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Nontuberculous mycobacteria otomastoiditis with facial palsy.

Nontuberculous mycobacteria otomastoiditis with facial palsy.

Spikenet, a targeted therapeutic agent for covid-19, reverses severe lung and brain dysfunction in mice

We established a murine hepatitis virus-1 (MHV-1) coronavirus model, to study disease mechanisms of Covid-19 (Viruses, 2021). With the goal of creating a therapeutic for pregnancy, using advanced imaging techniques, computational modeling, molecular dynamics and spectroscopy, we invented and tested a small peptide, SPIKENET (SPK) with high binding affinity to spike protein of MHV-1. SPK significantly reduced acute (7 days) and long term (1 year) consequences (mortality, pathology, and weight loss) (Front. Pharmacol, 2022, Mol Neurobiol 2022). Since we discovered the role of aquaporins (AQP) water channels in edema development, and that SPK reversed such an effect, we examined the molecular events in the development of lung and brain edema. Using our MHV-1 model (non-pregnant), we examined the involvement of factors known to modulate volume changes in lung and brain, namely [N-Methyl-D-Aspartate receptors (NMDAR1/2), and surfactant A]. Mice were inoculated with 5000 PFU intranasally, and divided into 5 groups (n=5/group): control (no infusion); control with Dulbecco’s Modified Eagle Medium; MHV-1; SPK 5mg/kg/d subcutaneous (s.c.) on days 2,4,6; MHV-1 plus SPK 5mg/kg/d s.c. on days 2,4,6. Mice were sacrificed 7 days post inoculation. Data were subjected to ANOVA and Tukey’s test with a level of significance p< 0.05. Lung NMDAR1/2 levels are increased (160.3 and 124.6%, respectively, p< 0.05) (Fig. 1). Similarly, brain NMDAR1 levels are increased (109.4%, p< 0.05), while brain NMDAR2 level are decreased (42.8%, p< 0.05) (Fig. 1). Surfactant A level decreased in the brain post-infection (57.4%, p< 0.05) while its level increased in the lung after infection (187.2%, p< 0.05) (Fig. 2). SPK normalized NMDAR1/2 and surfactant A levels in lung and brain. We report for the first time that lung and brain NMDA receptors and surfactant A are involved in the development of COVID-19 disease progression. Our invention, SPIKENET, abrogates these critical events, and together with our AQP findings, strongly suggest the potential therapeutic benefit of SPK in counteracting COVID-19.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Diverse cardiovascular risk of recurrent spontaneous abortion: A prospective cohort study using UK Biobank

Previous studies have reported that history of recurrent spontaneous abortion (RSA) can increase the risk for cardiovascular disease. However, previous studies mainly focused on atherosclerotic cardiovascular disease (ASCVD), such as coronary artery disease or stroke, hence the effect of RSA on non-atherosclerotic cardiovascular diseases (non-ASCVD) remains unknown. In the current study, we examined if women with a history of RSA have an increased risk for long-term cardiovascular outcomes including both ASCVD and non-ASCVD. The UK Biobank is a prospective cohort study that recruited participants 40 to 69 years old with ongoing follow-up. Among women enrolled in UK Biobank, those with at least one pregnancy history and without pre-existing cardiovascular disease were included. The new occurrence of ASCVD and non-ASCVD after enrollment were compared between the women with RSA history and without RSA history. To evaluate the incidence of cardiovascular outcomes, a Cox proportional hazard model was used with adjustment for covariates including age, race, BMI, nulliparity, use of hormones, smoking, early menopause, hysterectomy, prevalent diseases, and medication by Cox proportional hazards regression analysis. In the presence of a history of RSA, the risk of new occurrence of overall cardiovascular disease, was higher (adjusted hazard ratio (aHR), 1.24 (95% CI 1.15-1.35), Figure 1). Specifically, the incidence of coronary artery disease, myocardial infarction, peripheral artery disease, heart failure, mitral regurgitation, atrial fibrillation/flutter were all increased in cases with a history of RSA (Figure 2). The women with history of RSA had an increased long-term risk of not only ASCVD, but also non-ASCVD.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Association of obesity with outcomes of attempted operative vaginal delivery

To assess whether outcomes of attempted operative vaginal delivery (OVD) are associated with obesity among nulliparous individuals. This is a secondary analysis from the prospective cohort Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-To-Be study. This analysis included participants with cephalic liveborn non-anomalous singletons who delivered ≥34 weeks of gestation and had attempted OVD. The primary exposure was maternal obesity defined by body mass index (BMI) at delivery (obese: BMI ≥30 kg/m2 vs. non-obese: BMI < 30 kg/m2 [referent]). The primary outcome was failed OVD, defined as a cesarean delivery following attempted OVD, and secondarily maternal and neonatal adverse outcomes. Multivariable logistic regression was used to adjust for covariates, and statistical interaction between BMI and instrument type (forceps or vacuum) was assessed. When the interaction was significant, stratified analyses were performed and presented. Of 10,038 individuals in the parent study, 791 (7.9%) had an attempted OVD and were included in the analysis. 325 (41%) had BMI ≥30 at delivery. The type of instrument used was no different based on obesity status. Failed OVD, which occurred in 6.8% of attempts, was more frequent in those with obesity (10.1 vs 4.2%; p=0.005; aOR 2.23, 1.16-4.28), with no significant interaction by instrument type (Table 1). There was an interaction (p=0.046) between composite neonatal morbidity and instrument type. Stratified analysis revealed that composite neonatal morbidity was more likely following attempted vacuum in infants of people with obesity (32.7 vs 22.3%, aOR 1.61, 1.07-2.43) but not following forceps attempt. Other adverse outcomes were neither different by obesity status nor had significant interactions with instrument type (Table 2). Among nulliparas, attempted OVD was more likely to fail in people with obesity. Neonates of people with obesity who underwent attempted vacuum, but not attempted forceps, had higher composite morbidity than those with BMI < 30.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Gestational age-related risk of rupture of membranes in the setting of fetoscopy for twins

To describe, in twin pregnancies, the gestational age-related risk of postoperative rupture of membranes (ROM) < 34 weeks when fetoscopic surgery occurs from 16-26 weeks. Retrospective cohort study of twin pregnancies that underwent fetoscopy at a single fetal center from April 2010 to June 2019. Inclusion criteria was any twin pregnancy in which fetoscopic surgery was performed between 16-26 weeks. Exclusion criteria was aneuploidy, major congenital anomalies, higher order multiples. This study received IRB approval. Pregnancies were stratified by the week of fetoscopy. Primary outcome was the risk of ROM < 34 weeks gestation. Given that earlier surgery carries a longer latency between surgery and 34 weeks, to further measure the risk of ROM, Logrank analysis was used to evaluate the probability of having intact fetal membranes in the 8 weeks immediately post-op. For this analysis, surgeries were grouped into 3 gestational age ranges: surgery < 20 weeks, surgery from 20 0/7-22 6/7 weeks, and surgery from 23-25 6/7 weeks. 696 pregnancies met inclusion. 221 (32%) experienced ROM < 34 weeks. 118 (17%) experienced ROM within 8 weeks of fetoscopy. The risk of ROM with each week of gestation, as well as the 95% CI estimates are listed in table 1. There was a statistically significant decrease in ROM prior to 34 weeks when surgery occurred beyond 20 weeks gestation. Evaluating the probability of pregnancies having continued intact membranes in the 8 weeks immediately post-op revealed an intact membrane rate of 78% (95% CI 72-82%) when surgery occurred < 20 weeks, 87% (95% CI 82-90%) when surgery occurred between 20-22 6/7 weeks, and 79% (95% CI 71-85%) when surgery occurred between 23-25 6/7 weeks (p < 0.001), figure 1. The risk of ROM < 34 weeks decreases when fetoscopy occurs after 20 weeks. Compared to < 20 weeks, there is a lower risk of ROM in the subsequent 8 weeks when surgery occurs between 20-22 6/7 weeks. Interestingly, when surgery occurred < 20 weeks compared to 23-25 6/7 weeks, there was no difference in the risk of ROM in the 8 weeks immediately post-op.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Rates of preeclampsia in subsequent pregnancies by race/ethnicity

To assess whether race/ethnicity impacts rates of preeclampsia amongst pregnant persons with a history of preeclampsia in the previous pregnancy. A retrospective cohort study of two consecutive births in California between 2000-2012 among pregnant persons who had a history of preeclampsia in the index pregnancy. We included singleton, non-anomalous index pregnancies from gestational ages 23-42 weeks. We assessed rates of preeclampsia in the second pregnancy by race/ethnicity, age, BMI, educational attainment and insurance type in chi-squared analysis. We conducted a multivariable logistic regression for repeat cases of preeclampsia by race/ethnicity adjusting for pre-pregnancy BMI, age, education, and insurance type as potential confounders. Race/Ethnicity was stratified into patients who identified as Non-Hispanic White, Non-Hispanic Black, Non-Hispanic Asian, Hispanic, American Indian/American Native (Non-Hispanic), and Other. There were 22,096 births that met our inclusion criteria. Of those, 3,908 had preeclampsia in the subsequent pregnancy. Of those with preeclampsia in the second pregnancy, the majority (47%) identified as Hispanic, as did the majority of those without preeclampsia in the second pregnancy (49%). The rest of the populations racial/ethnic makeup were comparable. In our multivariable regression, compared to patients who identified as Non-Hispanic White, there were no significant difference in odds of having preeclampsia again in a subsequent pregnancy by race/ethnicity. Among patients who have had preeclampsia in a prior pregnancy, there were no significant differences in odds of having preeclampsia in the subsequent pregnancy by race/ethnicity.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

China has the momentum to eliminate measles

China has the momentum to eliminate measles

Maternal body mass index, maneuvers, and neonatal morbidity associated with shoulder dystocia

To compare the frequency and type of maneuvers used to resolve social dystocia (SD) by maternal pre-pregnancy body mass index (BMI) and the association between BMI and neonatal adverse outcomes following SD. We conducted a retrospective cohort study of pregnant individuals who experienced an SD at delivery from June 2012-July 2021 at a tertiary care center. We included singleton nonanomalous livebirths ≥36 weeks’ gestation. The primary exposure was pre-pregnancy BMI categorized as: < 30 kg/m2, 30-34.9- kg/m2, and ≥35 kg/m2. The composite neonatal outcome included neonatal injury, seizures, hypoxic ischemic encephalopathy, 5-minute APGAR < 7, and secondarily, NICU admission and neonatal acidemia (pH < 7.10). SD duration and number and types of maneuvers were compared by BMI groups. Multivariable logistic regression was used and adjusted for diabetes in pregnancy, operative vaginal delivery, and nulliparity. Among 883 individuals who experienced an SD at delivery, 608 (68.9%) had a BMI < 30, 161 (18.2%) were BMI 30-34.9, and 114 (12.9%) were BMI ≥35. The median duration of SD was 40 (IQR 30, 60) seconds and did not vary by maternal BMI. Deliveries complicated by BMI ≥35 were more likely to require ≥3 maneuvers compared to those with non-obese BMI (aOR 2.06, 95% CI 1.33-3.19). Suprapubic pressure (90.0%) and delivery of the posterior arm (40.9%) were the most commonly used maneuvers in all groups. Rubin’s and delivery of the posterior arm maneuvers were more commonly used in the BMI ≥35 group compared to BMI < 30 (RR 1.49, 95% CI 1.11-2.01; RR 1.32, 95% CI 1.08-1.61, respectively) categories. Composite neonatal adverse outcomes did not differ by BMI, but neonatal injury was more common in those with BMI ≥35 (aOR 2.03, 95% CI 1.11-3.75). Interaction between BMI category and number of maneuvers was not significant (p=0.09). Among pregnant individuals who experienced a SD, increased pre-pregnancy BMI was associated with increased number of maneuvers performed during a SD, but not its duration. Risk of neonatal injury following SD is higher if maternal BMI is ≥35 kg/m2.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Emergency Medicine Images: Headache After a Lumbar Puncture

A 34-year-old man presented to the emergency department for a persistent, positional headache 3 weeks after a routine lumbar puncture (LP) for the workup of multiple sclerosis. The headache started gradually approximately 1 week after the uneventful LP and consistently improved with lying flat and worsened when upright. At a previous ED visit for this headache, an epidural blood patch was considered for postdural puncture headache (PDPH); however, the anesthesia service did not think a blood patch would be better than conservative treatment, given the usual benign course and the expectation for near-term resolution of symptoms with PDPH. With the patient experiencing persistent symptoms affecting his daily activities despite home analgesics, the ED clinician ordered a noncontrast head computed tomography scan (CT) (Figures 1 and 2). Figure 2Coronal noncontrast head computed tomographyt. There are bilateral convexity subdural hematomas (arrows) and subdural hematoma along the interhemispheric fissure (chevrons). The lateral ventricles partially effaced. View Large Image Figure Viewer Download Hi-res image Brian J. Ahern is a Physician Assistant at the Department of Emergency Medicine, William Beaumont Army Medical Center, Fort Bliss, TX. ORCID identifier: http://orcid.org/0000-0002-5701-3561. Lisa M. Jin is a Physician Assistant at the Department of Emergency Medicine, William Beaumont Army Medical Center, Fort Bliss, TX. Sean M. Sylvia is a Physician Assistant at the Department of Emergency Medicine, William Beaumont Army Medical Center, Fort Bliss, TX.

Update 2.0 to “ViroCon: A software to compute multivariate extremes using the environmental contour method”

Update 2.0 to “ViroCon: A software to compute multivariate extremes using the environmental contour method”

Real-Time Infrared Spectroscopic Measurement of Natural Moisturizing Factor

Real-Time Infrared Spectroscopic Measurement of Natural Moisturizing Factor

Interpretable deep learning translation of GWAS and multi-omics findings to identify pathobiology and drug repurposing in Alzheimer's disease.

Translating human genetic findings (genome-wide association studies [GWAS]) to pathobiology and therapeutic discovery remains a major challenge for Alzheimer's disease (AD). We present a network topology-based deep learning framework to identify disease-associated genes (NETTAG). We leverage non-coding GWAS loci effects on quantitative trait loci, enhancers and CpG islands, promoter regions, open chromatin, and promoter flanking regions under the protein-protein interactome. Via NETTAG, we identified 156 AD-risk genes enriched in druggable targets. Combining network-based prediction and retrospective case-control observations with 10 million individuals, we identified that usage of four drugs (ibuprofen, gemfibrozil, cholecalciferol, and ceftriaxone) is associated with reduced likelihood of AD incidence. Gemfibrozil (an approved lipid regulator) is significantly associated with 43% reduced risk of AD compared with simvastatin using an active-comparator design (95% confidence interval 0.51-0.63, p<0.0001). In summary, NETTAG offers a deep learning methodology that utilizes GWAS and multi-genomic findings to identify pathobiology and drug repurposing in AD.

Necrolytic migratory erythema as a cutaneous manifestation of a pancreatic neuroendocrine tumor.

Glucagonoma syndrome is a rare entity defined by the existence of necrolytic migratory erythema (NME), elevated serum glucagon levels, and an underlying alpha-cell secreting tumor of the pancreas [ [1] John A.M. Schwartz R.A. Glucagonoma syndrome: a review and update on treatment. J Eur Acad Dermatology Venereol. 2016; 30: 2016-2022 Crossref PubMed Scopus (42) Google Scholar ]. We present the case of a female with clinical manifestations of this syndrome. In this paper, we describe the case of a 38-year-old woman referred to the dermatology department to investigate pruritic lesions located on the lower extremity, with subsequent extension to the axillae, groin, and intergluteal region, and pubis (Fig. 1). After several attempts, a skin biopsy specimen revealed histopathologic features suggestive of NME. Further evaluations revealed the presence of 8 centimeters nonmetastatic glucagonoma, located at the tail of the pancreas. 68Ga-DOTA TOC and an 18F-FDG PET identified a mild uptake of the lesion (Fig. 1). The glucagon level was >500 pg/mL. The patient was diagnosed with glucagonoma syndrome, and a caudal pancreatectomy was subsequently performed. Microscopy and the immunohistochemical study were consistent with a glucagonoma (Fig. 2). After surgery, the cutaneous manifestation was resolved, with normalization of glucagon levels. This uncommon case report adds information about an infrequent neuroendocrine tumor with cutaneous expression. Early recognition and diagnosis must support by radiological and nuclear medicine imaging tests [ [2] Jensen R.T. Cadiot G. Brandi M.L. et al. ENETS Consensus Guidelines for the management of patients with digestive neuroendocrine neoplasms: functional pancreatic endocrine tumor syndromes. Neuroendocrinology. 2012; 95: 98 Crossref PubMed Scopus (371) Google Scholar ]. Surgery is the initial treatment of choice. Fig. 2Skin biopsy revealing irregular acanthosis of the epidermis with loss of the stratum granulosum and edema of the superficial portion of the epidermis (A). Hematic extravasation and presence of abundant focal polynuclear cells alternating with areas of parakeratosis (B). Histological study reveals a nodular tumor of 8 × 4.5 × 3.5 cm, located in the tail of the pancreas with an intact capsular surface surrounded by adipose tissue (C). In the sections performed, a proliferation of neuroendocrine cells is identified, growing in an anastomosing, gyriform, pseudorosette trabecular pattern (D). Cells with ample eosinophilic cytoplasm and enlarged nuclei with central macronucleolus. Two mitoses are identified in 42 high magnification fields corresponding to less than one mitosis per 2 mm2 (E). Cells show intense positivity for chromogranin (F) and glucagon (G). View Large Image Figure Viewer Download Hi-res image

Isolating and targeting a highly active, stochastic dendritic cell subpopulation for improved immune responses.

Dendritic cell (DC) activation via pathogen-associated molecular patterns (PAMPs) is critical for antigen presentation and development of adaptive immune responses, but the stochastic distribution of DC responses to PAMP signaling, especially during the initial stages of immune activation, is poorly understood. In this study, we isolate a unique DC subpopulation via preferential phagocytosis of microparticles (MPs) and characterize this subpopulation of "first responders" (FRs). We present results that show these cells (1) can be isolated and studied via both increased accumulation of the micron-sized particles and combinations of cell surface markers, (2) show increased responses to PAMPs, (3) facilitate adaptive immune responses by providing the initial paracrine signaling, and (4) can be selectively targeted by vaccines to modulate both antibody and Tcell responses invivo. This study presents insights into a temporally controlled, distinctive cell population that influences downstream immune responses. Furthermore, it demonstrates potential for improving vaccine designs via FR targeting.

Systematic single-cell pathway analysis to characterize early Tcell activation.

Pathway analysis is a key analytical stage in the interpretation of omics data, providing a powerful method for detecting alterations in cellular processes. We recently developed a sensitive and distribution-free statistical framework for multisample distribution testing, which we implement here in the open-source R package single-cell pathway analysis (SCPA). We demonstrate the effectiveness of SCPA over commonly used methods, generate a scRNA-seq Tcell dataset, and characterize pathway activity over early cellular activation. This reveals regulatory pathways in Tcells, including an intrinsic type I interferon system regulating Tcell survival and a reliance on arachidonic acid metabolism throughout Tcell activation. A systems-level characterization of pathway activity in Tcells across multiple tissues also identifies alpha-defensin expression as a hallmark of bone-marrow-derived Tcells. Overall, this work provides a widely applicable tool for single-cell pathway analysis and highlights regulatory mechanisms of Tcells.

Potent and biostable inhibitors of the main protease of SARS-CoV-2

Potent and biostable inhibitors of the main protease (Mpro) of SARS-CoV-2 were designed and synthesized based on an active hit compound 5h (2). Our strategy was based not only on the introduction of fluorine atoms into the inhibitor molecule for an increase of binding affinity for the pocket of Mpro and cell membrane permeability but also on the replacement of the digestible amide bond by a surrogate structure to increase the biostability of the compounds. Compound 3 is highly potent and blocks SARS-CoV-2 infection invitro without a viral breakthrough. The derivatives, which contain a thioamide surrogate in the P2-P1 amide bond of these compounds (2 and 3), showed remarkably preferable pharmacokinetics in mice compared with the corresponding parent compounds. These data show that compounds 3 and its biostable derivative 4 are potential drugs for treating COVID-19 and that replacement of the digestible amide bond by its thioamide surrogate structure is an effective method.

Two Implantable Devices for Cardiac Rhythm Management

A 53-year-old, 104- kg, 165- cm woman with nonischemic cardiomyopathy with a reduced ejection fraction of 30%-to-35% secondary to cardiac sarcoidosis was admitted for decompensated heart failure. She previously had a single-chamber implantable cardioverter-defibrillator (ICD) placed via a left pectoral approach for the primary prevention of sudden cardiac death. Considering that the patient was on maximally tolerable guideline-directed medical therapy for heart failure with reduced ejection fraction, and was not a candidate for cardiac resynchronization therapy, the decision was made to augment her systolic function with a cardiac rhythm management device. After an uneventful implantation of her new device, a chest radiograph (Fig 1) and electrocardiogram showing changes (Fig 2, Fig 3) were obtained. What is the diagnosis? Fig 2Electrocardiogram with cardiac contractility modulation therapy OFF. View Large Image Figure Viewer Download Hi-res image Fig 3Electrocardiogram with cardiac contractility modulation therapy ON. View Large Image Figure Viewer Download Hi-res image

EXPLORATORY IN-CLINIC STUDY EVALUATING FEASIBILITY OF JVP HEIGHT ASSESSMENT BY EARLY PROTOTYPE OF MACHINE VISION ALGORITHM

EXPLORATORY IN-CLINIC STUDY EVALUATING FEASIBILITY OF JVP HEIGHT ASSESSMENT BY EARLY PROTOTYPE OF MACHINE VISION ALGORITHM

PROGNOSTIC VALUE OF EXERCISE RIGHT VENTRICULAR FREE WALL STRAIN IN PATIENTS WITH SICKLE CELL DISEASE

PROGNOSTIC VALUE OF EXERCISE RIGHT VENTRICULAR FREE WALL STRAIN IN PATIENTS WITH SICKLE CELL DISEASE

SMC complexes can traverse physical roadblocks bigger than their ring size.

Ring-shaped structural maintenance of chromosomes (SMC) complexes like condensin and cohesin extrude loops of DNA. It remains, however, unclear how they can extrude DNA loops in chromatin that is bound with proteins. Here, we use invitro single-molecule visualization to show that nucleosomes, RNA polymerase, and dCas9 pose virtually no barrier to loop extrusion by yeast condensin. We find that even DNA-bound nanoparticles as large as 200nm, much bigger than the SMC ring size, also translocate into DNA loops during extrusion by condensin and cohesin. This even occurs for a single-chain version of cohesin in which the ring-forming subunits are covalently linked and cannot open to entrap DNA. The data show that SMC-driven loop extrusion has surprisingly little difficulty in accommodating large roadblocks into the loop. The findings also show that the extruded DNA does not pass through the SMC ring (pseudo)topologically, hence pointing to a nontopological mechanism for DNA loop extrusion.