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Background: Real-world data on the efficacy and safety of onasemnogene abeparvovec (OA) in spinal muscular atrophy (SMA) are needed, especially to overcome uncertainties around its use in older and heavier children. This study evaluated the efficacy and safety of OA in patients with SMA type 1 in the UK, including patients ≥2 years old and weighing ≥13.5 kg., Methods: This observational cohort study used data from patients with genetically confirmed SMA type 1 treated with OA between May 2021 and January 2023, at 6 infusion centres in the United Kingdom. Functional outcomes were assessed using age-appropriate functional scales. Safety analyses included review of liver function, platelet count, cardiac assessments, and steroid requirements., Findings: Ninety-nine patients (45 SMA therapy-naïve) were treated with OA (median age at infusion: 10 [range, 0.6-89] months; median weight: 7.86 [range, 3.2-20.2] kg; duration of follow-up: 3-22 months). After OA infusion, mean ± SD change in CHOP-INTEND score was 11.0 ± 10.3 with increased score in 66/78 patients (84.6%); patients aged <6 months had a 13.9 points higher gain in CHOP-INTEND score than patients ≥2 years (95% CI, 6.8-21.0; P  < 0.001). Asymptomatic thrombocytopenia (71/99 patients; 71.7%), asymptomatic troponin-I elevation (30/89 patients; 33.7%) and transaminitis (87/99 patients; 87.9%) were reported. No thrombotic microangiopathy was observed. Median steroid treatment duration was 97 (range, 28-548) days with dose doubled in 35/99 patients (35.4%). There were 22.5-fold increased odds of having a transaminase peak >100 U/L (95% CI, 2.3-223.7; P  = 0.008) and 21.2-fold increased odds of steroid doubling, as per treatment protocol (95% CI, 2.2-209.2; P  = 0.009) in patients weighing ≥13.5 kg versus <8.5 kg. Weight at infusion was positively correlated with steroid treatment duration (r = 0.43; P  < 0.001). Worsening transaminitis, despite doubling of oral prednisolone, led to treatment with intravenous methylprednisolone in 5 children. Steroid-sparing immunosuppressants were used in 5 children to enable steroid weaning. Two deaths apparently unrelated to OA were reported., Interpretation: OA led to functional improvements and was well tolerated with no persistent clinical complications, including in older and heavier patients., Funding: Novartis Innovative Therapies AG provided a grant for independent medical writing services., Competing Interests: Vasantha Gowda has participated in scientific advisory boards, scientific symposia and teaching initiatives for Biogen, Roche, Novartis, Wave Life Sciences, PTC therapeutics and Pfizer, received honoraria from Neurology Academy, Roche, Novartis and has been involved as principal investigator with PTC therapeutics, Wave Life Sciences and Catabasis. Mark Atherton has received conference sponsorship from Novartis. Jennie Sheehan has participated in advisory boards for Roche, received conference sponsorships from Roche and Biogen and honoraria from Novartis. Mariacristina Scoto has been involved as principal investigator in clinical trials from Roche, Biogen and Novartis and has participated in Scientific Advisory boards and teaching initiatives for Roche, Novartis and Biogen. Giovanni Baranello has been involved as principal investigator of clinical trials sponsored by Roche, Novartis, Sarepta, Pfizer, NS Pharma, Reveragen, Scholar Rock, and has received speaker and/or consulting fees from Sarepta, PTC Therapeutics, Pfizer, Biogen, Novartis Gene Therapies, Inc. (AveXis), and Roche, and grants from Sarepta, Roche and Novartis Gene Therapies. Archana Murugan has received conference sponsorship from Roche. Anil Dhawan has participated in advisory boards for Novartis, BitBio, Aspect Bio, Astellas. Michael Eyre is supported by Action Medical Research and the British Paediatric Neurology Association. Laurent Servais reports participation in advisory boards and scientific symposia from Biogen, Roche, Novartis, Scholar Rock and BioHaven and grants from the aforementioned and Zentech, Perkin Almers. Francesco Muntoni reports participation in advisory boards and scientific symposia from Biogen, Roche and Novartis and funding from Biogen and Roche for the SMA REACH National database. Min Ong has participated in advisory boards for Biogen, Novartis, Roche & CSL Behring and has received conference sponsorship from Roche and speaker fees from Biogen, and honorarium from Neurology Academy. Imelda Hughes has received honoraria from Santhera, Roche, PTC Therapeutics, Sarepta, Biogen and Novartis, conference sponsorships from PTC Therapeutics, Novartis and Biogen. Heinz Jungbluth has participated in advisory board activities for Pfizer, Astellas, Audentes and Armgo. Elizabeth Wraige has undertaken consultancy work for Novartis. Maria Vanegas has received conference sponsorship from Novartis and meeting sponsorship from SMA Europe. Sandya Tirupathi has received conference sponsorships from Novartis and PTC. Marjorie Illingworth has received conference sponsorships from Roche and Biogen. Adnan Manzur received honorarium and meeting sponsorship from Pi Healthcare. Sarah D’Urso has received conference sponsorship from Biogen. Tracey Willis has received honorarium and conference sponsorship from Novartis. Sinead Warner has received conference sponsorship from Novartis and consultancy fees from Roche. No other disclosures were reported., (© 2023 The Author(s).)

Aim: This study aims to evaluate the efficacy of calcium phosphate-poly(lactide-co-glycolide) composite graft in the regeneration of intrabony defects in chronic periodontitis patients over a period of 12 months., Materials and Methods: A total of 11 systemically healthy chronic periodontitis patients with 22 graftable sites were treated with calcium phosphate cement (CPC) bone graft (control group) and CPC-poly(lactic-co-glycolic acid)(PLGA) composite (test group) after flap reflection and debridement. Clinical parameters such as probing pocket depth (PPD) and clinical attachment level (CAL) were recorded at baseline and 3, 6, 9, and 12 months. Bone probing depth (BPD) and radiographic parameters such as defect depth (DD), changes in alveolar crest level (ALR), defect depth reduction (DDR), and percentage in defect depth reduction (PDDR) were calculated at baseline, and 6 and 12 months. The data were recorded and statistically analyzed., Results: On intragroup comparison, there was a significant improvement in all the parameters over a period of 1 year (clinically and radiographically). However, there was no statistically significant difference between the two groups in any of the parameters though there was a slightly higher bone fill noted in the test group., Conclusion: Even though the CPC-PLGA composite bone graft showed a slight improvement in clinical and radiographic parameters as compared to the CPC graft, it was not statistically significant., Clinical Significance: A major drawback of Calcium Phosphate cements as bone grafts is their poor degradability. The PLGA microspheres degrade to expose macropores and interconnected pores in the graft substrate which in turn would promote the ingrowth of osteoblasts. Also, this composite graft is mouldable, and resorbable and has been shown to snugly fit into the defects making them a suitable scaffold material. How to cite this article: Ojha M, Pawar Chandrashekara Rao D, Gowda V. Clinical and Radiographic Evaluation of Calcium Phosphate-Poly(lactide-co-glycolide) Graft in Regeneration of Intrabony Defects: Randomized Control Trial. J Contemp Dent Pract 2023;24(12):921-927.

Background and Objectives: RYR1 -related myopathies are the most common congenital myopathies, but long-term natural history data are still scarce. We aim to describe the natural history of dominant and recessive RYR1 -related myopathies., Methods: A cross-sectional and longitudinal retrospective data analysis of pediatric cases with RYR1 -related myopathies seen between 1992-2019 in 2 large UK centers. Patients were identified, and data were collected from individual medical records., Results: Sixty-nine patients were included in the study, 63 in both cross-sectional and longitudinal studies and 6 in the cross-sectional analysis only. Onset ranged from birth to 7 years. Twenty-nine patients had an autosomal dominant RYR1 -related myopathy, 31 recessive, 6 de novo dominant, and 3 uncertain inheritance. Median age at the first and last appointment was 4.0 and 10.8 years, respectively. Fifteen% of patients older than 2 years never walked (5 recessive, 4 de novo dominant, and 1 dominant patient) and 7% lost ambulation during follow-up. Scoliosis and spinal rigidity were present in 30% and 17% of patients, respectively. Respiratory involvement was observed in 22% of patients, and 12% needed ventilatory support from a median age of 7 years. Feeding difficulties were present in 30% of patients, and 57% of those needed gastrostomy or tube feeding. There were no anesthetic-induced malignant hyperthermia episodes reported in this cohort. We observed a higher prevalence of prenatal/neonatal features in recessive patients, in particular hypotonia and respiratory difficulties. Clinical presentation, respiratory outcomes, and feeding outcomes were consistently more severe at presentation and in the recessive group. Conversely, longitudinal analysis suggested a less progressive course for motor and respiratory function in recessive patients. Annual change in forced vital capacity was -0.2%/year in recessive vs -1.4%/year in dominant patients., Discussion: This clinical study provides long-term data on disease progression in RYR1 -related myopathies that may inform management and provide essential milestones for future therapeutic interventions., (© 2023 American Academy of Neurology.)

Purpose: To evaluate the relationship between regional geography and sperm parameters in a cohort of American men using at-home mail-in semen collection kits with no previous self-reported history of male factor infertility., Materials and Methods: In this study, 5,822 men from six different regions of the United States (Northeast, Southeast, Midwest, West, Pacific, and Southwest) who self-requested semen analysis between 2019 and 2021 were enrolled., Results: Across the entire cohort, the mean sperm concentration was 43.79±55.43 ×10 6 sperm/mL; total sperm count 138.93±149.96 ×10 6 sperm/mL; total motile sperm 54.73±81.90 ×10 6 /ejaculate; total motility 30.18%±22.87%; progressive motility 21.61%±17.32%; sperm with normal morphology 8.79%±8.87%. Patients from the West region displayed lower median sperm concentration, total motile sperm, and total motility than men from the other four regional areas. A lower median total sperm count, and lower median progressive motility were also detected among patients in the Southwest region. Conversely, higher results were detected in patients from the Midwest (higher median total motile sperm, total and motility) and from the Northeast (higher median sperm concentration and total sperm count) regions. Men from the Southeast (OR, 1.3168; 95% CI, 1.1142-1.5563) and Southwest (OR, 1.3145; 95% CI, 1.0735-1.6096) regions were more likely to have oligozoospermia than those living elsewhere., Conclusions: This study provides the most comprehensive and up-to-date report on semen parameter variability among a cohort of men living in six different regions of the continental USA. This study will pave the way into a deeper discussion of the interplay between geography, social determinants of fertility care and semen quality., Competing Interests: Yana Aznavour, Jad Badreddine and Stephen Rhodes have no financial and personal relationships to disclose. Ramy Abou Ghayda, Felipe Navarrete, Vrushab Gowda, and Paul Simon are the Chief Medical Officer, Head of Research and Development, Head of Regulatory Affairs, and VP of Operations at Give Legacy, Inc, respectively. The authors declare that they have no competing interests regarding to the research described in this paper. They did not receive any additional funding, or financial or non-financial gains associated with this research. GiveLegacy, Inc. did not intervene nor influence the design, outcomes, materials, methods, or results of this manuscript. There is no direct or indirect gain for GiveLegacy, Inc. in relation to the publication of this study., (Copyright © 2023 Korean Society for Sexual Medicine and Andrology.)

The impact of ejaculatory abstinence on semen parameters using in-office semen analyses has been well-established; however, their variability has not been evaluated in men using mail-in semen analysis kits. Our study aims to describe how the sperm parameters using mail-in semen analysis tests change with abstinence and validate their equivalence to those seen with in-office semen analysis tests. We retrospectively reviewed the semen analysis results of men using mail-in semen analysis tests provided by Give Legacy, Inc (Legacy) facilities from 2019 to 2021. We collected their demographic information, abstinence duration, and semen parameters (conventional and kinematic) from their records. Semen samples were categorized as normozoospermic and oligozoospermic based on concentration. The shape of the relationship between abstinence duration and semen parameters was assessed via generalized additive models. We have collected 3,469 unique samples provided by 2,609 (75%) normozoospermic men and 860 (25%) oligozoospermic from all over the United States. In normozoospermic men, longer periods of sexual abstinence were linked to higher levels of sperm concentration, total sperm count, and total motile sperm. However, there was a decline in both total and progressive motility. Conversely, in oligozoospermic men, extended periods of abstinence led to a rapid decline in total motile sperm, as well as total and progressive motility. There was no significant correlation observed between sexual abstinence and variations in sperm morphology. Our study shows that variability of sperm parameters with abstinence, as measured through mail-in semen analysis tests, is comparable to the patterns observed with conventional in-office sperm testing.

Manipulative neuroparasites are a fascinating group of organisms that possess the ability to hijack the nervous systems of their hosts, manipulating their behavior in order to enhance their own survival and reproductive success. This review provides an overview of the different strategies employed by manipulative neuroparasites, ranging from viruses to parasitic worms and fungi. By examining specific examples, such as Toxoplasma gondii, Leucochloridium paradoxum, and Ophiocordyceps unilateralis, we highlight the complex mechanisms employed by these parasites to manipulate their hosts' behavior. We explore the mechanisms through which these parasites alter the neural processes and behavior of their hosts, including the modulation of neurotransmitters, hormonal pathways, and neural circuits. This review focuses less on the diseases that neuroparasites induce and more on the process of their neurological manipulation. We also investigate the fundamental mechanisms of host manipulation in the developing field of neuroparasitology, which blends neuroscience and parasitology. Finally, understanding the complex interaction between manipulative neuroparasites and their hosts may help us to better understand the fundamentals of behavior, neurology, and host-parasite relationships., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: The pandemic caused by SARS Corona Virus-2 (COVID-19) has caused widespread mortality globally. The hallmark of the disease is the "cytokine storm," which is caused due to dysregulated immune system activation. Numerous inflammatory markers are used to predict the severity and mortality of the infection. Serum Cystatin C levels are associated with immune responses to exogenous and endogenous antigens. Our study was done to assess serum cystatin C as a marker of severity and mortality among patients admitted with COVID-19 infection., Methodology: This cross-sectional study was conducted in a tertiary care center in South India. Sixty-nine patients with mild and severe COVID-19 infection admitted to the hospital were included in the study. Serum Cystatin C levels were estimated at admission. The levels were correlated with disease severity and mortality. Receiver operating characteristic curves (ROCs) was constructed for Cystatin C to predict severity and mortality. The computation of sensitivity, specificity, and positive and negative predictive values was done using optimal cut-off points. SPSS 18 was used for the statistical analysis. Version 18.0 of PASW Statistics for Windows. SPSS Inc., Chicago., Results: Out of 69 patients, 28 (40.5%) had a mild illness, and 41 patients (59.4%) had severe COVID-19 illness. Mean serum Cystatin C levels measured at the time of admission among patients with mild illness was 1.83 (SD-1.53), and among patients with severe illness was 3.84 (SD- 2.59) (p<0.001). The area under receiver operating characteristic curves (ROC) for serum cystatin C for predicting COVID-19 severity and mortality was 0.904 and 0.768, respectively (p<0.001)., Conclusion: Patients with severe COVID-19 disease had considerably higher serum levels of Cystatin C than those with mild COVID-19 illness. Cystatin C levels can be useful for predicting mortality and severity among patients admitted with COVID-19 infection., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Prasad et al.)

Contactin-associated protein-like 2 (CNTNAP2) gene encodes for CASPR2, a presynaptic type 1 transmembrane protein, involved in cell-cell adhesion and synaptic interactions. Biallelic CNTNAP2 loss has been associated with "Pitt-Hopkins-like syndrome-1" (MIM#610042), while the pathogenic role of heterozygous variants remains controversial. We report 22 novel patients harboring mono- (n = 2) and bi-allelic (n = 20) CNTNAP2 variants and carried out a literature review to characterize the genotype-phenotype correlation. Patients (M:F 14:8) were aged between 3 and 19 years and affected by global developmental delay (GDD) (n = 21), moderate to profound intellectual disability (n = 17) and epilepsy (n = 21). Seizures mainly started in the first two years of life (median 22.5 months). Antiseizure medications were successful in controlling the seizures in about two-thirds of the patients. Autism spectrum disorder (ASD) and/or other neuropsychiatric comorbidities were present in nine patients (40.9%). Nonspecific midline brain anomalies were noted in most patients while focal signal abnormalities in the temporal lobes were noted in three subjects. Genotype-phenotype correlation was performed by also including 50 previously published patients (15 mono- and 35 bi-allelic variants). Overall, GDD (p < 0.0001), epilepsy (p < 0.0001), hyporeflexia (p = 0.012), ASD (p = 0.009), language impairment (p = 0.020) and severe cognitive impairment (p = 0.031) were significantly associated with the presence of biallelic versus monoallelic variants. We have defined the main features associated with biallelic CNTNAP2 variants, as severe cognitive impairment, epilepsy and behavioral abnormalities. We propose CASPR2-deficiency neurodevelopmental disorder as an exclusively recessive disease while the contribution of heterozygous variants is less likely to follow an autosomal dominant inheritance pattern., (© 2023. The Author(s).)

Aims and Objective: Anti-seizure drugs that cause idiosyncratic drug-induced liver injury (DILI) are an important cause of morbidity and mortality in individuals exposed to these drugs. The clinical and demographic characteristics, the liver injury pattern, the outcome, and the agents responsible for hepatotoxicity have not been thoroughly studied. We investigated the aforementioned characteristics in a large cohort of DILI registry patients., Methods: Patients with anti-seizure DILI were studied from a large single-center DILI registry between 1998 and 2021. DILI was defined by international working group criteria with at least a probable relation with RUCAM. Immunoallergic features and organ-specific contribution to outcome were investigated., Results: Anti-seizure drugs accounted for 133 patients (12.5%) among 1067 patients with idiosyncratic DILI. Compared to other agents, patients with anti-seizure DILI were younger (31 vs 41 years; p = 0.31), were more often females (52% vs 46%; p = 0.19) and had a lower frequency of jaundice (41% vs 59%, p = 0.001), MELD score (14.5 vs 16.5; p = 0.02) and mortality (9.8% vs 15.7%, p = 0.03). Anti-seizure DILI exhibited a greater frequency of hypersensitivity skin rashes (75% vs 22%, p < 0.001), including DRESS (51% vs 13%, p < 0.001) and SJS/TEN (19% vs1%, p < 0.001). A total of 18 different anti-seizure agents were responsible for DILI, largely contributed by carbamazepine (n = 36), phenytoin (n = 71), phenobarbitone (n = 8) and valproate (n = 14) which accounted for 89% of cases and 85% of 13 deaths., Conclusions: Anti-seizure DILI are caused predominantly by first generation drugs. Newer agents account for < 10% of cases. Hypersensitivity reaction is the most common phenotypic presentation. Both severity and mortality are lower with anti-seizure DILI., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Acute appendicitis remains the most common general surgical emergency seen in most hospitals and the most common cause of acute abdomen requiring surgical intervention., Aim: The aim was to study the intraoperative features and postoperative outcomes of appendicular perforation in adults., Objectives: First, to study the incidence, clinical presentation, and complications of perforated appendicitis in a tertiary care hospital. Second, to study morbidity and mortality in an operated case of perforated appendicitis., Materials and Methods: This prospective observational study was conducted at a tertiary care centre in a government setup from August 2017 to July 2019. Data were collected from patients ( N =126) who had an intraoperative finding of perforated appendicitis. The inclusion criteria are as follows: patients over the age of 12 with a perforated appendix, as well as any patients with intraoperative findings like perforated appendicitis, gangrenous perforated appendicitis, or a disintegrated appendix. The exclusion criteria are as follows: all patients with appendicitis below 12 years of age with perforated appendicitis; all patients with appendicitis with intraoperative findings of acute nonperforated appendicitis; and all patients with intraoperative findings of an appendicular lump or mass., Results: Perforation was found in 13.8% of the cases of acute appendicitis in this study. With a mean age of 32.5 years, the most common age of presentation in perforated appendicitis was 21-30 years. The most prevalent presenting symptom in all patients (100%) was abdominal pain, followed by vomiting (64.3%) and fever (38.9%). Patients with perforated appendicitis had a 72.2% complication rate. Peritoneal pollution of more than 150 ml was linked to a 100% increase in morbidity and mortality (54.5%). The mean duration of the hospital stay in patients with a perforated appendix was 7.28±5 days. Surgical site infection (42%) was the most common early complication, followed by wound dehiscence (16.6%), intestinal obstruction (1.6%), and faecal fistula (1.6%). The most common late complications were intestinal obstruction (2.4%), intra-abdominal abscess (1.6%), and incisional hernia (1.6%). The mortality rate in patients with perforated appendicitis was 4.8%., Conclusion: To conclude, prehospital delay was an important factor contributing to appendicular perforation and leading to adverse outcomes. A higher rate of morbidity and prolonged duration of hospital stay were seen in patients with delayed presentation, with features of generalised peritonitis and perforation of the base of the appendix. Delayed presentations in as elderly population with underlying co-morbid conditions associated with severe peritoneal contamination were associated with higher mortality (26%) in perforated appendicitis. Conventional surgery and open procedures remain the preferred approach in a government setup like ours where laparoscopy may not be available during odd hours. Since this study was done over a short duration, certain long-term outcomes could not be assessed. Hence, there is still a need for further studies., Competing Interests: None declared.Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Patients with cirrhosis and subcentimeter lesions on liver ultrasound are recommended to undergo short-interval follow-up ultrasound because of the presumed low risk of primary liver cancer (PLC)., Aims: The aim of this study is to characterize recall patterns and risk of PLC in patients with subcentimeter liver lesions on ultrasound., Methods: We conducted a multicenter retrospective cohort study among patients with cirrhosis or chronic hepatitis B infection who had subcentimeter ultrasound lesions between January 2017 and December 2019. We excluded patients with a history of PLC or concomitant lesions ≥1 cm in diameter. We used Kaplan Meier and multivariable Cox regression analyses to characterize time-to-PLC and factors associated with PLC, respectively., Results: Of 746 eligible patients, most (66.0%) had a single observation, and the median diameter was 0.7 cm (interquartile range: 0.5-0.8 cm). Recall strategies varied, with only 27.8% of patients undergoing guideline-concordant ultrasound within 3-6 months. Over a median follow-up of 26 months, 42 patients developed PLC (39 HCC and 3 cholangiocarcinoma), yielding an incidence of 25.7 cases (95% CI, 6.2-47.0) per 1000 person-years, with 3.9% and 6.7% developing PLC at 2 and 3 years, respectively. Factors associated with time-to-PLC were baseline alpha-fetoprotein >10 ng/mL (HR: 4.01, 95% CI, 1.85-8.71), platelet count ≤150 (HR: 4.90, 95% CI, 1.95-12.28), and Child-Pugh B cirrhosis (vs. Child-Pugh A: HR: 2.54, 95% CI, 1.27-5.08)., Conclusions: Recall patterns for patients with subcentimeter liver lesions on ultrasound varied widely. The low risk of PLC in these patients supports short-interval ultrasound in 3-6 months, although diagnostic CT/MRI may be warranted for high-risk subgroups such as those with elevated alpha-fetoprotein levels., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Biotinidase deficiency is an autosomal recessive condition caused by pathogenic variants in the BTD gene. Resultant deficiency of free biotin leads to impaired activity of the enzyme carboxylase and related neurologic, dermatologic, and ocular symptoms. Many of these are reversible on treatment, but early recognition and commencement of biotin supplementation are critical. This practice is especially important in countries where routine neonatal screening for biotinidase deficiency is not performed. In this report comprising 14 patients from multiple centers, we demonstrate the MR imaging patterns of this disorder at various age groups. Knowledge of these patterns in the appropriate clinical context will help guide early diagnosis of this treatable metabolic disorder., (© 2023 by American Journal of Neuroradiology.)

The deposition of proteins in the form of amyloid fibrils is closely associated with several serious diseases. The events that trigger the conversion from soluble functional proteins into insoluble amyloid are not fully understood. Many proteins that are not associated with disease can form amyloid with similar structural characteristics as the disease-associated fibrils, which highlights the potential risk of cross-seeding of disease amyloid by amyloid-like structures encountered in our surrounding. Of particular interest are common food proteins that can be transformed into amyloid under conditions similar to cooking. We here investigate cross-seeding of amyloid-β (Aβ), a peptide known to form amyloid during the development of Alzheimer's disease, by 16 types of amyloid fibrils derived from food proteins or peptides. Kinetic studies using thioflavin T fluorescence as output show that none of the investigated protein fibrils accelerates the aggregation of Aβ. In at least two cases (hen egg lysozyme and oat protein isolate) we observe retardation of the aggregation, which appears to originate from interactions between the food protein seeds and Aβ in aggregated form. The results support the view that food-derived amyloid is not a risk factor for development of Aβ pathology and Alzheimer's disease., (© 2023. The Author(s).)

Background: Despite the generally accepted World Health Organization guidelines on semen analysis, an individual's results can display significant variation when performed across time or in different laboratories. Semen parameters are in fact highly variable measures that can differ significantly between various analyses. Numerous researchers have discovered a wide range of semen parameters within each individual male, but only a few studies included the analysis of semen parameters variability in patients with infertility. The aim of this study was to evaluate the inter- and intra-individual variability of semen parameters in men of reproductive age with normozoospermia and those with oligozoospermia., Methods: Five hundred and thirteen who provided ≥ 2 semen samples (798 samples in total) using an at-home mail-in kit over a period of about 2 years were enrolled in the study. Semen samples collection using Give Legacy at-home mail-in semen collection kit; semen analysis at a CLIA-certified laboratory., Results: The degree of intra-subject variation across all semen parameters was lower in men with normozoospermia compared to men with oligozoospermia. Men with normozoospermia furthermore demonstrated a level of intra-subject variation that was lower than inter-subject variation across all measured parameters. No association was observed between intra-subject coefficients of variation in any of the semen parameters, including sperm concentration, sperm count, motile sperm count, total motility, progressive motility, the percentage of sperm with normal morphology, and the age, duration of abstinence, and BMI of the men., Conclusion: The results of this observational study confirm the significant variability in semen parameters in men with normozoospermia and oligozoospermia, as measured from at-home semen collection kit samples. This further underscore the importance of securing multiple samples for analysis to provide a robust assessment of male fertility., (© 2022. The Author(s).)

Age-related macular degeneration (AMD) is a debilitating eye disease that tends to affect people over the age of 55. Lipofuscins are autofluorescent, toxic byproducts of the visual cycle thought to contribute toward the progression of the disease. Targeting the accumulation of lipofuscin through catabolism may serve as a method for the early treatment of AMD. Thus, an enzymatic approach capable of degrading lipofuscin, cycloretinal (all -trans retinal dimer), was examined. A peroxidase from the organism Marasmius scorodonius (MsP1) has shown capability of degrading this toxic metabolite into nontoxic byproducts. A catalytic triad within MsP1 (D228, H365, and R388) was identified through multiple-sequence alignment and homology modeling and confirmed by kinetic analysis. MsP1-associated cleavage products were detected by gas chromatography-mass spectrometry (GC-MS), high-performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LC-MS), and liquid chromatography-tandem mass spectrometry (LC-MSMS). MsP1 degradation byproducts of cycloretinal show reduced cytotoxicity within cell culture (ARPE-19), demonstrating its potential as a gene therapeutic to alleviate the buildup of lipofuscin within AMD.

Introduction: Immunoallergic drug-induced liver injury (DILI) presenting with features of drug reaction with eosinophilia and systemic symptoms (DRESS) is a distinct phenotype. We describe the clinical characteristics, hepatitis pattern, severity, complications, and implicated medications in DILI patients with and without DRESS., Methods: Using established criteria, we analyzed DILI registry patients with and without DRESS from 1998 to 2021., Results: DILI associated with DRESS (DwD) comprised 179 among 943 cases (19%) of DILI. Compared with the cohort without DRESS, patients with DwD are more often women and have shorter latency, lesser degrees of injury ( P < 0.01), and lower mortality (7.8%) than those without DRESS (16%). Antiepileptic drugs (36%), sulfonamides (19%), antituberculosis drugs (14%), antibiotics (10%), and antiretroviral drugs (8%) account for 87% of the cases of DwD., Discussion: A limited number of drugs cause DwD, representing a fifth of patients with DILI. DwD is characterized by lesser degrees of liver injury and mortality likely because of earlier presentation., (Copyright © 2022 by The American College of Gastroenterology.)

Competing Interests: There are no conflicts of interest.

Background: Although hypertriglyceridemia (HTG) is a well-established cause of acute pancreatitis (AP), there are no definitive management guidelines. Studies comparing clinical severity and outcome of hypertriglyceridemia-induced acute pancreatitis (HTGAP) and non- HTGAP are scarce. Hence, the present study was undertaken., Materials and Methods: All consecutive patients admitted with AP from January 2017 to August 2021 at university teaching hospital were included in this study. Data with regards to patient demographics; clinical, laboratory, and radiologic parameters; management strategies; and outcome were collected and compared between HTGAP and non-HTGAP patients., Results: Overall, 550 patients with AP were admitted during the study period, of which 21 (3.8%) were HTG related. Mean age of HTGAP patients was 34.3 years (M: F = 14:7), and the mean serum triglyceride (TG) levels on admission were 3,718.9 mg/dL (range 1,094-11,991). Insulin infusion therapy was used in 18 patients with HTGAP and the target TG levels of ≤500 mg/dL was achieved in 4.2 days (mean). Compared to non-HTGAP patients, HTGAP patients had higher body mass index (29.2 vs. 25.6), higher clinical (BISAP 2.6 vs. 2.06) and radiologic severity scores (CT severity score 7.5 v/s 4.8), and required prolonged hospital stay (12.9 vs. 6.5 days)., Conclusion: HTGAP occurred in young patients with high BMI and was associated with more severe disease, that required prolonged hospitalization than patients with non-HTGAP. Insulin infusion therapy was effective in reducing serum TG levels., Competing Interests: There are no conflicts of interest., (Copyright: © 2022 Indian Journal of Endocrinology and Metabolism.)

Premise: Hedychium J. Koenig (Zingiberaceae) is endemic to the Indo-Malayan Realm and is known for its colorful and fragrant flowers. Historically, two different pollination syndromes characterize Hedychium: diurnal or bird pollination, and nocturnal or moth pollination. In this study, we aim to understand the evolution of nocturnal and diurnal flowers, and to test its putative association with lineage diversification in Hedychium., Methods: A molecular tree of Hedychium was used as a scaffold upon which we estimated ancestral character states, phylogenetic signals, and correlations for certain categorical and continuous floral traits. Furthermore, we used phylomorphospace and trait-dependent diversification rate estimation analyses to understand phenotypic evolution and associated lineage diversification in Hedychium., Results: Although floral color and size lacked any association with specific pollinators, white or pale flowers were most common in the early branching clades when compared to bright-colored flowers, which were more widely represented in the most-derived clade IV. Five categorical and two continuous characters were identified to have informative evolutionary patterns, which also emphasized that ecology may have played a critical role in the diversification of Hedychium., Conclusions: From our phylogenetic analyses and ecological observations, we conclude that specializations in pollinator interactions are rare in the hyperdiverse clade IV, thus challenging the role of both moth-specialization and bird-specialization as central factors in the diversification of Hedychium. However, our results also suggest that clade III (predominantly island clade) may show specializations, and future studies should investigate ecological and pollinator interactions, along with inclusion of new traits such as floral fragrance and anthesis time., (© 2022 Botanical Society of America.)

A 25-year-old male patient presented with palmoplantar keratoderma, dystrophic nails, severe plantar pain and oral leukokeratosis since birth. On genetic analysis, a heterozygous KRT6A gene missense mutation (c.1381G > A, p.Glu461Lys in exon 7) was identified by next-generation sequencing technology, consistent with pachyonychia congenita 6a. Oral simvastatin 40 mg was started once daily, and after 16 weeks of therapy, excellent improvement was noted in palmoplantar keratoderma and plantar pain. The maximum thickness of his foot callosity reduced by 4 mm on ultrasonography, and the Dermatology Life Quality Index score dropped significantly by eight points. These benefits may be attributed to inhibition of KRT6A gene expression, modulation of autophagy and mitophagy and Keap1-Nrf2 signalling activation; the latter two mechanisms of statins previously undiscussed in the context of pachyonychia congenita. Simvastatin and other statins are pathogenesis-targeted, disease-modifying therapy in pachyonychia congenita, therefore qualifying as a promising treatment avenue and warranting further clinical trials., (© 2022 Australasian College of Dermatologists.)

Burnout is a significant issue confronting the medical profession, to which radiology is no exception. Addressing burnout demands a full-spectrum response, in keeping with its complexity, prevalence, and significance. This manuscript brings together key techniques at the individual, peer, and institutional levels to offer a multifaceted approach to ameliorating radiologist burnout. Such an approach would begin by equipping physicians with the skillset necessary to identify signs of burnout in themselves and others. Institutions can work to validate the radiologists they employ and work toward mitigating the impact of occupational stressors. Lastly, engaging in conversations about burnout throughout the course of one's medical career can affect a sea change in the way burnout is envisioned, and treated., Competing Interests: Declaration of Competing Interest All authors confirm there are no known conflicts of interest associated with this publication. There has been no financial support for this work., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The Indo-Malayan Realm is a biogeographic realm that extends from the Indian Subcontinent to the islands of Southeast Asia (Malay Archipelago). Despite being megadiverse, evolutionary hypotheses explaining taxonomic diversity in this region have been rare. Here, we investigate the role of geoclimatic events such as Himalayan orogeny and monsoon intensification in the diversification of the ginger-lilies (Hedychium J.Koenig: Zingiberaceae). We first built a comprehensive, time-calibrated phylogeny of Hedychium with 75% taxonomic and geographic sampling. We found that Hedychium is a very young lineage that originated in Northern Indo-Burma, in the Late Miocene (c. 10.6 Ma). This was followed by a late Neogene and early Quaternary diversification, with multiple dispersal events to Southern Indo-Burma, Himalayas, Peninsular India, and the Malay Archipelago. The most speciose clade IV i.e., the predominantly Indo-Burmese clade also showed a higher diversification rate, suggesting its recent rapid radiation. Our divergence dating and GeoHiSSE results demonstrate that the diversification of Hedychium was shaped by both the intensifications in the Himalayan uplift as well as the Asian monsoon. Ancestral character-state reconstructions identified the occurrence of vegetative dormancy in both clades I and II, whereas the strictly epiphytic growth behavior, island dwarfism, lack of dormancy, and a distinct environmental niche were observed only in the predominantly island clade i.e., clade III. Finally, we show that the occurrence of epiphytism in clade III corresponds with submergence due to sea-level changes, suggesting it to be an adaptive trait. Our study highlights the role of recent geoclimatic events and environmental factors in the diversification of plants within the Indo-Malayan Realm and the need for collaborative work to understand biogeographic patterns within this understudied region. This study opens new perspectives for future biogeographic studies in this region and provides a framework to explain the taxonomic hyperdiversity of the Indo-Malayan Realm., (Copyright © 2022. Published by Elsevier Inc.)

Mobile health (mHealth) technologies stand poised to find broad application in the radiology space. They hold considerable promise for millions of patients in the United States, enabling at-home imaging and augmenting clinical decision-making. However, they often lie outside the ambit of FDA regulation and process vast quantities of data largely unprotected by HIPAA. This article explores features of federal mHealth policy relevant to imaging practice and advocates for greater regulatory clarity to assist radiologists, developers, and ultimately, patients.

The nanostructure, primarily particle orientation, controls mechanical and functional (e.g., mouthfeel, cell compatibility, optical, morphing) properties when macroscopic materials are assembled from nanofibrils. Understanding and controlling the nanostructure is therefore an important key for the continued development of nanotechnology. We merge recent developments in the assembly of biological nanofibrils, X-ray diffraction orientation measurements, and computational fluid dynamics of complex flows. The result is a digital twin, which reveals the complete particle orientation in complex and transient flow situations, in particular the local alignment and spatial variation of the orientation distributions of different length fractions, both along the process and over a specific cross section. The methodology forms a necessary foundation for analysis and optimization of assembly involving anisotropic particles. Furthermore, it provides a bridge between advanced in operandi measurements of nanostructures and phenomena such as transitions between liquid crystal states and in silico studies of particle interactions and agglomeration.

Artificial intelligence technology promises to redefine the practice of radiology. However, it exists in a nascent phase and remains largely untested in the clinical space. This nature is both a cause and consequence of the uncertain legal-regulatory environment it enters. This discussion aims to shed light on these challenges, tracing the various pathways toward approval by the US Food and Drug Administration, the future of government oversight, privacy issues, ethical dilemmas, and practical considerations related to implementation in radiologist practice., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Evaluation of the biomechanical response of tooth with perforation repair is important to attain predictable prognosis. It may remain altered even after perforation repair due to the loss of tooth structure., Aim: The aim of this study is to assess and compare the effect of pulpal floor perforation repair of different sites with biodentine, on the biomechanical response of mandibular molar through 3-dimensional (3D) finite element analysis (FEA)., Materials and Methods: Five different 3D models were constructed based on the site of perforation on the pulpal floor using cone-beam computed tomographic images of an extracted mandibular molar. Perforation size was standardized and simulated to be repaired with calcium silicate-based cement. A force of 200 N was applied simulating normal occlusal loads. Static linear FEA was performed using the Ansys FEA software. Tensile stresses were evaluated (P max )., Statistical Analysis Used: The data were evaluated using the independent t-test ( P = 0.05)., Results: All the simulated models with perforation repair exhibited higher stress values than their equivalent sites in the control group. The P max values of the repaired models were highest in central furcal perforation, followed by buccal furcal perforation. However, there was no statistically significant difference in the stress accumulation among the different repaired perforation sites., Conclusion: The site of the pulpal floor perforation affected the stress distribution and accumulation. Central and buccal furcal perforation repairs on the pulpal floor with calcium silicate-based cement in mandibular molar are likely to have an increased risk of fracture., Competing Interests: There are no conflicts of interest., (Copyright: © 2022 Journal of Conservative Dentistry.)

Angiosperms possess various strategies to ensure reproductive success, such as stylar polymorphisms that encourage outcrossing. Here, we investigate the genetic basis of one such dimorphism that combines both temporal and spatial separation of sexual function, termed flexistyly. It is a floral strategy characterised by the presence of two morphs that differ in the timing of stylar movement. We performed a de novo assembly of the genome of Alpinia nigra using high-depth genomic sequencing. We then used Pool-seq to identify candidate regions for flexistyly based on allele frequency or coverage differences between pools of anaflexistylous and cataflexistylous morphs. The final genome assembly size was 2 Gb, and showed no evidence of recent polyploidy. The Pool-seq did not reveal large regions with high F ST values, suggesting large structural chromosomal polymorphisms are unlikely to underlie differences between morphs. Similarly, no region had a 1:2 mapping depth ratio which would be indicative of hemizygosity. We propose that flexistyly is governed by a small genomic region that might be difficult to detect with Pool-seq, or a complex genomic region that proved difficult to assemble. Our genome will be a valuable resource for future studies of gingers, and provides the first steps towards characterising this complex floral phenotype.

Protein nanofibrils (PNFs) represent a promising class of biobased nanomaterials for biomedical and materials science applications. In the design of such materials, a fundamental understanding of the structure-function relationship at both molecular and nanoscale levels is essential. Here we report investigations of the nanoscale morphology and molecular arrangement of amyloid-like PNFs of a synthetic peptide fragment consisting of residues 11-20 of the protein β-lactoglobulin (β-LG 11-20 ), an important model system for PNF materials. Nanoscale fibril morphology was analysed by atomic force microscopy (AFM) that indicates the presence of polymorphic self-assembly of protofilaments. However, observation of a single set of 13 C and 15 N resonances in the solid-state NMR spectra for the β-LG 11-20 fibrils suggests that the observed polymorphism originates from the assembly of protofilaments at the nanoscale but not from the molecular structure. The secondary structure and inter-residue proximities in the β-LG 11-20 fibrils were probed using NMR experiments of the peptide with 13 C- and 15 N-labelled amino acid residues at selected positions. We can conclude that the peptides form parallel β-sheets, but the NMR data was inconclusive regarding inter-sheet packing. Molecular dynamics simulations confirm the stability of parallel β-sheets and suggest two preferred modes of packing. Comparison of molecular dynamics models with NMR data and calculated chemical shifts indicates that both packing models are possible., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

KIAA0753-related skeletal ciliopathy is a recently described recessive disorder causing skeletal dysplasia and overlapping features of certain ciliopathies; Joubert, Jeune and Oro-facial-digital syndromes. We describe a ninth case that expands the phenotype; a 10-year-old girl with rhizomelic short stature (-5.6 SD), macrocephaly, developmental delay, CNS anomalies (thin corpus callosum, bilateral ventriculomegaly), cone-rod dystrophy, nystagmus, mild conductive hearing loss and recurrent chest infections secondary to confirmed ciliary dyskinesia. Testing for FGFR3 achondroplasia-related hotspots and mucopolysaccharidosis were negative. Whole-exome sequencing, aged eight, via skeletal dysplasia panel analysis and subsequent whole-genome sequencing (via the 100,000 genomes project) found no cause. WGS data reanalysis using exomiser uncovered compound heterozygous pathogenic KIAA0753 variants (frameshift and splice site). Further clinical and radiological surveys were consistent with the expected phenotype. We discuss the emerging phenotype of this uncommon disorder. This report details the sixth published case of skeletal dysplasia in all cases of KIAA0753-related disease and the first case to describe a novel c.1830-2A>G splice variant. Our case is the eldest woman reported to date (aged ten years) and the only known case to report associated hearing loss, leg-length discrepancy, pectus carinatum, respiratory ciliary dyskinesia and late-onset (9 years old) neuro-degenerative regression., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Given the renewed policy focus on drug pricing and pharmaceutical innovation, this article examines the historical backdrop of efforts to integrate comparative effectiveness research into the FDA drug review process. Noting previous policy efforts over a decade ago, we characterize industry challenges and suggest a path forward.

Competing Interests: The authors report no funding and conflicts of interest. Précis: The NIOSH B Reader Program conducts pneumoconiosis screening for exposed industrial workers. It faces a broadened mandate, but declining physician participation and potentially extensive conflicts of interest. AI tools may offer a solution to both.

Objective: Pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) is a severe immune-mediated disorder. We aim to report the neurologic features of children with PIMS-TS., Methods: We identified children presenting to a large children's hospital with PIMS-TS from March to June 2020 and performed a retrospective medical note review, identifying clinical and investigative features alongside short-term outcome of children presenting with neurologic symptoms., Results: Seventy-five patients with PIMS-TS were identified, 9 (12%) had neurologic involvement: altered conciseness (3), behavioral changes (3), focal neurology deficits (2), persistent headaches (2), hallucinations (2), excessive sleepiness (1), and new-onset focal seizures (1). Four patients had cranial images abnormalities. At 3-month follow-up, 1 child had died, 1 had hemiparesis, 3 had behavioral changes, and 4 completely recovered. Systemic inflammatory and prothrombotic markers were higher in patients with neurologic involvement (mean highest CRP 267 vs 202 mg/L, p = 0.05; procalcitonin 30.65 vs 13.11 μg/L, p = 0.04; fibrinogen 7.04 vs 6.17 g/L, p = 0.07; d-dimers 19.68 vs 7.35 mg/L, p = 0.005). Among patients with neurologic involvement, these markers were higher in those without full recovery at 3 months (ferritin 2284 vs 283 μg/L, p = 0.05; d-dimers 30.34 vs 6.37 mg/L, p = 0.04). Patients with and without neurologic involvement shared similar risk factors for PIMS-TS (Black, Asian and Minority Ethnic ethnicity 78% vs 70%, obese/overweight 56% vs 42%)., Conclusions: Broad neurologic features were found in 12% patients with PIMS-TS. By 3-month follow-up, half of these surviving children had recovered fully without neurologic impairment. Significantly higher systemic inflammatory markers were identified in children with neurologic involvement and in those who had not recovered fully., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: To describe the respiratory trajectories and their correlation with motor function in an international pediatric cohort of patients with type 2 and nonambulant type 3 spinal muscular atrophy (SMA)., Methods: This was an 8-year retrospective observational study of patients in the International SMA Consortium (iSMAc) natural history study. We retrieved anthropometrics, forced vital capacity (FVC) absolute, FVC percent predicted (FVC%P), and noninvasive ventilation (NIV) requirement. Hammersmith Functional Motor Scale (HFMS) and revised Performance of Upper Limb (RULM) scores were correlated with respiratory function. We excluded patients in interventional clinical trials and on nusinersen commercial therapy., Results: There were 437 patients with SMA: 348 with type 2 and 89 with nonambulant type 3. Mean age at first visit was 6.9 (±4.4) and 11.1 (±4) years. In SMA type 2, FVC%P declined by 4.2%/y from 5 to 13 years, followed by a slower decline (1.0%/y). In type 3, FVC%P declined by 6.3%/y between 8 and 13 years, followed by a slower decline (0.9%/y). Thirty-nine percent with SMA type 2% and 9% with type 3 required NIV at a median age 5.0 (1.8-16.6) and 15.1 (13.8-16.3) years. Eighty-four percent with SMA type 2% and 80% with type 3 had scoliosis; 54% and 46% required surgery, which did not significantly affect respiratory decline. FVC%P positively correlated with HFMS and RULM scores in both subtypes., Conclusions: In SMA type 2 and nonambulant type 3, lung function declines differently, with a common leveling after age 13 years. Lung and motor function correlated in both subtypes. Our data further define the milder SMA phenotypes and provide information to benchmark the long-term efficacy of new treatments for SMA., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

COVID-19 outbreak is major pandemic affecting lakhs of people all across the globe. Along with other nonspecific clinical features, reports mention anosmia to be an important symptom in COVID-19 positive patients. To study the prevalence of anosmia in confirmed COVID-19 patients, in Indian population and to ascertain its significance as a symptom of COVID 19. Study was done at a tertiary care COVID treating hospital. While eliciting detailed history from Covid-19 positive patients, all patients were asked about symptom of anosmia. Same was asked from control group of subjects who were COVID-19 negative. The history of anosmia was also elicited on discharge after the patients tested negative for COVID-19. 74 patients formed part of the study. 11 of 74 (14.8%) patients had anosmia. On using the chi square test for significance the difference was significant ( p  < .01), suggesting anosmia to be a significant clinical feature in COVID-19 patients. On comparing with world literature it was observed that the prevalence of anosmia is higher in European population as compared to Indian Also the symptom of anosmia improved when the patient recovered from the disease. Prevalence of new onset anosmia in Indian population with COVID-19 is 14.8%. Symptom of anosmia in present times should be considered as a important clinical feature and should raise a suspicion of COVID-19. The prevalence of anosmia in Indian population is much lesser than that reported in European population., Competing Interests: Conflict of interestThe authors declare that they have no conflict of interests., (© Association of Otolaryngologists of India 2020.)