Flaviviruses are emerging and re-emerging arthropod-borne pathogens responsible for significant mortality and morbidity worldwide. The genus comprises more than seventy small, positive-sense, single-stranded RNA viruses, which are responsible for a spectrum of human and animal diseases ranging in symptoms from mild, influenza-like infection to fatal encephalitis and haemorrhagic fever. Despite genomic and structural similarities across the genus, infections by different flaviviruses result in disparate clinical presentations. This review focusses on two haemorrhagic flaviviruses, dengue virus and yellow fever virus, and two neurotropic flaviviruses, Japanese encephalitis virus and Zika virus. We review current knowledge on host-pathogen interactions, virus entry strategies and tropism.

Facioscapulohumeral muscular dystrophy is a dominantly inherited myopathy associated with chromatin relaxation of the D4Z4 macrosatellite array on chromosome 4. DUX4 is encoded within each unit of the D4Z4 array where it is normally transcriptionally silenced and packaged as constitutive heterochromatin. Truncation of the array to less than 11 D4Z4 units (FSHD1) or mutations in SMCHD1 (FSHD2) results in chromatin relaxation and a small percentage of cultured myoblasts from these individuals exhibit infrequent bursts of DUX4 expression. There are no cellular or animal models to determine the trigger of the DUX4 producing transcriptional bursts and there has been a failure to date to detect the protein in significant numbers of cells from FSHD-affected individuals. Here, we demonstrate for the first time that myotubes generated from FSHD patients express sufficient amounts of DUX4 to undergo DUX4-dependent apoptosis. We show that activation of the Wnt/β-catenin signaling pathway suppresses DUX4 transcription in FSHD1 and FSHD2 myotubes and can rescue DUX4-mediated myotube apoptosis. In addition, reduction of mRNA transcripts from Wnt pathway genes β-catenin, Wnt3A and Wnt9B results in DUX4 activation. We propose that Wnt/β-catenin signaling is important for transcriptional repression of DUX4 and identify a novel group of therapeutic targets for the treatment of FSHD.

Background Neurodegeneration plays an important role in permanent disability in multiple sclerosis (MS). Objective To determine whether progressive neurodegeneration occurs in MS eyes without clinically-evident inflammation. Methods Retinal nerve fiver layer thickness (RNFLT) and ganglion cell-inner plexiform layer thickness (GCIPT) were measured using Cirrus optical coherence tomography (OCT) in 133 relapsing-remitting MS (RRMS) patients (149 no-ON, 97 ON eyes, last optic neuritis (ON) ≥6 months). 93 patients were scanned at two visits. Percents of abnormal GCIPT vs RNFLT (<5% of machine norms) in cross-sectional data were compared. Relations between RNFLT/GCIPT and MS duration (cross-sectional) and follow-up time (longitudinal) were assessed. Results GCIPT was abnormal in more eyes than RNFLT (27% vs 16% p=0.004 in no-ON, 82% vs 72% p=0.007 in ON). RNFLT and GCIPT decreased with MS duration by −0.49 µm/yr (p=0.0001) and −0.36 (p=0.005) for no-ON; −0.52 (p=0.003) and −0.41 (p=0.007) for ON. RNFLT and GCIPT decreased with follow-up time by −1.49 µm/yr (p<0.0001) and −0.53 (p=0.004) for no-ON, −1.27 (p=0.002) and −0.49 (p=0.04) for ON. Conclusions In RRMS eyes without clinically-evident inflammation, progressive loss of RNFLT and GCIPT occurred, supporting the need for neuroprotection in addition to suppression of auto-immune responses and inflammation.

Objective. To analyze region-specific T1r and T2 relaxation times of the hip joint cartilage in relation to presence or absence of radiographic hip osteoarthritis (OA) and presence or absence of magnetic resonance imaging (MRI)-detected cartilage defects.Methods. Weight-bearing radiographs and 3T MRI studies of the hip were obtained from 84 volunteers. Based on Kellgren/Lawrence (K/L) scoring of the radiographs, 54 subjects were classified as healthy controls (K/L grade £1) and 30 were classified as having mild or moderate radiographic hip OA (K/L grades 2 or 3, respectively). Two-dimensional fat-suppressed fast spin-echo MRI sequences were used for semiquantitative clinical scoring of cartilage defects, and a T1r/T2 sequence was used to quantitatively assess the cartilage matrix. The femoral and acetabular cartilage was then segmented into 8 regions and the mean T1r/T2 values were calculated. Differences in T1r and T2 relaxation times were compared between subjects with and those without radiographic hip OA, and those with and those without femoral or acetabular cartilage defects.Results. Higher T1r and T2 relaxation times in the anterior superior and central regions of the acetabular cartilage were seen in individuals with radiographic hip OA and those with acetabular cartilage defects compared to their respective controls (P < 0.05). In the femoral cartilage, the differences in T1r and T2 were not significant for any of the comparisons. Significant differences in the T1r and T2 values (each P < 0.05) were found in more subregions of the cartilage and across the whole cartilage when subjects were stratified based on the presence of MRI-detected cartilage defects than when they were stratified based on the presence of radiographic hip OA.Conclusion. T1r and T2 relaxation parameters are sensitive to the presence of cartilage degeneration. Both parameters may therefore support MRI evidence of cartilage defects of the hip.One in 4 individuals has a lifetime risk of developing symptomatic hip osteoarthritis (OA) by the age of 85 years (1). Individuals with hip OA experience substantial pain and disability, suggesting an urgent clinical need for diagnosis and prevention of hip OA (2,3). Hip OA is typically diagnosed through the use of radiographs, and semiquantitative clinical scores, such as the Kellgren/Lawrence (K/L) scores for radiographic damage (4), are used to quantify the severity of OA. However, diagnosis of OA with the use of radiographs is mostly focused on osteophytes and joint space narrowing, features that are indicative of advanced disease, whereas radiography lacks sensitivity for early changes of the soft tissues, such as cartilage and labrum. Magnetic resonance imaging (MRI) can provide information on hip degeneration at an earlier stage, by allowing visualization of morphologic abnormalities of the cartilage, bone marrow, and labrum (5-8).Early changes in OA consist of proteoglycan loss, changes in water content, and collagen disruption (9).

Background Severity of illness in COVID-19 is consistently lower in women. Focus on sex as a biologic factor may suggest a potential therapeutic intervention for this disease. We assessed whether adding progesterone to standard of care would improve clinical outcomes of hospitalized men with moderate to severe COVID-19. Research Question Does short-term subcutaneous administration of progesterone safely improve clinical outcome in hypoxemic men hospitalized with COVID-19? Study Design and Methods We conducted a pilot, randomized, open-label, controlled trial of subcutaneous progesterone in men hospitalized with confirmed moderate to severe COVID-19. Patients were randomly assigned to receive standard of care (SOC) plus progesterone (100 mg subcutaneously twice daily for up to five days) or SOC alone. In addition to assessment of safety, the primary outcome was change in clinical status at day 7. Length of hospital stay and number of days on supplemental oxygen were key secondary outcomes. Results Forty-two patients were enrolled from April - August 2020; 22 were randomized to the control group and 20 to the progesterone group. Two patients from the progesterone group withdrew from the study prior to receiving progesterone. There was a 1.5-point overall improvement in median clinical status score on a seven-point ordinal scale from baseline to Day 7 in patients in the progesterone group as compared to controls (95%CI:0.0-2.0; P=0.024). There were no serious adverse events attributable to progesterone. Patients treated with progesterone required 3 fewer days of supplemental oxygen (median of 4.5 vs 7.5 days) and were hospitalized for 2.5 fewer days (median of 7.0 vs 9.5 days) as compared to controls. Interpretation Progesterone at a dose of 100 mg, twice daily by subcutaneous injection in addition to SOC may represent a safe and effective approach for treatment in hypoxemic men with moderate to severe COVID-19.

In 2013, the WHO Strategic Advisory Group of Experts on Immunization (SAGE) requested WHO to develop a process and a plan to move the maternal immunization agenda forward in support of an increased alignment of data safety evidence, public health needs, and regulatory processes. A key challenge identified was the continued need for harmonization of maternal adverse event following immunization (AEFI) research and surveillance efforts within developing and developed country contexts. We conducted a systematic review as a preliminary step in the development of standardized AEFI definitions for use in maternal and neonatal clinical trials, post-licensure surveillance, and other vaccine studies. We documented the current extent and nature of variability in AEFI definitions and adverse event reporting among 74 maternal immunization studies, which reported a total of 240 different types of adverse events. Forty-nine studies provided explicit AEFI case definitions describing 35 separate types of AEFIs. We identified variability in how AEFIs were determined to be present, in how AEFI definitions were applied, and in the ways that AEFIs were reported. Definitions for key maternal/neonatal AEFIs differed on four discrete attributes: overall level of detail, physiological and temporal boundaries and cut-offs, severity strata, and standards used. Our findings suggest that investigators may proactively address these inconsistencies through comprehensive and consistent reporting of AEFI definitions and outcomes in future publications. In addition, efforts to develop standardized AEFI definitions should generate definitions of sufficient detail and consistency of language to avoid the ambiguities we identified in reviewed articles, while remaining practically applicable given the constraints of low-resource contexts such as limited diagnostic capacity and high patient throughput.

mfVEP and tVEP showed good reproducibility in normals and RRMS. TRV for mfVEP latency was larger in ON than normal or non-ON. mfVEP global latency's TRV was about half the respective values for tVEP in all groups, due to averaging of multiple responses.

Facioscapulohumeral Disease (FSHD) is a dominantly inherited progressive myopathy associated with aberrant production of the transcription factor, Double Homeobox Protein 4 (DUX4). The expression of DUX4 depends on an open chromatin conformation of the D4Z4 macrosatellite array and a specific haplotype on chromosome 4. Even when these requirements are met, DUX4 transcripts and protein are only detectable in a subset of cells indicating that additional constraints govern DUX4 production. Since the direction of transcription, along with the production of non-coding antisense transcripts is an important regulatory feature of other macrosatellite repeats, we developed constructs that contain the non-coding region of a single D4Z4 unit flanked by genes that report transcriptional activity in the sense and antisense directions. We found that D4Z4 contains two promoters that initiate sense and antisense transcription within the array, and that antisense transcription predominates. Transcriptional start sites for the antisense transcripts, as well as D4Z4 regions that regulate the balance of sense and antisense transcripts were identified. We show that the choice of transcriptional direction is reversible but not mutually exclusive, since sense and antisense reporter activity was often present in the same cell and simultaneously upregulated during myotube formation. Similarly, levels of endogenous sense and antisense D4Z4 transcripts were upregulated in FSHD myotubes. These studies offer insight into the autonomous distribution of muscle weakness that is characteristic of FSHD.