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A variety of putative virulence genes in Aeromonas hydrophila PPD134/9 were identified by analyzing both genomic subtraction and markers of genomic islands (GIs). It demonstrated that virulence in Aeromonas hydrophila is complex and involves multiple virulence factors which work in concerted nature of pathogenicity.

Background: Genetic disease has recently emerged as a cause of cardiac conduction disorders (CCDs), but the diagnostic yield of genetic testing and the contribution of the different genes to CCD is still unsettled., Objectives: This study sought to determine the diagnostic yield of genetic testing in young adults with CCD of unknown etiology requiring pacemaker implantation. We also studied the prevalence of rare protein-altering variants across individual genes and functional gene groups., Methods: We performed whole exome sequencing in 150 patients with CCD of unknown etiology who had permanent pacemaker implanted at age ≤60 years at 14 Spanish hospitals. Prevalence of rare protein-altering variants in patients with CCD was compared with a reference population of 115,522 individuals from gnomAD database (control subjects)., Results: Among 39 prioritized genes, patients with CCD had more rare protein-altering variants than control subjects (OR: 2.39; 95% CI: 1.75-3.33). Significant enrichment of rare variants in patients with CCD was observed in all functional gene groups except in the desmosomal genes group. Rare variants in the nuclear envelope genes group exhibited the strongest association with CCD (OR: 6.77; 95% CI: 3.71-13.87). Of note, rare variants in sarcomeric genes were also enriched (OR: 1.73; 95% CI: 1.05-3.10). An actionable genetic variant was detected in 21 patients (14%), with LMNA being the most frequently involved gene (4.6%)., Conclusions: Unrecognized rare genetic variants increase the risk of CCD in young adults with CCD of unknown etiology. Genetic testing should be performed in patients age ≤60 years with CCD of unknown etiology. The role of genetic variants in sarcomeric genes as a cause of CCD should be further investigated., Competing Interests: Funding Support and Author Disclosures This study has been funded by Instituto de Salud Carlos III (ISCIII) through the projects "PI17/01941 and PI20/01379” (cofunded by European Regional Development Fund/European Social Fund "A way to make Europe"/"Investing in your future"). The CNIC is supported by the ISCIII, MCIN, the Pro-CNIC Foundation, and the Severo Ochoa Centers of Excellence program (CEX2020-001041-S). The Hospital Universitario Puerta de Hierro, the Hospital Gregorio Marañón, and the Vall Hebron Hospital are members of the European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart: ERN GUARD-Heart. Dr Ochoa is employee of Health in Code. Dr Braza-Boïls is supported by Marató TV3 (736/C/2020) and Health Research Institute La Fe. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Transthyretin cardiac amyloidosis (ATTR-CA) is characterised by the deposition of transthyretin amyloid fibrils in the heart. ATTR-CA affects both men and women although there is evidence of sex differences in prevalence and clinical presentation. PURPOSE OF REVIEW: This review paper aims to comprehensively examine and synthesise the existing literature on sex differences in ATTR-CA. RECENT FINDINGS: The prevalence of ATTR-CA is higher in males although the male predominance is more apparent in older patients in the wild type form and in TTR genetic variants that predominantly result in a cardiac phenotype in the hereditary variant. Women tend to have less left ventricular hypertrophy (LVH) and a higher ejection fraction at clinical presentation which may contribute to a later diagnosis although the prognosis appears to be similar in both sexes. Female sex is a predictor of a good response to tafamidis 20 mg in TTR polyneuropathy but otherwise there are no data on sex differences in the efficacy of other treatments for ATTR-CA. It is crucial to define specific sex differences in ATTR-CA. A lower cut-off value for LVH in women may be needed to improve diagnosis. It is necessary to increase female representation in clinical trials to better understand possible sex differences in therapeutic management., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Biallelic variants in PPA2 gene cause a rare but lethal mitochondrial disorder. We describe the first four cases reported in Spain of PPA2 disease in two unrelated families. We have conducted a revision of the clinical history, necropsies, and postmortem genetic testing from probands, and clinical evaluation, genetic testing and blood transcript analysis in family members. All the cases harbored biallelic PPA2 variants in compound heterozygous status. Two brothers from family 1 suffered sudden death after a small first intake of alcohol in 2013 and 2022. The sister remains alive but affected with cardiomyopathy, extensive scar on cardiac imaging, and high sensitivity to alcohol intake. The three siblings carried PPA2 c.290A > G (p.Glu97Gly) novel missense variant and PPA2 c.513C > T (p.Cys171 = ) altering splicing site variant, both probably leading to mRNA degradation based on in-silico and transcript analyses. A teenager from family 2 suffered sudden death after a small intake of alcohol in 2018 and carried PPA2 c.683C > T (p.Pro228Leu) missense and PPA2 c.980_983del (p.Gln327fs) novel frameshift variant, both probably leading to abnormal protein structure. All cases were asymptomatic until adolescence. Furthermore, the sister in family 1 has survived as an asymptomatic adult. PPA2 disease can manifest as cardiac arrest in the young, especially after alcohol exposure. Our results show that PPA2 deficiency can be related to different pathogenicity mechanisms such as abnormal protein structure but also mRNA decay caused by synonymous or missense variants. Strict avoidance of alcohol consumption and early defibrillator implantation might prevent lethal arrhythmias in patients at risk., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Disease penetrance in genotype-positive (G+) relatives of families with dilated cardiomyopathy (DCM) and the characteristics associated with DCM onset in these individuals are unknown., Objectives: This study sought to determine the penetrance of new DCM diagnosis in G+ relatives and to identify factors associated with DCM development., Methods: The authors evaluated 779 G+ patients (age 35.8 ± 17.3 years; 459 [59%] females; 367 [47%] with variants in TTN) without DCM followed at 25 Spanish centers., Results: After a median follow-up of 37.1 months (Q1-Q3: 16.3-63.8 months), 85 individuals (10.9%) developed DCM (incidence rate of 2.9 per 100 person-years; 95% CI: 2.3-3.5 per 100 person-years). DCM penetrance and age at DCM onset was different according to underlying gene group (log-rank P = 0.015 and P <0.01, respectively). In a multivariable model excluding CMR parameters, independent predictors of DCM development were: older age (HR per 1-year increase: 1.02; 95% CI: 1.0-1.04), an abnormal electrocardiogram (HR: 2.13; 95% CI: 1.38-3.29); presence of variants in motor sarcomeric genes (HR: 1.92; 95% CI: 1.05-3.50); lower left ventricular ejection fraction (HR per 1% increase: 0.86; 95% CI: 0.82-0.90) and larger left ventricular end-diastolic diameter (HR per 1-mm increase: 1.10; 95% CI: 1.06-1.13). Multivariable analysis in individuals with cardiac magnetic resonance and late gadolinium enhancement assessment (n = 360, 45%) identified late gadolinium enhancement as an additional independent predictor of DCM development (HR: 2.52; 95% CI: 1.43-4.45)., Conclusions: Following a first negative screening, approximately 11% of G+ relatives developed DCM during a median follow-up of 3 years. Older age, an abnormal electrocardiogram, lower left ventricular ejection fraction, increased left ventricular end-diastolic diameter, motor sarcomeric genetic variants, and late gadolinium enhancement are associated with a higher risk of developing DCM., Competing Interests: Funding Support and Author Disclosures This study was funded by the Spanish Society of Cardiology (Grant in Inherited Cardiac Diseases 2022) and the Instituto de Salud Carlos III through the projects “PI18/0004, PI20/0320” (Co-funded by European Regional Development Fund/European Social Fund “A way to make Europe”/“Investing in your future”). The CNIC is supported by the ISCIII, MCIN, the Pro-CNIC Foundation, and the Severo Ochoa Centers of Excellence program (CEX2020-001041-S). The Hospital Universitario Puerta de Hierro, Hospital Clínic, Hospital Vall Hebron, Hospital Virgen del Rocío, Hospital Universitario Gregorio Marañon, and the Hospital Universitario Virgen de la Arrixaca are members of the European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart: ERN GUARD-Heart. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Pseudomonas aeruginosa is a Gram-negative bacillus that causes superficial and deep infections, which can be minor to life-threatening. Recently, P. aeruginosa has gained significant relevance due to the increased incidence of multidrug-resistant (MDR) strains that complicate antibiotic treatment. Due to MDR strains, alternative therapies, such as antimicrobial photodynamic therapy (PDT), are presented as a good option to treat nonsystemic infections. PDT combines a photosensitizer agent (PS), light, and oxygen to generate free radicals that destroy bacterial structures such as the envelope, matrix, and genetic material. This work aimed to identify the development stage of the PDT applied to P. aeruginosa to conclude which research stage should be emphasized more., Methods: Systematic bibliographic search in various public databases was performed. Related articles were identified using keywords, and relevant ones were selected using inclusion and exclusion criteria according to the PRISMA protocol., Results: We found 29 articles that meet the criteria, constituting a good body of evidence associated with using PDT against P. aeruginosa in vitro and less developed for in vivo research., Conclusions: We conclude that PDT could become an effective adjunct to antimicrobial therapy against P. aeruginosa. This effectiveness depends on the PS used and the location of the infection. Many PS already demonstrated efficacy in PDT, but the evidence is supported significantly by in vitro and very few in vivo studies. Therefore, we conclude that further research efforts should focus on demonstrating the safety and efficacy of these PSs in vivo in animal infection models., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Black patients have higher rates of stroke than White patients. Paradoxically, atrial fibrillation (AF) affects twice as many White patients compared with Black patients. Transthyretin cardiac amyloidosis (ATTR-CA) is associated with both AF and strokes. We hypothesized that although Black patients with ATTR-CA have a lower incidence of AF, when diagnosed with AF, they have increased thromboembolic events. Patients with ATTR-CA (n = 558) at 3 international centers were retrospectively identified. We compared baseline characteristics, presence of AF, outcomes of thromboembolism (stroke, transient ischemic attack, and peripheral embolism), major bleed, and mortality by race. Of all patients, 367 of 488 White patients (75%) were diagnosed with AF compared with 39 of 70 Black patients (56%) (p = 0.001). Black patients with AF had a hazard ratio of 5.78 (95% confidence interval 2.30 to 14.50) for time to first thromboembolic event compared with White patients. There were no racial differences in major bleeding. Black patients with AF more often lacked anticoagulation (p = 0.038) and had higher incidence of labile international normalized ratio (p <0.001). In conclusion, these data suggest that although Black patients with ATTR-CA have lower incidence of AF, they have increased thromboembolic events compared with White patients. These findings may be related to treatment discrepancies, time in therapeutic range for warfarin, and disparities in healthcare., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Transthyretin amyloid cardiomyopathy (ATTR-CM) is increasingly recognized as a treatable cause of heart failure (HF). Advances in diagnosis and therapy have increased the number of patients diagnosed at early stages, but prognostic data on patients without HF symptoms are lacking. Moreover, it is unknown whether asymptomatic patients benefit from early initiation of transthyretin (TTR) stabilizers., Objectives: The aim of this study was to describe the natural history and prognosis of ATTR-CM in patients without HF symptoms., Methods: Clinical characteristics and outcomes of patients with ATTR-CM without HF symptoms were retrospectively collected at 6 international amyloidosis centers., Results: A total of 118 patients (78.8% men, median age 66 years [IQR: 53.8-75 years], 68 [57.6%] with variant transthyretin amyloidosis, mean left ventricular ejection fraction 60.5% ± 9.9%, mean left ventricular wall thickness 15.4 ± 3.1 mm, and 53 [45%] treated with TTR stabilizers at baseline or during follow-up) were included. During a median follow-up period of 3.7 years (IQR: 1-6 years), 38 patients developed HF symptoms (23 New York Heart Association functional class II and 14 functional class III or IV), 32 died, and 2 required cardiac transplantation. Additionally, 20 patients received pacemakers, 13 developed AF, and 1 had a stroke. Overall survival was 96.5% (95% CI: 91%-99%), 90.4% (95% CI: 82%-95%), and 82% (95% CI: 71%-89%) at 1, 3, and 5 years, respectively. Treatment with TTR stabilizers was associated with improved survival (HR: 0.31; 95% CI: 0.12-0.82; P  = 0.019) and remained significant after adjusting for sex, age, ATTR-CM type, and estimated glomerular filtration rate (HR: 0.18; 95% CI: 0.06-0.55; P  = 0.002)., Conclusions: After a median follow-up period of 3.7 years, 1 in 3 patients with asymptomatic ATTR-CM developed HF symptoms, and nearly as many died or required cardiac transplantation. Treatment with TTR stabilizers was associated with improved prognosis., Competing Interests: This work was supported by grants from Instituto de Salud Carlos III (PI18/0765 and PI20/01379). Dr Gonzalez-Lopez has received speaker fees from Pfizer and Alnylam; has received consulting fees from Pfizer and Proclara; and has received research and educational support to her institution from Pfizer, BridgeBio, and Alnylam. Dr Obici has received speaker and consulting fees from Pfizer, Alnylam, and Akcea. Dr AbouEzzeddine has received research grant support from Pfizer. Dr Mussinelli has received speaker fees from Pfizer and Akcea. Dr Dispenzieri has received consulting fees from Janssen and Akcea; and has received research support from Pfizer, Alnylam, Celgene, and Takeda. Dr Perlini has received speaker and consulting fees from Pfizer, Alnylam, and Akcea. Dr Palladini has received speaker fees from Janssen-Cilag, Pfizer, and Siemens; and has participated on an advisory board for Janssen Cilag. Dr Damy has received research grants or consulting fees from Alnylam, Akcea, Pfizer, and Prothena. Dr Grogan has received research grant support and consulting fees to her institution from Alnylam, Eidos, Pfizer, and Prothena. Dr Maurer has received grant support from National Institutes of Health (R01HL139671-01, R21AG058348, and K24AG036778); has received consulting income from Pfizer, GlaxoSmithKline, Eidos, Prothena, Akcea, and Alnylam; and has received clinical trial funding to his institution from Pfizer, Prothena, Eidos, and Alnylam. Dr Garcia-Pavia has received speaker fees from Pfizer, BridgeBio, Alnylam, and Ionis; has received consulting fees from Pfizer, BridgeBio, AstraZeneca, NovoNordisk, Neuroimmune, Alnylam, Alexion, and Attralus; and has received research and educational support to his institution from Pfizer, BridgeBio, and Alnylam. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2022 The Authors.)

Aims: Although systemic embolism is a potential complication in transthyretin amyloid cardiomyopathy (ATTR-CM), data about its incidence and prevalence are scarce. We studied the incidence, prevalence and factors associated with embolic events in ATTR-CM. Additionally, we evaluated embolic events according to the type of oral anticoagulation (OAC) and the performance of the CHA 2 DS 2 -VASc score in this setting., Methods and Results: Clinical characteristics, history of atrial fibrillation (AF) and embolic events were retrospectively collected from ATTR-CM patients evaluated at four international amyloid centres. Overall, 1191 ATTR-CM patients (87% men, median age 77.1 years [interquartile range-IQR 71.4-82], 83% ATTRwt) were studied. A total of 162 (13.6%) have had an embolic event before initial evaluation. Over a median follow-up of 19.9 months (IQR 9.9-35.5), 41 additional patients (3.44%) had an embolic event. Incidence rate (per 100 patient-years) was 0 among patients in sinus rhythm with OAC, 1.3 in sinus rhythm without OAC, 1.7 in AF with OAC, and 4.8 in AF without OAC. CHA 2 DS 2 -VASc did not predict embolic events in patients in sinus rhythm whereas in patients with AF without OAC, only those with a score ≥4 had embolic events. There was no difference in the incidence rate of embolism between patients with AF treated with vitamin K antagonists (VKAs) (n = 322) and those treated with direct oral anticoagulants (DOACs) (n = 239) (p = 0.66)., Conclusions: Embolic events were a frequent complication in ATTR-CM. OAC reduced the risk of systemic embolism. Embolic rates did not differ with VKAs and DOACs. The CHA 2 DS 2 -VASc score did not correlate well with clinical outcome in ATTR-CM and should not be used to assess thromboembolic risk in this population., (© 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Hereditary Hemorrhagic Telangiectasia (HHT) is a rare disorder of vascular development. Common manifestations include epistaxis, telangiectasias and arteriovenous malformations in multiple organs. Different deletions or nonsense mutations have been described in the ENG (HHT1) or ACVRL1/ALK1 (HHT2) genes, all affecting endothelial homeostasis. A novel mutation in ACVRL1/ALK1 has been identified in a Peruvian family with a clinical history compatible to HHT. Subsequently, 23 DNA samples from oral exchanges (buccal swaps) of the immediate family members were analyzed together with their clinical histories. A routine cDNA PCR followed by comparative DNA sequencing between the founder and another healthy family member showed the presence of the aforementioned specific mutation. The single mutation detected (c.525 + 1G > T) affects the consensus splice junction immediately after exon 4, provokes anomalous splicing and leads to the inclusion of intron IV between exons 4 and 5 in the ACVRL1/ALK1 mRNA and, therefore, to ALK1 haploinsufficiency. Complete sequencing determined that 10 of the 25 family members analyzed were affected by the same mutation. Notably, the approach described in this report could be used as a diagnostic technique, easily incorporated in clinical practice in developing countries and easily extrapolated to other patients carrying such a mutation.

Objectives: This study aims to investigate the prognostic significance of late gadolinium enhancement (LGE) in patients without coronary artery disease and with normal range left ventricular (LV) volumes and ejection fraction., Background: Nonischemic patterns of LGE with normal LV volumes and ejection fraction are increasingly detected on cardiovascular magnetic resonance, but their prognostic significance, and consequently management, is uncertain., Methods: Patients with midwall/subepicardial LGE and normal LV volumes, wall thickness, and ejection fraction on cardiovascular magnetic resonance were enrolled and compared to a control group without LGE. The primary outcome was actual or aborted sudden cardiac death (SCD)., Results: Of 748 patients enrolled, 401 had LGE and 347 did not. The median age was 50 years (interquartile range: 38-61 years), LV ejection fraction 66% (interquartile range: 62%-70%), and 287 (38%) were women. Scan indications included chest pain (40%), palpitation (33%) and breathlessness (13%). No patient experienced SCD and only 1 LGE+ patient (0.13%) had an aborted SCD in the 11th follow-up year. Over a median of 4.3 years, 30 patients (4.0%) died. All-cause mortality was similar for LGE+/- patients (3.7% vs 4.3%; P = 0.71) and was associated with age (HR: 2.04 per 10 years; 95% CI: 1.46-2.79; P < 0.001). Twenty-one LGE+ and 4 LGE- patients had an unplanned cardiovascular hospital admission (HR: 7.22; 95% CI: 4.26-21.17; P < 0.0001)., Conclusions: There was a low SCD risk during long-term follow-up in patients with LGE but otherwise normal LV volumes and ejection fraction. Mortality was driven by age and not LGE presence, location, or extent, although the latter was associated with greater cardiovascular hospitalization for suspected myocarditis and symptomatic ventricular tachycardia., Competing Interests: Funding Support and Author Disclosures Supported by the Cardiovascular Research Centre at Royal Brompton and Harefield NHS Foundation Trust, the National Heart and Lung Institute, Imperial College London, the Alexander Jansons Myocarditis UK and the Wellcome Trust. Dr Lota was funded by a British Heart Foundation Clinical Research Training Fellowship (FS/17/21/32712). Dr Prasad has received funding from the Alexander Jansons Myocarditis UK, Rosetree Trust, British Heart Foundation, the Medical Research Council and the Coronary Artery Disease Research Association; and has received honoraria for talks from Bayer Schering. Dr Pennell has received research support from Siemens, has performed consultancy work for Bayer and Apotex and is a stockholder of CVIS. Dr Cleland has received non-financial research support from BSCI and Medtronic and speaker honoraria from Medtronic. Dr Cook is a consultant for Illumina and a shareholder in Enleofen Bio. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: One of the challenges in hypertrophic cardiomyopathy (HCM) is to determine the pathogenicity of genetic variants and to establish genotype/phenotype correlations. This study aimed to: (1) demonstrate that MYBPC3 c.2149-1G>A is a founder pathogenic variant, (2) describe the phenotype and clinical characteristics of mutation carriers and (3) compare these patients with those with the most frequent pathogenic HCM variants: MYBPC3 p.Arg502Trp/Gln., Methods: We reviewed genetic tests performed in HCM probands at our institution. We carried out transcript analyses to demonstrate the splicing effect, and haplotype analyses to support the founder effect of MYBPC3 c.2149-1G>A. Carriers with this mutation were compared with those from MYBPC3 p.Arg502Trp/Gln in terms of presentation features, imaging and outcomes., Results: MYBPC3 c.2149-1G>A was identified in 8 of 570 probands and 25 relatives. Penetrance was age and sex dependent, 50.0% of the carriers over age 36 years and 75.0% of the carriers over 40 years showing HCM. Penetrance was significantly higher in males: in carriers older than 30 years old, 100.0% of males vs 50.0% of females had a HCM phenotype (p=0.01). Males were also younger at diagnosis (32±13 vs 53±10 years old, p<0.001). MYBPC3 c.2149-1G>A resulted in an abnormal transcript that led to haploinsufficiency and was segregated in two haplotypes. However, both came from one founder haplotype. Affected carriers showed a better functional class and higher left ventricular ejection fraction (LVEF) than patients with MYBPC3 p.Arg502Trp/Gln (p<0.05 for both). Nevertheless, the rate of major adverse outcomes was similar between the two groups., Conclusions: MYBPC3 c.2149-1G>A splicing variant is a founder mutation. Affected males show an early onset of HCM and with higher penetrance than women. Carriers show better functional class and higher LVEF than MYBPC3 p.Arg502Trp/Gln carriers, but a similar rate of major adverse outcomes., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Several pharmacogenetic-based decision support tools for psychoactive medication selection are available. However, the scientific evidence of the gene-drug pairs analyzed is mainly based on pharmacogenetic studies in patients with major depression or schizophrenia, and their clinical utility is mostly assessed in major depression. This study aimed at evaluating the impact of individual genes, with pharmacogenetic relevance in other psychiatric conditions, in the response to treatment in bipolar depression. Seventy-six patients diagnosed with bipolar disorder and an index major depressive episode were included in an observational retrospective study. Sociodemographic and clinical data were collected, and all patients were genotyped using a commercial multigene pharmacogenomic-based tool (Neuropharmagen ® , AB-Biotics S.A., Barcelona, Spain). Multiple linear regression was used to identify pharmacogenetic and clinical predictors of efficacy and tolerability of medications. The pharmacogenetic variables response to serotonin-norepinephrine reuptake inhibitors (SNRIs) ( ABCB1 ) and reduced metabolism of quetiapine ( CYP3A4 ) predicted patient response to these medications, respectively. ABCB1 was also linked to the tolerability of SNRIs. An mTOR-related multigenic predictor was also associated with a lower number of adverse effects when including switch and autolytical ideation. Our results suggest that the predictors identified could be useful to guide the pharmacological treatment in bipolar disorder. Additional clinical studies are necessary to confirm these findings.

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease. Variants in MYBPC3, the gene encoding cardiac myosin-binding protein C (cMyBP-C), are the leading cause of HCM. However, the pathogenicity status of hundreds of MYBPC3 variants found in patients remains unknown, as a consequence of our incomplete understanding of the pathomechanisms triggered by HCM-causing variants. Here, we examined 44 nontruncating MYBPC3 variants that we classified as HCM-linked or nonpathogenic according to cosegregation and population genetics criteria. We found that around half of the HCM-linked variants showed alterations in RNA splicing or protein stability, both of which can lead to cMyBP-C haploinsufficiency. These protein haploinsufficiency drivers associated with HCM pathogenicity with 100% and 94% specificity, respectively. Furthermore, we uncovered that 11% of nontruncating MYBPC3 variants currently classified as of uncertain significance in ClinVar induced one of these molecular phenotypes. Our strategy, which can be applied to other conditions induced by protein loss of function, supports the idea that cMyBP-C haploinsufficiency is a fundamental pathomechanism in HCM., Competing Interests: Conflict of interest L. M. holds share in Health in Code. All other authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Hypertrophic cardiomyopathy (HCM) is a disease of the myocardium caused by mutations in sarcomeric proteins with mechanical roles, such as the molecular motor myosin. Around half of the HCM-causing genetic variants target contraction modulator cardiac myosin-binding protein C (cMyBP-C), although the underlying pathogenic mechanisms remain unclear since many of these mutations cause no alterations in protein structure and stability. As an alternative pathomechanism, here we have examined whether pathogenic mutations perturb the nanomechanics of cMyBP-C, which would compromise its modulatory mechanical tethers across sliding actomyosin filaments. Using single-molecule atomic force spectroscopy, we have quantified mechanical folding and unfolding transitions in cMyBP-C domains targeted by HCM mutations that do not induce RNA splicing alterations or protein thermodynamic destabilization. Our results show that domains containing mutation R495W are mechanically weaker than wild-type at forces below 40 pN and that R502Q mutant domains fold faster than wild-type. None of these alterations are found in control, nonpathogenic variants, suggesting that nanomechanical phenotypes induced by pathogenic cMyBP-C mutations contribute to HCM development. We propose that mutation-induced nanomechanical alterations may be common in mechanical proteins involved in human pathologies.

Farmers are among the most vulnerable populations because of the exposure to low levels of pesticides. Acetylcholinesterase and butyrylcholinesterase activities are considered as biomarkers of pesticides poisoning. However, biomarkers of oxidative stress are also playing an important role in toxicity of these contaminants. Further, increased activities of gamma-glutamyltransferase, alanine aminotransferase, urea and creatinine have been linked with hepatic and nephrotoxic cell damage, respectively. The aim of this study was to ascertain if the indirect exposure to pesticides leads to some biochemical parameter changes. Thus, cholinesterase activities, oxidative stress status (lipid and protein oxidation), hepatic function (AST and ALT levels), hormonal function (TSH, T4, FSH, LH and AMH), renal function (serum creatinine and urea), as well as possible subclinical kidney damage (urinary proteins and biomarkers of early kidney damage) were evaluated in farmer women who collect fruits and vegetables comparing with a group of women non-occupational exposed to pesticides but living in the same rural environment. Samples were taken periodically along one year to relate the observed effects to a chronic exposure. Our main results showed for the first time a subclinical kidney damage in a rural setting with indirect chronic exposure to pesticides.

Introduction and Objectives: Infective endocarditis (IE) is a complex disease with high in-hospital mortality. Prognostic assessment is essential to select the most appropriate therapeutic approach; however, international IE guidelines do not provide objective assessment of the individual risk in each patient. We aimed to design a predictive model of in-hospital mortality in left-sided IE combining the prognostic variables proposed by the European guidelines., Methods: Two prospective cohorts of consecutive patients with left-sided IE were used. Cohort 1 (n=1002) was randomized in a 2:1 ratio to obtain 2 samples: an adjustment sample to derive the model (n=688), and a validation sample for internal validation (n=314). Cohort 2 (n=133) was used for external validation., Results: The model included age, prosthetic valve IE, comorbidities, heart failure, renal failure, septic shock, Staphylococcus aureus, fungi, periannular complications, ventricular dysfunction, and vegetations as independent predictors of in-hospital mortality. The model showed good discrimination (area under the ROC curve=0.855; 95%CI, 0.825-0.885) and calibration (P value in Hosmer-Lemeshow test=0.409), which were ratified in the internal (area under the ROC curve=0.823; 95%CI, 0.774-0.873) and external validations (area under the ROC curve=0.753; 95%CI, 0.659-0.847). For the internal validation sample (observed mortality: 29.9%) the model predicted an in-hospital mortality of 30.7% (95%CI, 27.7-33.7), and for the external validation cohort (observed mortality: 27.1%) the value was 26.4% (95%CI, 22.2-30.5)., Conclusions: A predictive model of in-hospital mortality in left-sided IE based on the prognostic variables proposed by the European Society of Cardiology IE guidelines has high discriminatory ability., (Copyright © 2019 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.)

We demonstrate a pyrometric contact-less temperature sensor using a flexible fused silica fiber of 360 µm diameter able to measure down to 30°C with a precision better than 1°C at 10 Hz. Silica fibers, as opposed to dedicated mid-IR fibers, are non-degrading, low-cost, and bio-compatible. The large bandwidth (up to several kilohertz) and the broad temperature range (up to 235°C) of the sensor can be instrumental for time-resolved analysis and control of laser ablation and electrothermal surgery procedures.

Electrosurgery with argon plasma coagulation is a widespread technique used in various medical fields for applications which range from hemostasis to devitalization processes. Developing tools which provide feedback concerning tissue condition during these surgeries is fundamental for improving the safety and success of this treatment. We present here a method based on diffuse reflectance spectroscopy to monitor gastric mucosal devitalization treatments. The analysis of the diffusely reflected spectra of the tissue allows us to differentiate between ablation states by using linear discriminant analysis (LDA) as a classification algorithm. An ex vivo pilot study on several swine stomachs showed promising results, with 97.8% of correctly classified ablation states on a new unseen stomach, encouraging further tests with human tissue., (© 2019 The Authors. Journal of Biophotonics published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Local governments play an integral role in providing public services to their residents, yet the population health benefits are frequently overlooked, especially when services are outside the traditional health domain. With data from the U.S. Census of Governments and national birth records (spanning from 1992 to 2014), we examined whether local government expenditures on parks and recreation services (PRS) and housing and community development (HCD) predicted county low birth weight outcomes (population incidence and black-white disparities). Hypotheses were tested using bias-corrected county-by-period fixed effects models in a sample of 956 U.S. counties with a total of 3619 observations (observations were defined as three-year pooled estimates), representing 24 million births. Adjusting for prior county low birth weight incidence, levels of total operational, health, and hospital expenditures, and time-varying county sociodemographics, an increase in per capita county PRS expenditures of $50 was associated with 1.25 fewer low birth weight cases per 1000. Change in county HCD expenditures was not associated with low birth weight incidence, and, contrary to hypotheses, neither expenditure type was linked to county black-white disparities. Further examination of the benefits to birth outcomes from increasing parks and recreation services is warranted., Competing Interests: None.

Reelin is an extracellular glycoprotein involved in key cellular processes in developing and adult nervous system, including regulation of neuronal migration, synapse formation, and plasticity. Most of these roles are mediated by the intracellular phosphorylation of disabled-1 (Dab1), an intracellular adaptor molecule, in turn mediated by binding Reelin to its receptors. Altered expression and glycosylation patterns of Reelin in cerebrospinal and cortical extracts have been reported in Alzheimer's disease. However, putative changes in Reelin are not described in natural prionopathies or experimental models of prion infection or toxicity. With this is mind, in the present study, we determined that Reelin protein and mRNA levels increased in CJD human samples and in mouse models of human prion disease in contrast to murine models of prion infection. However, changes in Reelin expression appeared only at late terminal stages of the disease, which prevent their use as an efficient diagnostic biomarker. In addition, increased Reelin in CJD and in in vitro models does not correlate with Dab1 phosphorylation, indicating failure in its intracellular signaling. Overall, these findings widen our understanding of the putative changes of Reelin in neurodegeneration.