Gynecologic cancer care in the first year of the COVID-19 pandemic.

OBJECTIVE: To analyze the impact of the early COVID-19 pandemic on the diagnosis and initiation of treatment for patients with gynecologic cancer. METHODS: Patients diagnosed with gynecologic cancer in the National Cancer Database during 2017-2020 were included. For the first aim, incidence rate ratios were calculated to compare gynecologic cancer diagnosis in the first year of the COVID-19 pandemic to the three years prior, and factors associated with a reduction in diagnosis were identified. For the second aim, patients who experienced an 8-week delay in cancer treatment were compared to those who did not. Multivariate logistic regression was used to identify factors associated with treatment delay. Propensity score analysis was utilized to compare the rate of cancer treatment delay in patients who were diagnosed with COVID-19 to those who were not. RESULTS: The incidence rate ratio of being diagnosed with gynecologic cancer in 2020 versus 2017-2019 was 0.90 (95%CI 0.90-0.91). Factors associated with increased risk of missed or delayed diagnosis in 2020 included cervical cancer, earlier cancer stage, younger age, lower levels of medical comorbidity, and lack of health insurance. In 2020, factors associated with treatment delay included COVID-19 diagnosis (aOR 1.50, 95%CI 1.35-1.67), in addition to race and ethnicity, insurance type, comorbidity, cancer stage, and primary site. The risk of treatment delay remained significantly elevated in patients diagnosed with COVID-19 after propensity-score matching. CONCLUSIONS: Gynecologic cancer diagnosis and timely provision of care were negatively impacted during the first year of the COVID-19 pandemic, with certain subgroups at elevated risk.

Within-person changes in reproductive hormones and cognition in the menopause transition.

OBJECTIVES: Most women complain of cognitive deficits in the menopause transition, though the cause is unclear. The current study investigated the role that within-person changes in reproductive hormones, particularly estradiol, may play in triggering such perimenopausal cognitive difficulties. STUDY DESIGN: Participants were 43 women aged 45-55 years and currently in the menopause transition. Once a week for 12 weeks, participants provided a urine sample for the measurement of estrone glucuronide (E1G), a urinary metabolite of estradiol. Every three weeks across the 12-week period, participants also underwent cognitive testing, including assessments of immediate and delayed memory, attention, and executive function, and completed questionnaires assessing subjective cognitive performance. Potential confounding variables including sleep quality, vasomotor symptoms, and depressive symptoms were also assessed. RESULTS: Within-person E1G was positively associated with objective measures of attention, particularly the ability to passively register auditory information on the first pass, as well as subjective measures of memory, specifically relating to a lower frequency of forgetting things in everyday life. Perimenopausal women with lower estimated levels of intellectual functioning furthermore exhibited a stronger relationship between E1G changes and objective cognitive performance. While depressive mood, poor sleep, and vasomotor symptoms were all negatively associated with at least one aspect of cognitive function, the E1G-cognition relationship was not explained by these factors. CONCLUSIONS: This study provides evidence that validates perimenopausal women's cognitive complaints but also suggests that cognitive deficits are generally mild and transient.

The effect of physical activity on fertility: a mini-review.

Although lifestyle factors such as diet, cigarette smoking, and alcohol consumption are increasingly recognized as important contributors to the risk of subfertility, the role of exercise in fertility remains less clear. As such, it is challenging for healthcare providers to deliver clear, evidence-based recommendations to patients regarding the optimal frequency and intensity with which they should exercise to maximize their chances of conception. Therefore, this review provides a critical overview of the available research for various patient populations.

Menstrual cycle influences on cue-induced smoking cravings and heart rate variability.

Women experience greater difficulties in quitting smoking than men, though the hormonal factors contributing to this sex difference remain to be clarified. The current study aimed to examine menstrual cycle effects on smoking cue-induced cravings as well as examine dynamic reproductive hormone change as a potential mediator underlying any cycle effects observed. Twenty-one women who smoke underwent two laboratory sessions - one in the mid-follicular phase and the other in the late luteal phase - involving an in-vivo smoking cue task, administered before and after exposure to a psychosocial laboratory stressor. Heart rate variability (HRV) and subjective smoking cravings were assessed in response to the cue task. The degree of change in the urinary metabolites of estradiol and progesterone from 2 days before to the day of each laboratory session was measured. Results revealed that both before and following exposure to psychosocial stress, highly nicotine-dependent women exhibited smaller cue-induced increases in HRV relative to the follicular phase. In contrast, less nicotine-dependent women exhibit an increase in HRV in both menstrual cycle phases. Results furthermore suggest that menstrual cycle effects seen in highly nicotine-dependent women are driven by the decline in estradiol and progesterone occurring in the late luteal phase. Though limited by a small sample size, this study suggests that withdrawal from reproductive hormones in the late luteal phase may alter highly nicotine-dependent women's physiological response to smoking cues, which may reflect greater difficulty resisting temptation. These findings may provide some insight regarding women's greater difficulty in maintaining abstinence after quitting smoking.

Androgen receptor expression in low grade serous ovarian cancer; clinical considerations in the diagnosis, treatment and surveillance of disease in a transgender male.

•Low grade serous (LGS) ovarian cancer is an uncommon cancer.•Androgen receptor expression testing is not routinely performed in patients with LGS ovarian cancer.•Systemic androgen levels may be elevated in patients with PCOS or those taking exogenous testosterone.•Consideration should be made to include androgen receptor testing for these patients.

Engaging Multistakeholder Perspectives to Identify Patient-Centered Research Priorities Regarding Vaccine Uptake Among Adults With Autoimmune Conditions.

OBJECTIVE: The study objective was to prioritize topics for future patient-centered research to increase uptake of common vaccines, such as for pneumococcal pneumonia, influenza, herpes zoster, human papillomavirus, and severe acute respiratory syndrome coronavirus 2, among adults living with autoimmune conditions. METHODS: A steering committee (SC) was formed that included clinicians, patients, patient advocates, and researchers associated with rheumatic diseases (psoriatic arthritis, rheumatoid arthritis, vasculitis), inflammatory bowel disease, and multiple sclerosis. Through a scoping review and discussions, SC members identified research topics regarding vaccine uptake and/or hesitancy for prioritization. A larger multistakeholder alliance that included patients and patient advocates, clinicians, researchers, policy makers, regulators, and vaccine manufacturers conducted a modified Delphi exercise online with three rating rounds and one ranking round. Frequency analysis and comparisons across stakeholder groups were conducted. A weighted ranking score was generated for each item in the ranking round for final prioritization. RESULTS: Through the Delphi process, 33 research topics were identified, of which 13 topics were rated as critical by more than 70% of all stakeholders (n = 31). The two highest ranked critical topics per the full stakeholder group were "How well a vaccine works for adults with autoimmune conditions" and "How beliefs about vaccine safety affect vaccine uptake." CONCLUSION: A multistakeholder group identified key topics as critically important priorities for future research to decrease vaccine hesitancy and improve uptake of vaccines for adults with autoimmune conditions.

Health psychology and behavioral medicine researchers in Canada: An environmental scan.

The purpose of this study is to characterize contemporary Canadian health psychology through an environmental scan by identifying faculty, research productivity and strengths, and collaborator interconnectivity. Profiles at Canadian universities were reviewed for faculty with psychology doctorates and health psychology research programs. Publications were obtained through Google Scholar and PubMed (Jan/18-Mar/21). A total of 284 faculty were identified. Cancer, pain, and sleep were key research topics. The collaborator network analysis revealed that most were linked through a common network, with clusters organized around geography, topic, and trainee relationships. Canada is a unique and productive contributor to health psychology.

The Geographic Context of Racial Disparities in Aggressive Endometrial Cancer Subtypes: Integrating Social and Environmental Aspects to Discern Biological Outcomes.

The number of Endometrial Carcinoma (EC) diagnoses is projected to increase substantially in coming decades. Although most ECs have a favorable prognosis, the aggressive, non-endometrioid subtypes are disproportionately concentrated in Black women and spread rapidly, making treatment difficult and resulting in poor outcomes. Therefore, this study offers an exploratory spatial epidemiological investigation of EC patients within a U.S.-based health system's institutional cancer registry (n = 1748) to search for and study geographic patterns. Clinical, demographic, and geographic characteristics were compared by histotype using chi-square tests for categorical and t-tests for continuous variables. Multivariable logistic regression evaluated the impact of risks on these histotypes. Cox proportional hazard models measured risks in overall and cancer-specific death. Cluster detection indicated that patients with the EC non-endometrioid histotypes exhibit geographic clustering in their home address, such that congregate buildings can be identified for targeted outreach. Furthermore, living in a high social vulnerability area was independently associated with non-endometrioid histotypes, as continuous and categorical variables. This study provides a methodological framework for early, geographically targeted intervention; social vulnerability associations require further investigation. We have begun to fill the knowledge gap of geography in gynecologic cancers, and geographic clustering of aggressive tumors may enable targeted intervention to improve prognoses.

Baseline anxiety-sensitivity to estradiol fluctuations predicts anxiety symptom response to transdermal estradiol treatment in perimenopausal women - A randomized clinical trial.

BACKGROUND: The menopausal transition (perimenopause) is associated with an increased risk of major depression, characterized by anxiety and anhedonia phenotypes. Greater estradiol (E2) variability predicts the development of perimenopausal depression, especially within the context of stressful life events (SLEs). While transdermal E2 (TE2) reduces perimenopausal depressive symptoms, the mechanisms underlying TE2 efficacy and predictors of TE2 treatment response remain unknown. This study aimed at determining relationships between E2 fluctuations, mood symptoms, and physiologic stress-reactivity (cortisol and interleukin-6) and whether differences in mood-sensitivity to E2 fluctuations predict mood responses to TE2 treatment. METHODS: This randomized, double-blind, placebo-controlled trial investigated medically healthy women (46-60 years) in the early or late menopause transition. Baseline E2-sensitivity strength was calculated from eight weekly individual correlations between week-to-week E2 change and index week anxiety (State-Trait Anxiety Inventory) and anhedonia (Snaith-Hamilton Pleasure Scale). Women then received eight weeks of TE2 or transdermal placebo. RESULTS: Analyses included 73 women (active TE2 n = 35). Greater baseline E2 fluctuations predicted greater anhedonia (p = .002), particularly in women with more SLEs. Greater E2 fluctuations also predicted higher cortisol (p = .012) and blunted interleukin-6 (p = .02) stress-responses. Controlling for baseline symptoms, TE2 was associated with lower post-treatment anxiety (p < .001) and anhedonia (p < .001) versus placebo. However, the efficacy of TE2 for anxiety (p = .007) and also for somatic complaints (p = .05) was strongest in women with greater baseline E2 sensitivity strength. CONCLUSIONS: TE2 treatment reduced perimenopausal anxiety and anhedonia. The ability of baseline mood-sensitivity to E2 fluctuations to predict greater TE2 efficacy has implications for individualized treatment of perimenopausal anxiety disorders.

The role of estradiol fluctuation in the pathophysiology of perimenopausal depression: A hypothesis paper.

The menopause transition, which constitutes the five or so years surrounding the final menstrual period, has been established as a time of increased risk for depressive symptoms. While mounting research suggests that exposure to more extreme and fluctuating levels of estradiol (E2) plays a role, it remains unclear which specific trigger is most strongly implicated in the development of depressive mood: acute E2 withdrawal or extreme increases in E2. The current review summarises the literature supporting the role of each, considering research pertaining to perimenopausal depression as well as other reproductive mood disorders in which ovarian hormone change is believed to play a key role, namely premenstrual dysphoric disorder and postpartum depression. Taking together the available research pertaining to the various reproductive mood disorders, we propose that women may exhibit one of four E2 sensitivity profiles, each of which may have important implications for the expected timing and severity of depressive mood during the menopause transition: the E2-increase sensitive profile, developing depressive mood in response to elevations in E2, the E2-decrease sensitive profile, for whom E2 withdrawal triggers negative mood, the E2-change sensitive profile, characterised by mood sensitivity to E2 change in either direction, and the E2 insensitive profile for whom changes in E2 have negligible psychological effects. The evidence supporting the existence of such profiles are summarised, potential biological mechanisms are briefly highlighted, and implications for future research are discussed.

The Female Reproductive Tract Microbiome-Implications for Gynecologic Cancers and Personalized Medicine.

The microbial colonization of the lower female reproductive tract has been extensively studied over the past few decades. In contrast, the upper female reproductive tract including the uterine cavity and peritoneum where the ovaries and fallopian tubes reside were traditionally assumed to be sterile under non-pathologic conditions. However, recent studies applying next-generation sequencing of the bacterial 16S ribosomal RNA gene have provided convincing evidence for the existence of an upper female reproductive tract microbiome. While the vaginal microbiome and its importance for reproductive health outcomes has been extensively studied, the microbiome of the upper female reproductive tract and its relevance for gynecologic cancers has been less studied and will be the focus of this article. This targeted review summarizes the pertinent literature on the female reproductive tract microbiome in gynecologic malignancies and its anticipated role in future research and clinical applications in personalized medicine.

Testosterone and depressive symptoms during the late menopause transition.

BACKGROUND: The menopause transition is associated with an increased risk of depression. While the mechanisms behind this increased risk are not well understood, the changing perimenopausal hormonal environment has been hypothesized to play a role. The current study examined the potential influence of testosterone and the ratio of testosterone to estradiol as a potential contributor to depressed mood in the menopause transition. METHODS: Fifty non-depressed perimenopausal women ages 45-55 were recruited for this study. Once every 3 weeks, for a total of four times, the women completed the Centre for Epidemiological Studies-Depression (CES-D) scale for the measurement of depressive symptoms and provided a first-morning urine sample for the measurement of urinary testosterone as well as estrone-3-glucuronide (E1G), a urinary metabolite of estradiol. The week-to-week and mean effects of testosterone, E1G, and the testosterone/E1G ratio on CES-D score were examined. Self-reported sleep quality and vasomotor symptoms were also assessed at each of the four time points. RESULTS: Testosterone levels rose with increasing months since last menstrual period associated with testosterone levels (ß(SE) = 175.3(63.2), p = .006), though this effect was moderated by body mass index (p for the interaction = .001) such that overweight women showed a less pronounced increase over time. Past and current smokers also had higher testosterone levels compared to never smokers. Week-to-week testosterone/E1G ratio was positively associated with CES-D score (ß(SE) = 1.57(0.76), p = .041) but not sleep quality or vasomotor symptoms (ps > .05). Mean testosterone/E1G ratio was also positively associated with vasomotor symptom bother (ß(SE) = 0.14(0.06), p = .018) and poorer sleep quality (ß(SE) = - 0.34(0.09), p = .0001). CONCLUSION: These results suggest that, within the context of the menopause transition, times that are characterized by a higher testosterone-to-estradiol ratio may be associated with higher depressive symptoms. Perimenopausal women with a higher average ratio of testosterone relative to estradiol may also experience more sleep difficulties and vasomotor symptom bother.

The effect of reproductive hormones on women's daily smoking across the menstrual cycle.

BACKGROUND: Women attempt to quit smoking less often than men and are less likely to maintain abstinence. Reproductive hormones have been postulated as a reason for this sex difference, though this remains to be clarified. Research suggests that estradiol and progesterone may influence nicotine addiction, though various methodologies have led to inconsistent findings. The current study aimed to directly examine the effect of reproductive hormones on women's smoking behavior. METHODS: Over the course of one menstrual cycle, twenty-one female smokers recorded the number of cigarettes smoked in a day, as well as their perceived need for and enjoyment of cigarettes smoked. Additionally, they provided 12 urine samples for the measurement of the urinary metabolites of estradiol (estrone-3-glucuronide, E1G) and progesterone (pregnanediol glucuronide, PdG). Multilevel modeling was used to examine the effects of hormone levels as well as hormone change on smoking outcomes. RESULTS: When PdG levels were low, they were inversely associated with daily cigarettes smoked. Furthermore, E1G level was negatively associated with both self-reported need for and enjoyment of cigarettes smoked but not the number of cigarettes smoked. Examining the effect of hormonal change on smoking outcomes revealed a significant interaction between change in PdG and E1G on number of cigarettes smoked such that only a simultaneous drop or increase in both hormones was associated with a greater number of cigarettes. Hormonal change effects on need for and enjoyment of cigarettes were not significant. CONCLUSIONS: The present study suggests that (1) elevated progesterone levels lessen the propensity to smoke in women, (2) estrogen levels influence women's subjective experience of smoking, and (3) simultaneous drops or increases in these hormones are associated with increased smoking.

Endocrine and psychosocial moderators of mindfulness-based stress reduction for the prevention of perimenopausal depressive symptoms: A randomized controlled trial.

BACKGROUND: The menopause transition is associated with an increased risk of depressive symptoms. The current study aimed to test whether Mindfulness-Based Stress Reduction, an 8-week group intervention involving meditation and yoga, might reduce the risk of depressive symptoms among perimenopausal women. A secondary aim was to examine baseline characteristics, including sensitivity to estradiol fluctuation, as a moderator of treatment effects. METHODS: 104 healthy women from the community in the menopause transition were enrolled and randomized to MBSR (n = 52) or a waitlist control condition (n = 52). Randomization was carried out using a random number generator and opaque sealed envelopes. Depressive symptoms, the main outcome, were assessed every two weeks for 6 months using the Center for Epidemiologic Studies Depression Scale (CES-D). The occurrence of an elevated CES-D score (≥16) and of a major depressive episode were pre-identified secondary outcomes. The following surveys were used to assess additional outcomes of interest every two months: the Perceived Stress Scale, Spielberger Trait Anxiety Inventory, Connor-Davidson Resilience Scale, and Pittsburgh Sleep Quality Index. Baseline characteristics examined as potential moderators of treatment benefit included: baseline CES-D score, past depressive episodes, recent stressful life events, a history of physical or sexual abuse, and emotional sensitivity to reproductive hormone fluctuation. Outcome assessors were blinded to the participants' assigned treatment arm. RESULTS: Outcome data were available for 44 women assigned to MBSR and 51 women in the waitlist condition. Women randomized to MBSR reported fewer depressive symptoms, less perceived stress, less anxiety, increased resilience, and improved sleep (ps < 0.001). Furthermore, several baseline characteristics predicted a greater mood benefit of MBSR, including: a history of major depression (p for the interaction <0.001), a greater number of recent stressful life events (p < .001), being in the early menopause transition (p = .002), and an increased emotional sensitivity to reproductive hormone fluctuation (p = .004). There were no group differences in the occurrence of major depressive episodes (p > .05). CONCLUSIONS: MBSR appears to be an effective intervention for the prevention of depressive symptoms in the menopause transition.

Regulatory guidelines do not accurately predict tolvaptan and metabolite interactions at BCRP, OATP1B1, and OAT3 transporters.

Tolvaptan (TLV) was US Food and Drug Administration (FDA)-approved for the indication to slow kidney function decline in adults at risk of rapidly progressing autosomal dominant polycystic kidney disease in 2018. In vitro, TLV was a breast cancer resistance protein (BCRP) inhibitor, whereas the oxobutyric acid metabolite of TLV (DM-4013) was an inhibitor of organic anion transport polypeptide (OATP)1B1 and organic anion transporter (OAT)3. Based on the 2017 FDA guidance, potential for clinically relevant inhibition at these transporters was indicated for the highest TLV regimen. Consequently, two postmarketing clinical trials in healthy subjects were required. In trial 1, 5 mg rosuvastatin calcium (BCRP and OATP1B1 substrate) was administered alone, with 90 mg TLV or 48 h following 7 days of once daily 300 mg TLV (i.e., in the presence of DM-4103). In trial 2, 40 mg furosemide (OAT3 substrate) was administered alone and in presence of DM-4103. For BCRP, rosuvastatin geometric mean ratios (90% confidence intervals [CIs]) for maximum plasma concentration (Cmax ) were 1.54 (90% CI 1.26-1.88) and for area under the concentration-time curve from time 0 to the time of the last measurable concentration (AUCt ) were 1.69 (90% CI 1.34-2.14), indicating no clinically significant interaction. DM-4103 produced no clinically meaningful changes in rosuvastatin or furosemide concentrations, indicating no inhibition at OATP1B1 or OAT3. The BCRP prediction assumed the drug dose is completely soluble in 250 ml; TLV has solubility of ~0.01 g/250 ml. For OATP1B1/OAT3, if fraction unbound for plasma protein binding (PPB) is less than 1%, then 1% is assumed. DM-4103 has PPB greater than 99.8%. Use of actual drug substance solubility and unbound fraction in plasma would have produced predictions consistent with the clinical results.

Mood sensitivity to estradiol predicts depressive symptoms in the menopause transition.

BACKGROUND: The risk for depression markedly rises during the 5-6 years leading up to the cessation of menstruation, known as the menopause transition. Exposure to extreme estradiol levels may help explain this increase but few studies have examined individual sensitivity to estradiol in predicting perimenopausal depression. METHOD: The current study recruited 101 perimenopausal women. During Phase 1, we quantified each woman's sensitivity to changes in estradiol using 12 weekly measures of estrone-3-glucuronide (E1G), a urinary metabolite of estradiol, and concurrent depressive symptoms. The weekly cortisol awakening response was measured to examine the hypothalamic-pituitary-adrenal (HPA) axis in mediating mood sensitivity to estradiol. In Phase 2, depressive symptoms and major depression diagnoses were assessed monthly for 9 months. The relationship between Phase 1 E1G sensitivity and Phase 2 depressive symptoms and major depressive episodes was examined. Several baseline characteristics were examined as potential moderators of this relationship. RESULTS: The within-person correlation between weekly E1G and mood varied greatly from woman to woman, both in strength and direction. Phase 1 E1G mood sensitivity predicted the occurrence of clinically significant depressive symptoms in Phase 2 among certain subsets of women: those without a prior history of depression, reporting a low number of baseline stressful life events, and reporting fewer months since their last menstrual period. HPA axis sensitivity to estradiol fluctuation did not predict Phase 2 outcomes. CONCLUSION: Mood sensitivity to estradiol predicts risk for perimenopausal depression, particularly among women who are otherwise at low risk and among those who are early in the transition.

Perimenopausal transdermal estradiol replacement reduces serum HDL cholesterol efflux capacity but improves cardiovascular risk factors.

BACKGROUND: The cardiovascular (CV) safety of estrogen replacement therapy (ERT) in perimenopausal women remains uncertain. Although exogenous estrogens increase HDL cholesterol (HDL-C), estrogen-mediated effects on alternative metrics of HDL that may better predict CV risk are unknown. OBJECTIVE: To determine the effects of transdermal ERT on HDL composition and cholesterol efflux capacity (CEC), as well as the relationships between these metrics and CV risk factors. METHODS: Fasting plasma samples were analyzed from 101 healthy, perimenopausal women randomized to receive either transdermal placebo or transdermal estradiol (100 µg/24 h) with intermittent micronized progesterone. At baseline and after 6 months of treatment, serum HDL CEC, HDL particle concentration, HDL protein composition, insulin resistance and brachial artery flow-mediated dilatation (FMD) were measured. RESULTS: No difference between groups was found for change in plasma HDL-C (p = 0.69). Between-group differences were found for changes in serum HDL total CEC [median change from baseline -5.4 (-17.3,+8.4)% ERT group versus +5.8 (-6.3,+16.9)% placebo group, p = 0.01] and ABCA1-specific CEC [median change from baseline -5.3 (-10.7,+6.7)% ERT group versus +7.4 (-1.5,+18.1)% placebo group, p = 0.0002]. Relative to placebo, transdermal ERT led to reductions in LDL-C (p < 0.0001) and insulin resistance (p = 0.0002). An inverse correlation was found between changes in serum HDL total CEC and FMD (ß = -0.26, p = 0.004). CONCLUSIONS: Natural menopause leads to an increase in serum HDL CEC, an effect that is abrogated by transdermal ERT. However, transdermal ERT leads to favorable changes in major CV risk factors.

Consenso colombiano de expertos sobre recomendaciones informadas en la evidencia para la prevención, el diagnóstico y el manejo de la lesión renal aguda por SARS-CoV-2/COVID-19 / Colombian consensus of experts on recommendations informed in the evidence for the prevention, diagnosis and management of acute kidney injury by SARS-CoV-2/COVID-19

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Abstract Introduction: Acute kidney injury is a frequent complication in patients with COVID-19 and its occurrence is a potential indicator of multi-organ dysfunction and disease severity. Objective: Develop, through an expert consensus, evidence-based recommendations for the prevention, diagnosis, and management of acute kidney injury in patients with SARS CoV2 / COVID-19 infection. Materials and methods: Based on a rapid systematic review in Embase and Pubmed databases and documents from scientific societies, we made preliminary recommendations and consulted with an expert group through an online tool. Then we defined agreement after at least 70 % consensus approval. Quality evidence was evaluated according to the type of document included. The strength of the recommendations was graded as strong or weak. Results: Fifty clinical experts declared their conflict of interest; the consultation took place between May 2 and 29, 2020. The range of agreement ranged from 75.5 % to 100 %. Recommendations for prevention, diagnosis and management of acute kidney injury in patients with SARS CoV2 infection are presented. Conclusions: Although the good quality information available regarding acute kidney injury in patients with COVID-19 is scarce, the recommendations of clinical experts will guide clinical decision-making and strategies around patients with this complication, guaranteeing care focused on the people, with high quality standards, and the generation of safety, health and wellness policies for multidisciplinary care teams.

CRISPR based editing of SIV proviral DNA in ART treated non-human primates.

Elimination of HIV DNA from infected individuals remains a challenge in medicine. Here, we demonstrate that intravenous inoculation of SIV-infected macaques, a well-accepted non-human primate model of HIV infection, with adeno-associated virus 9 (AAV9)-CRISPR/Cas9 gene editing construct designed for eliminating proviral SIV DNA, leads to broad distribution of editing molecules and precise cleavage and removal of fragments of the integrated proviral DNA from the genome of infected blood cells and tissues known to be viral reservoirs including lymph nodes, spleen, bone marrow, and brain among others. Accordingly, AAV9-CRISPR treatment results in a reduction in the percent of proviral DNA in blood and tissues. These proof-of-concept observations offer a promising step toward the elimination of HIV reservoirs in the clinic.

Novel BAG3 Variants in African American Patients With Cardiomyopathy: Reduced ß-Adrenergic Responsiveness in Excitation-Contraction.

BACKGROUND: We reported 3 novel nonsynonymous single nucleotide variants of Bcl2-associated athanogene 3 (BAG3) in African Americans with heart failure (HF) that are associated with a 2-fold increase in cardiac events (HF hospitalization, heart transplantation, or death). METHODS AND RESULTS: We expressed BAG3 variants (P63A, P380S, and A479V) via adenovirus-mediated gene transfer in adult left ventricular myocytes isolated from either wild-type (WT) or cardiac-specific BAG3 haploinsufficient (cBAG3+/-) mice: the latter to simulate the clinical situation in which BAG3 variants are only found on 1 allele. Compared with WT myocytes, cBAG3+/- myocytes expressed approximately 50% of endogenous BAG3 levels and exhibited decreased [Ca2+]i and contraction amplitudes after isoproterenol owing to decreased L-type Ca2+ current. BAG3 repletion with WT BAG3 but not P380S, A479V, or P63A/P380S variants restored contraction amplitudes in cBAG3+/- myocytes to those measured in WT myocytes, suggesting excitation-contraction abnormalities partly account for HF in patients harboring these mutants. Because P63A is near the WW domain (residues 21-55) and A479V is in the BAG domain (residues 420-499), we expressed BAG3 deletion mutants (Δ1-61 and Δ421-575) in WT myocytes and demonstrated that the BAG but not the WW domain was involved in enhancement of excitation-contraction by isoproterenol. CONCLUSIONS: The BAG3 variants contribute to HF in African American patients partly by decreasing myocyte excitation-contraction under stress, and that both the BAG and PXXP domains are involved in mediating ß-adrenergic responsiveness in myocytes.