"ContraceptED": A Multidisciplinary Framework for Emergency Department-Initiated Contraception.

Emergency departments (EDs) are common access points for patients who are at high risk for unintended pregnancy. Low-barrier access to effective contraception represents a crucial and low-cost intervention to address this public health need. Same-day initiation of contraception during an ED visit is a unique opportunity to provide reproductive health care for high-risk patients with otherwise limited health care access. We collaborated with our obstetrics and gynecology (OB/GYN) department, pharmacists, and a team of community health advocates to support emergency clinicians (namely, emergency physicians and advanced practice providers) in assessing pregnancy and contraceptive readiness, increasing proficiency in contraception counseling, prescribing hormonal contraception, counseling on barrier and emergency contraception, and inserting (and removing) the Nexplanon implant, a form of long-acting reversible contraception. With this novel approach, we found that emergency clinicians voluntarily participated in trainings on contraception, including low-threshold long-acting reversible contraception initiation; and, after completing these trainings, clinicians integrated these skills into their workflow in the ED. We report our results after screening 38 patients during our current Pilot Phase of implementing this program.

The COVID-19 pandemic and access to health care in people with chronic kidney disease: A systematic review and meta-analysis.

AIM: This systematic review aims to evaluate the effect of the COVID-19 pandemic on access to health care for patients with CKD. METHODS: MEDLINE and EMBASE databases were searched up to July 2021 (PROSPERO CRD42021230831). Data relevant to access to health care before and during the COVID-19 pandemic were extracted, including outcomes related to access to general nephrology consultations, telehealth, dialysis services and kidney transplantations. Relative and absolute effects were pooled using a random effects model to account for between-study heterogeneity. Risk of bias was assessed using a modified Quality in Prognostic Studies tool. The certainty of the evidence was rated using the GRADE approach. RESULTS: Twenty-three studies across five WHO regions were identified. Reductions in transplantation surgeries were observed during the COVID-19 pandemic compared with the pre-COVID-19 era (risk ratio = 2.15, 95%CI = 1.51-3.06, I2  = 90%, p < .001). Additionally, six studies reported increased use of telehealth services compared with pre-COVID-19 times. Four studies found reduced access to in-person general nephrology services and six studies reported interruptions to dialysis services during the COVID-19 pandemic. CONCLUSION: Our findings suggest COVID-19 pandemic may have led to reductions in access to kidney transplantation, dialysis and in-person nephrology care. Meanwhile, whilst the use of telehealth has emerged as a promising alternate mode of health care delivery, its utility during the pandemic warrants further investigation. This study has highlighted major barriers to accessing care in a highly vulnerable chronic disease group.

Incidence and Outcomes of COVID-19 in People With CKD: A Systematic Review and Meta-analysis.

RATIONALE & OBJECTIVE: Coronavirus disease 2019 (COVID-19) disproportionately affects people with chronic diseases such as chronic kidney disease (CKD). We assessed the incidence and outcomes of COVID-19 in people with CKD. STUDY DESIGN: Systematic review and meta-analysis by searching MEDLINE, EMBASE, and PubMed through February 2021. SETTING & STUDY POPULATIONS: People with CKD with or without COVID-19. SELECTION CRITERIA FOR STUDIES: Cohort and case-control studies. DATA EXTRACTION: Incidences of COVID-19, death, respiratory failure, dyspnea, recovery, intensive care admission, hospital admission, need for supplemental oxygen, hospital discharge, sepsis, short-term dialysis, acute kidney injury, and fatigue. ANALYTICAL APPROACH: Random-effects meta-analysis and evidence certainty adjudicated using an adapted version of GRADE (Grading of Recommendations Assessment, Development and Evaluation). RESULTS: 348 studies (382,407 participants with COVID-19 and CKD; 1,139,979 total participants with CKD) were included. Based on low-certainty evidence, the incidence of COVID-19 was higher in people with CKD treated with dialysis (105 per 10,000 person-weeks; 95% CI, 91-120; 95% prediction interval [PrI], 25-235; 59 studies; 468,233 participants) than in those with CKD not requiring kidney replacement therapy (16 per 10,000 person-weeks; 95% CI, 4-33; 95% PrI, 0-92; 5 studies; 70,683 participants) or in kidney or pancreas/kidney transplant recipients (23 per 10,000 person-weeks; 95% CI, 18-30; 95% PrI, 2-67; 29 studies; 120,281 participants). Based on low-certainty evidence, the incidence of death in people with CKD and COVID-19 was 32 per 1,000 person-weeks (95% CI, 30-35; 95% PrI, 4-81; 229 studies; 70,922 participants), which may be higher than in people with CKD without COVID-19 (incidence rate ratio, 10.26; 95% CI, 6.78-15.53; 95% PrI, 2.62-40.15; 4 studies; 18,347 participants). LIMITATIONS: Analyses were generally based on low-certainty evidence. Few studies reported outcomes in people with CKD without COVID-19 to calculate the excess risk attributable to COVID-19, and potential confounders were not adjusted for in most studies. CONCLUSIONS: The incidence of COVID-19 may be higher in people receiving maintenance dialysis than in those with CKD not requiring kidney replacement therapy or those who are kidney or pancreas/kidney transplant recipients. People with CKD and COVID-19 may have a higher incidence of death than people with CKD without COVID-19.

A lipid atlas of human and mouse immune cells provides insights into ferroptosis susceptibility.

The cellular lipidome comprises thousands of unique lipid species. Here, using mass spectrometry-based targeted lipidomics, we characterize the lipid landscape of human and mouse immune cells ( www.cellularlipidatlas.com ). Using this resource, we show that immune cells have unique lipidomic signatures and that processes such as activation, maturation and development impact immune cell lipid composition. To demonstrate the potential of this resource to provide insights into immune cell biology, we determine how a cell-specific lipid trait-differences in the abundance of polyunsaturated fatty acid-containing glycerophospholipids (PUFA-PLs)-influences immune cell biology. First, we show that differences in PUFA-PL content underpin the differential susceptibility of immune cells to ferroptosis. Second, we show that low PUFA-PL content promotes resistance to ferroptosis in activated neutrophils. In summary, we show that the lipid landscape is a defining feature of immune cell identity and that cell-specific lipid phenotypes underpin aspects of immune cell physiology.

Synergistic Effect of Ketamine and Buprenorphine Observed in the Treatment of Buprenorphine Precipitated Opioid Withdrawal in a Patient With Fentanyl Use.

BACKGROUND: Optimal treatment of buprenorphine precipitated opioid withdrawal (BPOW) is unclear. Full agonist treatment of BPOW is limited by buprenorphine's high-affinity blockade at mu-opioid receptors (µORs). Buprenorphine's partial agonism (low intrinsic efficacy) at µORs can limit the effectiveness of even massive doses once BPOW has begun. Adjunct medications, such as clonidine, are rarely effective in severe BPOW. Ketamine is an N -methyl-D-aspartate receptor antagonist with a potentially ideal pharmacologic profile for treatment of BPOW. Ketamine reduces opioid withdrawal symptoms independently of direct µOR binding, synergistically potentiates the effectiveness of buprenorphine µOR signaling, reverses (resensitizes) fentanyl induced µOR receptor desensitization, and inhibits descending pathways of hyperalgesia and central sensitization. Ketamine's rapid antidepressant effects potentially address depressive symptoms and subjective distress that often accompanies BPOW. Ketamine is inexpensive, safe, and available in emergency departments. To date, neither ketamine as treatment for BPOW nor to support uncomplicated buprenorphine induction has been described. CASE DESCRIPTION: We report a case of an illicit fentanyl-using OUD patient who experienced severe BPOW during an outpatient low-dose cross taper buprenorphine induction (ie, "microdose"). The BPOW was successfully treated in the emergency department with a combination of ketamine (0.6 mg/kg intravenous over 1 hour) combined with high-dose buprenorphine (16 mg sublingual single dose); 3 days later he was administered a month-long dose of extended-release subcutaneous buprenorphine which was repeated monthly (300 mg). At 90 days the patient remained in treatment and reported continuous abstinence from fentanyl use. CONCLUSIONS: This single case observation raises important questions about the potential therapeutic role of ketamine as a treatment for BPOW. BPOW is an important clinical problem for which there is currently only limited guidance and no universally accepted approach. Prospective study comparing the effectiveness of differing pharmacologic approaches to treat BPOW is urgently needed.

The Social Context of Unhealthy Alcohol Use Among Emergency Department Patients: A Cross Sectional Study.

BACKGROUND: Housing status and additional social determinants of health are important data for clinicians and policy makers to design and implement effective interventions for emergency department (ED) patients with unhealthy alcohol use (UAU). METHODS: We surveyed patients in an urban, safety-net ED from June to August 2018. UAU was assessed by a validated single-item screening question endorsed by the National Institute on Alcohol Abuse and Alcoholism. Housing status was assessed using items validated for housing stability. RESULTS: Seven hundred fifty-eight patients completed the survey (60% response rate), and 296 (39%; 95% confidence interval: 36%-43%) reported UAU. Patients with and without UAU had the same rates of ED visits (median 2, interquartile range: 1-4; P = 0.69) and hospitalizations (median 0, interquartile range: 0-0; P = 0.31) in the 12 months before index visit. Patients with UAU were more likely to lack stable housing compared to patients without UAU (69% vs 59%; P = 0.006). Illicit drug use and prescription drug misuse was more common in patients with UAU compared to those without UAU (29% vs 14%, P < 0.001; and 18% vs 10%; P < 0.001, respectively). Only 60 (20.3%) of the 296 patients with UAU had a documented diagnosis of UAU in the medical record. CONCLUSIONS: UAU is common in the general ED patient population and usually not clinically recognized. Patients with UAU have high rates of homelessness and co-occurring substance use. Future studies should consider strategies to incorporate social determinants of health and harm reduction treatments into ED-based interventions for UAU.

Neurology trial registrations on ClinicalTrials.gov between 2007 and 2018: A cross-sectional analysis of characteristics, early discontinuation, and results reporting.

BACKGROUND: Increasing neurological disease burden and advancing treatment options require clinical trials to expand the evidence base of clinical care. We aimed to characterize neurology clinical trials registered between October 2007 and April 2018 and identify features associated with early discontinuation and results reporting. METHODS: We compared 16,994 neurology (9.4%) and 163,714 non-neurology comparison trials registered to ClinicalTrials.gov. Trials therapeutic focus within neurology was assigned via combination programmatic and manual review. We performed descriptive analyses of trial characteristics, cox regression of early discontinuation, and multivariable logistic regression for results reporting within 3 years of completion. RESULTS: Most neurology trials were academic-funded (58.5%) followed by industry (31.9%) and US-government (9.6%). Neurology trials focused more on treatment than prevention compared to non-neurology studies. Of neurology trials, 11.3% discontinued early, and 32.2% of completed trials reported results by April 30, 2018. In multivariable analysis accounting for time-to-event, neurology trials were at lower risk of discontinuation than non-neurology trials (adjusted hazard 0.83, p < 0.0001). Both academic and government-funded trials had greater risk of discontinuation than industry (adjusted hazard 0.57 and 0.46, respectively). Among completed trials, government-funded studies (adjusted odds ratio 2.12, p < 0.0001) had highest odds of results reporting while academic trials reported less (adjusted odds ratio 0.51, p < 0.0001). CONCLUSIONS: Funding source is associated with trial characteristics and outcomes in neurology. Improvements in trial completion and timely dissemination of results remain urgent goals for the field.

Discovery of novel and potent aryl diamines as leukotriene A4 hydrolase inhibitors.

The synthesis and biological evaluation of a series of aryl diamines as inhibitors of LTA(4)-h inhibitors are described. The optimization which led to the identification of the optimal para-substitution on the diphenyl ether moiety and diamine spacer is discussed. The resulting compounds such as 3l have excellent enzyme and cellular potency as well as desirable pharmacokinetic properties.

Synthesis of N-alkyl glycine amides as potent inhibitors of leukotriene A4 hydrolase.

The synthesis and biological evaluation of a series of N-alkyl glycine amide analogs as LTA(4)-h inhibitors and the importance of the introduction of a benzoic acid group to the potency and pharmacokinetic parameters of our analogs are described. The lead compound in the series, 4q, has excellent potency and oral bioavailability.

Synthesis of glutamic acid analogs as potent inhibitors of leukotriene A4 hydrolase.

Leukotriene B(4) (LTB(4)) is a potent pro-inflammatory mediator that has been implicated in the pathogenesis of multiple diseases, including psoriasis, inflammatory bowel disease, multiple sclerosis and asthma. As a method to decrease the level of LTB(4) and possibly identify novel treatments, inhibitors of the LTB(4) biosynthetic enzyme, leukotriene A(4) hydrolase (LTA(4)-h), have been explored. Here we describe the discovery of a potent inhibitor of LTA(4)-h, arylamide of glutamic acid 4f, starting from the corresponding glycinamide 2. Analogs of 4f are then described, focusing on compounds that are both active and stable in whole blood. This effort culminated in the identification of amino alcohol 12a and amino ester 6b which meet these criteria.

Does an Eczema Action Plan Improve Atopic Dermatitis? A Single-Site Randomized Controlled Trial.

The multitude of treatment options for atopic dermatitis (AD) makes management frustrating for providers and patients. Eczema action plans (EAPs) have been proposed to improve parental and provider management. We developed a single-site randomized controlled trial to evaluate the impact of an EAP on quality of life (QOL), provider knowledge, and comfort with AD management. Providers were randomized into an EAP-use group and a traditional care group. All patients completed validated AD QOL surveys, and those with AD were verbally administered the survey 1 month later. Providers' perceptions on managing AD were compared in the EAP and usual use groups. Parents in the EAP group demonstrated a significantly increased understanding of AD treatment, and providers in the EAP group had a significantly increased understanding and management of AD. The EAP is a feasible tool that can be integrated into a busy clinic practice with a positive impact on physicians and patients.

Thiophene-anthranilamides as highly potent and orally available factor Xa inhibitors.

There remains a high unmet medical need for a safe oral therapy for thrombotic disorders. The serine protease factor Xa (fXa), with its central role in the coagulation cascade, is among the more promising targets for anticoagulant therapy and has been the subject of intensive drug discovery efforts. Investigation of a hit from high-throughput screening identified a series of thiophene-substituted anthranilamides as potent nonamidine fXa inhibitors. Lead optimization by incorporation of hydrophilic groups led to the discovery of compounds with picomolar inhibitory potency and micromolar in vitro anticoagulant activity. Based on their high potency, selectivity, oral pharmacokinetics, and efficacy in a rat venous stasis model of thrombosis, compounds ZK 814048 (10b), ZK 810388 (13a), and ZK 813039 (17m) were advanced into development.

Development of a homogeneous time-resolved fluorescence leukotriene B4 assay for determining the activity of leukotriene A4 hydrolase.

Leukotriene A4 (LTA4) hydrolase catalyzes a rate-limiting final biosynthetic step of leukotriene B4 (LTB4), a potent lipid chemotactic agent and proinflammatory mediator. LTB4 has been implicated in the pathogenesis of various acute and chronic inflammatory diseases, and thus LTA4 hydrolase is regarded as an attractive therapeutic target for anti-inflammation. To facilitate identification and optimization of LTA4 hydrolase inhibitors, a specific and efficient assay to quantify LTB4 is essential. This article describes the development of a novel 384-well homogeneous time-resolved fluorescence assay for LTB4 (LTB4 HTRF assay) and its application to establish an HTRF-based LTA4 hydrolase assay for lead optimization. This LTB4 HTRF assay is based on competitive inhibition and was established by optimizing the reagent concentration, buffer composition, incubation time, and assay miniaturization. The optimized assay is sensitive, selective, and robust, with a Z' factor of 0.89 and a subnanomolar detection limit for LTB4. By coupling this LTB4 HTRF assay to the LTA4 hydrolase reaction, an HTRF-based LTA4 hydrolase assay was established and validated. Using a test set of 16 LTA4 hydrolase inhibitors, a good correlation was found between the IC50 values obtained using LTB4 HTRF with those determined using the LTB enzyme-linked immunoassay (R = 0.84). The HTRF-based LTA4 hydrolase assay was shown to be an efficient and suitable assay for determining compound potency and library screening to guide the development of potent inhibitors of LTA4 hydrolase.

A Pilot Randomized Trial of a Companion Robot for People With Dementia Living in the Community.

OBJECTIVES: To investigate the affective, social, behavioral, and physiological effects of the companion robot Paro for people with dementia in both a day care center and a home setting. DESIGN: A pilot block randomized controlled trial over 12 weeks. Participants were randomized to the intervention (Paro) or control condition (standard care). SETTING: Two dementia day care centers and participants' homes in Auckland, New Zealand. PARTICIPANTS: Thirty dyads (consisting of a care recipient with dementia and their caregiver) took part in this study. All care recipients attended dementia day care centers at Selwyn Foundation and had a formal diagnosis of dementia. INTERVENTION: Thirty-minute unstructured group sessions with Paro at the day care center were run 2 to 3 times a week for 6 weeks. Participants also had Paro at home for 6 weeks. MEASUREMENTS: At the day care centers, observations of the care recipients' behavior, affect, and social responses were recorded using a time sampling method. Observations of interactions with Paro for participants in the intervention were also recorded. Blood pressure and salivary cortisol were collected from care recipients before and after sessions at day care. In the home setting, level of cognition, depressive symptoms, neuropsychiatric symptoms, behavioral agitation, and blood pressure were measured at baseline, 6 weeks, and 12 weeks. Hair cortisol measures were collected at baseline and at 6 weeks. RESULTS: Observations showed that Paro significantly improved facial expressions (affect) and communication with staff (social interaction) at the day care centers. Subanalyses showed that care recipients with less cognitive impairment responded significantly better to Paro. There were no significant differences in care recipient dementia symptoms, nor physiological measures between the intervention and control group. CONCLUSION: Paro shows promise in enhancing affective and social outcomes for certain individuals with dementia in a community context. Larger randomized controlled trials in community settings, with longer time frames, are needed to further specify the contexts and characteristics for which Paro is most beneficial.

Homecare Robots to Improve Health and Well-Being in Mild Cognitive Impairment and Early Stage Dementia: Results From a Scoping Study.

OBJECTIVES: This scoping study is the first step of a multiphase, international project aimed at designing a homecare robot that can provide functional support, track physical and psychological well-being, and deliver therapeutic intervention specifically for individuals with mild cognitive impairment. DESIGN: Observational requirements gathering study. PARTICIPANTS AND SETTINGS: Semistructured interviews were conducted with 3 participant groups: (1) individuals with memory challenges, mild cognitive impairment (MCI), or mild dementia (patients; n = 9); (2) carers of those with MCI or dementia (carers; n = 8); and (3) those with expertise in MCI or dementia research, clinical care, or management (experts; n = 16). Interviews took place at the university, at dementia care facilities or other workplaces, at participant's homes, or via skype (experts only). MEASUREMENTS: Semistructured interviews were conducted, transcribed, and reviewed. RESULTS: Several key themes were identified within the 4 topics of: (1) daily challenges, (2) safety and security, (3) monitoring health and well-being, and (4) therapeutic intervention. CONCLUSIONS: A homecare robot could provide both practical and therapeutic benefit for the mildly cognitively impaired with 2 broad programs providing routine and reassurance; and tracking health and well-being. The next phase of the project aims to program homecare robots with scenarios developed from these results, integrate components from project partners, and then test the feasibility, utility, and acceptability of the homecare robot.

Radial Scar at Percutaneous Breast Biopsy That Does Not Require Surgery.

BACKGROUND: Surgical excision is currently recommended after pathologic radial scar is found on breast core needle biopsy because surgical upgrade to carcinoma is not uncommon. The goal of our study was to identify the true pathologic upgrade rate for a "pure" radial scar, those without associated proliferative lesion, based on indication for biopsy, biopsy type, and needle size. STUDY DESIGN: The pathology database of Continuum Health Partners was searched for the terms radial scar and radial sclerosing lesion, from January 2007 to December 2015. From review of 1,513 pathology reports, 292 cases of core biopsies without malignancy were identified. Age, indication for biopsy, type of biopsy, and excisional pathology were obtained. Data were then analyzed using SPSS. RESULTS: Two hundred nineteen (75%) of the 292 core biopsies showed pure radial scar without associated proliferative lesion, and 161 (74%) of these patients had surgical excision. Only 1 of these patients had disease that was upgraded to ductal carcinoma in situ-a 2-mm focus located 5 mm away from the radial scar biopsy cavity. This patient also had residual calcifications on mammography after the stereotactic biopsy. Six additional malignant upgrades were found in patients who had radial scar associated with atypical ductal hyperplasia (n = 5) or lobular neoplasia (n = 1) on needle biopsy. CONCLUSIONS: Surgical excision is unnecessary when radial scar is found at percutaneous needle biopsy without an associated proliferative lesion. Surgical excision is still indicated when radial scar is associated with atypical ductal hyperplasia or lobular neoplasia.

Characterization of a small molecule PAI-1 inhibitor, ZK4044.

Plasminogen activator inhibitor-1 (PAI-1) is a key negative regulator of the fibrinolytic system. In animal studies, inhibition of PAI-1 activity prevents arterial and venous thrombosis, indicating that PAI-1 inhibitors may be used as a new class of antithrombotics. In this study, we characterize a small molecule PAI-1 inhibitor, ZK4044, which was identified by high throughput screening and chemically optimized. In a chromogenic substrate-based urokinse (uPA)/PAI-1 assay and a tissue-type plasminogen activator (tPA)-mediated clot lysis assay, ZK4044 inhibited human PAI-1 activity with IC50 values of 644+/-255 and 100+/-90 nM, respectively. ZK4044 had no detectable inhibitory activity toward other serpins such as antithrombin III, alpha1-antitrypsin and alpha2-antiplasmin, indicating that ZK4044 is a specific PAI-1 inhibitor. ZK4044 was shown to bind directly to PAI-1 and prevent the binding of PAI-1 to tPA in a dose-dependent manner in surface plasmon resonance Biacore-based experiments. ZK4044 also prevented PAI-1/tPA complex formation, as analyzed by SDS/PAGE. ZK4044 had little effect on elastase-mediated cleavage of active PAI-1, indicating that the primary mode of action of ZK4044 is most likely to directly block the PAI-1/tPA interaction rather than to convert active PAI-1 to latent PAI-1. In the chromogenic substrate-based uPA/PAI-1 assay, ZK4044 was approximately 2-fold less potent against a mutant PAI-1 (14B-1), which contains four mutations at N150H, K154T, Q319L and M354I, compared with wild-type PAI-1, suggesting that the ZK4044 binding site on the surface of PAI-1 is close to these mutant residues. Together, our data show that ZK4044 represents a new class of small molecule PAI-1 inhibitors with anti-thrombotic potential.

Yawning, acute stressors, and arousal reduction in Nazca booby adults and nestlings.

Yawning is a familiar and phylogenetically widespread phenomenon, but no consensus exists regarding its functional significance. We tested the hypothesis that yawning communicates to others a transition from a state of physiological and/or psychological arousal (for example, due to action of a stressor) to a more relaxed state. This arousal reduction hypothesis predicts little yawning during arousal and more yawning (above baseline) during and after down-regulation of arousal. Experimental capture-restraint tests with wild adult Nazca boobies (Sula granti), a seabird, increased yawning frequency after release from restraint, but yawning was almost absent during tests. Natural maltreatment by non-parental adults also increased yawning by nestlings, but only after the maltreatment ended and the adult left. CORT (corticosterone) was a logical a priori element of the stress response affecting the stressor-yawning relationship under the arousal reduction hypothesis, and cannot be excluded as such for adults in capture-restraint tests but is apparently unimportant for nestlings being maltreated by adults. The arousal reduction hypothesis unites formerly disparate results on yawning: its socially contagious nature in some taxa, its clear pharmacological connection to the stress response, and its temporal linkage to transitions in arousal between consciousness and sleep.

Design, synthesis, and activity of a novel series of factor Xa inhibitors: optimization of arylamidine groups.

A novel series of diaryloxypyridines have been designed as selective nanomolar factor Xa (fXa) inhibitors for use as anticoagulants. In this paper, we describe our efforts to identify an additional interaction and a replacement for the distal amidine group that binds in the S3/S4 pocket of fXa. Introduction of a hydroxyl group para to the proximal amidine group increases the potency vs fXa by 1-2 orders of magnitude, which is the result of a hydrogen bond to Ser195 of the catalytic triad. A methyl imidazoline and a dimethylamide are good alternatives for the second amidine. These substitutions have increased the selectivity vs the related serine proteases trypsin and thrombin. The synthesis, in vitro activity, and hypothetical modes of binding to fXa based on trypsin crystallographic data are outlined.