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Abstract Background The purpose of this study was to investigate the association between diabetic retinopathy (DR) severity and macular choriocapillaris (CC) flow deficit percentage (FD %) in different macular regions using swept-source optical coherence tomography angiography (SS-OCTA). Methods Diabetic patients with SS-OCTA images were graded by severity and retrospectively assessed. CC FD % was calculated in four different regions of the OCTA image: inner, middle, outer, and full-field region. The generalized estimating equations (GEE) approach for clustered eye data was used to determine effect size and significance of age and disease severity on FD % for each region. Results 160 eyes from 90 total diabetic patients met inclusion criteria. Out of 90 patients, 33 had no DR, 17 had mild nonproliferative DR (NPDR), 8 had moderate NPDR, 10 had severe NPDR and 22 had proliferative DR. Age and DR severity had a significant positive association with FD % for each region studied with a greater effect in the two centermost regions. The increase in flow deficit percentage per year of age by region was: inner 0.12 (p

Abstract Background Pelvic floor muscles (PFM) and rectus abdominis muscles (RAM) of pregnant diabetic rats exhibit atrophy, co-localization of fast and slow fibers and an increased collagen type I/III ratio. However, the role of similar PFM or RAM hyperglycemic-related myopathy in women with gestational diabetes mellitus (GDM) remains poorly investigated. This study aims to assess the frequency of pelvic floor muscle disorders and pregnancy-specific urinary incontinence (PS-UI) 12 months after the Cesarean (C) section in women with GDM. Specifically, differences in PFM/RAM hyperglycemic myopathy will be evaluated. Methods The Diamater is an ongoing cohort study of four groups of 59 pregnant women each from the Perinatal Diabetes Research Centre (PDRC), Botucatu Medical School (FMB)-UNESP (São Paulo State University), Brazil. Diagnosis of GDM and PS-UI will be made at 24–26 weeks, with a follow-up at 34–38 weeks of gestation. Inclusion in the study will occur at the time of C-section, and patients will be followed at 24–48 h, 6 weeks and 6 and 12 months postpartum. Study groups will be classified as (1) GDM plus PS-UI; (2) GDM without PS-UI; (3) Non-GDM plus PS-UI; and (4) Non-GDM without PS-UI. We will analyze relationships between GDM, PS-UI and hyperglycemic myopathy at 12 months after C-section. The mediator variables to be evaluated include digital palpation, vaginal squeeze pressure, 3D pelvic floor ultrasound, and 3D RAM ultrasound. RAM samples obtained during C-section will be analyzed for ex-vivo contractility, morphological, molecular and OMICS profiles to further characterize the hyperglycemic myopathy. Additional variables to be evaluated include maternal age, socioeconomic status, educational level, ethnicity, body mass index, weight gain during pregnancy, quality of glycemic control and insulin therapy. Discussion To our knowledge, this will be the first study to provide data on the prevalence of PS-UI and RAM and PFM physical and biomolecular muscle profiles after C-section in mothers with GDM. The longitudinal design allows for the assessment of cause-effect relationships between GDM, PS-UI, and PFMs and RAMs myopathy. The findings may reveal previously undetermined consequences of GDM.

Ampakines are a class of orally available positive allosteric modulators of the AMPA-glutamate receptor (AMPAR) and have therapeutic implications for neurological/neuropsychiatric disorders in which AMPAR signaling is compromised. Low-impact ampakines are a distinct subclass of drugs that only modestly offset receptor desensitization and do not alter agonist binding affinity and thus lack the neurotoxicity and epileptogenic effects associated with other AMPAR modulators. In these studies, we describe the pre-clinical pharmacology of ampakine 1-(benzofurazan-5-ylcarbonyl)morpholine (CX717). CX717 modestly offsets desensitization in hippocampal patches and augments synaptic transmission in vivo. CX717 also enhances long-term potentiation in rats, which is crucial for learning and memory. CX717 enhances performance in the eight-arm radial maze and abrogates amphetamine-induced locomotor activity while being devoid of cataleptic activity in rats. CX717 also ameliorates alfentanil-induced respiratory depression in rats and is not toxic to cultured rat neurons. CX717 is active at doses of 0.3–10 mg/kg and lacked serious adverse events in safety studies in mice up to 2000 mg/kg. CX717 was also previously shown to be safe in humans and effective in reversing opiate-induced respiratory depression and hyperactivity and inattentiveness in adults with ADHD. These findings support the continued clinical investigation of CX717 in the treatment of ADHD, dementia, and opiate-induced respiratory depression. [ABSTRACT FROM AUTHOR]

α‐Amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor (AMPAR) positive allosteric modulators (AMPAkines) have a multitude of promising therapeutic properties. The pharmaceutical development of high impact AMPAkines has, however, been limited by the appearance of calcium‐dependent neuronal toxicity and convulsions in vivo. Such toxicity is not observed at exceptionally high concentrations of low impact AMPAkines. Because most AMPAR are somewhat impermeable to calcium, the current study sought to examine the extent to which different mechanisms contribute to the rise in intracellular calcium in the presence of high impact ampakines. In the presence of AMPA alone, cytosolic calcium elevation is shown to be sodium‐dependent. In the presence of high impact AMPAkines such as cyclothiazide (CTZ) or CX614, however, AMPAR potentiation also activates an additional mechanism that induces calcium release from endoplasmic reticular (ER) stores. The pathway that connects AMPAR to the ER system involves a Gq‐protein, phospholipase Cβ‐mediated inositol triphosphate (InsP3) formation, and ultimately stimulation of InsP3‐receptors located on the ER. The same linkage was not observed using high concentrations of the low impact AMPAkines, CX516 (Ampalex), and CX717. We also demonstrate that CX614 produces neuronal hyper‐excitability at therapeutic doses, whereas the newer generation low impact AMPAkine CX1739 is safe at exceedingly high doses. Although earlier studies have demonstrated a functional linkage between AMPAR and G‐proteins, this report demonstrates that in the presence of high impact AMPAkines, AMPAR also couple to a Gq‐protein, which triggers a secondary calcium release from the ER and provides insight into the disparate actions of high and low impact AMPAkines. [ABSTRACT FROM AUTHOR]

Ampakines—positive allosteric modulators of AMPA-type glutamate receptors (AMPARs)—are drug candidates that have shown substantial promise in pre-clinical models of various neurodegenerative and neuropsychiatric diseases. Much of the study of ampakines has focused on how these drugs modulate neuronal AMPARs to achieve certain therapeutic effects. However, astrocytes also express functional AMPARs and their physiology may be sensitive to modulation by ampakines. Herein, we investigate the effects of multiple ampakines on calcium levels in cortical astrocytes. We find that ampakines augment cytosolic calcium elevations in astrocytes to an extent far greater than that achieved by AMPA alone. This effect is amenable to competitive AMPAR blockade. Furthermore, calcium induction is sensitive to phospholipase Cβ antagonism and blockade of inositol triphosphate receptors located on the endoplasmic reticulum. Low-impact ampakines exerted weaker effects on cytosolic calcium levels in astrocytes and higher concentrations were required to observe an effect. Furthermore, high doses of the low-impact ampakine, CX717, were not toxic to cortical astrocytes at high concentrations, which may serve to differentiate low-impact ampakines from classical AMPAR positive modulators like cyclothiazide. As ampakines are further developed for clinical use, it would be prudent to determine the extent to and manner by which they affect astrocytes, as these effects may also underpin their therapeutic utility in CNS pathologies. [ABSTRACT FROM AUTHOR]

Fusion oncoproteins are associated with childhood cancers and have proven challenging to target, aside from those that include kinases. As part of its efforts for targeting childhood cancers, the National Cancer Institute recently conducted a series on Novel Chemical Approaches for Targeting Fusion Oncoproteins. Key learnings on leading platforms and technologies that can be used to advance the development of molecular therapeutics that target fusion oncoproteins in childhood cancers are described. Recent breakthroughs in medicinal chemistry and chemical biology provide new ground and creative strategies to exploit for the development of targeted agents for improving outcomes against these recalcitrant cancers. [ABSTRACT FROM AUTHOR]

The Phylum Cressdnaviricota consists of a large number of circular Rep‐encoding single‐stranded (CRESS)‐DNA viruses. Recently, metagenomic analyzes revealed their ubiquitous distribution in a diverse range of eukaryotes. Data relating to CRESS‐DNA viruses in humans remains scarce. Our study investigated the presence and genetic diversity of CRESS‐DNA viruses in human vaginal secretions. Vaginal swabs were collected from 28 women between 29 and 43 years old attending a fertility clinic in New York City. An exploratory metagenomic analysis was performed and detection of CRESS‐DNA viruses was confirmed through analysis of near full‐length sequences of the viral isolates. A phylogenetic tree was based on the REP open reading frame sequences of the CRESS‐DNA virus genome. Eleven nearly complete CRESS‐DNA viral genomes were identified in 16 (57.1%) women. There were no associations between the presence of these viruses and any demographic or clinical parameters. Phylogenetic analysis indicated that one of the sequences belonged to the genus Gemycircularvirus within the Genomoviridae family, while ten sequences represented previously unclassified species of CRESS‐DNA viruses. Novel species of CRESS‐DNA viruses are present in the vaginal tract of adult women. Although they be transient commensal agents, the potential clinical implications for their presence at this site cannot be dismissed. [ABSTRACT FROM AUTHOR]

There is no consensus on the outcomes needed for the recovery and reintegration of survivors of modern slavery and human trafficking. We developed the Modern Slavery Core Outcome Set (MSCOS) to address this gap. We conducted three English-language reviews on the intervention outcomes sought or experienced by adult survivors: a qualitative systematic review (4 databases, 18 eligible papers, thematic analysis), a rapid review of quantitative intervention studies (four databases, eight eligible papers, content analysis) and a gray literature review (2 databases, 21 websites, a call for evidence, 13 eligible papers, content analysis). We further extracted outcomes from 36 pre-existing interview transcripts with survivors, and seven interviews with survivors from underrepresented groups. We narrowed down outcomes via a consensus process involving: a three-stage E-Delphi survey (191 respondents); and a final consensus workshop (46 participants). We generated 398 outcomes from our 3 reviews, and 843 outcomes from interviews. By removing conceptual and literal duplicates, we reduced this to a longlist of 72 outcomes spanning 10 different domains. The E-Delphi produced a 14-outcome shortlist for the consensus workshop, where 7 final outcomes were chosen. Final outcomes were: "long-term consistent support," "secure and suitable housing," "safety from any trafficker or other abuser," "access to medical treatment," "finding purpose in life and self-actualisation," "access to education," and "compassionate, trauma-informed services." The MSCOS provides outcomes that are accepted by a wide range of stakeholders and that should be measured in intervention evaluation. [ABSTRACT FROM AUTHOR]

Abstract Background Increased mineralocorticoid activity is one of the plausible causes of chronic central serous chorioretinopathy (CSCR) and mineralocorticoid inhibitors such as eplerenone have been investigated as its potential therapy. This study investigates the short-term safety and efficacy of oral eplerenone in patients with chronic CSCR. Patients and methods Prospective study of 13 eyes of 13 patients with the diagnosis of chronic CSCR. All patients received eplerenone 50 mg/day for 4 weeks. Enhanced depth imaging optical coherence tomography (OCT) was obtained. Best corrected visual acuity (BCVA), and OCT parameters including sub retinal fluid (SRF), choroidal thickness (CT) and central macular thickness (CMT), were measured manually. Results The mean SRF height decreased slightly at 1-month follow-up as compared to baseline, but the change was not statistically significant (94.18 ± 17.53 vs. 113.15 ± 18.69; p = 0.08). Subfoveal CT and CMT was significantly reduced as compared to baseline (6.6% [p = 0.002] and 7.05% [p = 0.04], respectively). The BCVA did not change significantly (20/28 vs. 20/30 [p = 0.16]). Conclusion This study suggests that oral eplerenone may be used as a safe and potentially effective treatment in chronic CSCR, however there are minimal short-term effects on subretinal fluid or visual acuity therefore therapeutic trials longer than one month are necessary to test its benefits. Trial registration Clinicaltrials.gov identification number: NCT01822561. Registered 3/25/13, https://clinicaltrials.gov/ct2/show/study/NCT01822561

As clinical efforts towards breast-conserving therapy and prolonging survival of those with metastatic breast cancer increase, innovative approaches with the use of biologics are on the rise. Two areas of current focus are cancer immunotherapy and autophagy, both of which have been well-studied independently but have recently been shown to have intertwining roles in cancer. An increased understanding of their interactions could provide new insights that result in novel diagnostic, prognostic, and therapeutic strategies. In this breast cancer-focused review, we explore the interactions between autophagy and two clinically relevant immune checkpoint pathways; the programmed cell death-1 receptor with its ligand (PD-L1)/PD-1 and the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)/CD80 and CD86 (B7-1 and B7-2). Furthermore, we discuss emerging preclinical and clinical data supporting targeting both immunotherapy and autophagy pathway manipulation as a promising approach in the treatment of breast cancer.

Background: Previous reported neurologic sequelae associated with SARS-CoV-2 infection have mainly been confined to hospital-based patients in which viral detection was restricted to nasal/throat swabs or to IgM/IgG peripheral blood serology. Here we describe seven cases from Brazil of outpatients with previous mild or moderate COVID-19 who developed subacute cognitive disturbances.Methods: From June 1 to August 15, 2020, seven individuals 18 to 60 years old, with confirmed mild/moderate COVID-19 and findings consistent with encephalopathy who were observed >7 days after respiratory symptom initiation, were screened for cognitive dysfunction. Paired sera and CSF were tested for SARS-CoV-2 (IgA, IgG ELISA, and RT-PCR). Serum and intrathecal antibody dynamics were evaluated with oligoclonal bands and IgG index. Cognitive dysfunction was assessed by the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and the Clock Drawing Test (CDT).Results: All but one of our patients were female, and the mean age was 42.6 years. Neurologic symptoms were first reported a median of 16 days (IQR 15–33) after initial COVID-19 symptoms. All patients had headache and altered behavior. Cognitive dysfunction was observed mainly in phonemic verbal fluency (MoCA) with a median of six words/min (IQR 5.25–10.75) and altered visuospatial construction with a median of four points (IQR 4–9) (CDT). CSF pleocytosis was not detected, and only one patient was positive for SARS-CoConclusions: A subacute cognitive syndrome suggestive of SARS-CoV-2-initiated damage to cortico-subcortical associative pathways that could not be attributed solely to inflammation and hypoxia was present in seven individuals with mild/moderate COVID-19.

ABSTRACT OBJECTIVE To evaluate the performance of post mortem laboratory analysis in identifying the causes of hemorrhagic fever and/or neuroinvasive disease in deaths by arbovirus infection. METHODS Retrospective cross-sectional study based on the differential analysis and final outcome obtained in patients whose samples underwent laboratory testing for arboviruses at the Pathology Center of the Adolfo Lutz Institute, in São Paulo, Brazil. RESULTS Of the 1355 adults clinically diagnosed with hemorrhagic fever and/or neuroinvasive disease, the most commonly attributed cause of death and the most common final outcome was dengue fever. Almost half of the samples tested negative on all laboratory tests conducted. CONCLUSION The failure to identify the causative agent in a great number of cases highlights a gap in the diagnosis of deaths of unknown etiology. Additional immunohistochemical and molecular assessments need to be added to the post-mortem protocol if all laboratory evaluations performed fail to identify a causative agent. While part of our findings may be due to technical issues related to sample fixation, better information availability when making the initial diagnosis is crucial. Including molecular approaches might lead to a significant advancement in diagnostic accuracy.