Early Onset Research Articles

Canine Multiple System Degeneration Associated with Sequence Variants in SERAC1

Canine multiple system degeneration (CMSD) is an early onset, progressive movement disorder affecting Kerry Blue Terriers and Chinese Crested dogs. The associated pathologic lesions include degeneration of the cerebellum, caudate nucleus, and substantia nigra. CMSD is inherited as an autosomal recessive trait in both dog breeds. Previous linkage mapping localized the CMSD locus to a 15 MB region on canine chromosome 1 (CFA1). Next-generation sequencing was used to generate whole-genome sequences from the DNA of an affected dog from each breed. The resulting sequence reads were aligned to the NCBI canine reference genome (build 3.1). Among the homozygous sequence variants within the CFA1 target region, a nonsense variant in exon 15 of SERAC1 was identified in the affected Kerry Blue Terrier, while in the Chinese Crested dog, a 4 bp deletion in the SERAC1 exon 4 acceptor splice site was found. RT-PCR showed that this deletion resulted in exon 4 skipping. Genotyping of large cohorts of Kerry Blue Terriers and Chinese Crested dogs for the respective breed-specific SERAC1 variants showed complete concordance between genotype and disease phenotype. Genotype–phenotype concordance was also observed in offspring generated by cross breeding between SERAC1-heterozygous Kerry Blue Terrier and Chinese Crested dogs, with only the compound heterozygotes exhibiting the disease phenotype, further confirming the recessive inheritance of CMSD. Variants in human SERAC1 are associated with disorders with a range of ages of disease onset and patterns of clinical signs, but that are all characterized by movement abnormalities similar to those of the dogs with CMSD. Canine CMSD could serve as a valuable model to elucidate the mechanisms underlying SERAC1-deficiency disorders and to evaluate potential therapeutic interventions.

Clinical relevance of protein-truncating variants of germline DNA repair genes in prostate cancer

BackgroundInterpreting genetic variants remains a challenge in prostate cancer (PCa). Although many annotation tools are available for prioritizing causal variants, the clinical relevance of these variants is rarely studied.MethodsWe collected a cohort study that included 274 PCa patients from June 2017 to December 2020 and sequenced 19 DNA damage repair (DDR) genes in these patients and explored the clinical consequence of these different approaches. We also examined all-cause and PCa-specific survival in DDR gene mutation carriers compared to non-carriers after androgen receptor (AR)-directed therapy.ResultsWe identified 13 variants from 19 DDR genes in a total of 14 (5.1%) patients who had at least one presumed pathogenic mutation using different annotation methods. Four variants were annotated as pathogenic, 11 variants were predicted as protein-truncating variants (PTVs), four variants received proxy-deleterious (Combined Annotation-Dependent Depletion scores of > 30), and only one variant was identified as a pathogenic variant or as having a functional effect by all three methods. PCa patients with PTVs were significantly associated with early onset, high cancer stage, and a worse response to AR-directed treatment. However, patients carrying a proxy-deleterious variant were only associated with a higher T (tumor) stage and N (node) stage than those without such a variant, but not associated with other clinical characteristics. In patients treated with AR-directed therapy, patients with a PTV showed an increased risk of all-cause death (adjusted hazard ratio (aHR) = 3.51, 95% confidence interval (CI): 1.06 ~ 11.56) and PCa-specific death (aHR = 4.49, 95% CI: 1.87 ~ 10.77) compared to non-PTV carriers after adjustment. We were unable to examine gene-specific risks due to the small number of patients.ConclusionsPTVs may assist in guiding treatment and early screening in PCa, while population-specific data for pathogenic variants are still being amassed.

Late eating is associated with poor glucose tolerance, independent of body weight, fat mass, energy intake and diet composition in prediabetes or early onset type 2 diabetes

This study investigates the impact of habitual late calorie intake on glucose metabolism in adults with overweight or obesity and diet or metformin-controlled prediabetes or type 2 diabetes independently of body weight, fat mass, energy intake or diet composition. Participants (n = 26) were classified as Later Eaters (LE) if ≥45% daily calories were consumed after 5 pm and Early Eaters (EE) if not, based on daily caloric intake assessed over 2-wk. EE and LE did not differ in anthropometrics or daily energy intake, but LE consumed more carbohydrates (p = 0.038) and fats (p = 0.039) after 5 pm. Fasting glucose, insulin, and C-peptide did not differ between groups but LE exhibited higher glucose concentrations after an oral glucose tolerance test (p = 0.001), even after adjusting for body weight, fat mass, energy intake and diet composition (p < 0.05). Glucose results remained when participants with T2D were excluded (p = 0.031). After diabetes status adjustment, differences in glucose concentrations were higher in LE for time 30 (p = 0.028) and 60 min (p = 0.036). LE, compared to EE, had poorer glucose tolerance, independent of body weight, fat mass, daily energy intake and diet composition. ClinicalTrials.gov: NCT04465721.

A biogeochemical approach to examining sub-adult diet and the weaning process at Neolithic Tepecik-Çiftlik, Türkiye

Tepecik-Çiftlik, a Neolithic settlement located in the Cappadocia region of Central Anatolia, within the boundaries of Niğde province in modern Türkiye is crucial for helping us to better understand social behaviour and human mobility in the Neolithic, as well as relations between different groups. To investigate dietary habits, subsistence practices, and intra-societal variations stable carbon and nitrogen isotope ratio analysis has been conducted on the Neolithic human and faunal population. Further to this, 21 sub-adults were also sampled for stable carbon and nitrogen isotope ratio analysis to examine sub-adult diet, complementary feeding, and the cessation of breastfeeding as part of the weaning process. This isotopic investigation into the weaning process is complemented by a previously conducted study using Sr/Ca ratios from bone apatite of the same population. The δ13C values of the sampled sub-adults range from −19.8 ‰ to −19.0 ‰ and the δ15N values range from 8.0 ‰ to 15.2 ‰. The isotopic data suggest a very early onset of complementary feeding (ca. 0.2 years of age) and a brief breastfeeding period, relative to other prehistoric populations. The cessation of breastfeeding and this very brief weaning process was likely completed by ca. 1–1.5 years old. This early commencement of complementary feeding was most probably a deliberate social and cultural choice, supported by the presence of bowls and feeding spoons in the graves of very young babies and infants. However, this cultural choice may also have affected the mortality profile of the Neolithic population.

Long-Term Lung Function and Pseudomonas aeruginosa Infection in Genotyped Primary Ciliary Dyskinesia.

Rationale: Primary ciliary dyskinesia is a rare genetic disorder characterized by progressive lung disease. Pseudomonas aeruginosa is a major pathogen in this disease, known to impact lung function. Previous genotype-phenotype studies have been limited by cross-sectional designs, isolated adult or pediatric populations, small numbers, or short follow-up durations. Objectives: We aimed to explore long-term lung function in primary ciliary dyskinesia grouped by genotypes and ultrastructural defects, considering the influence of P. aeruginosa. Methods: In this retrospective, observational study, we analyzed 43 years of spirometry and 20 years of microbiology data. Using linear mixed-effects models, we estimated FEV1 z-score trends and compared them at ages 10, 25, and 50 years, while Generalized Estimating Equations were used to assess P. aeruginosa prevalence between groups. In a secondary analysis, we matched spirometry and microbiology samples to evaluate the influence of P. aeruginosa on lung function. Measurements and Main Results: We included 127 genotyped subjects, 6,691 spirometries and 10,082 microbiology samples. CCDC39 and CCDC40 variants showed early onset and sustained decline in lung function, while DNAH11 and HYDIN variants demonstrated relative stability. Lung function in the proximity of positive P. aeruginosa cultures were on average 0.06 z-score lower. Despite this, differences between groups remained largely unaffected by P. aeruginosa. Conclusion: Long-term lung function in primary ciliary dyskinesia follows discrete genotype specific profiles and appear independent of P. aeruginosa infection. We confirm and extend previous findings of CCDC39 and CCDC40 as variants associated with early onset severe lung function impairment persisting in the long term.

PALB2 analysis in the diagnostic process of breast cancer: An Italian monocentric experience.

The clinical utility of germline BRCA1 and BRCA2 testing is well established in patients with family history suggestive for hereditary breast and ovarian cancer syndrome. Recently, germline PALB2 pathogenic variants were also associated with an increased risk of breast and other cancers and, in the Italian population, it has been described in few studies without a systematic germline analysis of BRCA1, BRCA2 and PALB2. In this study, we described ASST Sette Laghi cancer genetic counselling services' experience in the analysis of 402 patients with suspected breast and ovarian cancer syndrome, by using BRCA1, BRCA2 and PALB2 germline genetic test. The frequency of PALB2 pathogenic variants was 1.2% compared to 3.5% and 3.2% for BRCA1 and BRCA2, respectively, whereas class 3 variants were detected in 0.3% and 0.5% of the BRCA1 and BRCA2 investigated patients, respectively. PALB2 pathogenic variants were identified in patients with a strong family history for breast cancer. Moreover, PALB2 variants were significantly associated with a younger age of breast cancer onset (mean age, 40.25 years) compared to wild-type patients (mean age 51.2 years, p-value = 0.0331). Similar to BRCA-associated breast cancer, the majority of PALB2 breast cancers were identified at an advanced clinical stage. Pedigree analysis revealed a family history of breast and ovarian cancer syndrome in all PALB2 pathogenic variants carriers (early breast cancer onset, bilateral breast cancer and ovarian cancer). In conclusion, the germline analysis of BRCA1, BRCA2 and PALB2 should be included in breast cancer clinical practice as a not negligible number of PALB2 carriers could be identified and referred to specific surveillance protocols.

GROWTH-FRIENDLY SPINAL SURGERY: REVIEW OF THE EFFECT ON TRUNCAL GROWTH

BackgroundPediatric spinal deformity surgery affects ultimate spinal height in the growing child. This effect on ultimate spinal height has also been shown to affect pulmonary development and ultimately pulmonary function. There has been an increasing trend toward growth-friendly spinal surgery in early onset scoliosis to minimize the negative consequences of early spinal fusion surgery. Such growth-friendly techniques include VEPTR, MCGR, and Shilla. Which technique allows for the most growth after initial implantation is still not clear. MethodsAn extensive literature review on the topic of pediatric spinal growth was undertaken. Topics reviewed include: normal growth, growth after intervention by various methods, and the effect on pulmonary function. We have summarized the literature for the techniques identified and compared these with normal population data.. ResultsThe data for various surgical techniques were reviewed. These included VEPTR, standard growing rods, and MCGR. The measurement techniques for determining ultimate spinal growth varied based upon the technique for measurement and the timing of initial and final measurements. The results of attained spinal growth were not directly correlated to pulmonary function values. ConclusionsThere is still no standardized ideal time or technique for assessing the best results in this area. We suggest that some of what is called growth from growth-friendly techniques is lengthening from the initial deformity correction. This nomenclature needs to be clarified. In addition, how and when to determine ultimate spinal growth from each surgical technique and by which radiographic technique needs to be standardized.

Problematic Use of Video Games in Schooled Adolescents: The Role of Passion

The present study aims to determine the predictive value of sociodemographic, academic, educational clinical psychological variables—ADHD diagnosis, emotional self-regulation, passion and emotional and behavioural symptoms—and modality of use of video games in adolescents who either make potentially problematic or severely problematic use of video games. This is a descriptive cross-sectional study in which 2.533 Galician students (region located in the northwest of Spain) aged between 11 and 20 years participated, who were selected through multistage random sampling. The mean age was 14.78 years (SD = 1.76). The analysis of the data seems to indicate that in the prediction of the problematic use of video games, different variables are combined, among which passion plays a capital role. In addition, the problematic use of video games is related to poor parental control, poor academic performance, use of addictive substances or to an earlier onset, as well as with the diagnosis of ADHD and with greater negative emotional and behavioural symptoms. The results of this study may be of interest for the design and implementation of preventive and corrective actions aimed at reducing the problematic or addictive use of video games.

The Impact of Pneumoperitoneum on Mean Expiratory Flow Rate: Observational Insights from Patients with Healthy Lungs

Background/Objectives: Surgical pneumoperitoneum (PP) significantly impacts volume-controlled ventilation, characterized by reduced respiratory compliance, elevated peak inspiratory pressure, and an accelerated expiratory phase due to an earlier onset of the airway pressure gradient. We hypothesized that this would shorten expiratory time, potentially increasing expiratory flow rate compared to pneumoperitoneum conditions. Calculations were performed to establish correlations between respiratory parameters and the mean increase in expiratory flow rate relative to baseline. Methods: Mechanical ventilation parameters were recorded for 67 patients both pre- and post-PP. Ventilator settings were standardized with a tidal volume of 6 mL/kg, a respiratory rate of 12 breaths per minute, a PEEP of 3 cmH2O, an inspiratory time of 2 s, and an inspiratory-to-expiratory ratio of 1:1.5 (I:E). Results: The application of PP increased both peak inspiratory pressure and mean expiratory flow rate by 28% compared to baseline levels. The elevated intra-abdominal pressure of 20 cmH2O resulted in a 34% reduction in dynamic chest compliance, a 50% increase in elastance, and a 20% increase in airway resistance. The mean expiratory flow rate increments relative to baseline showed a significant negative correlation with elastance (p = 0.0119) and a positive correlation with dynamic compliance (p = 0.0028) and resistance (p = 0.0240). Conclusions: A PP of 20 cmH2O resulted in an increase in the mean expiratory flow rate in the conventional I:E ratio in the volume-ventilated mode. PP reduces lung and chest wall compliance by elevating the diaphragm, compressing the thoracic cavity, and increasing airway pressures. Consequently, the lungs and chest wall stiffen, requiring greater ventilatory effort and accelerating expiratory flow due to increased airway resistance and altered pulmonary mechanics. Prolonging the inspiratory phase through I:E ratio adjustment helps maintain peak inspiratory pressures closer to baseline levels, and this method enhances the safety and efficacy of mechanical ventilation in maintaining optimal respiratory function during laparoscopic surgery.

The Good (Tumor Killing) and the Bad (Cardiovascular Complications) of Immunologic Checkpoint Inhibitors.

This review details the significant advancement in knowledge of Immune-checkpoint inhibitor (ICI) and its potential deleterious cardiac immune-related adverse effects (irAE). We explore their mechanisms on the cardiac tissue, providing guidance on risk factors, clinical presentations, diagnostic strategies along with treatment. Recent findings have provided insights of cardiac irAEs that exist beyond the previously well-known ICI-induced myocarditis. We have a better understanding of the wide variety of cardiac irAEs pathologies both early and late onset. Moreover, there is more data on mechanisms of cardiotoxicity and patient and therapy-related risk factors, supporting closer routine cardiac monitoring with biomarkers and imaging for prevention and early detection. Diagnosing cardiac irAEs is a challenge given its broad clinical presentation. A high-level of suspicion in addition to early work-up is crucial to prevent serious cardiac events. A multi-disciplinary team including Cardiologists and Oncologists is essential for closely monitor patients' cardiac status on ICI therapy. There is a need of updated guidelines to establish clear recommendations in patients on ICIs.

Senescent Syncytiotrophoblast Secretion During Early Onset Preeclampsia.

Preeclampsia is a severe hypertensive disorder in pregnancy that causes preterm delivery, maternal and fetal morbidity, mortality, and life-long sequelae. Understanding the pathogenesis of preeclampsia is a critical first step toward protecting mother and child from this syndrome and increased risk of cardiovascular disease later in life. However, effective early predictive tests and therapies for preeclampsia are scarce. To identify novel markers and signaling pathways for early onset preeclampsia, we profiled human maternal-fetal interface units (fetal villi and maternal decidua) from early onset preeclampsia and healthy controls using single-nucleus RNA sequencing combined with spatial transcriptomics. The placental syncytiotrophoblast is in direct contact with maternal blood and forms the barrier between fetal and maternal circulation. We identified different transcriptomic states of the endocrine syncytiotrophoblast nuclei with patterns of dysregulation associated with a senescence-associated secretory phenotype and a spatial dysregulation of senescence in the placental trophoblast layer. Elevated senescence markers were validated in placental tissues of clinical multicenter cohorts. Importantly, several secreted senescence-associated secretory phenotype factors were elevated in maternal blood already in the first trimester. We verified the secreted senescence markers, PAI-1 (plasminogen activator inhibitor 1) and activin A, as identified in our single-nucleus RNA sequencing model as predictive markers before clinical preeclampsia diagnosis. This indicates that increased syncytiotrophoblast senescence appears weeks before clinical manifestation of early onset preeclampsia, suggesting that the dysregulated preeclamptic placenta starts with higher cell maturation resulting in premature and increased senescence-associated secretory phenotype release. These senescence-associated secretory phenotype markers may serve as an additional early diagnostic tool for this syndrome.

The Enigma That Is ROHHAD Syndrome: Challenges and Future Strategies

Rapid-onset obesity with hypoventilation, hypothalamic dysfunction, and autonomic dysregulation (ROHHAD) is a rare syndrome presenting in early childhood associated with a high risk of mortality between 50 and 60%. It is characterised by rapid, early onset of obesity between 1.5–7 years, along with central hypoventilation and hypothalamic dysfunction, such as central hypothyroidism, hyperprolactinemia, disorders of sodium and water balance, growth hormone deficiency, adrenocortical insufficiency, or disorders of puberty and features of autonomic dysregulation. Up to half of cases have neural crest tumours, most commonly ganglioneuromas or ganglioneuroblastomas. The incidence of ROHHAD syndrome in any population is unknown. Currently, there is no specific diagnostic or genetic biomarker for ROHHAD, and diagnosis is based on clinical signs and symptoms, which is often challenging, and consequently may be delayed or unrecognised. Early diagnosis is important, as without intervention, ROHHAD is associated with high morbidity and mortality. Aetiology remains unclear; an autoimmune origin has been postulated, with immunosuppressive agents being used with variable benefit. With no cure, multidisciplinary management is largely supportive. Therefore, there are many unanswered questions in ROHHAD syndrome. In this review article, we outline the challenges posed by ROHHAD syndrome, including aetiology, genetics, diagnosis, screening, management, and prognosis. We present research priorities to tackle these issues to improve outcomes.

Mode of delivery in chorioamnionitis: impact on neonatal and maternal outcomes

BackgroundThe impact of mode of delivery in chorioamnionitis on neonatal outcomes is unclear. This retrospective cohort study compares the rate of early onset neonatal sepsis between vaginal delivery and cesarean section.MethodsSingleton pregnancies at greater than 24 + 0 weeks gestation with live birth and clinically-diagnosed chorioamnionitis from January 1, 2019 to December 31, 2021 were included. Cases with multiple gestations, terminations or histological chorioamnionitis alone were excluded. Rates of early onset neonatal sepsis, select secondary neonatal outcomes and a composite outcome of maternal infectious morbidity were compared using propensity score weighting. Subgroup analysis was done by indication for cesarean section.ResultsAfter chart review, 378 cases were included with 197 delivering vaginally and 181 delivering via cesarean section. The groups differed on age, parity, hypertension, renal disease, gestational age, corticosteroid use, magnesium sulfate use, presence of meconium and percentage meeting Gibbs criteria before propensity score weighting. Rate of early onset neonatal sepsis was greater in the cesarean section group (13.8% versus 3.1%, adjusted risk difference 8.3% [3.5–13.1], p < 0.001). Secondary neonatal outcomes were similar between groups. When compared by indication, the rate of early onset neonatal sepsis was greater in the cesarean section for abnormal fetal surveillance group compared to vaginal delivery but not in the cesarean section for other reasons group. Adjusted rates of secondary neonatal outcomes did not differ between groups. The rate of maternal infectious morbidity was greater with cesarean section. (13.8% versus 1.5% [adjusted risk difference 13.0% [7.1–18.9], p < 0.0001). No other difference in maternal secondary outcomes was identified.ConclusionsThe rate of early onset neonatal sepsis was highest in the cesarean section group, particularly in those with abnormal fetal surveillance. Fetuses affected by or vulnerable to sepsis likely have a greater need for cesarean section.

Hereditary Multiple Intestinal Atresia With a Novel TTC7A Pathogenic Variant: Gastrointestinal Manifestations in Two Cases.

Hereditary multiple intestinal atresia (HMIA) with TTC7A mutation is caused by homozygous or compound heterozygous TTC7A gene mutation. It is characterized by multiple small and large intestinal atresias and/or stenoses. TTC7A mutation is described in some patients with inflammatory bowel disease and mild-severe forms of severe combined immunodeficiency without intestinal atresia or stenosis. We present 2 cases of intestinal atresia and documented TTC7A mutation with a novel variant. Both cases had different clinical and pathological manifestations. The first case is a male infant born at 35 weeks of gestation with failure to pass meconium. Intestinal biopsy reveals apoptotic enteropathy with villous atrophy and increased mucosal eosinophils. The second case is referred at birth for antenatally detected umbilical hernia, polyhydramnios and possible upper intestinal obstruction. The resected specimen reveals ileal atresia with partial villous atrophy, decreased number of lamina propria inflammatory cells and absence of plasma cells. In conclusion, these cases reflect an emerging TTC7A pathogenic variant with different histological manifestations and leads to characterization as immune dysregulation disorder. There is a need to differentiate TTC7A mutation associated ones from cases labeled as very early onset IBD and rule out other hereditary immunodeficiencies.

Uncovering the Embryonic Origins of Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) is a severe degenerative muscle disease caused by mutations in the DMD gene, which encodes dystrophin. Despite its initial description in the late 19th century by French neurologist Guillaume Duchenne de Boulogne, and identification of causal DMD genetic mutations in the 1980s, therapeutics remain challenging. The current standard of care is corticosteroid treatment, which delays the progression of muscle dysfunction but is associated with significant adverse effects. Emerging therapeutic approaches, including AAV-mediated gene transfer, CRISPR gene editing, and small molecule interventions, are under development but face considerable obstacles. Although DMD is viewed as a progressive muscle disease, muscle damage and abnormal molecular signatures are already evident during fetal myogenesis. This early onset of pathology suggests that the limited success of current therapies may partly be due to their administration after aberrant embryonic myogenesis has occurred in the absence of dystrophin. Consequently, identifying optimal therapeutic strategies and intervention windows for DMD may depend on a better understanding of the earliest DMD disease mechanisms. As newer techniques are applied, the field is gaining increasingly detailed insights into the early muscle developmental abnormalities in DMD. A comprehensive understanding of the initial events in DMD pathogenesis and progression will facilitate the generation and testing of effective therapeutic interventions.

Adenomyosis and Adolescence: A Challenging Diagnosis and Complex Management

Adenomyosis is a chronic, hormone-related disease characterized by the presence of the endometrial glands and stroma within the myometrium. This condition can manifest in various features, focal or diffuse adenomyosis or as an adenomyoma, and it may involve different uterine walls (posterior, anterior, and/or lateral walls). The disease can also be classified into different degrees, as mild, moderate and severe, which can be associated with more intense symptoms, although this correlation is not always directly proportional. In fact, adenomyosis can be asymptomatic in about a third of cases or it can significantly impact patients’ quality of life through painful symptoms, such as dysmenorrhea and dyspareunia, abnormal uterine bleeding—particularly heavy menstrual bleeding—and potential effects on fertility. Historically, adenomyosis has been considered a disease primarily affecting premenopausal women over the age of 40, often multiparous, because the diagnosis was traditionally based on surgical reports from hysterectomies performed after the completion of reproductive desire. Data on the presence of adenomyosis in adolescent patients remain limited. However, in recent years, advancements in noninvasive diagnostic tools and increased awareness of this pathology have enabled earlier diagnoses. The disease appears to have an early onset during adolescence, with a tendency to progress in terms of extent and severity over time. Adenomyosis often coexists with endometriosis, which also has an early onset. Therefore, it is important, when diagnosing adenomyosis, to also screen for concomitant endometriosis, especially deep endometriosis in the posterior compartment. The aim of this narrative review is to investigate the prevalence of different types and degrees of adenomyosis in younger patients, assess the associated symptoms, and describe the most appropriate diagnostic procedures for effective therapeutic management and follow-up, with the goal of improving the quality of life for these young women.

Genotype-phenotype analysis of hearing function in patients with DFNB1A caused by the c.-23+1G>A splice site variant of the GJB2 gene (Cx26).

The audiological features of hearing loss (HL) in patients with autosomal recessive deafness type 1A (DFNB1A) caused by splice site variants of the GJB2 gene are less studied than those of patients with other variants of this gene. In this study, we present the audiological features of DFNB1A in a large cohort of 134 patients with the homozygous splice site variant c.-23+1G>A and 34 patients with other biallelic GJB2 genotypes (n = 168 patients with DFNB1A). We found that the preservation of hearing thresholds in the speech frequency range (PTA0.5,1.0,2.0,4.0 kHz) in patients with the c.[-23+1G>A];[-23+1G>A] genotype is significantly better than in patients with the "severe" c.[35delG];[35delG] genotype (p = 0.005) and significantly worse than in patients with the "mild" c.[109G>A];[109G>A] genotype (p = 0.041). This finding indicates a "medium" pathological effect of this splice site variant on hearing function. A detailed clinical and audiological analysis showed that in patients with the c.[-23+1G>A];[-23+1G>A] genotype, HL is characterized as congenital or early onset (57.5% onset before 12 months), sensorineural (97.8%), bilateral, symmetrical (82.8%), variable in severity (from mild to profound HL, median hearing threshold in PTA0.5,1.0,2.0,4.0 kHz is 86.73±21.98 dB), with an extremely "flat" audioprofile, and with a tendency toward slow progression (a positive correlation of hearing thresholds with age, r = 0.144, p = 0.041). In addition, we found that the hearing thresholds in PTA0.5,1.0,2.0,4.0 kHz were significantly better preserved in females (82.34 dB) than in males (90.62 dB) (p = 0.001). We can conclude that in patients with DFNB1A caused by the c.-23+1G>A variant, male sex is associated with deteriorating auditory function; in contrast, female sex is a protective factor.

A multimodality score strategy for assessing the risk of immune checkpoint inhibitors related cardiotoxicity

This study aimed to find the association between four common clinical biomarkers and subsequent ICICT, developing a risk scoring strategy to assess the ICICT risk. Three terminals for ICICT were : Terminal 1, cancer therapy-related cardiomyopathies; Terminal 2, myocarditis or heart failure; and Terminal 3, myocarditis, heart failure, myocardial infarction, cerebral infarction, atrial fibrillation, or death. The thresholds were : N-terminal-pro-B-type-natriuretic-peptide ≥ 125 pg/mL, cardiac troponin T ≥ 6 ng/L, high-sensitivity C-reactive protein ≥ 3 mg/L, and coronary artery calcium score > 10 U. Each of the four abnormal biomarkers received 1 point. The links between biomarkers, score stage, and ICICT were analyzed. 375 patients with a mean follow-up of 1.91 years were included. All four biomarkers measured before immunotherapy were associated with a higher risk of developing ICICT. These scores were also associated with ICICT risk. The highest risk was the very high stage (score = 4) has 7.29, 8.83, and 7.02 folder higher risk compared to low risk group for Terminal 1–3, respectively. The cumulation of incidences also showed that the higher stages of score had an earlier onset and higher incidence of ICICT. 4 biomarkers and the scoring strategy enables clinicians to assess risk easily.

Electrochemiluminescence of Carbon Dots and Nitrogen-Doped Carbon Dots from a Microwave-Assisted Method

This research focuses on the use of carbon dots (CDs) and nitrogen-doped carbon dots (NCDs) synthesized using a microwave-assisted method as electrochemiluminescence (ECL) luminophores. CDs have been synthesized using citric acid, while various concentrations of nitrogen-doped CDs have been successfully obtained by varying the amount of urea from 1 to 3 g with citric acid to produce NCD1, NCD,2 and NCD3. The ECL mechanism of CDs and NCDs on screen-printed electrodes has been studied using cyclic voltammetry (CV). ECL emission from as-prepared CDs and NCDs was observed in PBS with potassium persulfate (K2S2O8) as a co-reactant. The addition of potassium chloride (KCl) as a supporting electrolyte displays fast electroreduction of CDs and K2S2O8 to expedite the generation of CDs and peroxydisulfate radicals that simultaneously increase ECL intensity. Furthermore, as the concentration of nitrogen-doped CDs increases, so does the intensity of the ECL. NCD3 shows the highest ECL intensity by an increment of 86.4% in comparison to CDs in PBS with the addition of K2S2O8 and KCl. Finally, optimization of ECL measurement was carried out in terms of CV potential range, concentration of luminophore, supporting electrolyte, and co-reactant using NCD3 luminophore. The CV potential range at 0 to -2 V shows 50 mV of early CV reverse onset potential that resulted in an increase of 52.9% ECL intensity. Meanwhile, 30x dilution of NCD3, 0.1 M of supporting electrolyte KCl, and 0.1 M of co-reactant K2S2O8 show the optimum value to obtain high ECL intensity.

Hand therapy interventions for the prevention of chemotherapy-induced peripheral neuropathy of the hands in patients with pancreatic cancer

Abstract Background Chemotherapy-induced peripheral neuropathy (CIPN), a common problem, can impair function and quality of life in patients, potentially limiting chemotherapy and adversely affecting outcomes. Methods This trial compared investigational hand therapy intervention (Investigational) compared with a traditional occupational therapy approach (Traditional) to prevent CIPN in patients with pancreatic cancer receiving gemcitabine and albumin-bound paclitaxel containing regimens. Results forty-nine patients were enrolled with 40 evaluable for statistical analysis (21 Investigational/19 Traditional). CIPN in the hands was reported in 6 patients (28.6%) in Investigational, and 4 (21.1%) in Traditional P = .721. Kaplan-Meier analysis showed a mean time-to-event of 76.0 days (90% CI: 68.5, 83.6), and 75.8 (90% CI: 68.5, 83.2) days respectively, P = .614. Fifteen patients in each group (78.9% Traditional, 71.4% in Investigational) were censored as they did not develop CIPN. No correlation was found between CIPN risk and age, sex, BMI, disease stage, performance status, or chemotherapy dose. Conclusion Seventy-four percent of patients receiving gemcitabine, albumin-bound paclitaxel, and cisplatin did not develop CIPN of the hands by day 84. There was no statistical difference in time to onset of CIPN between the two groups. Early adaption of occupational therapy may prevent early onset CIPN in chemotherapy patients. ClinicalTrials.gov Identifier NCT05374876.