Biological constraints on stereotaxic targeting of functionally-defined cortical areas.

Understanding computational principles in hierarchically organized sensory systems requires functional parcellation of brain structures and their precise targeting for manipulations. Although brain atlases are widely used to infer area locations in the mouse neocortex, it has been unclear whether stereotaxic coordinates based on standardized brain morphology accurately represent functional domains in individual animals. Here, we used intrinsic signal imaging to evaluate the accuracy of area delineation in the atlas by mapping functionally-identified auditory cortices onto bregma-based stereotaxic coordinates. We found that auditory cortices in the brain atlas correlated poorly with the true complexity of functional area boundaries. Inter-animal variability in functional area locations predicted surprisingly high error rates in stereotaxic targeting with atlas coordinates. This variability was not simply attributed to brain sizes or suture irregularities but instead reflected differences in cortical geography across animals. Our data thus indicate that functional mapping in individual animals is essential for dissecting cortical area-specific roles with high precision.

Giving Meaning to Quality of Healthcare in Malaysia.

BACKGROUND: Ensuring quality in healthcare calls for a coordinated, systematic, congruous and sustained approach. Nevertheless, it demands defining what the quality of healthcare means in the local context. Presently the Malaysian healthcare system utilises various definitions of quality of healthcare across the different initiatives and levels of healthcare which can lead to fragmented or ineffective quality improvement. The study aims to describe the process undertaken in developing an explicit definition of the quality of healthcare tailored to the Malaysian context, which is currently lacking. METHODS: A pluralistic method was used to explore the different perspectives. Three distinct approaches were used to understand how quality is defined among the different stakeholder groups: 1) interactive policy-makers engagement sessions, 2) a review of local quality-related documents, and 3) an online survey engaging the public. The domains depicting quality of healthcare that emerged through these three approaches were mapped against a framework and synthesised to form the local definition of quality. A national quality-related technical working group convened on several sessions to achieve consensus and finalise the definition of quality of healthcare. RESULTS: Quality healthcare in Malaysia is defined as providing high quality healthcare that is safe, timely, effective, equitable, efficient, people-centred, and accessible [STEEEPA] which is innovative and responsive to the needs of the people, and is delivered as a team, in a caring and professional manner in order to improve health outcomes and client experience. CONCLUSION: The consensus-driven local definition of healthcare quality will guide policies and ensure standardisation in measuring quality, thereby steering efforts to improve the quality of healthcare services delivered in Malaysia.

In Semliki Forest virus encephalitis, suppressor of cytokine signaling 4 (SOCS4) is an essential modulator of immune responses that mediates the balance between immunopathology and virus clearance.

Central nervous system virus infections are a major cause of morbidity and mortality worldwide and a significant global public health concern. As in many tissues, inflammation and immune responses in the brain, despite their protective roles, can also be harmful. Control of brain inflammation is important in many neurological diseases from encephalitis to multiple sclerosis and neurogenerative disease. The suppressors of cytokine signaling (SOCS) proteins are a key mechanism controlling inflammatory and immune responses across all tissues including the brain. Using a mouse model system, we demonstrate that lack of SOCS4 results in changes in the pathogenesis and clinical outcome of a neurotropic virus infection. Relative to wild-type mice, SOCS4-deficient mice showed accelerated clearance of virus from the brain, lower levels of persisting viral RNA in the brain, increased neuroinflammation and more severe neuropathology. We conclude that, in the mouse brain, SOCS4 is a vital regulator of antiviral immunity that mediates the critical balance between immunopathology and virus persistence.

Development of the National Policy for Quality in Healthcare for Malaysia.

BACKGROUND: Quality in healthcare is a fundamental pillar of health systems performance, leading to improved health outcomes and reduced waste. The World Health Organization recommends that countries establish a national quality policy and strategy (NQPS) to steer the provision of safe and high-performing healthcare services and foster a quality culture. This paper describes the development process and key content of Malaysia's new 5-year National Policy for Quality in Healthcare. METHODS: The development process was managed by a technical working group led by the Institute for Health Systems Research in the Ministry of Health. Situational analysis was conducted through a multi-pronged approach, underpinned by a review of the past and present healthcare sectoral and quality plans and guided by the WHO NQPS framework. This approach involved: (i) review of quality-related policy documents, (ii) online surveys of healthcare providers and the public, (iii) key-informant facilitated discussions and (iv) mapping of existing quality improvement initiatives (QIIs). Data gathered from these approaches informed the content of the new policy. Following thematic analysis, the findings were grouped into specific domains, which were then organized into a strengths, weaknesses, opportunities, and threats (SWOT) framework. RESULTS: Ten key areas of concern identified were (i) a people-centred holistic approach, (ii) governance for quality, (iii) resources, (iv) quality culture, (v) stakeholder engagement, (vi) health management information system, (vii) workforce competency, (viii) knowledge exchange, (ix) quality indicators and (x) monitoring and evaluation of quality activities. These led to the formulation of seven strategic priorities  for the planning of improvements aimed at addressing the key areas of concern. The national definition of quality was affirmed. A total of 40 QIIs were mapped and grouped into three broad categories, namely (i) regulatory, (ii) domain-specific QIIs and (iii) Quality Improvement (QI) method. CONCLUSIONS: The National Policy for Quality in Healthcare for Malaysia was developed through a comprehensive situational analysis using a multi-method approach that identified priorities across national, state, institutional and community levels. This evidence-informed approach led to meaningful contextual adaptation of the NQPS framework to shape the strategic direction to advance quality and achieve effective and safe outcomes for all Malaysians.

Current Therapeutics for COVID-19, What We Know about the Molecular Mechanism and Efficacy of Treatments for This Novel Virus.

Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) has caused significant morbidity and mortality worldwide. Though previous coronaviruses have caused substantial epidemics in recent years, effective therapies remained limited at the start of the Coronavirus disease 19 (COVID-19) pandemic. The emergence and rapid spread throughout the globe of the novel SARS-CoV-2 virus necessitated a rapid development of therapeutics. Given the multitude of therapies that have emerged over the last two years and the evolution of data surrounding the efficacy of these therapies, we aim to provide an update on the major clinical trials that influenced clinical utilization of various COVID-19 therapeutics. This review focuses on currently used therapies in the United States and discusses the molecular mechanisms by which these therapies target the SARS-CoV-2 virus or the COVID-19 disease process. PubMed and EMBASE were used to find trials assessing the efficacy of various COVID-19 therapies. The keywords SARS-CoV-2, COVID-19, and the names of the various therapies included in this review were searched in different combinations to find large-scale randomized controlled trials performed since the onset of the COVID-19 pandemic. Multiple therapeutic options are currently approved for the treatment of SARS-CoV-2 and prevention of severe disease in high-risk individuals in both in the inpatient and outpatient settings. In severe disease, a combination of antiviral and immunomodulatory treatments is currently recommended for treatment. Additionally, anti-viral agents have shown promise in preventing severe disease and hospitalization for those in the outpatient setting. More recently, current therapeutic approaches are directed toward early treatment with monoclonal antibodies directed against the SARS-CoV-2 virus. Despite this, no treatment to date serves as a definitive cure and vaccines against the SARS-CoV-2 virus remain our best defense to prevent further morbidity and mortality.

An exploratory study to evaluate visual function endpoints in non-advanced age-related macular degeneration.

BACKGROUND: To prevent irreversible vision loss in age-related macular degeneration (AMD), it is critical to detect retinal dysfunction before permanent structural loss occurs. In the current study we evaluated a series of visual function tests to identify potential endpoints to detect visual dysfunction in non-advanced AMD. METHODS: A series of visual function tests were performed on 23 non-advanced AMD subjects (AREDS grade 1-4 on simplified scale) and 34 age-matched normals (AREDS grade 0). Tests included some commonly used endpoints such as ETDRS visual acuity (VA), low luminance (LL) 2.0ND ETDRS VA, MNREAD as well as newly developed tests such as the Ora-VCF™ test, Ora-tablet reading test, color sensitivity etc. Differences between the two groups were compared for each test. Test-retest repeatability and reproducibility was assessed on a subset of subjects and percent agreement was calculated. RESULTS: There was no difference in standard ETDRS VA between non-advanced AMD (0.06 ± 0.02 logMAR) and normal groups (0.04 ± 0.02 logMAR) (p = 0.57). LL 2.0 ETDRS VA and MNREAD showed no difference between the groups (p > 0.05). Ora-VCF™ test was significantly worse in the non-advanced AMD group compared to normals (0.67 ± 0.07 in AMD; 0.45 ± 0.04 in normals, p = 0.005). Non-advanced AMD subjects also had significantly worse reading performance using the Ora-tablet with LL 2.0ND (114.55 ± 11.22 wpm in AMD; 145.17 ± 9.55 wpm in normals p = 0.049). No significant difference between the groups was noted using other tests. Repeatability was 82% for Ora-VCF™ test and 92% for Ora-tablet LL 2.0ND reading. Reproducibility was 89% for both Ora-VCF™ test and Ora-tablet LL 2.0ND reading. CONCLUSION: While there was no significant difference between non-advanced AMD and normal groups using some current common endpoints such as ETDRS VA, LL 2.0 ETDRS VA or MNREAD, Ora-VCF™ test and Ora-tablet LL 2.0ND reading tests were able to identify significant visual dysfunction in non-advanced AMD subjects. These tests show promise as endpoints for AMD studies.

Wnt/ß-catenin signaling suppresses DUX4 expression and prevents apoptosis of FSHD muscle cells.

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/ß-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 ß-catenin, Wnt3A and Wnt9B results in DUX4 activation. We propose that Wnt/ß-catenin signaling is important for transcriptional repression of DUX4 and identify a novel group of therapeutic targets for the treatment of FSHD.

Reproducibility of multifocal visual evoked potential and traditional visual evoked potential in normal and multiple sclerosis eyes.

PURPOSE: To establish reproducibility of multifocal visual evoked potential (mfVEP) and traditional pattern-reversal VEP (tVEP) in normals and relapsing-remitting multiple sclerosis (RRMS). METHODS: mfVEP (60-sector dartboard) was recorded twice within a month in 40 normals and 40 RRMS patients [25 eyes with last optic neuritis (ON) ≥6 months, 34 non-ON]. mfVEP amplitude and latency (ms) were calculated as mean logSNR and median relative latency, respectively, for all 60 sectors (global) and 9 regions. tVEP was recorded (15', 60' and 120' checks) in subsets of 34 normals and 30 RRMS patients. tVEP N75-P100 amplitude (µV) and P100 latency (ms) were obtained. Reproducibility was evaluated using intraclass correlation coefficient (ICC) and test-retest variability (TRV). ICC ≥ 0.75 was considered good. RESULTS: ICCs for global and regional mfVEP were >0.80 in all groups. ICCs for tVEP were >0.75 for all except latency in ON (0.52-0.68). For mfVEP or tVEP, TRV for amplitude was similar among all groups; TRV for latency (ms) was larger in ON (5.3 for mfVEP global, 10.3 for 60' tVEP) compared with non-ON (3.1, 8.3) and normal (2.3, 5.7) (p < 0.05 for all). When tVEP was analyzed using similar methods as mfVEP (logSNR and relative latency), mfVEP global measures showed better ICC and TRV than tVEP in all groups. CONCLUSIONS: 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.

Longitudinal Evaluation of Visual Function in Multiple Sclerosis.

PURPOSE: To evaluate longitudinal changes of visual function in relapsing-remitting multiple sclerosis (RRMS). METHODS: Multifocal visual evoked potential (mfVEP), contrast sensitivity (CS), and Humphrey visual fields (HVFs) were obtained at two visits (mean follow-up, 1.5 [±0.9] years) in both eyes of 57 RRMS patients (53 eyes with optic neuritis [ON]: 14 ON within 6 months of first visit [ON < 6 months] and 39 ON ≥ 6 months; 57 non-ON). Longitudinal changes were assessed using mfVEP amplitude (log signal-to-noise ratio [logSNR]), latency, CS, and HVF mean deviation based on established 95% tolerance limits of test-retest variability. RESULTS: A significant percentage of eyes in the ON < 6 months group exceeded 95% tolerance limits for mfVEP logSNR (21%, p < 0.05), latency (35%, p < 0.01), and CS (31% p < 0.001); more improved than worsened over time (14% vs. 7% for logSNR, 21% vs. 14% for latency, and 31% vs. 0% for CS). Multifocal visual evoked potential latency decreased in 11% of non-ON eyes and in 10% of eyes in the ON ≥ 6 months group, and increased in 21% and 10%, respectively (p < 0.01 for all). Latency changes correlated negatively with baseline latency (r = -0.43 and -0.45 for non-ON and ON ≥ 6 months; p = 0.0008). Although a nonsignificant percentage of non-ON and ON ≥ 6 months eyes exceeded tolerance limits for logSNR, CS, or HVF, logSNR and latency changes correlated, and both measures correlated with changes in CS (r = 0.47 to 0.79, p < 0.01). CONCLUSIONS: Multifocal visual evoked potential, particularly latency, is potentially useful for assessing neuroprotective and remyelinating strategies in RRMS.

Tracking changes over time in retinal nerve fiber layer and ganglion cell-inner plexiform layer thickness in multiple sclerosis.

BACKGROUND: Neurodegeneration plays an important role in permanent disability in multiple sclerosis (MS). OBJECTIVE: The objective of this paper is 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 non-optic neuritis (ON), 97 ON eyes, last ON ≥6 months). Ninety-three patients were scanned at two visits. Percentages 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 non-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 non-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 non-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 autoimmune responses and inflammation.

Cortical determinants of loudness perception and auditory hypersensitivity.

Parvalbumin-expressing inhibitory neurons (PVNs) stabilize cortical network activity, generate gamma rhythms, and regulate experience-dependent plasticity. Here, we observed that activation or inactivation of PVNs functioned like a volume knob in the mouse auditory cortex (ACtx), turning neural and behavioral classification of sound level up or down over a 20dB range. PVN loudness adjustments were "sticky", such that a single bout of 40Hz PVN stimulation sustainably suppressed ACtx sound responsiveness, potentiated feedforward inhibition, and behaviorally desensitized mice to loudness. Sensory sensitivity is a cardinal feature of autism, aging, and peripheral neuropathy, prompting us to ask whether PVN stimulation can persistently desensitize mice with ACtx hyperactivity, PVN hypofunction, and loudness hypersensitivity triggered by cochlear sensorineural damage. We found that a single 16-minute bout of 40Hz PVN stimulation session restored normal loudness perception for one week, showing that perceptual deficits triggered by irreversible peripheral injuries can be reversed through targeted cortical circuit interventions.

Radiologic reporting of MRI-proven thoracolumbar epidural metastases on body CT: 12-Year single-institution experience.

RATIONALE AND OBJECTIVES: Metastatic epidural masses are an important radiological finding. The purpose of this study is to determine factors associated with non-reporting of thoracolumbar epidural metastases on body CT. MATERIALS AND METHODS: In a study population of 166 patients from a single institution over a 12-year period, 293 body CT examinations were identified which were performed within 30 days before or after a spine MRI diagnosis of epidural metastasis. Associations were sought between patient diagnosis, CT examination characteristics, reporting radiologist (n = 17), and lesion characteristics with respect to whether an epidural metastasis was reported on CT. RESULTS: In retrospective consensus review comprised of 3 radiologists, epidural metastases reported on spine MRI were clearly visible in 80.5% (236/293) of body CT examinations, however 65.3% (154/236) of the body CT reports omitted reporting their presence, even in cases where there was a preceding MRI diagnosis within 30 days (65.4%, 74/113). The identity of the reporting radiologist was statistically significantly associated with the accurate diagnostic reporting of epidural metastasis on body CT (p = 0.04). The only lesion features which were statistically significantly associated with CT reporting were lesion volume (p = 0.03) on noncontrast CT, and lesion volume (p = 0.006) and percentage of spinal canal stenosis (p = 0.001) on intravenous contrast-enhanced CT. The presence or absence of intravenous contrast was not significantly associated with CT reporting (p = 1.0). CONCLUSION: Using spine MRI as the reference standard for the presence of epidural tumor, the majority of body CT reports omit describing thoracolumbar epidural metastases which are clearly visible in retrospect.

Prevalence of RPGR-mutated X-linked retinitis pigmentosa among males.

BACKGROUND: X-linked retinitis pigmentosa (XLRP) is a rare inherited retinal disease predominantly affecting males. MATERIALS AND METHODS: A comprehensive literature review was conducted to determine the prevalence of retinitis pigmentosa GTPase regulator (RPGR)-mutated XLRP. Identified studies were used to estimate four components among males: the prevalence of retinitis pigmentosa (RP), the proportion of RP that was X-linked, the proportion of misclassified inheritance type among RP cases, and the proportion of XLRP that was RPGR-mutated. Studies providing a direct estimate of XLRP prevalence were also included. The components' sample size-weighted averages were combined to determine an overall prevalence estimate. RESULTS: The prevalence of XLRP was estimated to be between 2.7-3.5 per 100,000 males in the US, Europe, and Australia. After correction for misclassification, the prevalence increased to 4.0-5.2 per 100,000 males. Finally, the proportion of XLRP cases due to RPGR mutations was applied, resulting in an RPGR-mutated XLRP estimate of 3.4-4.4 per 100,000 males. Studies from other countries were consistent with the results for the overall XLRP prevalence but were not included in the final calculation because of regional variations and lack of detailed information. CONCLUSIONS: These findings address an important gap in the understanding of RPGR-mutated XLRP by summarizing the global burden of this condition.

Immature Brain Cortical Neurons Have Low Transcriptional Competence to Activate Antiviral Defences and Control RNA Virus Infections.

Virus infections of the central nervous system (CNS) cause important diseases of humans and animals. As in other tissues, innate antiviral responses mediated by type I interferons (IFNs) are crucially important in controlling CNS virus infections. The maturity of neuronal populations is an established critical factor determining the outcome of CNS virus infection. Using primary cultures of mouse cortical neurons, we investigated the relationships between neuronal maturation, type I IFN responses, and the outcome of Semliki Forest virus infection. The virus replicated better, infected more cells, and produced higher titres of infectious viruses in immature neurons. Complete transcriptome analysis demonstrated that resting immature neurons have low transcriptional competence to mount antiviral responses. They had no detectable transcription of the genes Ddx58 and Ifih1, which encode key RNA virus cytoplasmic sensors RIG-I and MDA5, and very low expression of genes encoding key regulators of associated signalling pathways. Upon infection, immature neurons failed to mount an antiviral response as evidenced by their failure to produce chemokines, IFNs, and other cytokines. Treatment of immature neurons with exogenous IFNß prior to infection resulted in antiviral responses and lower levels of virus replication and infectious virus production. In contrast, resting mature neurons generated a robust antiviral response. This was augmented by pretreatment with IFNß. Infection of mature neurons derived from IFNAR-/- mice did not make an antiviral response and replicated virus to high levels.

Effects of chronic mild hyperoxia on retinal and choroidal blood flow and retinal function in the DBA/2J mouse model of glaucoma.

PURPOSE: To test the hypothesis that mild chronic hyperoxia treatment would improve retinal function despite a progressive decline in ocular blood flow in the DBA/2J mouse model of glaucoma. MATERIALS AND METHODS: DBA/2J mice were treated with chronic mild hyperoxia (30% O2) beginning at 4.5 months of age or were untreated by giving normal room air. Retinal and choroidal blood flow (RBF and ChBF, respectively) were measured at 4, 6, and 9 months of age by MRI. Blood flow was additionally measured under hypercapnia challenge (5% CO2 inhalation) to assess vascular reactivity. Intraocular pressure (IOP) was measured using a rebound tonometer at the same time points. Scotopic flash electroretinograms (ERGs) were recorded at 9 months of age. RESULTS: Both ChBF and RBF were reduced and significantly affected by age (p < 0.01), but neither were significantly affected by O2-treatment (p > 0.05). ChBF significantly increased in response to hypercapnia (p < 0.01), which was also unaffected by O2-treatment. Significant effects of age (p < 0.001) and of the interaction of age with treatment (p = 0.028) were found on IOP. IOP significantly decreased in O2-treated mice at 6 months compared to 4 months of age (p < 0.001), while IOP trended to increase with age in untreated mice. The amplitude of the b-wave from ERG was significantly increased in O2-treated DBA/2J compared to the untreated mice (p = 0.012), while the a-wave and oscillatory potentials were not significantly affected (p > 0.05). CONCLUSION: This study investigated the effects of chronic mild hyperoxia on retinal function and on retinal and choroidal blood flow in a mouse model of glaucoma. Retinal function was improved in the O2-treated mice at late stage, despite a progressive decline of RBF and ChBF with age that was comparable to untreated mice.

Diabetic mice have retinal and choroidal blood flow deficits and electroretinogram deficits with impaired responses to hypercapnia.

PURPOSE: The purpose of this study was to investigate neuronal and vascular functional deficits in the retina and their association in a diabetic mouse model. We measured electroretinography (ERG) responses and choroidal and retinal blood flow (ChBF, RBF) with magnetic resonance imaging (MRI) in healthy and diabetic mice under basal conditions and under hypercapnic challenge. METHODS: Ins2Akita diabetic (Diab, n = 8) and age-matched, wild-type C57BL/6J mice (Ctrl, n = 8) were studied under room air and moderate hypercapnia (5% CO2). Dark-adapted ERG a-wave, b-wave, and oscillatory potentials (OPs) were measured for a series of flashes. Regional ChBF and RBF under air and hypercapnia were measured using MRI in the same mice. RESULTS: Under room air, Diab mice had compromised ERG b-wave and OPs (e.g., b-wave amplitude was 422.2±10.7 µV in Diab vs. 600.1±13.9 µV in Ctrl, p < 0.001). Under hypercapnia, OPs and b-wave amplitudes were significantly reduced in Diab (OPs by 30.3±3.0% in Diab vs. -3.0±3.6% in Ctrl, b-wave by 17.9±1.4% in Diab vs. 1.3±0.5% in Ctrl). Both ChBF and RBF had significant differences in regional blood flow, with Diab mice having substantially lower blood flow in the nasal region (ChBF was 5.4±1.0 ml/g/min in Diab vs. 8.6±1.0 ml/g/min in Ctrl, RBF was 0.91±0.10 ml/g/min in Diab vs. 1.52±0.24 ml/g/min in Ctrl). Under hypercapnia, ChBF increased in both Ctrl and Diab without significant group difference (31±7% in Diab vs. 17±7% in Ctrl, p > 0.05), but an increase in RBF was not detected for either group. CONCLUSIONS: Inner retinal neuronal function and both retinal and choroidal blood flow were impaired in Diab mice. Hypercapnia further compromised inner retinal neuronal function in diabetes, while the blood flow response was not affected, suggesting that the diabetic retina has difficulty adapting to metabolic challenges due to factors other than impaired blood flow regulation.

Progesterone in Addition to Standard of Care vs Standard of Care Alone in the Treatment of Men Hospitalized With Moderate to Severe COVID-19: A Randomized, Controlled Pilot Trial.

BACKGROUND: Severity of illness in COVID-19 is consistently lower in women. A focus on sex as a biological factor may suggest a potential therapeutic intervention for this disease. We assessed whether adding progesterone to standard of care (SOC) 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 SOC plus progesterone (100 mg subcutaneously twice daily for up to 5 days) or SOC alone. In addition to assessment of safety, the primary outcome was change in clinical status on 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 2020 to 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 before 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 with control subjects (95% CI, 0.0-2.0; P = .024). There were no serious adverse events attributable to progesterone. Patients treated with progesterone required three fewer days of supplemental oxygen (median, 4.5 vs 7.5 days) and were hospitalized for 2.5 fewer days (median, 7.0 vs 9.5 days) as compared with control subjects. 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. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT04365127; URL: www.clinicaltrials.gov.

Early Ophthalmic Changes in Macula Does Not Correlate with Visual Function.

PURPOSE: Early detection and treatment of age-related macular degeneration require a clear understanding of the early progress of the disease. The purpose of this study was to investigate whether minimal macular ophthalmoscopic changes corresponded to changes in visual function. METHODS: Color macular photos from a group of older subjects who were classified as grade 0 on AREDS simplified grading were further evaluated by a retinal specialist using 5x magnification for possible minimal macular anomalies. Group 0-A (N = 15) were defined as subjects with no visible macular anomalies while Group 0-B (N = 19) comprised subjects for whom minimal macular mottling, pigment changes or very small drusen (< 63 µm) were observed in the study eye. All subjects had best VA of 20/25 or better and had no evidence of other retinal diseases in the study eye. All subjects underwent a series of visual function tests such as standard ETDRS VA, low luminance ETDRS VA, Pelli-Robson contrast sensitivity, variable contrast flicker (VCF) sensitivity, and reading speed (words per minute, wpm) using both MNRead and low luminance reading on a tablet. RESULTS: There was no significant difference between the mean age between the two groups (74.8 ± 5.2 years for 0-A vs 74.5 ± 4.4 for 0-B, p = 0.82). None of the visual function tests identified any significant difference between the two groups. Mean ETDRS VA was 0.0 ± 0.11 for 0-A subjects and 0.08 ± 0.12 for 0-B (p = 0.063). Mean Pelli-Robson log contrast sensitivity was 1.75 ± 0.29 for 0-A and 1.78 ± 0.17 for the 0-B group (p = 0.73). VCF threshold was 0.47 ± 0.25 for 0-A and 0.43 ± 0.22 for 0-B (p = 0.64). Reading speed using MNRead was 214 ± 47.4 wpm for 0-A and 210 ± 64.7 for 0-B (p = 0.85). Low luminance tablet reading speed was 137 ± 71.8 wpm for 0-A and 151 ± 39.4 (0-B) (p = 0.49). CONCLUSION: A panel of psychophysical tests did not demonstrate significant differences between subjects with and without minimal macular changes.

Multifocal visual evoked potentials and contrast sensitivity correlate with ganglion cell-inner plexiform layer thickness in multiple sclerosis.

OBJECTIVE: To examine the relationship between optical coherence tomography (OCT) macular ganglion cell-inner plexiform layer thickness (GCIPLT), peripapillary retinal nerve fiber layer thickness (RNFLT) and visual function in relapsing-remitting multiple sclerosis (RRMS). METHODS: Cirrus OCT, VERIS 60-sector multifocal visual evoked potential (mfVEP) and Pelli-Robson contrast sensitivity (CS) were obtained for 53 eyes with last optic neuritis (ON) > 6 months and 105 non-ON eyes in 90 patients. One eye (43 ON, 73 non-ON) was used for correlations when both had the same history. Global (G, 60 sectors) and central 5.6° (C, 24 sectors) mfVEP amplitude and latency were calculated as mean logSNR and median latency. RESULTS: Eyes showing abnormal mfVEP (amplitude or latency) vs OCT (GCIPLT or RNFLT) was 77% vs 69% (p = 0.33) in ON, 45% vs 22% (p < 0.0005) in non-ON. In ON and non-ON, mfVEP measures and CS correlated with GCIPLT and RNFLT (r = -0.24 to 0.78, p = 0.03-0.0001). In ON, mfVEP amplitude (C,G) correlated better with GCIPLT (r = 0.78, 0.76) than RNFLT (r = 0.43, 0.58; p < 0.001, 0.01). CONCLUSIONS: MfVEP measures and CS correlated well with GCIPLT and RNFLT in ON and non-ON. MfVEP amplitudes were more highly correlated with GCIPLT than RNFLT in ON. MfVEP detected significantly more defects than OCT in non-ON. SIGNIFICANCE: GCIPLT, mfVEP and CS provide useful measures of optic nerve integrity in RRMS.

An Alternative Psychophysical Diagnostic Indicator of the Aging Eye.

PURPOSE: Impaired adaptation to changes in lighting levels as well as mesopic visual function is a common complaint in those over the age of 65. The use of photostress is a well-established method to test the adaption rate and the response of the visual cycle. In this study, we test visual function recovery to mesopic luminance stimuli following a long duration photostress in young and elderly subjects. If successful in strongly differentiating aging macular function, these methods may also be useful in the study of pathologies such as age-related macular degeneration. METHODS: A group of 12 older normal subjects (mean age 75.1 ± 4.79) and a control group of 5 younger normal subjects (mean age 26.2 ± 4.19) were subjected to macular photostress using the OraLux photostress system. The OraLux system provides a diffuse light source bleaching 84% of cone photopigment while maintaining an exposure safety factor of 200 times less than the maximum safe exposure. After each photostressing session, macular recovery was tracked using a foveal, variable contrast, flickering stimulus of mean luminance in the high mesopic range. Recovery was tracked for 300 seconds. The endpoint was time to recovery to each individual's baseline sensitivity as determined by two static sensitivity trials prior to photostress. RESULTS: Proportional hazards analysis of recovery time yielded a statistically significant difference between the older group and the young group (HR = 0.181; p=0.0289). The estimated hazard ratio of 0.181 indicates that older subjects return to baseline at less than one-fifth the rate of younger subjects. The hazards ratio remained statistically significant after adjusting for visual acuity (HR = 0.093; p=0.0424). CONCLUSION: Photostress recovery of flicker sensitivity under mesopic conditions is a strong differentiator of aging macular function. This agrees with subject-reported complaints in reduced luminance conditions after exposure to bright lights such as night driving. The qualitative similarity between the aging retina and changes in early AMD suggests that flicker recovery following photostress may be useful as a surrogate endpoint in AMD clinical trials.