Comprehensive interrogation of human skeletal muscle reveals a dissociation between insulin resistance and mitochondrial capacity.

Insulin resistance and blunted mitochondrial capacity in skeletal muscle are often synonymous, however, this association remains controversial. The aim of this study was to perform an in-depth multifactorial comparison of skeletal muscle mitochondrial capacity between individuals who were lean and active (Active, n = 9), individuals with obesity (Obese, n = 9), and individuals with obesity, insulin resistance, and type 2 diabetes (T2D, n = 22). Mitochondrial capacity was assessed by ex vivo mitochondrial respiration with fatty-acid and glycolytic-supported protocols adjusted for mitochondrial content (mtDNA and citrate synthase activity). Supercomplex assembly was measured by Blue Native (BN)-PAGE and immunoblot. Tricarboxylic (TCA) cycle intermediates were assessed with targeted metabolomics. Exploratory transcriptomics and DNA methylation analyses were performed to uncover molecular differences affecting mitochondrial function among the three groups. We reveal no discernable differences in skeletal muscle mitochondrial content, mitochondrial capacity, supercomplex assembly, TCA cycle intermediates, and mitochondrial molecular profiles between obese individuals with and without T2D that had comparable levels of confounding factors (body mass index, age, and aerobic capacity). We highlight that lean, active individuals have greater mitochondrial content, mitochondrial capacity, supercomplex assembly, and TCA cycle intermediates. These phenotypical changes are reflected at the level of DNA methylation and gene transcription. The collective observation of comparable muscle mitochondrial capacity in individuals with obesity and T2D (vs. individuals without T2D) underscores a dissociation from skeletal muscle insulin resistance. Clinical trial number: NCT01911104.NEW & NOTEWORTHY Whether impaired mitochondrial capacity contributes to skeletal muscle insulin resistance is debated. Our multifactorial analysis shows no differences in skeletal muscle mitochondrial content, mitochondrial capacity, and mitochondrial molecular profiles between obese individuals with and without T2D that had comparable levels of confounding factors (BMI, age, aerobic capacity). We highlight that lean, active individuals have enhanced skeletal muscle mitochondrial capacity that is also reflected at the level of DNA methylation and gene transcription.

Autoimmune encephalitis and seizures, cerebrospinal fluid, imaging, and EEG findings: a case series.

Antibody-mediated encephalitides constitute a group of inflammatory brain diseases characterized by prominent neuropsychiatric symptoms and are associated with antibodies against neuronal cell-surface proteins, ion channels, or receptors. The diagnosis and management of autoimmune encephalitis include evaluation of the clinical presentation, brain imaging, cerebrospinal fluid (CSF) findings, antibody detection, and electroencephalography (EEG) findings. This is a retrospective study of adults 18 years or older with autoimmune encephalitis due to antibodies against membrane surface antigens as well as anti-glutamic acid decarboxylase (anti-GAD) antibodies. The electronic medical record was reviewed for demographic data, clinical data, laboratory results, EEG, and imaging findings. Antibody screening was requested for 341 patients between May 2014 and December 2019. Antibody screening was positive in 37 patients presenting with seizures and/or encephalopathy. Of these, 10 patients tested positive for antibodies against neuronal surface antigens or anti-GAD antibodies-2 patients had anti-GAD antibody encephalitis, 5 had anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis, and 3 had anti-leucine-rich glioma-inactivated 1 (anti-LGI1) encephalitis. Demographics, clinical presentation, EEG, imaging, and CSF findings are reported. Autoimmune encephalitides are a diverse group of disorders with a few common clinical features and MRI findings. MRI, EEG, and CSF findings can be normal or show nonspecific findings in autoimmune encephalitis. Therefore, early diagnosis of these disorders requires a high level of suspicion to avoid delaying the diagnosis. Carefully looking for diagnostic clinical features (e.g., faciobrachial dystonic seizures in anti-LGI1 encephalitis), significant findings in MRI (e.g., limbic encephalitis), and some EEG patterns (e.g., extreme delta brush and generalized rhythmic delta activity in anti-NMDAR encephalitis) may help in early diagnosis.

A neuromuscular-based analysis of the open payments program.

INTRODUCTION: In August 2013, the Centers for Medicare and Medicaid Services (CMS) Open Payments Program (OPP) made eligible payment information publicly available. Data about industry payments to neuromuscular neurologists are lacking. METHOD: Financial relationships were investigated between industry and US neuromuscular neurologists from January 2014 through December 2018 using the CMS OPP database. RESULTS: The total annual payments increased more than 6-fold during the study period. The top 10% of physician-beneficiaries collected 80% to 90% of total industry payments except in 2014. In 2018, the most common drugs associated with payments to neuromuscular neurologists were nusinersen, vortioxetine, eteplirsen, alglucosidase alpha, edaravone, and intravenous immunoglobulin. DISCUSSION: A substantial increase in the annual payments to neuromuscular physicians during the study period is likely due to the development of new treatments, including gene therapy.

Isolated primary neurolymphomatosis with cranial multineuritis: a case presentation.

BACKGROUND: Isolated primary neurolymphomatosis (NL) of cranial multineuritis is a very rare condition that refers to the lymphomatous invasion of cranial nerves only. There are sparse cases of isolated cranial nerves NL reported worldwide. CASE PRESENTATION: We present magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) findings of a 63-year-old female patient suffering from isolated neurolymphomatosis of cranial multineuritis with a wide constellation of syndromes including binocular diplopia, left facial paralysis and pain, syncope episodes, and progressive dysphagia. A contrasted MRI brain showed multiple cranial nerves enhancement. Extensive workup for infectious, autoimmune, neoplastic, paraneoplastic, or inflammatory etiologies had been unrevealing except CSF cytology revealed large atypical monotypic B cells that were suspicious for non-Hodgkin lymphoma on the third large volume tap. The decision of biopsy was deferred after the risks and benefits discussion. Following the four cycles of empiric methotrexate-based induction chemotherapy, the patient's symptoms resolved, and a complete radiographic response was achieved without whole-brain radiation or autologous hematopoietic cell transplantation. In the latest follow-up, she is independent with her daily activities and remains in clinical and radiographic remission more than 3 years since initial chemotherapy. CONCLUSION: Isolated NL of cranial nerves can present diagnostic and management pitfalls for the neurologist, neurosurgeons, and oncologists. Since current diagnostic modalities have modest sensitivity and a pathological diagnosis is often difficult, empiric treatment once other possibilities are ruled out can carry a good prognosis.

Criteria for Emergency Brain MRI During Stroke-Alert.

OBJECTIVES: Intravenous (IV) tissue plasminogen activator (tPA) should be given to patients with acute ischemic stroke (AIS) and avoided in stroke mimics (SM). Select use of emergency brain magnetic resonance imaging (eMRI-brain) in stroke-alerts aids diagnosis, but accepted utilization criteria for eMRI-brain do not currently exist. We developed criteria for eMRI-brain and report the yield of eMRI-brain in stroke-alert patients. MATERIALS AND METHODS: We developed three history-based criteria for performing eMRI-brain during stroke-alerts: (1) history of previous similar deficits, (2) change in consciousness at onset of symptoms, (3) symptom presentation consistent with migraine aura. We then performed a retrospective chart review of patients who presented as a stroke-alert over a 5-year period and determined how these criteria affected administration of IV tPA to AIS and SM patients. RESULTS: Among 3,512 stroke-alerts, 230 (8.1%) patients met our criteria for eMRI-brain exams: 217 (92.6%) had SM and 17 (7.4%) had AIS. Our IV tPA decision-making analysis showed that based on eMRI-brain IV tPA was less frequently administered to SM patients (PCC-0.841, p=0.036) with less failures to administer IV tPA to patients with AIS (PCC -0.907, p-value=0.013, Pearson correlation coefficient). No patients became ineligible for IV tPA due to MRI-related time delays. CONCLUSIONS: Our history based criteria for performing eMRI-brain during stroke-alerts show a high yield of stroke mimics. Selective eMRI-brain improves decision-making accuracy regarding IV tPA administration.

Industry Payment to Vascular Neurologists: A 6-Year Analysis of the Open Payments Program From 2013 Through 2018.

Background and Purpose- Industry payments to physicians raise concerns regarding conflicts of interest that could impact patient care. We explored nonresearch and nonownership payments from industry to vascular neurologists to identify trends in compensation. Methods- Using Centers for Medicare and Medicaid Services and American Board of Psychiatry and Neurology data, we explored financial relationships between industry and US vascular neurologists from 2013 to 2018. We analyzed payment characteristics, including payment categories, payment distribution among physicians, regional trends, and biomedical manufacturers. Furthermore, we analyzed the top 1% (by compensation) of vascular neurologists with detailed payment categories, their position, and their contribution to stroke guidelines. Results- The number of board certified vascular neurologist increased from 1169 in 2013 to 1746 in 2018. The total payments to vascular neurologist increased from $99 749 in 2013 to $1 032 302 in 2018. During the study period, 16% to 17% of vascular neurologists received industry payments. Total payments from industry and mean physician payments increased yearly over this period, with consulting fee (31.1%) and compensation for services other than consulting (30.7%) being the highest paid categories. The top 10 manufacturers made the majority of the payments, and the top 10 products changed from drug or biological products to devices. Physicians from south region of the United States received the highest total payment (38.72%), which steadily increased. Payments to top 1% vascular neurologists increased from 64% to 79% over the period as payments became less evenly distributed. Among the top 1%, 42% specialized in neuro intervention, 11% contributed to American Heart Association/American Stroke Association guidelines, and around 75% were key leaders in the field. Conclusions- A small proportion of US vascular neurologists consistently received the majority of industry payments, the value of which grew over the study period. Only 11% of the top 1% receiving industry payments have authored American Heart Association/American Stroke Association guidelines, but ≈75% seem to be key leaders in the field. Whether this influences clinical practice and behavior requires further investigation.

Spectrum of neuropsychiatric manifestations in COVID-19.

Corona Virus Disease 2019 (COVID-19) emerged in December 2019 from Wuhan, China. It typically presents with mild upper respiratory tract infection symptoms and may have life threatening complications, including acute respiratory distress syndrome, acute stroke, myocardial infarction, kidney failure, shock, and even death. Coronavirus infections are known to have neuroinvasive potential with consequent neuropsychiatric manifestations. We analyzed COVID-19 adult patients in the TriNetX database, which is a global health collaborative clinical research platform collecting real-time electronic medical records data from a network of health care organizations (HCOs) from January 20, 2020 to June 10th, 2020. 40,469 patients were diagnosed with COVID-19 among whom 9086 (22.5%) patients had neuropsychiatric manifestations. The most common neurologic manifestations included headache (3.7%) and sleep disorders (3.4%), Encephalopathy (2.3%), Stroke and transient ischemic attack (TIA) (1.0%) and 0.6% had seizures. Most common psychiatric manifestations included anxiety and other related disorders (4.6%), mood disorders (3.8%), while 0.2% patients had suicidal ideation. Early recognition and prompt management of neuropsychiatric manifestations in these patients have a potential to decrease overall morbidity and mortality.

Industry payments to hospitalist physicians: a 5-year analysis of the Open Payments programme from 2014 to 2018.

We analysed Open Payments programme data (https://openpaymentsdata.cms.gov) on industry-to-physician payments to hospitalists for the years 2014 to 2018. Payments to hospitalists increased by 106.5% from 2014 to 2018 with food and beverage (38.5%) and compensation for services other than consulting (24.3%) being the highest-paid categories. Industry payment to hospitalists was highly skewed with top 10 hospitalists receiving more than 30% of the total payments during the study period. The most common drugs associated with payments were anticoagulant medications (apixaban and rivaroxaban). Industry seems to be spending a significant amount of money to increase awareness of medications among hospitalists. Identification of these trends and potential motives of industry spending is critical to address any potential physician bias.

In Vitro Granuloma Models of Tuberculosis: Potential and Challenges.

Despite intensive research efforts, several fundamental disease processes for tuberculosis (TB) remain poorly understood. A central enigma is that host immunity is necessary to control disease yet promotes transmission by causing lung immunopathology. Our inability to distinguish these processes makes it challenging to design rational novel interventions. Elucidating basic immune mechanisms likely requires both in vivo and in vitro analyses, since Mycobacterium tuberculosis is a highly specialized human pathogen. The classic immune response is the TB granuloma organized in three dimensions within extracellular matrix. Several groups are developing cell culture granuloma models. In January 2018, NIAID convened a workshop, entitled "3-D Human in vitro TB Granuloma Model" to advance the field. Here, we summarize the arguments for developing advanced TB cell culture models and critically review those currently available. We discuss how integrating complementary approaches, specifically organoids and mathematical modeling, can maximize progress, and conclude by discussing future challenges and opportunities.

Essential Role of Endothelial MCPIP in Vascular Integrity and Post-Ischemic Remodeling.

MCP-1-induced protein (MCPIP, also known as Zc3h12a or Regnase-1), a newly identified suppressor of cytokine signaling, is expressed in endothelial cells (ECs). To investigate the role of endothelial MCPIP in vascular homeostasis and function, we deleted the MCPIP gene specifically in ECs using the Cre-LoxP system. EC-specific MCPIP deletion resulted in systemic inflammation, increased vessel permeability, edema, thrombus formation, and premature death in mice. Serum levels of cytokines, chemokines, and biomarkers of EC dysfunction were significantly elevated in these mice. Upon lipopolysaccharide (LPS) challenge, mice with EC-specific MCPIP depletion were highly susceptible to LPS-induced death. When subjected to ischemia, these mice showed defective post-ischemic angiogenesis and impaired blood flow recovery in hind limb ischemia. In aortic ring cultures, the MCPIP-deficient ECs displayed significantly impaired vessel sprouting and tube elongation. Mechanistically, silencing of MCPIP by small interfering RNAs in cultured ECs enhanced NF-κΒ activity and dysregulated synthesis of microRNAs linked with elevated cytokines and biomarkers of EC dysfunction. Collectively, these results establish that constitutive expression of MCPIP in ECs is essential to maintaining endothelial homeostasis and function by serving as a key negative feedback regulator that keeps the inflammatory signaling suppressed.

The perilipin-like PPE15 protein in Mycobacterium tuberculosis is required for triacylglycerol accumulation under dormancy-inducing conditions.

Mycobacterium tuberculosis (Mtb) causes latent tuberculosis infection in one-third of the world population and remains quiescent in the human body for decades. The dormant pathogen accumulates lipid droplets containing triacylglycerol (TAG). In mammals, perilipin regulates lipid droplet homeostasis but no such protein has been identified in Mtb. We identified an Mtb protein (PPE15) that showed weak amino acid sequence identities with mammalian perilipin-1 and was upregulated in Mtb dormancy. We generated a ppe15 gene-disrupted mutant of Mtb and examined its ability to metabolically incorporate radiolabeled oleic acid into TAG, accumulate lipid droplets containing TAG and develop phenotypic tolerance to rifampicin in two in vitro models of dormancy including a three-dimensional human granuloma model. The mutant showed a significant decrease in the biosynthesis and accumulation of lipid droplets containing TAG and in its tolerance of rifampicin. Complementation of the mutant with a wild-type copy of the ppe15 gene restored the lost phenotypes. We designate PPE15 as mycobacterial perilipin-1 (MPER1). Our findings suggest that the MPER1 protein plays a critical role in the homeostasis of TAG -containing lipid droplets in Mtb and influences the entry of the pathogen into a dormant state.

Mycobacterium tuberculosis lysine-ɛ-aminotransferase a potential target in dormancy: Benzothiazole based inhibitors.

MTB lysine-ɛ-aminotransferase (LAT) was found to play a crucial role in persistence and antibiotic tolerance. LAT serves as a potential target in the management of latent tuberculosis. In present work we attempted to derivatize the benzothiazole lead identified through high throughput virtual screening of Birla Institute of Technology and Science in house database. For Structure activity relationship purpose 22 derivatives were synthesized and characterized. Among synthesized compounds, eight compounds were found to be more efficacious in terms of LAT inhibition when compared to lead compound (IC50 10.38±1.21µM). Compound 22 exhibits bactericidal action against nutrient starved Mycobacterium tuberculosis (MTB). It also exhibits significant activity in nutrient starvation model (2.9log folds) and biofilm model (2.3log folds).

Transcription factors STAT6 and KLF4 implement macrophage polarization via the dual catalytic powers of MCPIP.

Macrophage polarization plays a critical role in tissue homeostasis, disease pathogenesis, and inflammation and its resolution. IL-4-induced macrophage polarization involves induction of STAT6 and Krüppel-like factor 4 (KLF4), which induce each other and promote M2 polarization. However, how these transcription factors implement M2 polarization is not understood. We report that in murine macrophages MCP-1-induced protein (MCPIP), induced by KLF4, inhibits M1 polarization by inhibiting NF-κB activation and implements M2 polarization using both its deubiquitinase and RNase activities that cause sequential induction of reactive oxygen species (ROS), endoplasmic reticulum (ER) stress, and autophagy required for M2 polarization. MCPIP also induces C/EBPß and PPARγ, which promote M2 polarization. Macrophages from mice with myeloid-targeted overexpression of MCPIP show elevated expression of M2 markers and reduced response to LPS, whereas macrophages from mice with myeloid-specific deletion of MCPIP manifest elevated M1 polarization with enhanced phagocytic activity. Thus, both in vivo and in vitro experiments demonstrate that the transcription factors STAT6 and KLF4 implement IL-4-induced M2 polarization via the dual catalytic activities of MCPIP.

Regulation of calcium clock-mediated pacemaking by inositol-1,4,5-trisphosphate receptors in mouse sinoatrial nodal cells.

KEY POINTS: Inositol-1,4,5-trisphosphate receptors (IP3 Rs) modulate pacemaking in embryonic heart, but their role in adult sinoatrial node (SAN) pacemaking is uncertain. We found that stimulation of IP3 Rs accelerates spontaneous pacing rate in isolated mouse SAN cells, whereas inhibition of IP3 Rs slows pacing. In atrial-specific sodium-calcium exchanger (NCX) knockout (KO) SAN cells, where the Ca(2+) clock is uncoupled from the membrane clock, IP3 R agonists and antagonists modulate the rate of spontaneous Ca(2+) waves, suggesting that IP3 R-mediated Ca(2+) release modulates the Ca(2+) clock. IP3 R modulation also regulates Ca(2+) spark parameters, a reflection of ryanodine receptor open probability, consistent with the effect of IP3 signalling on Ca(2+) clock frequency. Modulation of Ca(2+) clock frequency by IP3 signalling in NCX KO SAN cells demonstrates that the effect is independent of NCX. These findings support development of IP3 signalling modulators for regulation of heart rate, particularly in heart failure where IP3 Rs are upregulated. ABSTRACT: Cardiac pacemaking initiated by the sinus node is attributable to the interplay of several membrane currents. These include the depolarizing 'funny current' (If ) and the sodium-calcium exchanger current (INCX ). The latter is activated by ryanodine receptor (RyR)-mediated calcium (Ca(2+) ) release from the sarcoplasmic reticulum (SR). Another SR Ca(2+) release channel, the inositol-1,4,5-triphosphate receptor (IP3 R), has been implicated in the generation of spontaneous Ca(2+) release in atrial and ventricular cardiomyocytes. Whether IP3 R-mediated Ca(2+) release also influences SAN automaticity is controversial, in part due to the confounding influence of periodic Ca(2+) flux through the sarcolemma accompanying each beat. We took advantage of atrial-specific sodium-calcium exchanger (NCX) knockout (KO) SAN cells to study the influence of IP3 signalling on cardiac pacemaking in a system where periodic intracellular Ca(2+) cycling persists despite the absence of depolarization or Ca(2+) flux across the sarcolemma. We recorded confocal line scans of spontaneous Ca(2+) release in WT and NCX KO SAN cells in the presence or absence of an IP3 R blocker (2-aminoethoxydiphenyl borate, 2-APB), or during block of IP3 production by the phospholipase C inhibitor U73122. 2-APB and U73122 decreased the frequency of spontaneous Ca(2+) transients and waves in WT and NCX KO cells, respectively. Alternatively, increased IP3 production induced by phenylephrine increased Ca(2+) transient and wave frequency. We conclude that IP3 R-mediated SR Ca(2+) flux is crucial for initiating and modulating the RyR-mediated Ca(2+) cycling that regulates SAN pacemaking. Our results in NCX KO SAN cells also demonstrate that RyRs, but not NCX, are required for IP3 to modulate Ca(2+) clock frequency.

Multimodal monitoring: practical recommendations (dos and don'ts) in challenging situations and uncertainty.

With the advancements in modern medicine, new methods are being developed to monitor patients in the intensive care unit. Different modalities evaluate different aspects of the patient's physiology and clinical status. The complexity of these modalities often restricts their use to the realm of clinical research, thereby limiting their use in the real world. Understanding their salient features and their limitations can aid physicians in interpreting the concomitant information provided by multiple modalities to make informed decisions that may affect clinical care and outcomes. Here, we present a review of the commonly used methods in the neurological intensive care unit with practical recommendations for their use.

Prebiotics in New-Born and Children's Health.

At present, prebiotics, like probiotics, are receiving more attention as a promising tool for health maintenance. Many studies have recognized the role of prebiotics in preventing and treating various illnesses including metabolic disorders, gastrointestinal disorders, and allergies. Naturally, prebiotics are introduced to the human body in the first few hours of life as the mother breastfeeds the newborn. Prebiotic human milk oligosaccharides (HMOs) are the third largest constituent of human breastmilk. Studies have proven that HMOs modulate an infant's microbial composition and assist in the development of the immune system. Due to some health conditions of the mother or beyond the recommended age for breastfeeding, infants are fed with formula. Few types of prebiotics have been incorporated into formula to yield similar beneficial impacts similar to breastfeeding. Synthetic HMOs have successfully mimicked the bifidogenic effects of breastmilk. However, studies on the effectiveness and safety of consumption of these synthetic HMOs are highly needed before massive commercial production. With the introduction of solid foods after breastfeeding or formula feeding, children are exposed to a range of prebiotics that contribute to further shaping and maturing their gut microbiomes and gastrointestinal function. Therefore, this review evaluates the functional role of prebiotic interventions in improving microbial compositions, allergies, and functional gastrointestinal disorders in children.

Source of nicotinamide governs its metabolic fate in cultured cells, mice, and humans.

Metabolic routing of nicotinamide (NAM) to NAD+ or 1-methylnicotinamide (MeNAM) has impacts on human health and aging. NAM is imported by cells or liberated from NAD+. The fate of 2H4-NAM in cultured cells, mice, and humans was determined by stable isotope tracing. 2H4-NAM is an NAD+ precursor via the salvage pathway in cultured A549 cells and human PBMCs and in A549 cell xenografts and PBMCs from 2H4-NAM-dosed mice and humans, respectively. 2H4-NAM is a MeNAM precursor in A549 cell cultures and xenografts, but not isolated PBMCs. NAM released from NAD+ is a poor MeNAM precursor. Additional A549 cell tracer studies yielded further mechanistic insight. NAMPT activators promote NAD+ synthesis and consumption. Surprisingly, NAM liberated from NAD+ in NAMPT activator-treated A549 cells is also routed toward MeNAM production. Metabolic fate mapping of the dual NAM sources across the translational spectrum (cells, mice, humans) illuminates a key regulatory node governing NAD+ and MeNAM synthesis.

Transcriptional suppression of connexin43 by TBX18 undermines cell-cell electrical coupling in postnatal cardiomyocytes.

T-box transcription factors figure prominently in embryonic cardiac cell lineage specifications. Mesenchymal precursor cells expressing Tbx18 give rise to the heart's pacemaker, the sinoatrial node (SAN). We sought to identify targets of TBX18 transcriptional regulation in the heart by forced adenoviral overexpression in postnatal cardiomyocytes. Neonatal rat cardiomyocytes (NRCMs) transduced with GFP showed sarcolemmal, punctate Cx43 expression. In contrast, TBX18-transduced NRCMs exhibited sparse Cx43 expression. Both the transcript and protein levels of Cx43 were greatly down-regulated within 2 days of TBX18 transduction. Direct injection of TBX18 in the guinea pig heart in vivo inhibited Cx43 expression. The repressor activity of TBX18 on Cx43 was highly specific; protein levels of Cx45 and Cx40, which comprise the main gap junctions in the SAN and conduction system, were unchanged by TBX18. A reporter-based promoter assay demonstrated that TBX18 directly represses the Cx43 promoter. Phenotypically, TBX18-NRCMs exhibited slowed intercellular calcein dye transfer kinetics (421 ± 54 versus control 127 ± 43 ms). Intracellular Ca(2+) oscillations in control NRCM monolayers were highly synchronized. In contrast, TBX18 overexpression led to asynchronous Ca(2+) oscillations, demonstrating reduced cell-cell coupling. Decreased coupling led to slow electrical propagation; conduction velocity in TBX18 NRCMs slowed by more than 50% relative to control (2.9 ± 0.5 versus 14.3 ± 0.9 cm/s). Taken together, TBX18 specifically and directly represses Cx43 transcript and protein levels. Cx43 suppression leads to significant electrical uncoupling, but the preservation of other gap junction proteins supports slow action potential propagation, recapitulating a key phenotypic hallmark of the SAN.

Bilateral Carotid-Cavernous Fistula: A Diagnostic and Therapeutic Challenge.

Carotid-cavernous fistula (CCF) is an aberrant communication between the main trunk or branches of carotid artery and the cavernous sinus. Most of the cases of CCF occur following head trauma, but congenital and spontaneous cases have been reported. We report an interesting case of bilateral CCF with no history of trauma, thus most likely spontaneous form. Since it is rare, it was a diagnostic challenge. The suspicion of this diagnosis was made due to clinical features of headache, signs of increased Intracranial Pressure (ICP) (nausea, vomiting, and worsening headaches during Valsalva), exophthalmos, periorbital edema, periorbital erythema, chemosis, and conjunctival injection in both eyes. It was diagnosed with a 4-vessel angiography (digital subtraction angiography) which is the gold standard and was managed successfully with endovascular coil embolization.

Predictors of No-Show in Neurology Clinics.

In this study, we aim to identify predictors of a no-show in neurology clinics at our institution. We conducted a retrospective review of neurology clinics from July 2013 through September 2018. We compared odds ratio of patients who missed appointments (no-show) to those who were present at appointments (show) in terms of age, lead-time, subspecialty, race, gender, quarter of the year, insurance type, and distance from hospital. There were 60,012 (84%) show and 11,166 (16%) no-show patients. With each day increase in lead time, odds of no-show increased by a factor of 1.0019 (p < 0.0001). Odds of no-show were higher in younger (p ≤ 0.0001, OR = 0.49) compared to older (age ≥ 60) patients and in women (p < 0.001, OR = 1.1352) compared to men. They were higher in Black/African American (p < 0.0001, OR = 1.4712) and lower in Asian (p = 0.03, OR = 0.6871) and American Indian/Alaskan Native (p = 0.055, OR = 0.6318) as compared to White/Caucasian. Patients with Medicare (p < 0.0001, OR = 1.5127) and Medicaid (p < 0.0001, OR = 1.3354) had higher odds of no-show compared to other insurance. Young age, female, Black/African American, long lead time to clinic appointments, Medicaid/Medicare insurance, and certain subspecialties (resident and stroke clinics) are associated with high odds of no show. Possible suggested interventions include better communication and flexible appointments for the high-risk groups as well as utilizing telemedicine.