Sng1,2 1Department of Women’s Anaesthesia, KK Women’s and Children’s Hospital, Singapore; 2Anaesthesiology and Perioperative Sciences Academic Clinical Program, Duke-NUS Medical School, Singapore; 3Centre for Quantitative Medicine, Duke-NUS Medical School, Singapore; 4Department of Psychological Medicine, KK Women’s and Children’s Hospital, Singapore; 5Paediatrics Academic Clinical Program, Duke-NUS Medical School, SingaporeCorrespondence: Ban Leong Sng Tel +65 6394 1081Fax +65 62912661Email sng.ban.leong@singhealth.com.sgPurpose: Postnatal depression (PND) is associated with maternal morbidity and socioeconomic burden. Recent studies have shown an association between pain catastrophizing, increased labor pain, and subsequent adverse postnatal adjustment; however, little is known on its role in PND development. We aimed to investigate the association between pain catastrophizing and probable PND.Methods: Parturients planning to undergo epidural labor analgesia were recruited. Predelivery questionnaires, including the Pain Catastrophizing Scale (PCS) and Edinburgh Postnatal Depression Scale (EPDS), were administered during early labor. A phone survey at 5– 9 weeks postdelivery was conducted to determine postdelivery EPDS and Spielberger’s State–Trait–Anxiety Inventory scores. The primary outcome was a binary variable of postdelivery EPDS with cutoff of ≥ 10, whereas the secondary outcome was a continuous variable on increases in EPDS score.Results: Probable PND (EPDS ≥ 10) occurred in 10.5% (95% CI 8.0%– 13.5%, 55 of 525) of women who underwent epidural labor analgesia. We found that high pain catastrophizing (PCS ≥ 25) was associated with increased postdelivery EPDS scores (adjusted β estimate 0.36, 95% CI 0.15– 0.57; p=0.0008), but did not meet significance for increased risk of probable PND (p=0.1770). Additionally, presence of breakthrough pain during epidural analgesia (adjusted β estimate 0.24, 95% CI 0.02– 0.46; p=0.0306) and lower BMI at term (adjusted β estimate − 0.04, 95% CI − 0.07 to − 0.01; p=0.0055) were associated with increased postdelivery EPDS scores.Conclusion: No significant association was found between high pain catastrophizing and probable PND; however, high predelivery pain catastrophizing, presence of breakthrough pain during epidural analgesia, and lower BMI at term were associated with increased postdelivery EPDS scores. Further research will be needed to validate this association in the context of the risk of PND development.Keywords: pain catastrophizing, breakthrough pain, epidural analgesia, postnatal depressive states

USP16 (also known as UBP-M) has emerged as a histone H2AK119 deubiquitylase (DUB) implicated in the regulation of chromatin-associated processes and cell cycle progression. Despite this, available evidence suggests that this DUB is also present in the cytoplasm. How the nucleo-cytoplasmic transport of USP16, and hence its function, is regulated has remained elusive. Here, we show that USP16 is predominantly cytoplasmic in all cell cycle phases. We identified the nuclear export signal (NES) responsible for maintaining USP16 in the cytoplasm. We found that USP16 is only transiently retained in the nucleus following mitosis and then rapidly exported from this compartment. We also defined a non-canonical nuclear localization signal (NLS) sequence that plays a minimal role in directing USP16 into the nucleus. We further established that this DUB does not accumulate in the nucleus following DNA damage. Instead, only enforced nuclear localization of USP16 abolishes DNA double-strand break (DSB) repair, possibly due to unrestrained DUB activity. Thus, in contrast to the prevailing view, our data indicate that USP16 is actively excluded from the nucleus and that this DUB might indirectly regulate DSB repair.This article has an associated First Person interview with the first author of the paper.