Microglia, Trem2, and Neurodegeneration.

Microglia are a specialized type of neuroimmune cells that undergo morphological and molecular changes through multiple signaling pathways in response to pathological protein aggregates, neuronal death, tissue injury, or infections. Microglia express Trem2, which serves as a receptor for a multitude of ligands enhancing their phagocytic activity. Trem2 has emerged as a critical modulator of microglial activity, especially in many neurodegenerative disorders. Human TREM2 mutations are associated with an increased risk of developing Alzheimer disease (AD) and other neurodegenerative diseases. Trem2 plays dual roles in neuroinflammation and more specifically in disease-associated microglia. Most recent developments on the molecular mechanisms of Trem2, emphasizing its role in uptake and clearance of amyloid ß (Aß) aggregates and other tissue debris to help protect and preserve the brain, are encouraging. Although Trem2 normally stimulates defense mechanisms, its dysregulation can intensify inflammation, which poses major therapeutic challenges. Recent therapeutic approaches targeting Trem2 via agonistic antibodies and gene therapy methodologies present possible avenues for reducing the burden of neurodegenerative diseases. This review highlights the promise of Trem2 as a therapeutic target, especially for Aß-associated AD, and calls for more mechanistic investigations to understand the context-specific role of microglial Trem2 in developing effective therapies against neurodegenerative diseases.

Increases in regional brain volume across two native South American male populations.

Industrialized environments, despite benefits such as higher levels of formal education and lower rates of infections, can also have pernicious impacts upon brain atrophy. Partly for this reason, comparing age-related brain volume trajectories between industrialized and non-industrialized populations can help to suggest lifestyle correlates of brain health. The Tsimane, indigenous to the Bolivian Amazon, derive their subsistence from foraging and horticulture and are physically active. The Moseten, a mixed-ethnicity farming population, are physically active but less than the Tsimane. Within both populations (N = 1024; age range = 46-83), we calculated regional brain volumes from computed tomography and compared their cross-sectional trends with age to those of UK Biobank (UKBB) participants (N = 19,973; same age range). Surprisingly among Tsimane and Moseten (T/M) males, some parietal and occipital structures mediating visuospatial abilities exhibit small but significant increases in regional volume with age. UKBB males exhibit a steeper negative trend of regional volume with age in frontal and temporal structures compared to T/M males. However, T/M females exhibit significantly steeper rates of brain volume decrease with age compared to UKBB females, particularly for some cerebro-cortical structures (e.g., left subparietal cortex). Across the three populations, observed trends exhibit no interhemispheric asymmetry. In conclusion, the age-related rate of regional brain volume change may differ by lifestyle and sex. The lack of brain volume reduction with age is not known to exist in other human population, highlighting the putative role of lifestyle in constraining regional brain atrophy and promoting elements of non-industrialized lifestyle like higher physical activity.

Unusual presentation of orbital compartment syndrome due to complicated herpes zoster ophthalmicus: A case report.

Herpesvirus reactivates from a latent infection in older adults and critically ill and immunocompromised individuals. Herpes zoster ophthalmicus (HZO) is a latent infection that affects the fifth cranial nerve. It is an infrequent cause of increased intraocular pressure. We present the case of a 50-year-old man with a reactivation of latent varicella-zoster virus infection involving the ophthalmic branch of the fifth cranial nerve. The patient was initially managed as an outpatient with an antiviral, but his clinical evolution worsened and required urgent surgical decompression. Lateral canthotomy was performed with cantholysis of the inferior crus of the lateral canthal tendon. Only partial decompression was achieved, so cantholysis of the upper crus was performed with significant tissue tension release. The patient evolved well and was discharged after 6 days without symptoms for outpatient management.

Colgajo pectoral mayor para la reconstrucción de defecto cutáneo en región esternoclavicular

Introducción: La ortoplastia fusiona conceptos y técnicas comunes a la traumatología y a la cirugía plástica, pero no siempre se logra la cooperación entre estas especialidades. Por ello el cirujano ortopédico debe aprender técnicas de cobertura cutánea que utilicen escasos recursos. Este trabajo presenta una alternativa quirúrgica para la cobertura de defectos complejos en la región esternoclavicular mediante un colgajo miocutáneo del pectoral mayor. Objetivo: Exponer el resultado funcional de la cobertura cutánea mediante la aplicación de un colgajo miocutáneo pectoral mayor contralateral. Presentación de caso: Paciente masculino de 21 años que presentó necrosis, exposición ósea y subluxación de la articulación esternoclavicular izquierda después de una cirugía vascular. Acudió a consulta de ortopedia para solucionar este defecto de partes blandas. Conclusiones: El colgajo miocutáneo del pectoral mayor es una técnica quirúrgica muy versátil y segura para la cobertura de defectos en la parte superior del tórax y el cuello con resultado funcional y estético satisfactorios.

Introduction: Orthoplasty merges concepts and techniques common to traumatology and plastic surgery; but achieving the cooperation between these specialties is not always easy. Therefore, the orthopedic surgeon must learn skin coverage techniques that use few resources. This paper presents a surgical alternative for the coverage of complex defects in the sternoclavicular region by means of a pectoralis major myocutaneous flap. Objective: To expose the functional result of skin coverage by applying a contralateral pectoral major myocutaneous flap. Case report: The case of a 21-year-old male patient who had necrosis, bone exposure, and subluxation of the left sternoclavicular joint after vascular surgery. He went to an orthopedic clinic to solve this soft tissue defect. Conclusions: The pectoralis major myocutaneous flap is a very versatile and safe surgical technique for covering defects in the upper part of the thorax and neck with satisfactory functional and aesthetic results.

Colgajo homodigital resensibilizado de circulación invertida para pérdidas de sustancia compleja del pulpejo digital

Introducción: Existen numerosas técnicas para la cobertura cutánea de las pérdidas de sustancia del pulpejo digital. Se destacan la cicatrización dirigida, los injertos de piel total o parcial, los colgajos de avances en V-Y y rectangulares, los neurovascularizados de circulación directa o retrógrada, y los trasplantes microquirúrgicos parciales de artejo. Objetivo: Presentar un caso con pérdida de sustancia compleja del pulpejo digital y la aplicación de un colgajo neurovascularizado de circulación retrógrada. Presentación del caso: Paciente masculino de 35 años. Sufrió herida a nivel de la falange distal del dedo índice de la mano derecha y se le diagnosticó una amputación traumática en zona 2. La cicatrización dirigida fracasó y mantuvo exposición ósea, por tanto, se le realizó un colgajo neurovascularizado de circulación retrógrada. Conclusiones: El colgajo neurovascularizado de circulación retrógrada constituye una opción para las pérdidas complejas de sustancia del pulpejo digital porque aporta resultados satisfactorios.

Introduction: There are numerous techniques for skin coverage in the substance loss of the digital ball. These include targeted scarring, total or partial skin grafts, V-Y and rectangular breakthrough flaps, neurovascularized direct or retrograde circulation, and joint´s partial microsurgical transplants. Objective: To present a case with loss of complex substance of the digital ball and the application of a neurovascularized flap of retrograde circulation. Presentation of the case: 35-year-old male patient. He suffered an injury at the level of the distal phalanx of the index finger of the right hand and was diagnosed with a traumatic amputation in zone 2. The targeted scarring failed and maintained bone exposure, therefore, a neurovascularized flap of retrograde circulation was performed. Conclusions: The neurovascularized retrograde circulation flap is an option for complex losses of substance of the digital ball because it provides satisfactory results.

Interrelated dataset of rebound numbers, ultrasonic pulse velocities and compressive strengths of drilled concrete cores from an existing structure and new fabricated concrete cubes.

Two test series were examined using nondestructive measuring methods by six independent laboratories before determining their compressive strength. The nondestructive test methods used were the rebound hammer and ultrasonic pulse velocity measurement. Two types of geometries were investigated: drilled cores and cubes. The measurement procedure for each of these datasets is conditioned to the geometry and is therefore different. The first series consists of 20 drilled cores (approximately diameter/height = 10 cm/20 cm) from the 55-year-old Lahntal Viaduct near Limburg, Germany. After preparation in the first laboratory, the lateral surface of the drilled cores was tested with the rebound hammer using a given pattern. Every laboratory tested every drilled core at different locations. Ultrasonic measurements in transmission were performed repeatedly at predefined points on the flat surfaces of the specimen. The second series consisted of 25 newly manufactured concrete cubes of a mix with a target concrete strength class of C30/37. The edge length was 15 cm. Each laboratory received five specimens of this test series. Thus, contrary to the first series, each specimen was tested by only one laboratory. Two side faces of each cube were tested with the rebound hammer. In addition, ultrasonic measurements were performed by one laboratory. The time of flight was measured between the tested side faces of the rebound hammer at different positions. For both series, rebound hammers were used to determine the R-value as well as the Q-value. The rebound hammer models within the laboratories were always the same, while they differed between the laboratories. The ultrasonic measurements took place with different measurement systems and couplants. Finally, both specimen series were tested destructively for compressive strength. The dataset contains the raw data summarized in tabular form. In addition, relevant calculated data are included in some cases. For the ultrasonic measurements, the time of flight has already been converted into the ultrasonic velocity. Besides, in addition to the raw data of the compressive strength test (force, weight, and geometry values), the calculated compressive strengths and densities are also provided.

Impact of Hyperkalemia in Heart Failure and Reduced Ejection Fraction: A Retrospective Study.

(1) Background: Hyperkalemia is a common finding in patients with heart failure and reduced ejection fraction (HFrEF), though its prognostic significance is controversial. There is no consensus on optimal potassium levels in these patients. The primary endpoint of this study was to determine the 5-year incidence of hyperkalemia in a cohort of patients with HFrEF. Secondary endpoints were to determine predictors of hyperkalemia and its impact on overall 5-year mortality; (2) Methods: retrospective, longitudinal, single-center observational study of patients with HFrEF followed-up in a specialized unit between 2011 and 2019. Hyperkalemia was considered as potassium concentration > 5.5 mEq/L; (3) Results: Hyperkalemia was observed in 170 (16.8%) of the 1013 patients. The 5-year hyperkalemia-free survival rate was 82.1%. Hyperkalemia was more frequent at the beginning of follow-up. Factors associated with hyperkalemia in the multivariate analysis were baseline potassium (HR 3.13, 95%CI 2.15-4.60; p < 0.001), creatinine clearance (HR 0.99, 95%CI 0.98-0.99; p = 0.013), right ventricular function (HR 0.95, 95%CI 0.91-0.99; p = 0.016) and diabetes mellitus (HR 1.40, 95%CI 1.01-1.96; p = 0.047). The overall survival rate at 5 years was 76.4%. Normal-high potassium levels (5-5.5 mEq/L) were inversely associated with mortality (HR 0.60, 95%CI 0.38-0.94; p = 0.025); (4) Conclusions: Hyperkalemia is a common finding in patients with HFrEF with an impact on the optimization of neurohormonal treatment. In our retrospective study, potassium levels in the normal-high range seem to be safe and are not associated with increased mortality.

Using artificial intelligence to reduce orthopedic surgical site infection surveillance workload: Algorithm design, validation, and implementation in 4 Spanish hospitals.

BACKGROUND: Surgical site infection (SSI) surveillance is a labor-intensive endeavor. We present the design and validation of an algorithm for SSI detection after hip replacement surgery, and a report of its successful implementation in 4 public hospitals in Madrid, Spain. METHODS: We designed a multivariable algorithm, AI-HPRO, using natural language processing (NLP) and extreme gradient boosting to screen for SSI in patients undergoing hip replacement surgery. The development and validation cohorts included data from 19,661 health care episodes from 4 hospitals in Madrid, Spain. RESULTS: Positive microbiological cultures, the text variable "infection", and prescription of clindamycin were strong markers of SSI. Statistical analysis of the final model indicated high sensitivity (99.18%) and specificity (91.01%) with an F1-score of 0.32, AUC of 0.989, accuracy of 91.27%, and negative predictive value of 99.98%. DISCUSSION: Implementation of the AI-HPRO algorithm reduced the surveillance time from 975 person/hours to 63.5 person/hours and permitted an 88.95% reduction in the total volume of clinical records to be reviewed manually. The model presents a higher negative predictive value (99.98%) than algorithms relying on NLP alone (94%) or NLP and logistic regression (97%). CONCLUSIONS: This is the first report of an algorithm combining NLP and extreme gradient-boosting to permit accurate, real-time orthopedic SSI surveillance.

Brain volume, energy balance, and cardiovascular health in two nonindustrial South American populations.

Little is known about brain aging or dementia in nonindustrialized environments that are similar to how humans lived throughout evolutionary history. This paper examines brain volume (BV) in middle and old age among two indigenous South American populations, the Tsimane and Moseten, whose lifestyles and environments diverge from those in high-income nations. With a sample of 1,165 individuals aged 40 to 94, we analyze population differences in cross-sectional rates of decline in BV with age. We also assess the relationships of BV with energy biomarkers and arterial disease and compare them against findings in industrialized contexts. The analyses test three hypotheses derived from an evolutionary model of brain health, which we call the embarrassment of riches (EOR). The model hypothesizes that food energy was positively associated with late life BV in the physically active, food-limited past, but excess body mass and adiposity are now associated with reduced BV in industrialized societies in middle and older ages. We find that the relationship of BV with both non-HDL cholesterol and body mass index is curvilinear, positive from the lowest values to 1.4 to 1.6 SDs above the mean, and negative from that value to the highest values. The more acculturated Moseten exhibit a steeper decrease in BV with age than Tsimane, but still shallower than US and European populations. Lastly, aortic arteriosclerosis is associated with lower BV. Complemented by findings from the United States and Europe, our results are consistent with the EOR model, with implications for interventions to improve brain health.

False-Positive Nodes With Axillary Silicone Lymphadenopathy in an Oncologic Patient With a Rare Breast Cancer and Implant Rupture.

In this case, a 43-year-old woman with a rare breast tumor and a history of augmentation mammoplasty is presented. The patient arrived at the clinic reporting a palpable lump in the right mammary gland and two ipsilateral axillary nodes with pain on palpation. Mammography and ultrasound confirmed the presence of a 4 cm tumor and 2 metastatic lymph nodes of 2 cm each, histopathological diagnosis was an encapsulated papillary cancer and two siliconomas, respectively. Interestingly, these nodes were able to take up technetium 99 and methylene blue contrast media. Due to these findings, adequate patient management was carried out with a skin-sparing mastectomy and hormonal treatment with tamoxifen. This report is relevant as it shows that axillary lymphadenopathy caused by silicone must be considered in the evaluation of a patient with a cancer diagnosis and history of augmentation mammoplasty, especially breast cancer as the node siliconomas present a high risk of being considered a false positive metastasis.

Prevalence of dementia and mild cognitive impairment in indigenous Bolivian forager-horticulturalists.

INTRODUCTION: We evaluated the prevalence of dementia and mild cognitive impairment (MCI) in indigenous Tsimane and Moseten, who lead a subsistence lifestyle. METHODS: Participants from population-based samples ≥ 60 years of age (n = 623) were assessed using adapted versions of the Modified Mini-Mental State Examination, informant interview, longitudinal cognitive testing and brain computed tomography (CT) scans. RESULTS: Tsimane exhibited five cases of dementia (among n = 435; crude prevalence = 1.2%, 95% confidence interval [CI]: 0.4, 2.7); Moseten exhibited one case (among n = 169; crude prevalence = 0.6%, 95% CI: 0.0, 3.2), all age ≥ 80 years. Age-standardized MCI prevalence was 7.7% (95% CI: 5.2, 10.3) in Tsimane and 9.8% (95% CI: 4.9, 14.6) in Moseten. Cognitive impairment was associated with visuospatial impairments, parkinsonian symptoms, and vascular calcification in the basal ganglia. DISCUSSION: The prevalence of dementia in this cohort is among the lowest in the world. Widespread intracranial medial arterial calcifications suggest a previously unrecognized, non-Alzheimer's disease (AD) dementia phenotype.

Narrative Review of the Role of Patient-Reported Outcomes and Inhaler Handling Errors in the Control of Asthma and COPD.

PURPOSE OF REVIEW: Asthma and chronic obstructive pulmonary disease (COPD) are chronic respiratory diseases that remain uncontrolled in many patients, despite the wide range of therapeutic options available. This review analyzes the available clinical evidence on 3 budesonide/formoterol DPI devices, Spiromax®, Turbuhaler®, and Easyhaler®, in terms of patient-reported outcomes (PROs), inhaler errors, and asthma and COPD control. RECENT FINDINGS: The effectiveness of dry powder inhalers (DPI) depends largely on the device and the patient's inhaler technique. Equally important are the patient's perception of the inhaler and adherence. Given the high burden of these diseases, it is important that efforts be made to select the best DPI for each patient and to analyze the impact of these variables to help improve the health and quality of life of our patients. This review provides a comprehensive overview of the present knowledge about PROs, inhaler handling errors, and asthma and COPD control achieved by Spiromax®, Turbuhaler®, and Easyhaler®.

Dequalinium chloride is an antagonists of α7 nicotinic acetylcholine receptors.

Dequalinium chloride has been used primarily as antiseptic compounds, but recently has been investigated for its effects on specific targets, including muscarinic acetylcholine receptors. Here we investigated dequalinium chloride as an antagonist to α7 nicotinic acetylcholine receptors. The pharmacological properties of dequalinium were established using cell lines stably co-transfected with the calcium-permeable human α7 nicotinic acetylcholine receptors and its chaperone NACHO, calcium dye fluorescent measurements or a calcium-sensitive protein reporter, and patch clamp recording of ionic currents. Using calcium dye fluorescence plate reader measurements, we find dequalinium chloride is an antagonist of α7 nicotinic acetylcholine receptors with an IC50 of 672 nM in response to activation with 500 µM acetylcholine chloride and positive allosteric modulator PNU-120596. However, using a membrane-tethered GCAMP7s calcium reporter allowed detection of α7-mediated calcium flux in the absence of PNU-120596. Using this approach revealed an IC50 of 157 nM for dequalinium on 300 µM acetylcholine-evoked currents. Using patch clamp recordings with 300 µM acetylcholine chloride and 10 µM PNU-120596, we find lower concentrations are sufficient to block ionic currents, with IC50 of 120 nM for dequalinium chloride and 54 nM for the related UCL 1684 compound. In summary, we find that dequalinium chloride and UCL1684, which are generally used to block SK-type potassium channels, are also highly effective antagonists of α7 nicotinic acetylcholine receptors. This finding, in combination with previous studies of muscarinic acetylcholine receptors, clearly establishes dequalinium compounds within the class of general anti-cholinergic antagonists.

Comparative Analysis of the Efficiency of Two Treatment Protocols for Posterior Canal Benign Paroxysmal Positional Vertigo.

BACKGROUND AND OBJECTIVE: Benign paroxysmal positional vertigo (BPPV) is the most common vertigo of labyrinthine origin, its social and healthcare impact is remarkable. It has recently been shown that single session treatment is as safe and effective as weekly treatment, which could have impact on direct and indirect costs related to the disease. The objective of this study is to determine whether single session treatment of unilateral posterior canal BPPV canalolithiasis is more efficient than conventional treatment. MATERIALS AND METHODS: A prospective randomized controlled trial was performed in 53 consecutive patients diagnosed with unilateral posterior canal BPPV canalolithiasis previously untreated: 26 patients were assigned to single session treatment and 27 patients to weekly treatment. Average and total cost of care, consultation time and the impact in terms of temporary disability and loss of productivity for the company due to patients' medical visits were compared. RESULTS: Average and total cost of care and loss of productivity for the company due to patients' medical visits were significantly lower in the single session group. Consultation time was also better in this group when travelling time was considered. CONCLUSIONS: The single session protocol is fast, effective and reduces direct and indirect cost of care related to disease justifying high resolution consultations.

Tumor de células gigantes en el extremo distal del radio / Giant Cell Tumor Of The Distal Radius

Introducción: El tumor de células gigantes de hueso es uno de los tumores menos frecuentes y su comportamiento local es agresivo. Objetivo: Presentar un caso afectado por un tumor de células gigantes tratado con resección en bloque y artrodesis de la articulación de la muñeca. Presentación del caso: Paciente masculino de 29 años de edad, con antecedentes relativos de salud, que presentaba desde hacía 5 meses aumento de volumen e impotencia funcional al realizar flexo extensión activa de la muñeca izquierda, con empeoramiento progresivo. Se diagnosticó tumor óseo de células gigantes con marcada actividad proliferativa estromal en el extremo distal del radio, se realizó resección en bloque y artrodesis del extremo distal del radio con márgenes oncológicos y transferencia del flexor radial corto al extensor común y del palmar menor al extensor y abductor del pulgar. Conclusiones: La resección en bloque y artrodesis es una de las opciones a tener en cuenta en la cirugía reconstructiva de la extremidad superior con un resultado satisfactorio(AU)

Introduction: Giant cell tumor of bone is one of the least frequent tumors and the local behavior is aggressive. Objective: To report a case with giant cell tumor treated with en bloc resection and arthrodesis of the wrist joint. Case report: A relative healthy 29-year-old male patient had had increased volume and functional impotence when performing active flexor extension of the left wrist for 5 months, with progressive worsening. A giant cell bone tumor with marked stromal proliferative activity was diagnosed in the distal end of the radius. En bloc resection and arthrodesis of the distal end of the radius were performed with oncological margins and the transfer of the flexor radialis brevis to the common extensor and the palmaris minor to the extensor and abductor pollicis. Conclusions: En bloc resection and arthrodesis is one of the options to consider in reconstructive surgery of the upper extremity with a satisfactory result(AU)

Impact of Anti-Immigrant Rhetoric on Latinx Families' Perceptions of Child Safety and Health Care Access.

BACKGROUND: Political rhetoric from the former U.S. president influences Latinx adults' feelings of safety and their decisions to seek care in the emergency department (ED). OBJECTIVE: Our aim was to examine the impact of political rhetoric on feelings of safety and health care access in the pediatric population. METHODS: This was a cross-sectional study of undocumented Latinx families (ULF), Latinx U.S. citizen families (LCF), and non-Latinx U.S. citizen families (NLF) conducted from November 2018 through February 2020 by means of interviewing a convenience sample of parents and guardians who brought their child to a pediatric clinic and two EDs in California. RESULTS: Of 705 parents approached, 449 (63.7%) agreed to participate: 138 ULF, 150 LCF, and 158 NLF. Most ULF (95%), LCF (88%), and NLF (78%) parents and guardians had heard anti-immigrant statements from the former U.S. president and most (94% ULF, 90% LCF, 86% NLF) believed these measures against immigrants were being enacted or will be enacted. More ULF (75%, 95% confidence interval [CI] 67-81%) reported that these statements made them concerned about their child's safety in the United States compared with 36% (95% CI 28-45%) and 34% (95% CI 26-43%) of LCF and NLF, respectively. More ULF 17% (95% CI 11-24%) said that these statements made them afraid to bring their child for medical care, compared with 5% (95% CI 2-10%) and 3% (95% CI 1-7%) of LCF and NLF, respectively. CONCLUSIONS: Most parents heard statements against undocumented immigrants by the former U.S. president and most believed measures were being enacted. This rhetoric had a substantial negative impact on ULF parents in terms of safety concerns for their child and fear of accessing health care.

Genotype-phenotype correlations in hypertrophic cardiomyopathy: a multicenter study in Portugal and Spain of the TPM1 p.Arg21Leu variant.

INTRODUCTION AND OBJECTIVES: TPM1 is one of the main hypertrophic cardiomyopathy (HCM) genes. Clinical information on carriers is relatively scarce, limiting the interpretation of genetic findings in individual patients. Our aim was to establish genotype-phenotype correlations of the TPM1 p.Arg21Leu variant in a serie of pedigrees. METHODS: TPM1 was evaluated by next-generation sequencing in 10 561 unrelated probands with inherited heart diseases. Familial genetic screening was performed by the Sanger method. We analyzed TPM1 p.Arg21Leu pedigrees for cosegregation, clinical characteristics, and outcomes. We also estimated the geographical distribution of the carrier families in Portugal and Spain. RESULTS: The TPM1 p.Arg21Leu variant was identified in 25/4099 (0.61%) HCM-cases, and was absent in 6462 control individuals with other inherited cardiac phenotypes (P<.0001). In total, 83 carriers (31 probands) were identified. The combined LOD score for familial cosegregation was 3.95. The cumulative probability of diagnosis in carriers was 50% at the age of 50 years for males, and was 25% in female carriers. At the age of 70 years, 17% of males and 46% of female carriers were unaffected. Mean maximal left ventricular wall thickness was 21.4 ±7.65mm. Calculated HCM sudden death risk was low in 34 carriers (77.5%), intermediated in 8 (18%), and high in only 2 (4.5%). Survival free of cardiovascular death or heart transplant was 87.5% at 50 years. Six percent of carriers were homozygous and 18% had an additional variant. Family origin was concentrated in Galicia, Extremadura, and northern Portugal, suggesting a founder effect. CONCLUSIONS: TPM1 p.Arg21Leu is a pathogenic HCM variant associated with late-onset/incomplete penetrance and a generally favorable prognosis.

Alpha-protein kinase 3 (ALPK3) truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy.

AIMS: The aim of this study was to determine the frequency of heterozygous truncating ALPK3 variants (ALPK3tv) in patients with hypertrophic cardiomyopathy (HCM) and confirm their pathogenicity using burden testing in independent cohorts and family co-segregation studies. METHODS AND RESULTS: In a discovery cohort of 770 index patients with HCM, 12 (1.56%) were heterozygous for ALPK3tv [odds ratio(OR) 16.11, 95% confidence interval (CI) 7.94-30.02, P = 8.05e-11] compared to the Genome Aggregation Database (gnomAD) population. In a validation cohort of 2047 HCM probands, 32 (1.56%) carried heterozygous ALPK3tv (OR 16.17, 95% CI 10.31-24.87, P < 2.2e-16, compared to gnomAD). Combined logarithm of odds score in seven families with ALPK3tv was 2.99. In comparison with a cohort of genotyped patients with HCM (n = 1679) with and without pathogenic sarcomere gene variants (SP+ and SP-), ALPK3tv carriers had a higher prevalence of apical/concentric patterns of hypertrophy (60%, P < 0.001) and of a short PR interval (10%, P = 0.009). Age at diagnosis and maximum left ventricular wall thickness were similar to SP- and left ventricular systolic impairment (6%) and non-sustained ventricular tachycardia (31%) at baseline similar to SP+. After 5.3 ± 5.7 years, 4 (9%) patients with ALPK3tv died of heart failure or had cardiac transplantation (log-rank P = 0.012 vs. SP- and P = 0.425 vs. SP+). Imaging and histopathology showed extensive myocardial fibrosis and myocyte vacuolation. CONCLUSIONS: Heterozygous ALPK3tv are pathogenic and segregate with a characteristic HCM phenotype.

Very Low Prevalence and Incidence of Atrial Fibrillation among Bolivian Forager-Farmers.

Background: Atrial fibrillation is the most common arrhythmia in post-industrialized populations. Older age, hypertension, obesity, chronic inflammation, and diabetes are significant atrial fibrillation risk factors, suggesting that modern urban environments may promote atrial fibrillation. Objective: Here we assess atrial fibrillation prevalence and incidence among tropical horticulturalists of the Bolivian Amazon with high levels of physical activity, a lean diet, and minimal coronary atherosclerosis, but also high infectious disease burden and associated inflammation. Methods: Between 2005-2019, 1314 Tsimane aged 40-94 years (52% female) and 534 Moseten Amerindians aged 40-89 years (50% female) underwent resting 12-lead electrocardiograms to assess atrial fibrillation prevalence. For atrial fibrillation incidence assessment, 1059 (81% of original sample) Tsimane and 310 Moseten (58%) underwent additional ECGs (mean time to follow up 7.0, 1.8 years, respectively). Findings: Only one (male) of 1314 Tsimane (0.076%) and one (male) of 534 Moseten (0.187%) demonstrated atrial fibrillation at baseline. There was one new (female) Tsimane case in 7395 risk years for the 1059 participants with >1 ECG (incidence rate = 0.14 per 1,000 risk years). No new cases were detected among Moseten, based on 542 risk years. Conclusion: Tsimane and Moseten show the lowest levels of atrial fibrillation ever reported, 1/20 to ~1/6 of rates in high-income countries. These findings provide additional evidence that a subsistence lifestyle with high levels of physical activity, and a diet low in processed carbohydrates and fat is cardioprotective, despite frequent infection-induced inflammation. Findings suggest that atrial fibrillation is a modifiable lifestyle disease rather than an inevitable feature of cardiovascular aging.