Clinical Management Of Individuals Research Articles

Exercise stress echocardiography detects patients with paroxysmal/persistent atrial fibrillation

Abstract Background Atrial fibrillation (AF) is the most prevalent atrial tachyarrhythmia, affecting an estimated 2-4% of adults worldwide. AF is a well-recognized and treatable risk factor for stroke, but it often remains asymptomatic or subclinical, leading to underdiagnosis. This study aimed to identify distinguishing signs during exercise stress echocardiography (ESE) among patients in sinus rhythm (SR), with and without history of paroxysmal/persistent AF (PAF). Methods An international prospective cohort comprising 1035 consecutive patients was initially considered from 12 cardiology institutions. These patients were referred for clinically-driven ESE as part of the Stress Echo 2020-2030 study network. All patients underwent comprehensive ESE with the ABCDE protocol, which included assessment of B-lines, left ventricle contractile reserve (LVCR), ECG-based heart rate reserve (HRR), LV ejection fraction (EF), LV end-diastolic volume, E/e’, pulmonary artery systolic pressure estimation, tricuspid annular plane sytolic excursion (TAPSE), left atrium volume index (LAVi) and left atrium reservoir phase strain (LASr) at rest and with exercise. Results After excluding 89 patients who were in AF during the ESE, 946 patients in SR were included as the main study cohort (101 with and 845 without a history of PAF). A scoring system was then constructed using all independent variables that differentiate the two groups (those with and without history of PAF). Presence of systemic hypertension, rest LAVI>31ml/m2, rest |LASr|< 21%, stress LAVI >29 ml/m2, stress |LASr| <24%, stress E/e’ >7, ∆TAPSE <4.5 mm, HRR<1.87, and LVCR<1.6 were identified as the discriminators between patients with and without PAF. The composite score, summing all 9 items (with a total score range from 0 to 9), yielded a score of >4 as the best balance between sensitivity (87%) and specificity (60%) in predicting those with PAF. The receiver operating characteristic curve analysis of the scoring model showed an AUC of 0.79 (p-value <0.0001), Figure. Conclusion ESE evaluation can be a valuable adjunct for identifying patients in SR with history of PAF. This multifaceted approach enhances the potential for more accurate detection and clinical management of individuals in SR at risk for AF, who could be considered for aggressive monitoring programs to prevent the development of new onset AF and subsequent increase in cardiovascular risk.

Phenotype-driven genomics enhance diagnosis in children with unresolved neuromuscular diseases.

Establishing a molecular diagnosis remains challenging in half of individuals with childhood-onset neuromuscular diseases (NMDs) despite exome sequencing. This study evaluates the diagnostic utility of combining genomic approaches in undiagnosed NMD patients. We performed deep phenotyping of 58 individuals with unsolved childhood-onset NMDs that have previously undergone inconclusive exome studies. Genomic approaches included trio genome sequencing and RNASeq. Genetic diagnoses were reached in 23 out of 58 individuals (40%). Twenty-one individuals carried causal single nucleotide variants (SNVs) or small insertions and deletions, while 2 carried pathogenic structural variants (SVs). Genomic sequencing identified pathogenic variants in coding regions or at the splice site in 17 out of 21 resolved cases, while RNA sequencing was additionally required for the diagnosis of 4 cases. Reasons for previous diagnostic failures included low coverage in exonic regions harboring the second pathogenic variant and involvement of genes that were not yet linked to human diseases at the time of the first NGS analysis. In summary, our systematic genetic analysis, integrating deep phenotyping, trio genome sequencing and RNASeq, proved effective in diagnosing unsolved childhood-onset NMDs. This approach holds promise for similar cohorts, offering potential improvements in diagnostic rates and clinical management of individuals with NMDs.

Sex Differences in Personality Disorder and Childhood Maltreatment of Patients with Schizophrenia.

Despite numerous studies investigating personality disorder (PD) and childhood maltreatment (CM) characteristics in individuals with schizophrenia (SZ), there remains a scarcity of research focusing on sex differences in PD and CM within large samples of SZ patients. A total of 592 participants (257 males, 335 females) were consecutively sampled from patients diagnosed with SZ at the psychiatric and psycho-counseling clinics at Shanghai Mental Health Center. PDs were assessed using a self-reported personality diagnostic questionnaire and a structured clinical interview, while CMs were evaluated using the Chinese version of the Child Trauma Questionnaire Short Form. Male patients exhibited a prominent self-reported trait of antisocial PD (t=1.972, p=0.049), while female patients demonstrated a notable emphasis on histrionic PD traits (t=-2.057, p=0.040). Structured interviews for PD diagnoses further indicated a higher comorbidity of schizotypal (χ2=4.805, p=0.028) and schizoid (χ2=6.957, p=0.008) PDs among male patients compared to female patients. Additionally, male patients reported a higher degree (t=2.957, p=0.003) and proportion (χ2=5.277, p=0.022) of experiences of physical abuse in their self-reported CM. Logistic regression analyses highlight distinct factors: higher antisocial PD traits and physical abuse are associated with male patients, while histrionic PD traits and emotional abuse are associated with female patients. These findings underscore the importance of recognizing and addressing sex-specific manifestations of personality pathology and the nuanced impact of CM in the clinical management of individuals with SZ. The study advocates for tailored interventions that consider the distinct needs associated with sex differences in both personality traits and CM experiences among SZ patients.

Machine learning models reveal distinct disease subgroups and improve diagnostic and prognostic accuracy for individuals with pathogenic SCN8A gain-of-function variants.

Distinguishing clinical subgroups for patients suffering with diseases characterized by a wide phenotypic spectrum is essential for developing precision therapies. Patients with gain-of-function (GOF) variants in the SCN8A gene exhibit substantial clinical heterogeneity, viewed historically as a linear spectrum ranging from mild to severe. To test for hidden clinical subgroups, we applied two machine-learning algorithms to analyze a dataset of patient features collected by the International SCN8A Patient Registry. We used two research methodologies: a supervised approach that incorporated feature severity cutoffs based on clinical conventions, and an unsupervised approach employing an entirely data-driven strategy. Both approaches found statistical support for three distinct subgroups and were validated by correlation analyses using external variables. However, distinguishing features of the three subgroups within each approach were not concordant, suggesting a more complex phenotypic landscape. The unsupervised approach yielded strong support for a model involving three partially ordered subgroups rather than a linear spectrum. Application of these machine-learning approaches may lead to improved prognosis and clinical management of individuals with SCN8A GOF variants and provide insights into the underlying mechanisms of the disease.

Observing Extracellular Vesicles Originating from Endothelial Cells in Vivo Demonstrates Improved Astrocyte Function Following Ischemic Stroke via Aggregation-Induced Emission Luminogens.

Extracellular vesicles (EVs) obtained from endothelial cells (ECs) have significant therapeutic potential in the clinical management of individuals with ischemic stroke (IS) because they effectively treat ischemic stroke in animal models. However, because molecular probes with both high labeling efficiency and tracer stability are lacking, monitoring the actions of EC-EVs in the brain remains difficult. The specific intracellular targets in the brain that EC-EVs act on to produce their protective effects are still unknown, greatly impeding their use in clinical settings. For this research, we created a probe that possessed aggregation-induced emission (AIE) traits (namely, TTCP), enabling the effective labeling of EC-EVs while preserving their physiological properties. In vitro, TTCP simultaneously had a higher EC-EV labeling efficiency and better tracer stability than the commercial EV tags PKH-67 and DiI. In vivo, TTCP precisely tracked the actions of EC-EVs in a mouse IS model without influencing their protective effects. Furthermore, through the utilization of TTCP, it was determined that astrocytes were the specific cells affected by EC-EVs and that EC-EVs exhibited a safeguarding impact on astrocytes following cerebral ischemia-reperfusion (I/R) injury. These protective effects encompassed the reduction of the inflammatory reaction and apoptosis as well as the enhancement of cell proliferation. Further analysis showed that miRNA-155-5p carried by EC-EVs is responsible for these protective effects via regulation of the c-Fos/AP-1 pathway; this information provided a strategy for IS therapy. In conclusion, TTCP has a high EC-EV labeling efficiency and favorable in vivo tracer stability during IS therapy. Moreover, EC-EVs are absorbed by astrocytes during cerebral I/R injury and promote the restoration of neurological function through the regulation of the c-Fos/AP-1 signaling pathway.

Investigating Adiposity-Related Metabolic Health Phenotypes in Patients with Hidradenitis Suppurativa: A Cross-Sectional Study.

Obesity and hidradenitis suppurativa (HS) are related through meta-inflammation and are both associated with increased cardiometabolic risk. Notwithstanding, cardiometabolic pathology is not uniform in obesity and a subset of individuals with excess adiposity exhibit a healthy metabolic profile. Whilst the incidence of cardiometabolic endpoints and transitions across different adiposity-related body composition phenotypes within several populations and across different ethnicities have been investigated, data regarding metabolic health (MetH) and body composition phenotypes in individuals with HS are lacking. The objective of this study was to evaluate the relationship between different body composition phenotypes in individuals with HS. This was a cross-sectional study of 632 individuals with and without HS from a population with a high prevalence of both obesity and HS. A total of four body composition phenotypes were generated based on BMI and metabolic status (defined using either the metabolic syndrome definition or the homeostasis model of insulin resistance (HOMA-IR)): metabolically healthy overweight/obese (MHOWOB), metabolically unhealthy overweight/obese (MUOWOB), metabolically healthy normal weight (MHNW), and metabolically unhealthy normal weight (MUNW). Generally, subjects with HS exhibited a worse metabolic profile with higher levels of indices of central adiposity measures (including Visceral Adiposity Index and waist circumference), systolic blood pressure and markers of insulin resistance, as well as a higher prevalence of the metabolic syndrome. Moreover, when sub-stratified into the different body composition phenotypes, individuals with HS typically also demonstrated adverse metabolic characteristics relative to controls matched for both adiposity and metabolic health, particularly in the normal weight category and despite being classified as metabolically healthy. Being metabolically unhealthy in addition to being overweight/obese increases an individual's risk of HS. Metabolic risk-assessment should be prioritized in the clinical management of individuals with HS even in those who are lean. Patients attending HS clinics provide a valuable opportunity for targeted cardiovascular risk reduction with respect to the management of both obesity and metabolic health.

Updated protocol for genetic testing, screening and clinical management of individuals at risk of NF2-related schwannomatosis.

Genetic testing and management of individuals at risk for NF2-related schwannomatosis is complicated by the high rate of mosaicism resulting in a milder, later onset, more asymmetrical disease and the phenotypic overlap with the related schwannomatosis conditions. This updated protocol has been devised for the English NF2-related schwannomatosis service. It provides those affected with mosaic NF2-related schwannomatosis estimated risks of having an affected child; and management guidelines both for individuals at risk of NF2-related schwannomatosis, or with potential disease, due to having features that fall short of consensus diagnostic criteria. Risks of mosaicism and inferred transmission risks were derived from genetic testing of over 1000 individuals through the Manchester NF2 genetic testing service. This updated protocol, reflects the lower transmission risks now inferred in mosaic NF2-related schwannomatosis, informed by the greater sensitivity of Next Generation Sequencing in detecting low levels of mosaicism in blood, along with improved ability to analyse tumour DNA. Screening for features of NF2-related schwannomatosis is proposed until the risk of having the condition falls below a pragmatic threshold of 1%. Using these revised transmission figures, this threshold can now be reached at a younger age in many of those at risk, with earlier reassurance and discharge.

Isolated Diastolic Hypertension and Risk of Cardiovascular Disease: Controversies in Hypertension - Pro Side of the Argument.

Isolated diastolic hypertension (IDH), defined as diastolic blood pressure in the hypertensive range but systolic blood pressure not in the hypertensive range, is not uncommon (<20%) among adults with hypertension. IDH often manifests in concurrence with other cardiovascular risk factors. Individuals with IDH tend to have lower awareness of their hypertension compared with those with both systolic and diastolic hypertension. IDH appears to be a largely underrated risk factor for cardiovascular disease events, which may be explained by inconsistent association of IDH with cardiovascular disease events. The inconsistency suggests that IDH is heterogeneous. One size does not seem to fit all in the clinical management of individuals with IDH. Rather than treating IDH as a monolithic low-risk condition, detailed phenotyping in the context of individual comprehensive cardiovascular risk would seem to be most useful to assess an individual's expected net benefit from therapy. In this review, we highlight that the clinical relevance of IDH differs by individual clinical characteristics, and elucidate groups of individuals with IDH that should be wary of cardiovascular disease risks.

Obesity in young women is positively associated with periodontitis.

This cross-sectional study was performed to investigate the association between excess body weight and periodontitis in adults, stratified by sex and age, and using different criteria for obesity. Enrolled in the study were 345 individuals with a minimum age of 18years who had attended the Public Health Service in the city of Salvador, Bahia, Brazil. All individuals underwent a complete periodontal examination and anthropometric measurements and answered a questionnaire regarding their socioeconomic, demographic, health, and lifestyle conditions. Excess body weight (exposure factor) was defined using body mass index (BMI) and waist circumference (WC). Prevalence ratios (PRs) and 95% confidence intervals (95%CI) were obtained by Poisson regression analysis with robust variance. Periodontitis was found in 74.2% of study participants, with the disease being more prevalent among those individuals with increased WC. The occurrence of overweight was 44.4% and that of obesity ranged from 29.9 to 70.8%, dependent upon the specific definition of obesity that was used. There was a positive association between obesity (WC > 88cm) and periodontitis only among women, after adjustment for age, smoking habit, education level, diabetes, and family income (PRadjusted: 1.20; 95%CI: [1.01-1.44]). The magnitude of this positive association was higher among women aged 18 to 49years when the outcome was severe periodontitis, and the exposure was obesity defined by WC. The findings draw attention to the high frequency of the diseases investigated: overweight, obesity and periodontitis. Moreover, obesity was positively associated with periodontitis in women and younger individuals, demonstrating that among those with obesity, there is a higher probability of having periodontitis. The smaller number study of men in the may have influenced the non-statistically significant association found in that group. Obese females and younger people are more likely to also have periodontitis. Periodontal evaluation and clinical management of individuals with obesity is recommended.

Three Novel De Novo ZEB2 Variants Identified in Three Unrelated Chinese Patients With Mowat-Wilson Syndrome and A Systematic Review.

Background: ZEB2 gene mutations or deletions cause Mowat-Wilson syndrome (MWS), which is characterized by distinctive facial features, global developmental delay, intellectual disability, epilepsy, friendly and happy personalities, congenital heart disease, Hirschsprung disease and multiple congenital anomalies. Currently, more than 300 MWS patients have been described in the literature, and nearly 280 variants in ZEB2 have been identified. Methods: In this study, we report three unrelated Chinese patients presenting multiple congenital anomalies that were consistent with those of MWS. Whole-exome sequencing (WES) was used to identify the causative variants. Results: WES identified two novel de novo frameshift variants in ZEB2 (NM_014795.4:c.2136delC, p. Lys713Serfs*3 and c.2740delG, p. Gln914Argfs*16) in patients 1 and 2, respectively, and a novel de novo splicing variant in ZEB2 (NM_014795.4:c.808-2delA) in patient 3, all of which were confirmed by Sanger sequencing. Next, we systematically reviewed the clinical characteristics of Chinese and Caucasian MWS patients. We revealed a higher incidence of constipation in Chinese MWS patients compared to that previously reported in Caucasian cohorts, while the incidence of Hirschsprung disease and happy demeanor was lower in Chinese MWS patients and that epilepsy in Chinese MWS patients could be well-controlled compared to that in Caucasian MWS individuals. Conclusion: Our study expanded the mutation spectrum of ZEB2 and enriched our understanding of the clinical characteristics of MWS. Definitive genetic diagnosis is beneficial for the genetic counseling and clinical management of individuals with MWS.

Strategy lessons from a new clinical trial in psoriatic arthritis.

Treatment guidelines for psoriatic arthritis are limited by a paucity of strategy studies to inform management decisions as well as an absence of consensus on treatment goals. Few studies providing quality data exist to guide advanced therapy (eg, changes in treatment regimen and the use of combination regimens) among individuals for whom initial treatment has been unsuccessful. Clinical management of individuals with psoriatic arthritis is complicated by different treatment guidelines proposed by the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR).

An overview of the trajectory of Brazilian individuals with 22q11.2 deletion syndrome until diagnosis

Background22q11.2 deletion syndrome (22q11.2DS) is a rare disease with an important characteristic—clinical heterogeneity. The diversity of organs, regions, and systems of the body that can be affected requires periodic updating of health professionals so that they can recognize these clinical signs as belonging to 22q11.2DS. Updated professionals are equally important for the appropriate and timely clinical management of individuals with a positive diagnosis. In this context, this article aimed to map and analyze the access to healthcare for individuals with 22q11.2DS until the moment of diagnosis.ResultsWe analyzed the clinical data of 111 individuals with 22q11.2DS registered in the Brazilian Database on Craniofacial Anomalies (BDCA) from 2008 to 2020. In this study, individuals were diagnosed at a median age of 9 years (mean = 9.7 years). Before the genetic investigation, they accessed 68.75% of the internationally recommended evaluations available at BDCA. Recurrent 22q11.2DS clinical manifestations such as delayed neuropsychomotor development, lip and/or palate defects, cardiac malformation and/or hematological/immunological alteration co-occurred in at least 72.06% of individuals. Cardiac malformation was the only clinical alteration that lowered the median diagnostic age, corresponding to 6.5 years of age with a cardiac malformation versus 11 years of age without one (p = 0.0006).ConclusionsIn Brazil, 22q11.2 DS is under-recognized, and early diagnosis and management of affected individuals are still a distant reality. In this sense, 22q11.2 DS suspicion followed by the elimination of obstacles for its diagnosis confirmation is essential to increase life expectancy and improve the quality of life of these individuals in Brazil.

European Medical Education Initiative on Noonan syndrome: A clinical practice survey assessing the diagnosis and clinical management of individuals with Noonan syndrome across Europe

IntroductionNoonan syndrome (NS) is a rare genetic disorder caused by mutations in genes encoding components of the RAS/mitogen-activated protein kinase (MAPK) signalling pathway. Patients with NS exhibit certain characteristic features, including cardiac defects, short stature, distinctive facial appearance, skeletal abnormalities, cognitive deficits, and predisposition to certain cancers. Here, a clinical practice survey was developed to learn more about differences in the diagnosis and management of this disease across Europe. The aim was to identify gaps in the knowledge and management of this rare disorder. Materials and methodsThe European Medical Education Initiative on NS, which comprised a group of 10 experts, developed a 60-question clinical practice survey to gather information from European physicians on the diagnosis and clinical management of patients with diseases in the NS phenotypic spectrum. Physicians from three specialities (clinical genetics, paediatric endocrinology, paediatric cardiology) were invited to complete the survey by several national and European societies. Differences in answers provided by respondents between specialities and countries were analysed using contingency tables and the Chi-Squared test for independence. The Friedman's test was used for related samples. ResultsData were analysed from 364 respondents from 20 European countries. Most respondents came from France (21%), Spain (18%), Germany (16%), Italy (15%), United Kingdom (8%) and the Czech Republic (6%). Respondents were distributed evenly across three specialities: clinical genetics (30%), paediatric endocrinology (40%) and paediatric cardiology (30%). Care practices were generally aligned across the countries participating in the survey. Delayed diagnosis did not emerge as a critical issue, but certain unmet needs were identified, including transition of young patients to adult medical services and awareness of family support groups. ConclusionData collected from this survey provide a comprehensive summary of the diagnosis and clinical management practices for patients with NS across different European countries.

Clinical management of individuals with Intellectual Disability: The outbreak of Covid-19 pandemic as experienced in a clinical and research center Research in Developmental Disabilities

During the COVID-19 pandemic, the Oasi Research Institute of Troina (Italy) became an important hotbed for infection; in fact, 109 patients with different levels of Intellectual Disability (ID) tested positive for COVID-19. The procedures and interventions put in place at the Oasi Research Institute due to the COVID-19 pandemic are exhaustively reported in this paper. The description of the clinical procedures as well as remote/in person psychological support services provided to people with ID and their families are here divided into three different sections: Phase I (or Acute phase), Phase II (or Activity planning), and Phase III (or Activity consolidation). In each section, the main psycho-pathological characteristics of patients, the reactions of family members and the multidisciplinary interventions put in place are also described.

Clinical Characteristics and Pharmacological Treatment of Individuals With and Without Intellectual Disability in Pre-trial Assessment-A Population-Based Study.

Background: The current lack of knowledge about intellectual disability (ID) in forensic psychiatric contexts can compromise the legal certainty of these individuals during the medico-legal process. To address ambiguous results in previous literature, the aim of the current study was to estimate the prevalence of ID in a pre-trial forensic psychiatric settings. Moreover, as little is known about the characteristics of offenders with ID, we conducted a clinical characterization of individuals with and without ID being subject to forensic psychiatric assessment.Methods: Using data from several Swedish national registers, we conducted a population-based retrospective observational study on 8,442 individuals being subject to pre-trial forensic psychiatric assessments in Sweden in 1997–2013. We performed univariate analyses to compare the characteristics of individuals with (n = 537) and without ID (n = 7,905).Results: The prevalence of ID was 6.4% in the Swedish pre-trial forensic psychiatric context during the observational period. Compared with individuals without ID, individuals with ID were younger at the time of assessment, had a lower educational level, and had less frequently started families. ID was associated with lower frequency of diagnosed psychotic and bipolar disorders. However, a similar prescription rate of antipsychotics, and a comparable rate of previous inpatient care was observed among individuals with and without ID. Individuals with ID had more often been prescribed anti-libidinal treatments often used for treating sexual disorders, although did not present a higher prevalence of sexual disorder.Conclusions: The prevalence of ID among pre-trial individuals being subject to forensic psychiatric assessment was more than twice as high as assumed in the general population. Our results suggest that individuals with ID received pharmacotherapy without clear indication. Remaining challenges in the clinical management of individuals with ID were indicated by the discrepancy between the occurrence of psychiatric diagnoses, pharmacological treatment patterns, and rates of inpatient care.

Radiologically Isolated Syndrome: 10-Year Risk Estimate of a Clinical Event.

We have previously identified male sex, younger age, and the presence of spinal cord lesions as independent factors that increase the 5-year risk for evolution from radiologically isolated syndrome (RIS) to multiple sclerosis. Here, we investigate risk factors for the development of a clinical event using a 10-year, multinational, retrospectively identified RIS dataset. RIS subjects were identified according to 2009 RIS criteria and followed longitudinally as part of a worldwide cohort study. We analyzed data from 21 individual databases from 5 different countries. Associations between clinical and magnetic resonance imaging (MRI) characteristics and the risk of developing a first clinical event were determined using multivariate Cox regression models. Additional follow-up data were available in 277 of 451 RIS subjects (86% female). The mean age at RIS diagnosis was 37.2 years (range, 11-74 years), with a median clinical follow-up of 6.7 years. The cumulative probability of a first clinical event at 10 years was 51.2%. Age, positive cerebrospinal fluid for oligoclonal bands, infratentorial lesions on MRI, and spinal cord lesions, were baseline independent predictors associated with a subsequent clinical event. The presence of gadolinium-enhanced lesions during follow-up was also associated with the risk of a seminal event. The reason for MRI and gadolinium-enhancing lesions at baseline did not influence the risk of a subsequent clinical event. Approximately half of all individuals with RIS experience a first clinical event within 10 years of the index MRI. The identification of independent predictors of risk for symptom onset may guide education and clinical management of individuals with RIS. ANN NEUROL 2020;88:407-417.

Sex-related differences in markers of immune activation in virologically suppressed HIV-infected patients

ObjectivesGender-specific studies remain a neglected area of biomedical research. Recent reports have emphasized that sex-related biological factors may affect disease progression during HIV-1 infection. The aim of this study was to investigate the influence of sex on the levels of immune activation in the gut and in peripheral blood of individuals with HIV treated with fully suppressive antiretroviral therapy (ART).MethodsThirty individuals with HIV undergoing long-term fully suppressive ART were enrolled in this study. Lamina propria lymphocytes (LPL) and peripheral blood mononuclear cells (PBMCs) were isolated from gut biopsies collected by pancolonoscopy and peripheral blood samples. The expression of markers of immune activation was evaluated by multi-parametric flow cytometry. This is a sub analysis of ClinicalTrials.gov Identifier: NCT02276326ResultsWe observed differences in the levels of immune activation in the gut and in PBMCs, with values higher in the gut compartment compared to PBMCs.In addition, we found that the mean value of the levels of immune activation was higher in the women than in the men. Finally, we measured the markers of immune activation by mean relative difference (MRD) and confirmed the higher value in the women.ConclusionA significant sex-related difference in the level of immune activation was observed in a population of individuals with HIV on long-term ART. A more complete characterization of these differences may support the introduction of sex-specific approaches in the clinical management of individuals with HIV.

Diagnostic yield of a custom-designed multi-gene cancer panel in Irish patients with breast cancer.

Breast cancer is genetically heterogeneous, and parellel multi-gene sequencing is the most cost- and time-efficient manner to investigate breast cancer predisposition. Numerous multi-gene panels (MGPs) are commercially available, but many include genes with weak/unproven associaton with breast cancer, or with predisposition to cancer of other types. This study investigates the utility of a custom-designed multi-gene panel in an Irish cohort with breast cancer. A custom panel comprising 83 genes offered by 19 clinical "breast cancer predisposition" MGPs was designed and applied to germline DNA from 91 patients with breast cancer and 77 unaffected ethnicially matched controls. Variants were identified and classified using a custom pipeline. Nineteen loss-of-function (LOF) and 334 missense variants were identified. After removing common and/or benign variants, 15 LOF and 30 missense variants were analysed. Variants in known breast cancer susceptibility genes were identified, including in BRCA1 and ATM in cases, and in NF1 and CHEK2 in controls. Most variants identified were in genes associated with predisposition to cancers other than breast cancer (BRIP1, RAD50, MUTYH, and mismatch repair genes), or in genes with unknown or unproven association with cancer. Using multi-gene panels enables rapid, cost-effective identification of individuals with high-risk cancer predisposition syndromes. However, this approach also leads to an increased amount of uncertain results. Clinical management of individuals with particular genetic variants in the absence of a matching phenotype/family history is challenging. Further population and functional evidence is required to fully elucidate the clinical relevance of variants in genes of uncertain significance.

Hearing loss in individuals with osteogenesis imperfecta in North America: Results from a multicenter study.

Hearing loss (HL) is an extra-skeletal manifestation of the connective tissue disorder osteogenesis imperfecta (OI). Systematic evaluation of the prevalence and characteristics of HL in COL1A1/COL1A2-related OI will contribute to a better clinical management of individuals with OI. We collected and analyzed pure-tone audiometry data from 312 individuals with OI who were enrolled in the Linked Clinical Research Centers and the Brittle Bone Disorders Consortium. The prevalence, type, and severity of HL in COL1A1/COL1A2-related OI are reported. We show that the prevalence of HL in OI is 28% and increased with age in Type I OI but not in Types III and IV. Individuals with OI Types III and IV are at a higher risk to develop HL in the first decade of life when compared to OI Type I. We also show that the prevalence of SNHL is higher in females with OI compared to males. This study reveals new insights regarding prevalence of HL in OI including a lower general prevalence of HL in COL1A1/COL1A2-related OI than previously reported (28.3 vs. 65%) and high prevalence of SNHL in females. Our data support the need in early routine hearing evaluation in all types of OI that can be adjusted to the severity of the skeletal disease.

Neutrophil-lymphocyte ratio as a predictor of kidney function decline among individuals with diabetes and prediabetes: A 3-year follow-up study.

HighlightsThis study is the first study to confirm that the neutrophil–lymphocyte ratio (NLR) is an independent predictive factor for kidney function decline among individuals with diabetes and prediabetes.Calculating the NLR is easy and inexpensive, so we believe that with more research support the NLR will be used as an effective indicator in the clinical management of individuals with diabetes and prediabetes.