Whole genome sequencing of families diagnosed with cardiac channelopathies reveals structural variants missed by whole exome sequencing.

Cardiac channelopathies are a group of heritable disorders that affect the heart's electrical activity due to genetic variations present in genes coding for ion channels. With the advent of new sequencing technologies, molecular diagnosis of these disorders in patients has paved the way for early identification, therapeutic management and family screening. The objective of this retrospective study was to understand the efficacy of whole-genome sequencing in diagnosing patients with suspected cardiac channelopathies who were reported negative after whole exome sequencing and analysis. We employed a 3-tier analysis approach to identify nonsynonymous variations and loss-of-function variations missed by exome sequencing, and structural variations that are better resolved only by sequencing whole genomes. By performing whole genome sequencing and analyzing 25 exome-negative cardiac channelopathy patients, we identified 3 pathogenic variations. These include a heterozygous likely pathogenic nonsynonymous variation, CACNA1C:NM_000719:exon19:c.C2570G:p. P857R, which causes autosomal dominant long QT syndrome in the absence of Timothy syndrome, a heterozygous loss-of-function variation CASQ2:NM_001232.4:c.420+2T>C classified as pathogenic, and a 9.2 kb structural variation that spans exon 2 of the KCNQ1 gene, which is likely to cause Jervell-Lange-Nielssen syndrome. In addition, we also identified a loss-of-function variation and 16 structural variations of unknown significance (VUS). Further studies are required to elucidate the role of these identified VUS in gene regulation and decipher the underlying genetic and molecular mechanisms of these disorders. Our present study serves as a pilot for understanding the utility of WGS over clinical exomes in diagnosing cardiac channelopathy disorders.

Performance predication of a solar assisted desiccant air conditioning system using radial basis function neural network: An integrated machine learning approach.

In this Paper solar desiccant air conditioning system integrated with cross flow Maisotsenko cycle (M-cycle) indirect evaporative cooler is used to investigate the performance of whole system in different range of parameters. Solar evacuated tube electric heater is used to supply the regeneration temperature to the desiccant wheel, whereas, Desiccant Wheel (DW) and M-cycle is used to handle latent load and sensible load separately. Major contribution of this research is to predict system level performance parameters of a Solar Assisted Desiccant Air Conditioning (Sol-DAC) system using Radial Basis Function Neural Network (RBF-NN) under real transient experimental inlet conditions. Nine parameters are mainly considered as input parameters to train the RBF-NN model, which are, supply Air temperature at the process side of desiccant wheel, supply air humidity ratio at process side of the desiccant wheel, outlet temperature from the desiccant wheel at process side, outlet humidity ratio from the desiccant wheel at process side, regeneration temperature at regeneration side of the DW, outlet temperature from the heat recovery wheel at process side, outlet humidity ratio out from the Heat Recovery Wheel (HRW) at process side, temperature before heat recovery wheel regeneration side of the system, humidity ratio before heat recovery wheel regeneration side of the system. Four parameters are considered as the output of the RBF-NN model, namely: output temperature, output humidity, Cooling Capacity (CC), and Coefficient of Performance (COP). The results of the RBF-NN model shows that the best Mean Squared Error (MSE) and Regression coefficient (R) for outlet temperature prediction are 0.00998279 and 0.99832 when regeneration temperature is 70 °C and inlet humidity at 18 g/kg. Best MSE and R for predication of outlet humidity are 0.0102932 and 0.99485 when the regeneration temperature is 70 °C and inlet humidity at 16 g/kg. Best MSE and R for predication of COP are 0.0106691 and 0.9981 when the regeneration temperature is 70 °C and inlet humidity 12 g/kg. Best MSE and R for predication of CC are 0.0144943 and 0.99711 when the regeneration temperature is 70 °C and inlet humidity 14 g/kg. Experimental and predicted performance parameters were in close agreement and showed minimal deviation. Investigations of predicted results revealed that trained RBF-NN model was capable of predicting the trend of output result under the varying input condition.

Mapping Genetic Markers Associated with Antigenicity and Host Range in H9N2 Influenza A Viruses Infecting Poultry in Pakistan.

The aim of the current study was to map the genetic diversity in the haemagglutinin (HA) glycoprotein of influenza A viruses (IAVs) of the H9N2 subtype. Twenty-five H9N2 IAVs were isolated from broiler chickens from March to July 2019. The HA gene was amplified, and phylogenetic analysis was performed to determine the evolutionary relationship. Important antigenic amino acid residues of HA attributed to immune escape and zoonotic potential were compared among H9N2 IAVs. Phylogenetic analysis revealed that sublineage B2 under the G1 lineage in Pakistan was found to be diversified, and newly sequenced H9N2 isolates were nested into two clades (A and B). Mutations linked to the antigenic variation and potential immune escape were observed as G72E (1/25, 4%), A180T (3/25, 12%), and A180V (1/25, 4%). A twofold significant reduction (P < 0.01) in log2 hemagglutination inhibition titers was observed with H9N2 IAV naturally harboring amino acid V180 instead of A180 in HA protein. Moreover, in the last 20 years, complete substitution at residues (T127D, D135N, and L150N) and partial substitution at residues (72, 74, 131, 148, 180, 183, 188, 216, 217, and 249, mature H9 HA numbering) associated with changes in antigenicity were observed. The presence of L216 in all H9N2 IAV isolates and T/V180 in four isolates in the receptor-binding site reveals the potential of these viruses to cross the species barrier to infect human or mammals. The current study observed the circulation of antigenically diverse H9N2 IAV variants that possess potential mutations that can escape the host immune system.

Nota de investigación- Mapeo de marcadores genéticos asociados con la antigenicidad y el rango de huéspedes en los virus de la influenza tipo A subtipo H9N2 que infectan a la avicultura en Pakistán. El objetivo del presente estudio fue mapear la diversidad genética en la glicoproteína hemaglutinina (HA) de los virus de la influenza A (IAV) del subtipo H9N2. Se aislaron veinticinco virus de influenza H9N2 de pollos de engorde de marzo a julio del 2019. Se amplificó el gene HA y se realizó un análisis filogenético para determinar la relación evolutiva. Se compararon importantes residuos de aminoácidos antigénicos de la hemaglutinina atribuidos al escape inmunológico y al potencial zoonótico entre los virus de la influenza aviar H9N2. El análisis filogenético reveló que el sublinaje B2 bajo el linaje G1 en Pakistán estaba diversificado, y los aislados de H9N2 recién secuenciados se agruparon en dos clados (A y B). Se observaron mutaciones relacionadas con la variación antigénica y el posible escape inmunológico como los residuos de aminoácidos G72E (1/25, 4%), A180T (3/25, 12%) y A180V (1/25, 4%). Se observó una reducción significativa al doble (P < 0.01) en los títulos de inhibición de la hemaglutinación log2 cuando el virus de la influenza aviar H9N2 albergaba naturalmente el aminoácido V180 en lugar del A180 en la proteína HA. Además, en los últimos 20 años, sustitución completa en los residuos (T127D, D135N y L150N) y sustitución parcial en los residuos (72, 74, 131, 148, 180, 183, 188, 216, 217 y 249, de acuerdo con la numeración de la HA subtipo madura) asociados con cambios en la antigenicidad. La presencia del residuo L216 en todos los aislados de influenza aviar H9N2 y T/V180 en cuatro aislados en el sitio de unión al receptor revela el potencial de estos virus para cruzar la barrera de las especies para infectar a humanos o mamíferos. El estudio actual observó la circulación de variantes antigénicamente diversas del virus de influenza aviar H9N2 que poseen mutaciones potenciales que pueden escapar del sistema inmunológico del huésped.

The Practicality of the Robotic Total Hip Arthroplasty for the Treatment of Complex Bilateral Adult Hip Dysplasia. Technology Makes It Easy.

Adult hip dysplasia provides many challenges for joint surgeons. Due to the abnormal bone morphology and altered biomechanics of the hip, surgeons must ensure accurate implant positioning to avoid postoperative complications. We present a 56-year-old female with a history of bilateral Legg-Calve-Perthes disease and subsequent dysplasia who underwent bilateral total hip arthroplasty using robotic navigation. We highlight the utility of robotic navigation in adult hip dysplasia to improve implant positioning and ensure optimal patient outcomes.

Arthrofibrosis in Robotic Total Knee Arthroplasty: An Investigation Into How Robotic Assistance May Contribute to a Tight Knee.

INTRODUCTION: Arthrofibrosis after total knee arthroplasty (TKA) can lead to pain and restricted range of motion. Matching native knee kinematics is crucial in avoiding arthrofibrosis postoperatively. However, manual jig-based instruments have demonstrated variability and inaccuracy during primary TKA. Robotic-arm-assisted surgery was developed to increase the precision and accuracy of bone cuts and component alignment. In the literature, limited information on arthrofibrosis after robotic-assisted TKA (RATKA) exists. The purpose of this study was to compare the incidence of arthrofibrosis after manual TKA (mTKA) with RATKA by examining the need for manipulation under anesthesia (MUA) postoperatively and evaluating preoperative and postoperative radiographic parameters. METHODS: A retrospective analysis of patients who underwent primary TKA from 2019 to 2021 was conducted. Rates of MUA were evaluated and perioperative radiographs were analyzed to determine posterior condylar offset ratio, Insall-Salvati Index, and posterior tibial slope (PTS) in patients who underwent mTKA versus RATKA. Range of motion was recorded for patients who required MUA. RESULTS: A total of 1234 patients were included, of which 644 underwent mTKA, and 590 underwent RATKA. Thirty-seven RATKA patients compared with 12 mTKA patients required MUA postoperatively (P < 0.0001). A significant decrease in PTS postoperatively was seen in the RATKA (7.10° ± 2.4° preoperatively versus 2.46° ± 1.2° postoperatively), with a mean decrease of the tibial slope of -4.6° ± 2.5° (P < 0.0001). In patients requiring MUA, a larger decrease was seen in the RATKA group when compared with the mTKA group (mean -5.5 ± 2.0 versus -5.3 ± 0.78, P = 0.6585). No significant difference was seen in the posterior condylar offset ratio and Insall-Salvati Index in both groups. DISCUSSION: When conducting RATKA, it is important to match PTS close to the native tibial slope to decrease the incidence of arthrofibrosis postoperatively, as a decrease in PTS can lead to decreased postoperative knee flexion and poor functional outcomes.

Molecular Characterization and Selection of Indigenous SARS-CoV-2 Delta Variant for the Development of the First Inactivated SARS-CoV-2 Vaccine of Pakistan.

Vaccines are one of the efficient means available so far for preventing and controlling the infection rate of COVID-19. Several researchers have focused on the whole virus's (SARS-CoV-2) inactivated vaccines which are economically efficient to produce. In Pakistan, multiple variants of SARS-CoV-2 have been reported since the start of the pandemic in February 2020. Due to the continuous evolution of the virus and economic recessions, the present study was designed to develop an indigenous inactivated SARS-CoV-2 vaccine that might help not only to prevent the COVID-19 in Pakistan, it will also save the country's economic resources. The SARS-CoV-2 were isolated and characterized using the Vero-E6 cell culture system. The seed selection was carried out using cross-neutralization assay and phylogenetic analysis. The selected isolate of SARS-CoV-2 (hCoV-19/Pakistan/UHSPK3-UVAS268/2021) was inactivated using beta-propiolactone followed by vaccine formulation using Alum adjuvant, keeping the S protein concentration as 5 µg/dose. The vaccine efficacy was evaluated by in vivo immunogenicity testing in laboratory animals and in in vitro microneutralization test. The phylogenetic analysis revealed that all the SARS-CoV-2 isolates reported from Pakistan nested into different clades, representing multiple introductions of the virus into Pakistan. The antisera raised against various isolates from different waves in Pakistan showed a varied level of neutralization titers. However, the antisera produced against a variant (hCoV-19/Pakistan/UHSPK3-UVAS268/2021; fourth wave) efficiently neutralized (1:64-1:512) all the tested SARS-CoV-2 isolates. The inactivated whole virus vaccine of SARS-CoV-2 was safe and it also elicited a protective immune response in rabbits and rhesus macaques on the 35th-day post-vaccination. The activity of neutralizing antibodies of vaccinated animals was found at 1:256-1:1024 at 35 days post-vaccination, indicating the effectiveness of the double-dose regime of the indigenous SARS-CoV-2 vaccine.

Early Superior Clinical Outcomes in Robotic-Assisted TKA Compared to Conventional TKA in the Same Patient: A Comparative Analysis.

Robotic-assisted total knee arthroplasty (RA-TKA) has demonstrated improved alignment and outcome scores when compared with manual total knee arthroplasty (M-TKA); however, few studies compare differences in the same patient. This study is a retrospective review that assesses clinical outcomes of 36 patients who underwent a primary RA-TKA and had undergone a prior contralateral M-TKA. All surgeries were performed by a single surgeon at the same institution. Patients were assessed for differences in hospital length of stay, improvement in pre- versus postoperative range of motion, Knee Injury and Osteoarthritis Outcome Score (KOOS), and Western Ontario and McMaster Universities Arthritis Index (WOMAC) scores. Student's t-test and Fisher's exact test were utilized to detect significant differences. Patient demographics showed a mean age of 64.5, 24 females (67%), and mean body mass index of 35.1 ± 5.7. The average follow-up time was 2.9 years for M-TKA and 1.3 years for RA-TKA. Hospital length of stay was decreased by 5.5 hours for RA-TKA (p = 0.03). Total postoperative WOMAC score was not statistically different between RA-TKA and M-TKA (p = 0.061); however, pain and stiffness components were statistically improved in RA-TKA (p = 0.041 and p = 0.007), respectively. KOOS was higher in RA-TKA, which approached statistical significance (p = 0.005). Pre- versus postoperative knee flexion improved significantly in both cohorts. There was a significant difference in pre- versus postoperative range of motion at 3, 6, and 12 months follow-up after RA-TKA in comparison to M-TKA (p < 0.05). There were no postoperative complications. Patients who underwent RA-TKA demonstrated early improvement at 1-year follow-up in pain, stiffness, and knee flexion when compared with their prior contralateral M-TKA. There was a significant decrease in postoperative length of stay by 5.5 hours in the RA-TKA group. Limitations include a small sample size and differences in follow-up times between RA-TKA and M-TKA.

Rate of Multiple Viral and Bacterial CoInfection(s) in Influenza A/H9N2-Infected Broiler Flocks.

Repeated cases of low pathogenic influenza A/H9N2 virus (IAV/H9N2) have been reported in commercial chickens since its emergence in 1998 in Pakistan. However, recently increased mortality and severe respiratory complications under field conditions have been noticed, suggesting concomitant influenza infections with respiratory viral and/or bacterial pathogens. Therefore, the present study aimed to investigate the presence of IAV/H9N2 coinfecting with multiple viral and bacterial pathogens in broiler chicken flocks. We surveyed 60 broiler flocks with respiratory signs from March through July 2019 in Punjab, Pakistan. Suspected flocks were screened for the presence of IAV using a lateral-flow device. Tracheal, cloacal, and bone marrow samples were collected and further tested for seven viral agents (chicken anemia; Newcastle disease; infectious bronchitis; infectious laryngeotracheitis [ILT]; and IAV subtypes H9, H7, and H5) and three bacterial agents (Mycoplasma gallisepticum; Mycoplasma synovae; Ornithobacterium rhinotracheale [ORT]) using PCR assays. Upon initial screening for IAV, 35/60 (58.3%) flocks tested positive. The coinfection of IAV/H9N2 with other pathogens was detected in 25 (71.4%) flocks and only IAV/H9N2 was detected in 10 (28.6%) flocks out of total positive IAV flocks (n = 35). IAV subtypes H5 and H7, ILT, and ORT were not detected throughout the study period. The detection rate of double, triple, and quadruple combinations of coinfections with IAV/H9N2 were 37% (13 flocks), 26% (9 flocks), 9% (3 flocks), respectively. Higher average mortality (28.5%) was found in broiler chicken flocks coinfected with viral and/or bacterial pathogens than in flocks where only H9 low pathogenic IAV/H9N2 was detected (20.8%). In conclusion, higher circulation of IAV/H9N2 with other viral and bacterial pathogens may contribute to higher production and economic losses at the farm level.

Nota de investigación- Tasa de coinfecciones virales y bacterianas múltiples en parvadas de pollos de engorde infectadas con virus influenza A/H9N2. Se han reportado varios casos del virus de influenza A de baja patogenicidad H9N2 (IAV/H9N2) en pollos comerciales desde su aparición en 1998 en Pakistán. Sin embargo, recientemente se ha observado un aumento de la mortalidad y complicaciones respiratorias graves en condiciones de campo, lo que sugiere infecciones concomitantes de influenza con patógenos respiratorios virales y/o bacterianos. Por lo tanto, el presente estudio tuvo como objetivo investigar la presencia del virus de influenza aviar H9N2 coinfectando con múltiples patógenos virales y bacterianos en parvadas de pollos de engorde. Se evaluaron 60 parvadas de pollos de engorde con signos respiratorios desde marzo hasta julio del año 2019 en Punjab, Pakistán. Las parvadas sospechosas fueron analizadas para detectar la presencia del virus de influenza aviar utilizando un dispositivo de flujo lateral. Se recolectaron muestras traqueales, cloacales y de médula ósea y se analizaron para detectar siete agentes virales (anemia infecciosa aviar, enfermedad de Newcastle, bronquitis infecciosa, laringeotraqueítis infecciosa [ILT] y subtipos H9, H7 y H5 de influenza aviar) y tres agentes bacterianos (Mycoplasma gallisepticum ; Mycoplasma sinovae; Ornithobacterium rhinotracheale [ORT]) utilizando ensayos de PCR. Tras la detección inicial del virus de la influenza aviar, 35/60 (58.3 %) parvadas resultaron positivas. La coinfección del virus de la influenza H9N2 con otros patógenos se detectó en 25 (71.4 %) parvadas y el virus de influenza aviar H9N2 fue detectado solo en 10 (28.6 %) parvadas del total de parvadas positivas (n = 35). Los subtipos H5 y H7 del virus de influenza, ILT y ORT no se detectaron durante el período de estudio. La tasa de detección de combinaciones dobles, triples y cuádruples de coinfecciones con el virus de influenza H9N2 fue del 37 % (13 parvadas), del 26% (9 parvadas), del 9 % (3 parvadas), respectivamente. Se encontró una mortalidad promedio más alta (28.5 %) en lotes de pollos de engorde coinfectados con patógenos virales y/o bacterianos que en lotes donde solo se detectó al virus de influenza H9 de baja patogenicidad (20.8%). En conclusión, una mayor circulación del virus de influenza aviar H9N2 con otros patógenos virales y bacterianos puede contribuir a mayores pérdidas en la producción y económicas a nivel de granja.

Left atrial appendage closure using WATCHMAN device in chronic kidney disease and end-stage renal disease patients.

BACKGROUND: Chronic kidney disease (CKD) and end-stage renal disease are considered independent risk factors for developing atrial fibrillation (AF). Percutaneous occlusion of left atrial appendage (LAAC) using WATCHMAN device is a widely accepted alternative to anticoagulation therapy to prevent ischemic stroke in AF in patients who are not candidates for anticoagulation. There is limited data regarding the utilization and periprocedural safety of this intervention in patients with CKD/ESRD. METHODS: We retrospectively reviewed all hospitalizations from 2016 to 2017 with (ICD-10) procedure diagnosis code of LAA closure using WATCHMAN procedure with and without a secondary diagnosis of CKD/ESRD in acute-care hospitals across the United States using the national inpatient sample. Demographic variables (gender, race, income, hospital characteristics, medical comorbidities) were collected and compared. The primary outcomes were inpatient mortality, hospital length, and cost of stay. RESULTS: There were over 71 million discharges included in the combined 2016 and 2017 NIS database. Sixteen thousand five hundred five hospitalizations were for adult patients with a procedure code for LAA closure via watchman procedure. Of 16,505 patients, 3245 (19.66%) had CKD and ESRD. There was no statistically significant difference in mortality, length, and cost of stay in patients with and without CKD/ESRD. There were no statistically significant differences in periprocedural cerebrovascular accidents in both groups. CONCLUSION: Patients with and without ESRD/CKD who undergo LAA occlusion with Watchman have similar procedure related, in-hospital mortality, and complications.

An Insight Into Lyme Prosthetic Joint Infection in Knee Arthroplasty: A Literature Review.

Lyme prosthetic joint infection (PJI) is a rare event, but it is imperative to include Lyme disease as a possible cause of PJI in a Lyme-endemic region. The purpose of this article was to review the reported cases of Lyme PJIs in knee arthroplasty and to initiate the development of a treatment strategy. We found five cases of Lyme PJI in the literature. All patients lived in the northeastern region of the United States. Four patients were successfully treated with surgical intervention and postoperative antibiotics. One patient was successfully treated with intravenous and oral antibiotics for 6 weeks, without surgical intervention. Synovial fluid Lyme polymerase chain reaction and serological tests were positive in all patients. On follow-up visits, after completion of their treatment, all patients were asymptomatic with a painless functional knee. We recommend considering Lyme disease as a cause of culture-negative PJIs in endemic regions. Additional research is needed to clearly define a treatment algorithm. Based on our literature review, we cannot recommend a single best treatment modality for the treatment of Lyme PJI. However, early irrigation and débridement with administration of postoperative antibiotics may improve early clinical outcomes.

Learning Curve of Robotic-Assisted Total Knee Arthroplasty for Non-Fellowship-Trained Orthopedic Surgeons.

BACKGROUND: Total knee arthroplasty (TKA) serves as a reliable treatment option for patients with end-stage arthritis, but patient dissatisfaction rate remains high. With the projected increase in the volume of arthroplasty operations, surgeons have aimed for methods in which to improve the patient outcomes. Robotic-assisted TKA has become increasingly popular. The learning curve for such technology has been investigated, but these prior studies have only been performed by fellowship-trained arthroplasty surgeons. The goal of this study was to investigate the learning curve for non-fellowship-trained orthopedic surgeons to ameliorate any concerns about increased operative time. METHODS: Retrospective analysis of robotic-assisted TKAs and manual TKAs, performed by two non-fellowship-trained orthopedic surgeons, was conducted on a total of 160 patients. For each individual surgeon, the robotic-assisted TKAs were divided into 3 cohorts of 20 consecutive patients. Data from 20 consecutive manual TKAs were also gathered for each surgeon. The mean operative times were compared. Cohorts were then grouped together for both surgeons and compared in a similar fashion. RESULTS: For surgeon 1, mean operative times were significantly increased for robotic-assisted cohorts compared with those for the manual cohort. For surgeon 2, the first robotic-assisted cohort was significantly longer. However, there were no significant differences for the second and third robotic-assisted cohorts. In the combined surgeon group, there was no significant difference between operative times for the third robotic cohort and the manual cohort. CONCLUSION: This study demonstrates that the general orthopedic surgeon in a community hospital may be able to adequately perform robotic-assisted surgery in a similar timeframe to their manual TKA within their first 40 robotic-arm-assisted TKA.

Improving Postoperative Acute Kidney Injury Rates Following Primary Total Joint Arthroplasty.

BACKGROUND: Perioperative hip and knee arthroplasty complications remain a significant clinical and financial burden. Our institution has shifted to developing protocols to decrease these perioperative complications. This study focuses on acute kidney injury (AKI) rate status post primary total joint arthroplasty (TJA). Current literature demonstrates a 2%-15% incidence of AKI following TJA. However, there is a paucity of published literature on protocols that have effectively reduced AKI rates following TJA. The purpose of this study is to evaluate the effect that our institutionally developed perioperative renal protocol had on the postoperative AKI rates. METHODS: A retrospective cohort study was performed. Patient demographics, baseline creatinine, and postoperative creatinine values during the patient's hospitalization were collected and analyzed. The preintervention cohort data contained all patients at our institution who underwent a primary TJA from November 1, 2016 to January 1, 2018. The postintervention cohort included all primary TJA patients from July 1, 2018 to February 2, 2020. AKI was defined using the AKI Network classification system comparing baseline and postoperative creatinine values. A multivariate analysis was performed to determine the statistical significance of our results. RESULTS: Before intervention 1013 patients underwent a primary TJA with 68 patients developing an AKI postoperatively. After intervention 2169 patients underwent primary TJA with 90 patients developing an AKI (6.71% vs 4.15%; P = .0015, odds ratio = 0.59, 95% confidence interval = 0.42-0.82). CONCLUSION: This study demonstrated that implementation of a perioperative renal protocol can significantly reduce AKI rates. A reduction in AKI rates following TJA will result in improved outcomes and secondarily decrease the financial impact of postoperative complications seen following TJA.

Inappropriate sinus tachycardia: a review.

Inappropriate sinus tachycardia (IST) has been defined as a resting heart rate of >100 beats per minute and an average 24-hour heart rate >90 bpm with distressing symptoms resulting from the persistent tachycardia. IST is prevalent in 1% of the middle-aged population, mostly females. Rarely can elderly patients also present with IST. Possible mechanisms of IST include intrinsic sinus node abnormality, beta-adrenergic receptor stimulating autoantibody, beta-adrenergic receptor supersensitivity, muscarinic receptor autoantibody, or hyposensitivity, impaired baroreflex control, depressed efferent parasympathetic/vagal function, nociceptive stimulation, central autonomic overactivity, aberrant neurohumoral modulation, etc. Symptoms associated with IST are palpitations, chest pain, fatigue, shortness of breath, presyncope, and syncope. Despite these distressing symptoms, IST has not been associated with tachycardia-associated cardiomyopathy or increased major cardiovascular events. Various treatment options for patients with IST are ivabradine, beta-adrenergic blockers, calcium channel blockers, psychiatric evaluation, and exercise training. Although, endocardial radiofrequency ablation targeting the sinus node has been used as a treatment modality for otherwise treatment-refractory IST, the results have been dismal. The other modalities used for refractory IST treatment are endocardial modification of the sinus node using radiofrequency energy, combined endo and epicardial ablation of the sinus node, thoracoscopic epicardial ablation of the sinus node, sinus node sparing thoracoscopic and endocardial hybrid ablation. The goal of this review is to provide the readership with the pathophysiological basis of IST and its management options.

Management strategies for vasovagal syncope.

Vasovagal syncope (VVS) (or neurocardiogenic syncope) is a common clinical condition that is challenging to both physicians and patients alike. Severe episodes of recurrent syncope can result in physical injury as well as psychological distress. This article provides a brief overview of current management strategies and a detailed overview of therapeutic modalities such as closed loop stimulation (CLS) and cardioneuroablation (CNA).

What Is the Response Seen During Para-Hisian Pacing?

We present an interesting tracing of para-Hisian pacing in a 45-year-old man with an episode of narrow complex tachycardia and past recurrent palpitations.

Genetic Characterization of Highly Pathogenic Avian Influenza A(H5N8) Virus in Pakistani Live Bird Markets Reveals Rapid Diversification of Clade 2.3.4.4b Viruses.

The highly pathogenic (HPAI) avian influenza A(H5N1) viruses have undergone reassortment with multiple non-N1-subtype neuraminidase genes since 2008, leading to the emergence of H5Nx viruses. H5Nx viruses established themselves quickly in birds and disseminated from China to Africa, the Middle East, Europe and North America. Multiple genetic clades have successively evolved through frequent mutations and reassortment, posing a continuous threat to domestic poultry and causing substantial economic losses. Live bird markets are recognized as major sources of avian-to-human infection and for the emergence of zoonotic influenza. In Pakistan, the A(H5N1) virus was first reported in domestic birds in 2007; however, avian influenza surveillance is limited and there is a lack of knowledge on the evolution and transmission of the A(H5) virus in the country. We collected oropharyngeal swabs from domestic poultry and environmental samples from six different live bird markets during 2018-2019. We detected and sequenced HPAI A(H5N8) viruses from two chickens, one quail and one environmental sample in two markets. Temporal phylogenetics indicated that all novel HPAI A(H5N8) viruses belonged to clade 2.3.4.4b, with all eight genes of Pakistan A(H5N8) viruses most closely related to 2017 Saudi Arabia A(H5N8) viruses, which were likely introduced via cross-border transmission from neighboring regions approximately three months prior to virus detection into domestic poultry. Our data further revealed that clade 2.3.4.4b viruses underwent rapid lineage expansion in 2017 and acquired significant amino acid mutations, including mutations associated with increased haemagglutinin affinity to human α-2,6 receptors, prior to the first human A(H5N8) infection in Russian poultry workers in 2020. These results highlight the need for systematic avian influenza surveillance in live bird markets in Pakistan to monitor for potential A(H5Nx) variants that may arise from poultry populations.

Lyme Prosthetic Joint Infection in Total Knee Arthroplasty: A Case Report.

CASE: An 81-year-old man from the northeastern United States presented with an acute Borrelia burgdorferi prosthetic joint infection (PJI) 15 years after undergoing a right total knee arthroplasty. He had no complications until his recent presentation. He was treated with irrigation and debridement with implant retention. Synovial fluid Lyme polymerase chain reaction and serological tests were positive. Postoperatively, he received oral doxycycline and at 6 weeks was asymptomatic. Four months later, he died of neuroborreliosis vasculitis, a complication of Lyme. CONCLUSION: We recommend considering Lyme disease as a cause of culture-negative PJIs in endemic regions. Early surgical treatment may mitigate adverse outcomes of Lyme.

An unusual case of Adrenocortical Adenocarcinoma with Biochemical Masquerade of Pheochromocytoma.

Adrenocortical carcinoma (ACC) is a rare malignancy that arises from the adrenal cortex and often presents as adrenal incidentaloma on abdominal scans with rise in the use of imaging modalities. ACC often presents as Cushing's syndrome or virilization. On the other hand, pheochromocytoma is an adrenal medullary tumor. It is rare for ACC to present as pheochromocytoma even though both may coexist. Moreover, ACC tumors have radiological and histological features suggestive of aggressive nature of the disease. We present a case of a 65-year-old lady who initially presented with a 3cm left adrenal incidentaloma. All of her adrenal hormones were in normal range. She was lost to follow up for several years and returned with a much enlarged lesion. Biochemical work up showed mildly increased catecholamines and metanephrines suggestive of pheochromocytoma. She didn't have any signs or symptoms of pheochromocytoma. She was treated with alpha blockers before surgery as a prophylactic measure. Surgical pathology was consistent with the diagnosis of primary adrenal adenocarcinoma. We recommend that adrenal incidentalomas should be followed annually for up to five years as per American association of Endocrinology and the Endocrine Society guidelines to prevent morbidity and mortality in patients.

Morbid Obesity Due to Prolactinoma and Significant Weight Loss After Dopamine Agonist Treatment.

OBJECTIVE: Morbid obesity may be related to a prolactinoma, although uncommon, and can lead to adverse effects like insulin resistance and metabolic syndrome. Recent research suggests that hyperprolactinemia causes an abnormal lipid profile, weight gain, and cardiovascular diseases. Moreover, high prolactin levels lead to decreased testosterone production by disrupting 17-b-estradiol synthesis. Our objective was to present a case of prolactinoma with morbid obesity, hypogonadism, and then significant weight loss after dopamine agonist treatment. METHODS: The clinical course, in addition to serial laboratory and imaging results, are presented. These include prolactin levels, testosterone levels, thyroid function tests, blood sugar levels, and serial lipid profiles. RESULTS: In this report, we discuss a case of 30-year-old male with prolactin-secreting macroadenoma with clinical features of hypogonadism, hypothyroidism, and morbid obesity. He showed marked improvement in obesity and hypogonadism with dopamine agonist therapy supplemented with clomiphene citrate. CONCLUSION: Prolactinomas with morbid obesity can be successfully treated contingent upon proper medication and compliance with medications. Insulin resistance, hypogonadism, prolactin levels, body mass index, and tumor size all improved by regular follow-up and treatment adherence.