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Supplemental Digital Content is available in the text., Background: The microvasculature, the smallest blood vessels in the body, has key roles in maintenance of organ health and tumorigenesis. The retinal fundus is a window for human in vivo noninvasive assessment of the microvasculature. Large-scale complementary machine learning-based assessment of the retinal vasculature with phenome-wide and genome-wide analyses may yield new insights into human health and disease. Methods: We used 97 895 retinal fundus images from 54 813 UK Biobank participants. Using convolutional neural networks to segment the retinal microvasculature, we calculated vascular density and fractal dimension as a measure of vascular branching complexity. We associated these indices with 1866 incident International Classification of Diseases–based conditions (median 10-year follow-up) and 88 quantitative traits, adjusting for age, sex, smoking status, and ethnicity. Results: Low retinal vascular fractal dimension and density were significantly associated with higher risks for incident mortality, hypertension, congestive heart failure, renal failure, type 2 diabetes, sleep apnea, anemia, and multiple ocular conditions, as well as corresponding quantitative traits. Genome-wide association of vascular fractal dimension and density identified 7 and 13 novel loci, respectively, that were enriched for pathways linked to angiogenesis (eg, vascular endothelial growth factor, platelet-derived growth factor receptor, angiopoietin, and WNT signaling pathways) and inflammation (eg, interleukin, cytokine signaling). Conclusions: Our results indicate that the retinal vasculature may serve as a biomarker for future cardiometabolic and ocular disease and provide insights into genes and biological pathways influencing microvascular indices. Moreover, such a framework highlights how deep learning of images can quantify an interpretable phenotype for integration with electronic health record, biomarker, and genetic data to inform risk prediction and risk modification.

To use optical modeling to compare a 6.0 mm and 7.0 mm intraocular lens (IOL) optic diameters on peripheral retinal illumination with implications for negative dysphotopsia.Mayo Clinic, Rochester, Minnesota, and Simpson Optics LLC, Arlington, Texas.Model eye.Ray-tracing software was used to simulate retinal illumination from an extended light source for a pseudophakic eye with in-the-bag biconvex IOLs (refractive index [n] = 1.46 and 1.55) and a 2.5 mm pupil. Ray-tracing diagrams and simulated retina illumination profiles were compared using the 6.0 mm and 7.0 mm optic diameter IOLs. Retinal locations were scaled to relative visual angles from 70 to 110 degrees horizontally.A 7.0 mm optic (n = 1.46) expands the image field by 2.8 degrees compared with a 6.0 mm optic. High-angle input light misses a 7.0 mm optic at a larger visual angle than a 6.0 mm optic, shifting illumination of the peripheral retina by this light anteriorly by 5.6 degrees. Consequently, a region of nonilluminated peripheral nasal retina is enlarged and shifted peripherally using a 7.0 mm optic (visual angle, 86.3 to 96.3 degrees) compared with a 6.0 mm optic (visual angle, 83.5 to 90.7 degrees). Similar illumination changes were seen modeling a 1.55 n IOL.A narrow dark region in the nasal retina when using a 6.0 mm optic is changed to a broader, more peripheral dark region when using a 7.0 mm optic. An extended, more peripheral dark nasal region may make a temporal shadow less bothersome and explain lower negative dysphotopsia rates using a 7.0 mm optic.

Genetic variants are vital in informing clinical phenotypes, aiding physical diagnosis, guiding genetic counseling, understanding the molecular basis of disease, and potentially stimulating drug development. Here we describe two families with an ultrarare ACVR1 gain-of-function pathogenic variant (codon 375, Arginine > Proline; ACVR1R375P ) responsible for a mild nonclassic fibrodysplasia ossificans progressiva (FOP) phenotype. Both families include people with the ultrarare ACVR1R375P variant who exhibit features of FOP while other individuals currently do not express any clinical signs of FOP. Thus, the mild ACVR1R375P variant greatly expands the scope and understanding of this rare disorder.

Little is known about peripheral auditory function in young adults with HIV, who might be expected to show early evidence of hearing loss if HIV infection or treatment does affect peripheral function. The goal of this study was to compare peripheral auditory function in 2 age- and gender-matched groups of young adults with clinically normal hearing with and without HIV.Matched cohort study with repeated measures.Infectious disease center in Dar es Salaam, Tanzania.Participants included HIV-positive (n = 38) and HIV-negative (n = 38) adults aged 20 to 30 years who had clinically normal hearing, defined as type A tympanograms, air conduction thresholds ≤25 dB HL bilaterally from 0.5 to 8 kHz, and distortion product otoacoustic emissions (DPOAEs)6 dB above the noise floor bilaterally from 1.5 to 8 kHz. Participants were tested multiple times over 6-month intervals (average, 2.7 sessions/participant) for a total of 208 observations. Primary outcome measures included tympanograms, air conduction audiograms, DPOAEs, and click-evoked auditory brainstem responses.HIV groups did not significantly differ in age, static immittance, or air conduction thresholds. HIV-positive status was independently associated with approximately 3.7-dB lower DPOAE amplitudes from 2 to 8 kHz (95% CI, 1.01-6.82) in both ears and 0.04-µV lower (95% CI, 0.003-0.076) auditory brainstem response wave I amplitudes in the right ear.Young adults living with HIV have slightly but reliably smaller DPOAEs and auditory brainstem response wave I amplitudes than matched HIV-negative controls. The magnitude of these differences is small, but these results support measuring peripheral auditory function in HIV-positive individuals as they age.

The President of The University of Texas at Austin discusses UTIMCO's investment strategy with its Chief Investment Officer.As the administrator of a perpetual endowment for the University of Texas and Texas AM(2) the health of the leveraged loan market;and (3) the search for new and better exit opportunities. All agreed that deal pricing was a perennial challenge, and that PE firms must work to develop a special “edge” in an intensely competitive market, where some firms consider a thousand deals a year to close on just two or three.The founder of Benchmark Capital begins by mentioning his firm's almost exclusive focus on early‐stage ventures and preference for being “the first money in.” He also notes Benchmark's different ownership structure;perhaps unique among venture firms, it is an equal partnership in which all partners have “the same economics,” the new as well as the oldest.The main investment advice offered is that, with interest rates so low, and some public company stocks trading at 30 to 50 times revenue, investors should remain as liquid as possibleThe recent popularity of SPACs is viewed as a response by issuers to “a broken IPO system” whose main symptom is runaway IPO underpricing and wealthy bankers. Noting that the amount of first‐day underpricing of IPOs has risen from $2 billion in 2016 to $30 billion in 2020, Gurley predicts that direct IPO listings, or DLs, will become much more common in the future.As for the recent frenzy of retail trading and the rise of Robinhood, Gurley says of the new trading firm's CEO,He tells the world that he's democratizing investing, but I don't think this is about investing at all. I think he's gamifying speculation… and I strongly suspect that the success rate of retail investors in options is really crappy. It should also scare the Biden administration that a lot of the money in Robinhood accounts came from stimulus checks this summer.

Purpose To investigate the association among widefield swept-source (SS) OCT angiography (OCTA) metrics and systemic parameters and vitreous hemorrhage (VH) occurrence in eyes with proliferative diabetic retinopathy (PDR). Design Prospective, observational study. Participants Fifty-five eyes from 45 adults with PDR, with no history of VH, followed up for at least 3 months. Methods All patients underwent widefield SS OCTA (Montage 15 × 15 mm and high-definition (HD)-51 line scan) imaging. Images were evaluated independently by 2 graders for quantitative and qualitative widefield SS OCTA metrics defined a priori. Systemic and ocular parameters and widefield SS OCTA metrics were screened using least absolute shrinkage and selection operator and logistic or Cox regression for variable selection. Firth’s bias-reduced logistic regression models (outcome, occurrence of VH) and Cox regression models (outcome, time to occurrence of VH) were used to identify parameters associated with VH occurrence. Main Outcome Measures Occurrence of VH. Results Over a median follow-up of 363 days (range, 28–710 days), 13 of 55 PDR eyes (24%) demonstrated VH during the follow-up period. Presence of extensive neovascularizations (odds ratio, 8.05; 95% confidence interval [CI], 1.43–58.56; P = 0.02), defined as neovascularizations with total area of more than 4 disc diameters, and forward neovascularizations (odds ratio, 5.42; 95% CI, 1.26–35.16; P = 0.02) that traversed the posterior hyaloid face into the vitreous were associated with the occurrence of VH. The presence of flat neovascularizations (odds ratio, 0.25; 95% CI, 0.04–1.01; P = 0.05) confined to the posterior hyaloid face was associated with a lower risk of VH with borderline significance. Similarly, presence of extensive neovascularizations (hazard ratio, 18.24; 95% CI, 3.51–119.47; P Conclusions Widefield SS OCTA is useful for evaluating neovascularizations and their relationship with the vitreous. The presence of forward and extensive neovascularizations was associated with the occurrence of VH in patients with PDR. Larger samples and longer follow-up are needed to verify the risk factors and imaging biomarkers for diabetic VH.

The extant literature on precision in accounting standards suggests that financial statement preparers are less likely to make aggressive financial reporting decisions under less precise, principle...

Purpose: This work reports a case of left atrial myxoma presenting with cilioretinal artery occlusion. Methods: A case report is discussed. Results: A 57-year-old man was referred for acute vision loss in the left eye after a workup including electrocardiogram, magnetic resonance imaging of the brain without contrast, computed tomography angiography of the head and neck, erythrocyte sedimentation rate, and C-reactive protein had negative results. Examination revealed cilioretinal artery occlusion with visible emboli. Because an echocardiogram was not performed, the patient was referred to the emergency department. Echocardiogram revealed a large left atrial mass prolapsing into the left ventricle. The mass was excised, and pathology showed myxoma. Conclusions: This is the first case to our knowledge of isolated cilioretinal artery occlusion as the initial presentation of an atrial myxoma. Thorough and complete workup was crucial to averting further morbidity and mortality.

Modeling complements surveillance data to inform coronavirus disease 2019 (COVID-19) public health decision making and policy development. This includes the use of modeling to improve situational awareness, assess epidemiological characteristics, and inform the evidence base for prevention strategies. To enhance modeling utility in future public health emergencies, the Centers for Disease Control and Prevention (CDC) launched the Infectious Disease Modeling and Analytics Initiative. The initiative objectives are to: (1) strengthen leadership in infectious disease modeling, epidemic forecasting, and advanced analytic work; (2) build and cultivate a community of skilled modeling and analytics practitioners and consumers across CDC; (3) strengthen and support internal and external applied modeling and analytic work; and (4) working with partners, coordinate government-wide advanced data modeling and analytics for infectious diseases. These efforts are critical to help prepare the CDC, the country, and the world to respond effectively to present and future infectious disease threats.

Focused ion beam sources have recently been commercialized and are increasingly utilized for applications in nanotechnology. There is a desire to pattern large designs, millimeter in scale, while still achieving sub-nanometer resolution in the smallest features. However, focused helium ion beams are restricted to fields of view of roughly 100 micrometers. Recently, we have developed an automated process for layout designs with feature sizes from sub-nanometer to millimeter scales, using Raith lithography software in a Zeiss Orion Plus helium ion microscope. The technique relies on stitching writefields together and incorporating automated focusing algorithms in the Raith software. This procedure was demonstrated by scaling and automating the process of producing ion-damaged Josephson junctions in arrays in the high-temperature superconducting material YB $_2$ C $_3$ O $_{7-\delta }$ . We demonstrate that the automated process reduces operator input while maintaining consistency at the smallest resolutions.

Superconducting logic circuits based on low transition temperature ( $T_c$ ) are attractive due to their intrinsic low power consumption and high operating frequency. They have a wide variety of applications (particularly in future computing), but are difficult to use because they require cooling with liquid helium to operate. The current high $T_c$ logic circuit based on YBa $_{2}$ Cu $_{3}$ O $_{7-\delta }$ (YBCO) already has the ability to operate at a temperature above 4 K. However, this material is difficult to integrate into large-scale circuits by the traditional YBCO junction fabrication process. The limits of fabrication methods are the bottleneck stifling this material's potential for integration into logic circuits. As such, in this paper we aim to advance the state of the art in junction fabrication technology. Here we report the demonstration of a high $T_c$ superconducting single flux quantum (SFQ) circuit made by a focused helium ion beam that is easily fabricated and can readily be incorporated into a large-scale integration with nano-scale junctions for future applications. An inductively coupled readout superconducting quantum interference device (SQUID) is employed to reduce the circuit complexity. The circuit parameters and performance are discussed.

This study evaluates the correlation between the bone end and soft tissue end of the quadriceps tendon–patellar bone autograft (QPA) size and pre-operative MRI measurements of the quadriceps tendon along sections to be included in the graft harvest in adolescents. We also assessed association between graft diameter and anthropometric measures (height, weight, and BMI), age, and sex. Patients (10–18 years) who underwent QPA ACL reconstruction and had a pre-operative MRI were considered for inclusion. Age, height, and weight, tibial and femoral side graft diameter, and patellar bone block dimensions were collected. Using a pre-operative 2D sagittal plane MRI, we measured the quadriceps at 10-mm increments above the patella, up to 40 mm. We assessed correlation between the bone-end graft diameter and the AP measure at 10 mm above the patella, and correlation between the soft-tissue end graft diameter and the most proximal AP measure. A total of 103 patients were included. A significant correlation between the soft-tissue side graft diameter and most proximal AP measurement was observed (rs = 0.51; p

Bipolar disorder (BD) is highly heritable. Identifying objective biomarkers reflecting pathophysiological processes predisposing to, versus protecting against BD, can help identify BD risk in offspring of BD parents. We recruited 21 BD participants with a first-degree relative with BD, 25 offspring of BD parents, 27 offspring of comparison parents with non-BD psychiatric disorders, and 32 healthy offspring of healthy parents. In at-risk groups, 23 had non-BD diagnoses and 29, no Axis-I diagnoses(healthy). Five at-risk offspring who developed BD post scan(Converters) were included. Diffusion imaging(dMRI) analysis with tract segmentation identified between-group differences in the microstructure of prefrontal tracts supporting emotional regulation relevant to BD: forceps minor, anterior thalamic radiation(ATR), cingulum bundle(CB), and uncinate fasciculus(UF). BD participants showed lower fractional anisotropy (FA) in the right CB (anterior portion) than other groups (q q qs qs qs

Affective disorders (AD, including bipolar disorder, BD, and major depressive disorder) are severe recurrent illnesses. Identifying neural markers of processes underlying AD development in at-risk youth can provide objective, “early-warning” signs that may predate onset or worsening of symptoms. Using data (n = 34) from the Bipolar Offspring Study, we examined relationships between neural response in regions supporting executive function, and those supporting self-monitoring, during an emotional n-back task (focusing on the 2-back face distractor versus the 0-back no-face control conditions) and future depressive and hypo/manic symptoms across two groups of youth at familial risk for AD: Offspring of parents with BD (n = 15, age = 14.15) and offspring of parents with non-BD psychopathology (n = 19, age = 13.62). Participants were scanned and assessed twice, approximately 4 years apart. Across groups, less deactivation in the mid-cingulate cortex during emotional regulation (Rate Ratio = 3.07(95% CI:1.09–8.66), χ(2)(1) = 4.48, p = 0.03) at Time-1, and increases in functional connectivity from Time-1 to 2 (Rate Ratio = 1.45(95% CI:1.15–1.84), χ(2)(1) = 8.69, p = 0.003) between regions that showed deactivation during emotional regulation and the right caudate, predicted higher depression severity at Time-2. Both effects were robust to sensitivity analyses controlling for clinical characteristics. Decreases in deactivation between Times 1 and 2 in the right putamen tail were associated with increases in hypo/mania at Time-2, but this effect was not robust to sensitivity analyses. Our findings reflect neural mechanisms of risk for worsening affective symptoms, particularly depression, in youth across a range of familial risk for affective disorders. They may serve as potential objective, early-warning signs of AD in youth.

To investigate factors associated with positive postpartum depression (PPD) screen in pregnancies complicated by fetal congenital cardiac anomaly. We reviewed all records of pregnancies complicated by fetal congenital cardiac anomaly receiving prenatal, intrapartum and postpartum care at our single center, October 2016-October 2019. Maternal, obstetric, and neonatal data were compared between women with and without a positive PPD screen at the 6-week postpartum visit. Out of 415 women referred for fetal congenital cardiac anomaly, 86 women had complete inclusion criteria. Twenty-four women (28%) had a positive PPD screen. The frequencies of planned future infant surgery (73.9 vs. 26.2%, p = 0.01) and neonatal death prior to postpartum visit (12.5 vs. 0%, p = 0.02) were significantly higher among women with a positive PPD screen. In pregnancies complicated by fetal congenital cardiac anomaly, mothers of infants with planned future surgery or neonatal death are at significant risk for postpartum depression.

Background The Global Enteric Multicenter Study (GEMS) determined the etiologic agents of moderate-to-severe diarrhea (MSD) in children under 5 years old in Africa and Asia. Here, we describe the prevalence and antimicrobial susceptibility of nontyphoidal Salmonella (NTS) serovars in GEMS and examine the phylogenetics of Salmonella Typhimurium ST313 isolates. Methods Salmonella isolated from children with MSD or diarrhea-free controls were identified by classical clinical microbiology and serotyped using antisera and/or whole-genome sequence data. We evaluated antimicrobial susceptibility using the Kirby-Bauer disk-diffusion method. Salmonella Typhimurium sequence types were determined using multi-locus sequence typing, and whole-genome sequencing was performed to assess the phylogeny of ST313. Results Of 370 Salmonella-positive individuals, 190 (51.4%) were MSD cases and 180 (48.6%) were diarrhea-free controls. The most frequent Salmonella serovars identified were Salmonella Typhimurium, serogroup O:8 (C2-C3), serogroup O:6,7 (C1), Salmonella Paratyphi B Java, and serogroup O:4 (B). The prevalence of NTS was low but similar across sites, regardless of age, and was similar among both cases and controls except in Kenya, where Salmonella Typhimurium was more commonly associated with cases than controls. Phylogenetic analysis showed that these Salmonella Typhimurium isolates, all ST313, were highly genetically related to isolates from controls. Generally, Salmonella isolates from Asia were resistant to ciprofloxacin and ceftriaxone, but African isolates were susceptible to these antibiotics. Conclusions Our data confirm that NTS is prevalent, albeit at low levels, in Africa and South Asia. Our findings provide further evidence that multidrug-resistant Salmonella Typhimurium ST313 can be carried asymptomatically by humans in sub-Saharan Africa., In agreement with prior studies, we show that nontyphoidal Salmonella is prevalent in stool of children

The SARS-Cov-2 (COVID-19) pandemic remains a major worldwide public health issue. Initially, improved supportive and anti-inflammatory intervention, often employing known drugs or technologies, provided measurable improvement in management. We have recently seen advances in specific therapeutic interventions and in vaccines. Nevertheless, it will be months before most of the world’s population can be vaccinated to achieve herd immunity. In the interim, hyperbaric oxygen (HBO2) treatment offers several potentially beneficial therapeutic effects. Three small published series, one with a propensity-score-matched control group, have demonstrated safety and initial efficacy. Additional anecdotal reports are consistent with these publications. HBO2 delivers oxygen in extreme conditions of hypoxemiaand tissue hypoxia, even in the presence of lung pathology. It provides anti-inflammatory and anti-proinflammatory effects likely to ameliorate the overexuberant immune response common to COVID-19. Unlike steroids, it exerts these effects without immune suppression. One study suggests HBO2 may reduce the hypercoagulability seen in COVID patients. Also, hyperbaric oxygen offers a likely successful intervention to address the oxygen debt expected to arise from a prolonged period of hypoxemia and tissue hypoxia. To date, 11 studies designed to investigate the impact of HBO2 on patients infected with SARS-Cov-2 have been posted on clinicaltrials.gov. This paper describes the promising physiologic and biochemical effects of hyperbaric oxygen in COVID-19 and potentially in other disorders with similar pathologic mechanisms.

Primary cerebral amyloidoma is an exceedingly rare condition that refers to localized tumor-like deposition of amyloid in the brain without evidence of an underlying systemic process such as multiple myeloma. Reported cases of primary cerebral amyloidoma to date have described restricted light-chain deposition (AL amyloid); we report two cases of primary cerebral amyloidoma with additional heavy-chain deposition (ALH amyloid). Overall, when localized disease is present, therapy such as surgery or radiation therapy is considered to limit the risk of progression. However, in part due to the rarity of the condition, defining optimal treatment has been problematic. Here we discuss definitive management of ALH primary cerebral amyloidoma treated with focal radiation therapy.

INTRODUCTION: Isolated and confined environments (ICEs), such as spaceflight, are challenging psychologically. We have been evaluating self-directed tools to sustain and improve psychological well-being in these settings. The Expedition Application for Peak Psychological Performance (Expedition-APPP) is an interactive media-based set of self-directed tools that address conflict resolution, stress management, and depression treatment. Virtual reality (VR) of nature scenes is a tool to improve attention and relieve stress by providing users with an immersive nature experience. We evaluated both Expedition-APPP and VR in an ICE.METHODS: The Expedition-APP was evaluated during three, and nature VR during two, deployments at the HI-SEAS habitat, where crews of six were isolated for 812 mo. Participants used both the Expedition-APPP and VR and shared their feedback and experiences after the deployments in semistructured interviews. These interviews were evaluated using qualitative analysis techniques to gather generalizable insights into implementing autonomous mental health programs for people living and working in ICEs.RESULTS: Expedition-APPP modules provided a shared culture, language, and tools for working through challenges. VR allowed for access to emotions and experiences that were unavailable in the habitat. Suggestions for improvement included making refresher training easily available and providing a wider range of content to address different individuals coping styles.DISCUSSION: Both the Expedition-APPP and VR were appreciated and used, although a wider range of content and experiences was desired by participants.Lyons KD, Slaughenhaupt RM, Mupparaju SH, Lim JS, Anderson AA, Stankovic AS, Cowan DR, Fellows AM, Binsted KA, Buckey JC. Autonomous psychological support for isolation and confinement. Aerosp Med Hum Perform. 2020; 91(11):876885.

Overactivity of the sympathetic nervous system and high blood pressure are implicated in the development and progression of chronic kidney disease (CKD) and independently predict cardiovascular events in end-stage renal disease. To assess the role of renal nerves, we determined whether renal denervation (RDN) altered the hypertension and sympathoexcitation associated with a rabbit model of CKD. The model involves glomerular layer lesioning and uninephrectomy, resulting in renal function reduced by one-third and diuresis. After 3-week CKD, blood pressure was 13±2 mm Hg higher than at baseline ( P P =0.01). The depressor response to ganglion blockade was also +8.0±3 mm Hg greater, but total norepinephrine spillover was 8.7±3.7 ng/min lower (both P

Chronic kidney disease (CKD) is associated with greater sympathetic nerve activity but it is unclear if this is a kidney-specific response or due to generalized stimulation of sympathetic nervous system activity. To determine this, we used a rabbit model of CKD in which quantitative comparisons with control rabbits could be made of kidney sympathetic nerve activity and whole-body norepinephrine spillover. Rabbits either had surgery to lesion 5/6th of the cortex of one kidney by electro-lesioning and two weeks later removal of the contralateral kidney, or sham lesioning and sham nephrectomy. After three weeks, the blood pressure was statistically significantly 20% higher in conscious rabbits with CKD compared to rabbits with a sham operation, but their heart rate was similar. Strikingly, kidney nerve activity was 37% greater than in controls, with greater burst height and frequency. Total norepinephrine spillover was statistically significantly lower by 34%, and kidney baroreflex curves were shifted to the right in rabbits with CKD. Plasma creatinine and urine output were elevated by 38% and 131%, respectively, and the glomerular filtration rate was 37% lower than in sham-operated animals (all statistically significant). Kidney gene expression of fibronectin, transforming growth factor-β, monocyte chemotactic protein1, Nox4 and Nox5 was two- to eight-fold greater in rabbits with CKD than in control rabbits. Overall, the glomerular layer lesioning model in conscious rabbits produced a moderate, stable degree of CKD characterized by elevated blood pressure and increased kidney sympathetic nerve activity. Thus, our findings, together with that of a reduction in total norepinephrine spillover, suggest that kidney denervation, rather than generalized sympatholytic treatments, may represent a preferable management for CKD associated hypertension.

Optical coherence tomography angiography (OCT-A) is a novel imaging modality for the diagnosis of chorioretinal diseases. A number of FDA-approved OCT-A devices are currently commercially available, each with unique algorithms and scanning protocols. Although several published studies have compared different combinations of OCT-A machines, there is a lack of agreement on the consistency of measurements across OCT-A devices. Therefore, we conducted a prospective quantitative comparison of four available OCT-A platforms. Subjects were scanned on four devices: Optovue RTVue-XR, Heidelberg Spectralis OCT2 module, Zeiss Plex Elite 9000 Swept-Source OCT, and Topcon DRI-OCT Triton Swept-Source OCT. 3 mm × 3 mm images were utilized for analysis. Foveal avascular zone (FAZ) area was separately and independently measured by two investigators. Fractal dimension (FD), superficial capillary plexus (SCP), and deep capillary plexus (DCP) vessel densities (VD) were calculated from binarized images using the Fiji image processing software. SCP and DCP VD were further calculated after images were skeletonized. Repeated measures ANOVA, post hoc tests, and interclass correlation coefficient (ICC) were performed for statistical analysis. Sixteen healthy eyes from sixteen patients were scanned on the four devices. Images of five eyes from the Triton device were excluded due to poor image quality; thus, the authors performed two sets comparisons, one with and one without the Triton machine. FAZ area showed no significant difference across devices with an ICC of > 95%. However, there were statistically significant differences for SCP and DCP VD both before and after skeletonization (p < 0.05). Fractal analysis revealed no significant difference of FD at the SCP; however, a statistically significant difference was found for FD at the DCP layer (p < 0.05). The results showed that FAZ measurements were consistent across all four devices, while significant differences in VD and FD measurements existed. Therefore, we suggest that for both clinical follow-up and research studies, FAZ area is a useful parameter for OCT-A image analysis when measurements are made on different machines, while VD and FD show significant variability when measured across devices.

SUMMARY Internal control over financial reporting (ICFR) audits have been the subject of intensive examination by the Public Company Accounting Oversight Board (PCAOB) and researchers but the process through which auditors make ICFR judgments is largely a “black box.” To understand ICFR judgments, we conducted semi-structured interviews with 20 audit partners. Common themes in our interviews suggest that the subjectivity inherent in the ICFR evaluation task contributes to resistance against ICFR audit findings and cougnterarguments from management. Moreover, auditors perceive that their judgments are being second-guessed by PCAOB inspectors. Auditors believe that managers have difficulty accepting that material weaknesses can exist without a detected error, that management's reflexive reaction is to deny/avoid a material weakness finding, and managers routinely claim that management review controls (MRCs) would have caught the detected control deficiency. Auditors cope with management's defenses by consulting with their national office and leveraging support from strong audit committees. Data Availability: Requests for the data should be accompanied by a description of intended uses.

Objective To test the hypothesis that human immunodeficiency virus (HIV) affects auditory-neurophysiological functions. Methods A convenience sample of 68 HIV+ and 59 HIV- normal-hearing adults was selected from a study set in Dar es Salaam, Tanzania. The speech-evoked frequency-following response (FFR), an objective measure of auditory function, was collected. Outcome measures were FFRs to the fundamental frequency (F0) and to harmonics corresponding to the first formant (F1), two behaviorally relevant cues for understanding speech. Results The HIV+ group had weaker responses to the F1 than the HIV- group; this effect generalized across multiple stimuli (d = 0.59). Responses to the F0 were similar between groups. Conclusions Auditory-neurophysiological responses differ between HIV+ and HIV- adults despite normal hearing thresholds. Significance The FFR may reflect HIV-associated central nervous system dysfunction that manifests as disrupted auditory processing of speech harmonics corresponding to the first formant.

To compare different scan protocols of wide-field swept-source optical coherence tomography angiography (SS-OCTA) for the detection of diabetic retinopathy (DR) lesions.Comparison of diagnostic approaches.A prospective, observational study was conducted at Massachusetts Eye and Ear from December 2018 to July 2019. Proliferative diabetic retinopathy (PDR), nonproliferative diabetic retinopathy (NPDR), and diabetic patients without DR were included. All patients were imaged using SS-OCTA using the following scan protocol: 3- × 3-mm Angio centered on the fovea; 6- × 6-mm Angio centered on the fovea and the optic disc; 15- × 9-mm Montage; and 12- × 12-mm Angio centered on the fovea and the optic disc. Images were independently evaluated by 2 graders for the presence or absence of DR lesions including microaneurysms, intraretinal microvascular abnormalities, neovascularization, nonperfusion areas, venous looping, and hard exudates. All statistical analyses were performed using commercial software.A total of 176 eyes in 119 participants were included in the study. The detection rate of neovascularization on 6- × 6-mm Angio centered on the fovea was approximately one-half that on 15- × 9-mm Montage (P.05) imaging. Combining 6- × 6-mm Angio imaging centered on the fovea and the optic disc could increase the rate to approximately two-thirds (P.05). The 12- × 12-mm Angio imaging centered on the combination of fovea and optic disc had detection rates comparable to those of 15- × 9-mm Montage imaging for all DR lesions (P.05). For microaneurysms, 6- × 6-mm Angio had better performance than 15- × 9-mm Montage (P.05).Wide-field SS-OCTA images were useful in detecting DR lesions. The 12- × 12-mm Angio imaging centered on the fovea and on the optic disc may be an optimal balance between speed and efficacy for evaluation of DR in clinical practice.

Objective To characterize the microvascular retinal changes after repair of macula-off rhegmatogenous retinal detachment (RRD) using optical coherence tomography angiography (OCT-A). Patients and methods A retrospective review of patients who underwent repair of macula-off RRD. Fellow unaffected eyes were used as controls. Post-operative OCT-A allowed comparison of vessel density (VD) and foveal avascular zone (FAZ) area in the superficial and deep retinal capillary plexus (DCP) as well as VD in the choriocapillaris layer. Results Seventeen eyes of 17 RRD patients were included in the final analysis. There was a reduction in VD of the deep retinal capillary plexus in affected eyes compared to fellow eyes (p = 0.046). RRD eyes with reduced VD in DCP compared with their fellow control eyes had worse visual acuity after repair compared to those without (p = 0.032). No significant microvasculature changes were detected in the FAZ area and VD in the superficial capillary plexus and choriocapillaris compared to fellow eyes. Conclusion In macula-off RRD eyes, significant microvascular changes were detected in the DCP using OCT-A even after successful anatomical repair. Decreased VD in the DCP compared to the fellow healthy eyes was correlated with worse visual acuity.

Increased iron levels and dysregulated iron homeostasis, or both, occur in several lung diseases. Here, the effects of iron accumulation on the pathogenesis of pulmonary fibrosis and associated lung function decline was investigated using a combination of murine models of iron overload and bleomycin-induced pulmonary fibrosis, primary human lung fibroblasts treated with iron, and histological samples from patients with or without idiopathic pulmonary fibrosis (IPF). Iron levels are significantly increased in iron overloaded transferrin receptor 2 (Tfr2) mutant mice and homeostatic iron regulator (Hfe) gene-deficient mice and this is associated with increases in airway fibrosis and reduced lung function. Furthermore, fibrosis and lung function decline are associated with pulmonary iron accumulation in bleomycin-induced pulmonary fibrosis. In addition, we show that iron accumulation is increased in lung sections from patients with IPF and that human lung fibroblasts show greater proliferation and cytokine and extracellular matrix responses when exposed to increased iron levels. Significantly, we show that intranasal treatment with the iron chelator, deferoxamine (DFO), from the time when pulmonary iron levels accumulate, prevents airway fibrosis and decline in lung function in experimental pulmonary fibrosis. Pulmonary fibrosis is associated with an increase in Tfr1+ macrophages that display altered phenotype in disease, and DFO treatment modified the abundance of these cells. These experimental and clinical data demonstrate that increased accumulation of pulmonary iron plays a key role in the pathogenesis of pulmonary fibrosis and lung function decline. Furthermore, these data highlight the potential for the therapeutic targeting of increased pulmonary iron in the treatment of fibrotic lung diseases such as IPF. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Objective: Pediatric primary care sports medicine physicians and pediatric sports medicine orthopedic surgeons, in conjunction with physician assistants (PAs), often manage patients with fractures....

Hypertension is a risk factor for the vascular permeability and neovascularization that threatens vision in diabetic retinopathy. Excess reactive oxygen species derived from the Nox (NADPH oxidase) isoforms, Nox1 and Nox4, contributes to vasculopathy in diabetic retinopathy; however, if Nox1/4 inhibition is beneficial in hypertensive diabetic retinopathy is unknown. Here, we determined that diabetic spontaneously hypertensive rats had exacerbated retinal vascular permeability and expression of angiogenic and inflammatory factors, compared with normotensive diabetic Wistar Kyoto rats. GKT136901, a specific dual inhibitor of Nox1 and Nox4, prevented these events in diabetic Wistar Kyoto rats and spontaneously hypertensive rats. Retinal neovascularization does not develop in diabetic rodents, and therefore, the oxygen-induced retinopathy model is used to evaluate this pathology. We previously demonstrated that Nox1/4 inhibition reduced retinal neovascularization in oxygen-induced retinopathy. However, although Nox5 is expressed in human retina, its contribution to retinopathy has not been studied in vivo, largely due to its absence from the rodent genome. We generated transgenic mice with inducible human Nox5 expressed in endothelial cells (vascular endothelial-cadherin + Nox5 + mice). In vascular endothelial-cadherin + Nox5 + mice with oxygen-induced retinopathy, retinal vascular permeability and neovascularization, as well as the expression of angiogenic and inflammatory factors, were increased compared with wild-type littermates. In bovine retinal endothelial cells, which express Nox1, Nox4, and Nox5, Nox1/4 inhibition, as well as Nox5 silencing RNA, reduced the high glucose–induced upregulation of oxidative stress, angiogenic, and inflammatory factors. Collectively, these data indicate the potential of Nox1, Nox4, and Nox5 inhibition to reduce vision-threatening damage to the retinal vasculature.

Obsessive-compulsive disorder (OCD) is characterized by intrusive thoughts and repetitive, compulsive behaviors. Neuroimaging studies have implicated altered connectivity among the functional networks of the cerebral cortex in the pathophysiology of OCD. However, there has been no comprehensive investigation of the cross-talk between the cerebellum and functional networks in the cerebral cortex.This functional neuroimaging study was completed by 44 adult participants with OCD and 43 healthy control participants. We performed large-scale data-driven brain network analysis to identify functional connectivity patterns using resting-state functional magnetic resonance imaging data.Participants with OCD showed lower functional connectivity within the somatomotor network and greater functional connectivity among the somatomotor network, cerebellum, and subcortical network (e.g., thalamus and pallidum; all p.005). Network-based statistics analyses demonstrated one component comprising connectivity within the somatomotor network that showed lower connectivity and a second component comprising connectivity among the somatomotor network, and motor regions in particular, and the cerebellum that showed greater connectivity in participants with OCD relative to healthy control participants. In participants with OCD, abnormal connectivity across both network-based statistics-derived components positively correlated with OCD symptom severity (p = .006).To our knowledge, this study is the first comprehensive investigation of large-scale network alteration across the cerebral cortex, subcortical regions, and cerebellum in OCD. Our findings highlight a critical role of the cerebellum in the pathophysiology of OCD.

Cissampelos sympodialis Eichler, Menispermaceae, is a native Brazilian plant used in folk medicine to treat asthma and has central nervous system effects. Anxiety is a prevalent comorbidity of asthma raising the potential for the development of monotherapy for both diseases. We evaluated the effectiveness of the alcoholic fraction of leaves of C. sympodialis and its isolated alkaloid warifteine in treating anxiety- and asthma-like symptoms in mice with ovalbumin-induced allergic airway disease. Ovalbumin-sensitized BALB/c mice were treated with the plant extract or alkaloid orally, or with diazepam or dexamethasone controls, before ovalbumin challenge. Plant extract and warifteine treatments ameliorated anxiety-like symptoms and improved respiratory rate similar to diazepam in conscious allergic mice but did not ameliorate airway hyper-responsiveness. Plant extract and warifteine also reduced leukocyte migration into the airways and Th2 cytokine levels in bronchoalveolar lavage and lung tissue similar to dexamethasone. Our data indicate that C. sympodialis and its isolated alkaloid warifteine represent potential monotherapies to treat anxiety and asthma symptoms.

Objective Determine whether an electronic tablet-based Wireless Automated Hearing-Test System can perform high-quality audiometry to assess schoolchildren for hearing loss in the field in Nicaragua. Study design Cross-sectional. Setting A school and hospital-based audiology clinic in Jinotega, Nicaragua. Subjects and methods Second and third graders (n = 120) were randomly selected for hearing testing in a school. Air conduction hearing thresholds were obtained bilaterally using a Wireless Automated Hearing-Test System at 1000, 2000, and 4000 Hz. Referral criteria were set at more than 25 dBHL at one or more frequencies. A cohort of children was retested with conventional audiometry in a hospital-based sound booth. Factors influencing false-positive examinations, including ambient noise and behavior, were examined. Results All children with hearing loss were detected using an automated, manual, or two-step (those referred from automated testing were tested manually) protocol in the school (sensitivity = 100%). Specificity was 76% for automated testing, 97% for manual testing, and 99% for the two-step protocol. The variability between thresholds obtained with automated testing was greater than manual testing when compared with conventional audiometry. The percentage of participant responses when no stimulus tone was presented during automated testing was higher in children with false-positive examinations. Conclusion A Wireless Automated Hearing-Test System identified all children with hearing loss in a challenging field setting. A two-step protocol (those referred from automated testing are tested manually) reduced false-positive examinations and unnecessary referrals. Children who respond frequently when no tone is presented are more likely to have false-positive automated examinations and should be tested manually.

PURPOSE To determine factors associated with 360-degree laser retinopexy (360LR) during primary pars plana vitrectomy ± scleral buckle for rhegmatogenous retinal detachment (RRD) and its impact on surgical outcomes. METHODS This is a multicenter, retrospective, interventional study. Patients undergoing primary pars plana vitrectomy or primary pars plana vitrectomy + scleral buckle for noncomplex primary RRD in 2015 were evaluated. Primary outcomes were single surgery anatomical success (SSAS) and final anatomical success. Secondary outcomes included final logarithm of the minimum angle of resolution visual acuity, epiretinal membrane formation, cystoid macular edema development, and number of subsequent vitrectomies. Multivariate regressions were performed. RESULTS Two thousand two hundred and forty-eight surgeries by 61 surgeons were included; of which, 516 underwent 360LR. Younger age (P = 0.01), more retinal breaks (P = 0.01), more extensive RRD (P < 0.001), and surgeon ID (P < 0.001) were significantly associated with 360LR. No significant associations between 360LR and single surgery anatomical success (P = 0.44), epiretinal membrane formation (P = 0.14), cystoid macular edema development (P = 0.28), or number of subsequent vitrectomies (P = 0.41) were found. Controlling for case complexity, 360LR was significantly associated with lower final anatomical success (P < 0.001) and worse final logarithm of the minimum angle of resolution visual acuity (P < 0.001). CONCLUSION Multiple factors influenced whether 360LR was performed during primary pars plana vitrectomy ± scleral buckle for RRD. However, 360LR was not associated with improved surgical outcomes, and in fact, it may be associated with poorer outcomes.

A 66-year-old man was referred for management of a visually significant epiretinal membrane (ERM) with persistent cystoid macular edema after surgery for recurrent retinal detachment with proliferative vitreoretinopathy. The membrane was noted to be particularly thick and vascularized on preoperative optical coherence tomography. During the subsequent vitrectomy, the “membrane” was found to be an inverted retinal flap and successfully removed. The inverted retinal flap was thought to have been related to retinal slippage during prior surgery. This is the first report of an epimacular inverted flap simulating an ERM and highlights the importance of careful review of preoperative imaging. [ Ophthalmic Surg Lasers Imaging Retina . 2021;52:293–295.]

Background: Osteochondritis dissecans (OCD) occurs most commonly in the knees of young individuals. This condition is known to cause pain and discomfort in the knee and can lead to disability and early knee osteoarthritis. The cause is not well understood, and treatment plans are not well delineated. The Research in Osteochondritis Dissecans of the Knee (ROCK) group established a multicenter, prospective cohort to better understand this disease. Purpose: To provide a baseline report of the ROCK multicenter prospective cohort and present a descriptive analysis of baseline data for patient characteristics, lesion characteristics, and clinical findings of the first 1000 cases enrolled into the prospective cohort. Study Design: Cross-sectional study; Level of evidence, 3. Methods: Patients were recruited from centers throughout the United States. Baseline data were obtained for patient characteristics, sports participation, patient-reported measures of functional capabilities and limitations, physical examination, diagnostic imaging results, and initial treatment plan. Descriptive statistics were completed for all outcomes of interest. Results: As of November 2020, a total of 27 orthopaedic surgeons from 17 institutions had enrolled 1004 knees with OCD, representing 903 patients (68.9% males; median age, 13.1 years; range, 6.3-25.4 years), into the prospective cohort. Lesions were located on the medial femoral condyle (66.2%), lateral femoral condyle (18.1%), trochlea (9.5%), patella (6.0%), and tibial plateau (0.2%). Most cases involved multisport athletes (68.1%), with the most common primary sport being basketball for males (27.3% of cases) and soccer for females (27.6% of cases). The median Pediatric International Knee Documentation Committee (Pedi-IKCD) score was 59.9 (IQR, 45.6-73.9), and the median Pediatric Functional Activity Brief Scale (Pedi-FABS) score was 21.0 (IQR, 5.0-28.0). Initial treatments were surgical intervention (55.4%) and activity restriction (44.0%). When surgery was performed, surgeons deemed the lesion to be stable at intraoperative assessment in 48.1% of cases. Conclusion: The multicenter ROCK group has been able to enroll the largest knee OCD cohort to date. This information is being used to further understand the pathology of OCD, including its cause, associated comorbidities, and initial presentation and symptoms. The cohort having been established is now being followed longitudinally to better define and elucidate the best treatment algorithms based on these presenting signs and symptoms.

Chronic obstructive pulmonary disease (COPD) is the third leading cause of morbidity and death worldwide. Inhalation of cigarette smoke (CS) is the major cause in developed countries. Current therapies have limited efficacy in controlling disease or halting its progression. Aberrant expression of microRNAs (miRNAs) is associated with lung disease, including COPD. We performed miRNA microarray analyses of the lungs of mice with CS-induced experimental COPD. miR-21 was the second highest up-regulated miRNA, particularly in airway epithelium and lung macrophages. Its expression in human lung tissue correlated with reduced lung function in COPD. Prophylactic and therapeutic treatment with a specific miR-21 inhibitor (Ant-21) inhibited CS-induced lung miR-21 expression in mice; suppressed airway macrophages, neutrophils, and lymphocytes; and improved lung function, as evidenced by decreased lung hysteresis, transpulmonary resistance, and tissue damping in mouse models of COPD. In silico analyses identified a potential miR-21/special AT-rich sequence–binding protein 1 (SATB1)/S100 calcium binding protein A9 (S100A9)/nuclear factor κB (NF-κB) axis, which was further investigated. CS exposure reduced lung SATB1 in a mouse model of COPD, whereas Ant-21 treatment restored SATB1 and reduced S100A9 expression and NF-κB activity. The beneficial effects of Ant-21 in mice were reversed by treatment with SATB1-targeting small interfering RNA. We have identified a pathogenic role for a miR-21/SATB1/S100A9/NF-κB axis in COPD and defined miR-21 as a therapeutic target for this disease.

Background and aimsFunctional dyspepsia is characterised by chronic symptoms of post- prandial distress or epigastric pain not associated with defined structural pathology. Increased peripheral gut-homing T cell have been previously identified in patients. To date, it is unknown if these T cells were antigen-experienced, or if a specific immunophenotype was associated with FD. This study aimed to characterise immune populations in the blood and duodenal mucosa of FD patients that may be implicated in disease pathophysiology.MethodsWe identified duodenal T cell populations from 23 controls and 49 Rome III FD patients by flow cytometry. We also analysed duodenal eosinophils and T cell populations in peripheral blood from 37 controls and 49 patients and investigated if subtyping patients based on reported symptoms or co-morbidity identified specific immunophenoptypes.ResultsIn addition to increased duodenal mucosal CD4+ effector cells, FD patients demonstrated a shift in the T helper cell balance compared to controls. Patients had increased duodenal mucosal Th2 populations in the effector (13.03±16.11, 19.84±15.51, p=0.038), central memory (23.75±18.97, 37.52±17.51, p=0.007) and effector memory (9.80±10.50 vs 20.53±14.15, p=0.001) populations. Th17 populations were also increased in the effector (31.74±24.73 vs 45.57±23.75, p=0.03) and effector memory (11.95±8.42 vs 18.44±15.63, p=0.027) subsets.ConclusionOur findings confirm the involvement of adaptive responses in the aetiopathogenesis of FD, specifically a Th2 and Th17 signature in the duodenal mucosa. The presence of effector and memory cells suggest that the microinflammation in FD is antigen driven.

Background Media-based educational materials (EMs) are becoming prominent. The purpose of this study was to compare print versus media-based EMs given to caregivers of pediatric and young adult patients undergoing surgery. We aimed to see whether print or media-based EMs lead to greater caregiver satisfaction, comfort, and preparedness for outpatient peripheral nerve catheter and pain pump management. We also assessed caregiver preference for EM modality. Hypothesis We hypothesized that media-based EMs would demonstrate greater overall efficacy and thus generate higher caregiver preference. Study design Randomized control trial. Methods After IRB approval, clinicaltrials.gov registration (17-0638), and informed consent, caregivers were randomized to either media or print-based EM groups. Caregivers reviewed their assigned EM and completed a standardized assessment of their comprehension. We assessed caregiver satisfaction, preparedness, and comfort level with the content on a 5-point Likert scale. On postoperative days 1 to 2, caregivers reported satisfaction, comfort, and preference for EM modality. An intent-to-treat analysis was used to compare the 2 groups. Results From our final cohort of 135 caregivers, we found no difference [P>0.05] in satisfaction, comfort level, level of preparedness, or discharge readiness scores between groups. After the caregivers were given both EMs, they were evenly split in their preference for print (49.6%) versus video (50.4%) based methods. Conclusions We did not detect a significant difference in caregiver preference or feelings of preparedness between groups. Interestingly, a significant proportion of caregivers (25%) did not feel comfortable managing the peripheral nerve catheter and its pain pump at home. Future studies should work to improve caregiver comfort with educational content before patient discharge. Clinical relevance Providers and institutions should feel comfortable providing both print and media-based patient and caregiver education. Caregiver education may be best suited based on caregiver preference of one EM modality versus the other. Level of evidence Level I.

The prevalence of diabetes is growing at an alarming rate with increased disability, morbidity, and often premature mortality because of the various complications of this disorder. Chronic hyperglycemia, dyslipidemia, and other metabolic alterations lead to the development and progression of macro- and microvascular complications of diabetes including cardiovascular, retinal and kidney disease. Despite advances in glucose and lipid lowering treatments, a large number of diabetic individuals develop one or more types of these complications, ultimately leading to end-organ damage over the time. Atherosclerosis is the major macro-vascular complications of diabetes and the primary underlying cause of cardiovascular disease (CVD) posing heavy burden on the health care system. In this review, we discuss the involvement of dyslipidemia in the progression of atherosclerosis by activating the pro-inflammatory cytokines and oxidative stress-related factors. In addition, we also provide information on various pharmacological agents that provides protection against diabetic atherosclerosis by reducing inflammation and oxidative stress.

Community Health Nursing is one of the major areas in the nursing profession, yet it is not given many highlights in some circumstances. This condition puts new emphasis on the need for more research about this field of nursing. Consequently, this research study explored the lived experiences of registered nurses employed under the Nurse Deployment Program of the DOH. Furthermore, it involved seven qualified participants from the Rural Health Unit of Nagcarlan, Laguna. The researcher used descriptive, cross-sectional qualitative research, particularly a phenomenological approach by Husserl.The process includes four steps: bracketing, intuiting, analyzing and describing. The researcher facilitated a face-to-face, semi-structured interview in which the process was audio recorded to garner subjective data accurately. Thus, the researcher prepared a written topic guide, which is a list of open-ended questions to be answered by the participants, also known as procedural questions. The statements of participants were transcribed into text and then categorized into different themes. On the validation of the study, the researcher used triangulation Several themes were identified and fit into two factors: first are the intrinsic factors which include proper time and stress management, and career advancement and personal growth; while the others are the extrinsic factors which include fair workload and compensation, and resolution of issues related to working experiences. Based on the findings, the researcher developed a thematic framework that shows that extrinsic and intrinsic factors contributed to the satisfaction of the participants with their job, and made them stay in their chosen field. Hence, this calls for another research study using a mixed-method that approaches specifically the sequential exploratory design.

Rationale: Necroptosis, mediated by RIPK3 (receptor-interacting protein kinase 3) and MLKL (mixed lineage kinase domain-like), is a form of regulated necrosis that can drive tissue inflammation and destruction; however, its contribution to chronic obstructive pulmonary disease (COPD) pathogenesis is poorly understood. Objectives: To determine the role of necroptosis in COPD. Methods: Total and active (phosphorylated) RIPK3 and MLKL were measured in the lung tissue of patients with COPD and control subjects without COPD. Necroptosis-related mRNA and proteins as well as cell death were examined in lungs and pulmonary macrophages of mice with cigarette smoke (CS)-induced experimental COPD. The responses of Ripk3(-/-) and Mlkl(-/-) mice to acute and chronic CS exposure were compared with those of wild-typemice. The combined inhibition of apoptosis (with the pan-caspase inhibitor quinoline-Val-Asp-difluorophenoxymethylketone [qVD-OPh]) and necroptosis (with deletion of Mlkl in mice) was assessed. Measurements and Main Results: The total MLKL protein in the epithelium and macrophages and the pRIPK3 and pMLKL in lung tissue were increased in patients with severe COPD compared with never-smokers or smoker control subjects without COPD. Necroptosis-related mRNA and protein levels were increased in the lungs and macrophages in CS-exposed mice and experimental COPD. Ripk3 or Mlkl deletion prevented airway inflammation upon acute CS exposure. Ripk3 deficiency reduced airway inflammation and remodeling as well as the development of emphysematous pathology after chronic CS exposure. Mlkl deletion and qVD-OPh treatment reduced chronic CS-induced airway inflammation, but only Mlkl deletion prevented airway remodeling and emphysema. Ripk3 or Mlkl deletion and qVD-OPh treatment reduced CS-induced lung-cell death. Conclusions: Necroptosis is induced by CS exposure and is increased in the lungs of patients with COPD and in experimental COPD. Inhibiting necroptosis attenuates CS-induced airway inflammation, airway remodeling, and emphysema. Targeted inhibition of necroptosis is a potential therapeutic strategy in COPD.

It is known that the COVID-19 spread mainly from having close contact with people who have histories of exposure to the novel Corona virus (2019-nCoV or SARS-CoV-2). Though some countries have succeeded in developing the vaccine, its arrival remains a challenge in most countries like the Philippines. For this purpose, strict health protocols and contact tracing remain to be the principal public health interventions and preventive measures to limit the spread of COVID-19. With the number of available contact tracing applications that use Bluetooth and GPS technologies, this study focused on the development and pilot testing of GoTrace, a web-based contact tracing application that uses Quick Response (QR) codes. GoTrace integrates the collection of daily health surveys and location tracking data of the end-users on a digital and web platform to generate real-time, accurate, and reliable contact tracing reports. With the positive feedback of the participants during the pilot testing, GoTrace will offer a promising mobile contact tracing technology that can be adopted in various environments through its dynamic, flexible, and user-friendly architecture.

Energy security is a very important requirement for economic growth and stability. Renewable energy (RE) growth is one of the key elements of this area. The utility-type or the large-scale use of solar photovoltaic (PV) panels to produce electricity is becoming one of the most cost-effective energy sources. Solar generation costs have declined over the past few years, driven by an explosion in PV cell output and production. The objective of this study was to present the viability – both the technical and the economic feasibility of a 5 MWp solar photovoltaic (PV) farm in a specific location in Butuan City, Philippines. This paper performed the technical and economic analysis based on present market conditions and the availability of local materials from solar panels to power inverters, the build-on-systems (BOS), and cost considerations in putting up the large-scale PV utility using the PVSyst Software as the simulation tool. For a 5 MWp system, the investment could reach close to 300 million pesos (or USD6.25M). However, the results of the simulations revealed very promising financial benefits over a long period or in the lifespan of the solar power farm. The payback period is at 4.23 years, the return of investments or the ROI is at 506.2%, and other economic indicators are all positives and great support for establishing the solar PV farm. Over the lifetime of the PV farm, a total of 109,828.4 tons of CO2 will be avoided using the solar farm project. The authors highly recommend the proposed solar farm project to be implemented based on the results of this study.

IntroductionAge-related macular degeneration (AMD) is a blinding condition for which there is currently no early-stage clinical biomarker. AMD is characterized by thinning of the outer retina and drusen formation leading to thickening of the Bruch’s membrane and RPE complex, but the timing between these two events, as well as the role of genetic variants in these processes, are unclear. Here, we jointly analyzed genomic, electronic health record, and optical coherence tomography (OCT) data across 44,823 individuals from the UK Biobank to characterize the epidemiological and genetic associations between retinal layer thicknesses and AMD.MethodsThe Topcon Advanced Boundary Segmentation algorithm was used for automated retinal layer segmentation. We associated 9 retinal layer thicknesses with prevalent AMD (present at enrollment) in a logistic regression model, and with incident AMD (diagnosed after enrollment) in a Cox proportional hazards model. Next, we tested the association of AMD-associated genetic alleles, individually and as a polygenic risk score (PRS), with retinal layer thicknesses. All analyses were adjusted for age, age2, sex, smoking status, and principal components of ancestry.ResultsPhotoreceptor segment (PS) thinning was observed throughout the lifespan of individuals analyzed and accelerated at age 45, while retinal pigment epithelium and Bruch’s membrane complex (RPE+BM) thickening started after age 57. Each standard deviation (SD) of PS thinning and RPE+BM thickening were associated with prevalent AMD (PS: OR 1.37, 95% CI 1.25-1.49, P=2.5×10−12; RPE+BM: OR=1.34, 95% CI 1.27-1.41, P=8.4×10−28) and incident AMD (PS: HR 1.35, 95% CI 1.23-1.47, P=3.7×10−11; RPE+BM: HR 1.14, 95% CI 1.06-1.22, P=0.00024). An AMD polygenic risk score (PRS) was associated with PS thinning (Beta -0.21 SD per 2-fold genetically increased risk of AMD, 95% CI -0.23 to -0.19, P=2.8×10−74), and its association with RPE+BM was U-shaped (thinning with AMD PRSndpercentile and thickening with AMD PRS>92ndpercentile suggestive of drusen formation). The loci with strongest support were AMD risk-raising variantsCFH:rs570618-T,CFH:10922109-C, andARMS2/HTRA1:rs3750846-C on PS thinning, andSYN3/TIMP3:rs5754227-T on RPE+BM thickening.ConclusionsEpidemiologically, PS thinning precedes RPE+BM thickening by decades, and is the retinal layer most strongly predictive of future AMD risk. Genetically, AMD risk variants are associated with decreased PS thickness. Overall, these findings support PS thinning as an early-stage clinical biomarker for future AMD development.

A patient developed a reticulated gray-brown rash after completing a 21-day unclothed African survival challenge. During the challenge, the patient slept near a fire and inside a rock igloo. Exam and history were consistent with erythema ab igne, a rash related to heat exposure from fire or other heating sources.

Number of involved lymph nodes (LNs) is a crucial stratification factor in staging of numerous disease sites, but has not been incorporated for endometrial cancer. We evaluated whether number of involved LNs provide improved prognostic value.Patients diagnosed with node-positive endometrial adenocarcinoma without distant metastasis were identified in the National Cancer Database. We trained a machine-learning based model of overall survival. Shapley additive explanation values (SHAP) based on the model were used to identify cutoffs of number of LNs involved. Results were validated using a Cox proportional hazards regression model.We identified 11,381 patients with endometrial cancer meeting the inclusion criteria. Using the SHAP values, we selected the following thresholds: 1-3 LNs, 4-5 LNs, and 6+ LNs. The 3-year OS was 82.0% for 1-3 LNs, 74.3% for 4-5 LNs (hazard ratio [HR] 1.38; p 0.001), and 59.9% for 6+ LNs (HR 2.23; p 0.001). On univariate Cox regression, PA nodal involvement was a significant predictor of OS (HR 1.20; p 0.001) but was not significant on multivariate analysis when number of LNs was included (HR 1.05; p = 0.273). Additionally, we identified an interaction between adjuvant therapy and number of involved LNs. Patients with 1-3 involved LNs had 3-year OS of 85.2%, 78.7% and 74.2% with chemoradiation (CRT), chemotherapy, and radiation, respectively. Patients with 6+ involved LNs had 3-yr OS of 67.8%, 49.6%, and 48.9% with CRT, chemotherapy, and radiation, respectively (p 0.001).Number of involved LNs is a stronger prognostic and predictive factor compared to PA node involvement.