Pathogenic SCN2A variants cause early-stage dysfunction in patient-derived neurons.

Pathogenic heterozygous variants in SCN2A, which encodes the neuronal sodium channel NaV1.2, cause different types of epilepsy or intellectual disability (ID)/autism without seizures. Previous studies using mouse models or heterologous systems suggest that NaV1.2 channel gain-of-function typically causes epilepsy, whereas loss-of-function leads to ID/autism. How altered channel biophysics translate into patient neurons remains unknown. Here, we investigated iPSC-derived early-stage cortical neurons from ID patients harboring diverse pathogenic SCN2A variants [p.(Leu611Valfs*35); p.(Arg937Cys); p.(Trp1716*)] and compared them with neurons from an epileptic encephalopathy (EE) patient [p.(Glu1803Gly)] and controls. ID neurons consistently expressed lower NaV1.2 protein levels. In neurons with the frameshift variant, NaV1.2 mRNA and protein levels were reduced by ~ 50%, suggesting nonsense-mediated decay and haploinsufficiency. In other ID neurons, only protein levels were reduced implying NaV1.2 instability. Electrophysiological analysis revealed decreased sodium current density and impaired action potential (AP) firing in ID neurons, consistent with reduced NaV1.2 levels. In contrast, epilepsy neurons displayed no change in NaV1.2 levels or sodium current density, but impaired sodium channel inactivation. Single-cell transcriptomics identified dysregulation of distinct molecular pathways including inhibition of oxidative phosphorylation in neurons with SCN2A haploinsufficiency and activation of calcium signaling and neurotransmission in epilepsy neurons. Together, our patient iPSC-derived neurons reveal characteristic sodium channel dysfunction consistent with biophysical changes previously observed in heterologous systems. Additionally, our model links the channel dysfunction in ID to reduced NaV1.2 levels and uncovers impaired AP firing in early-stage neurons. The altered molecular pathways may reflect a homeostatic response to NaV1.2 dysfunction and can guide further investigations.

Knowledge gaps and confidence in counseling about aneuploidy screening and testing: A survey of prenatal care clinicians.

OBJECTIVES: Comprehensive counseling on prenatal genetic screening and diagnostic testing is challenging for clinicians. We sought to identify baseline clinician knowledge of prenatal genetic screening and diagnostic testing and needs to promote counseling aligned with ACOG recommendations. METHODS: We performed an anonymous, cross-sectional survey of clinicians at two unaffiliated, tertiary academic institutions to assess the knowledge of, confidence in, and time spent counseling on prenatal genetic screening and diagnostic testing. Stata (Version 17, College Station, TX) was used to perform descriptive statistics. Deductive and inductive coding was used to analyze responses regarding ideal education resources. RESULTS: The survey response rate was 78% (100/129). Only 36% of respondents correctly answered knowledge questions about prenatal genetic screening and diagnostic testing. A majority, 59% (16/39), of those confident or extremely confident in counseling were unable to answer all questions accurately. Respondents reported a median of 5.6 min (95% CI 4.9-6.4 min) spent counseling. Thematic analysis of free responses revealed desire for visual tools that discuss financial costs and patient values. CONCLUSIONS: Surveyed clinicians demonstrated deficiencies in knowledge about prenatal genetic counseling. To provide better and more comprehensive care, we noted a desire for the development of formalized resources for clinician and patient education.

Optimization of CO fermentation by Clostridium carboxidivorans in batch reactors: Effects of the medium composition.

OBJECTIVES: The objective of this study was to investigate the effects of medium composition on CO fermentation by Clostridium carboxidivorans. The focus was to reduce the medium cost preserving acceptable levels of solvent production. METHODS: Yeast extract (YE) concentration was set in the range of 0-3 g/L. Different reducing agents were investigated, including cysteine-HCl 0.6 g/L, pure cysteine 0.6 g/L, sodium sulphide (Na2S) 0.6 g/L, cysteine-sodium sulphide 0.6 g/L and cysteine-sodium sulphide 0.72 g/L. The concentration of the metal solution was decreased down to 25 % of the standard value. Fermentation tests were also carried out with and without tungsten or selenium. RESULTS: The results demonstrated that under optimized conditions, namely yeast extract (YE) concentration set at 1 g/L, pure cysteine as the reducing agent and trace metal concentration reduced to 75 % of the standard value, reasonable solvent production was achieved in less than 150 h. Under these operating conditions, the production levels were found to be 1.39 g/L of ethanol and 0.27 g/L of butanol. Furthermore, the study revealed that selenium was not necessary for C. carboxidivorans fermentation, whereas the presence of tungsten played a crucial role in both cell growth and solvent production. CONCLUSIONS: The optimization of the medium composition in CO fermentation by Clostridium carboxidivorans is crucial for cost-effective solvent production. Tuning the yeast extract (YE) concentration, using pure cysteine as the reducing agent and reducing trace metal concentration contribute to reasonable solvent production within a relatively short fermentation period. Tungsten is essential for cell growth and solvent production, while selenium is not required.

Pediatric emergency care admissions for somatic symptom disorders during the COVID-19 pandemic.

During the COVID-19 pandemic, children and adolescents with psychiatric disorders experienced an exacerbation of their symptoms with more access to the emergency department (ED). However, little is known about the experience of somatic symptom disorders (SSDs) during the COVID-19 pandemic in children. Therefore, we aimed to compare the rates of pediatric ED admissions for SSDs before and during the COVID-19 pandemic and to understand whether the relative risk of ED admissions for SSDs changed between the two periods. We retrospectively enrolled all children between 4 and 14 years admitted for SSDs in the pediatric ED of Santobono-Pausilipon Hospital, Naples, Italy, from March 11th, 2020, to March 11th, 2021 (pandemic period), and in the same time period of the previous year (pre-pandemic period). We identified 205/95,743 (0,21%) children with SSDs presenting in ED in the pre-pandemic year and 160/40,165 (0,39%) in the pandemic year (p < 0.05). Considering the accesses for age, we observed a relative decrease of the accesses for SSDs over 12 years old (IRR 0,59; CI 0,39-0,88), while we found no differences under 12 years old (IRR 0,87; CI 0,68-1,10).   Conclusion: In this study, we found that despite the massive decrease in pediatric admissions due to the COVID-19 pandemic, somatic symptom disorders' admissions to the pediatric ED increased, suggesting an impact of the pandemic also on pediatric psychiatric disorders. What is Known: • During the COVID -19 pandemic, children and adolescents with a psychiatric disorder experienced exacerbation of their symptoms with more accesses in Emergency Department. What is New: • We found that despite the massive decrease of the pediatric admissions due to the COVID-19 pandemic, somatic symptom disorders admissions in healthy children to the pediatric Emergency Department increased ,suggesting an impact of the pandemic also on the pediatric psychiatric disorders.

The Erice 58 Charter on 'The health of migrants. An equity challenge for the public health system'.

Abstract: The Erice 58 Charter titled "The Health of Migrants: a Challenge of Equity for the Public Health System", was unanimously approved at the conclusion of the 58th Residential Course of the School of Epidemiology and Preventive Medicine 'Giuseppe D'Alessandro' entitled "The Health of Migrants: a Challenge of Equity for the Public Health System. Epidemiological, clinical-relational, regulatory, organisational, training and public communication aspects at international, national and local level', which took place from 28 March to 2 April 2022 in Erice (Sicily, Italy), at the 'Ettore Majorana' Foundation and Centre for Scientific Culture. The Course was promoted by the Italian Society of Migration Medicine (S.I.M.M.) and the Italian Society of Hygiene, Preventive Medicine and Public Health (SItI), with the collaboration and patronage of the Istituto Superiore di Sanità (ISS). 72 learners participated (mainly resident doctors in 'Hygiene and Preventive Medicine' but also other health service professionals), whose average age was 37 years; on the basis of territorial origin, 13 of the 20 Italian regions were represented. During the intense learning experience, which consisted of 18 frontal lessons (with 20 lecturers from the bio-medical, socio-anthropological and journalistic fields) and 7 working group sessions (supported by 4 classroom tutors in addition to the lecturers) in 'blended learning' mode, the various dimensions and critical issues related to the possibility of guaranteeing truly inclusive health policies for foreigners/migrants, throughout the country, were identified and discussed from an 'Health Equity' perspective. This enabled a small editorial group to draw up the basic document that, in the last session of the Course, was discussed and modified by all participants into the version of the 'Erice 58 Charter' presented here.

Comparison of cost changes due to the COVID-19 pandemic for Dermatology residency applications in the USA.

We performed a cost estimation of dermatology residency applications prior to COVID-19 pandemic restrictions (2016-2020) and during the COVID-19 pandemic (2021) and surveyed dermatology programme directors to assess the impact of virtual interviews. We found that COVID-19 virtual interviews significantly reduced the cost of applications. We understand that the changes forced by the pandemic were challenging and not ideal; however, the online aspect of interviews provided a way for applicants to save a significant amount of money.

Patients with Lemierre syndrome have a high risk of new thromboembolic complications, clinical sequelae and death: an analysis of 712 cases.

BACKGROUND: Lemierre syndrome is characterized by head/neck vein thrombosis and septic embolism usually complicating an acute oropharyngeal bacterial infection in adolescents and young adults. We described the course of Lemierre syndrome in the contemporary era. METHODS: In our individual-level analysis of 712 patients (2000-2017), we included cases described as Lemierre syndrome if these criteria were met: (i) primary site of bacterial infection in the head/neck; (ii) objectively confirmed local thrombotic complications or septic embolism. The study outcomes were new or recurrent venous thromboembolism or peripheral septic lesions, major bleeding, all-cause death and clinical sequelae. RESULTS: The median age was 21 (Q1-Q3: 17-33) years, and 295 (41%) were female. At diagnosis, acute thrombosis of head/neck veins was detected in 597 (84%) patients, septic embolism in 582 (82%) and both in 468 (80%). After diagnosis and during in-hospital follow-up, new venous thromboembolism occurred in 34 (5.2%, 95% CI 3.8-7.2%) patients, new peripheral septic lesions became evident in 76 (11.7%; 9.4-14.3%). The rate of either was lower in patients who received anticoagulation (OR: 0.59; 0.36-0.94), higher in those with initial intracranial involvement (OR: 2.35; 1.45-3.80). Major bleeding occurred in 19 patients (2.9%; 1.9-4.5%), and 26 died (4.0%; 2.7-5.8%). Clinical sequelae were reported in 65 (10.4%, 8.2-13.0%) individuals, often consisting of cranial nerve palsy (n = 24) and orthopaedic limitations (n = 19). CONCLUSIONS: Patients with Lemierre syndrome were characterized by a substantial risk of new thromboembolic complications and death. This risk was higher in the presence of initial intracranial involvement. One-tenth of survivors suffered major clinical sequelae.

Serial scanning with 99mTc-3, 3-diphosphono-1, 2-propanodicarboxylic acid (99mTc-DPD) for early detection of cardiac amyloid deposition and prediction of clinical worsening in subjects carrying a transthyretin gene mutation.

BACKGROUND: To determine the capability of 99mTc-DPD scintigraphy to detect early cardiac involvement and predict clinical worsening in transthyretin (TTR) gene mutation patients. METHODS: Eleven mutated subjects with normal interventricular septum (IVS) thickness, NT-proBNP level and no cardiac symptoms underwent three seriate 99mTc-DPD scans (visually and semiquantitatively analyzed), and was followed-up for 5-8-years. RESULTS: Six patients showed no myocardial accumulation in all scans. Increased IVS thickness occurring in one patient 4 years after the last scan was the only abnormal finding in these patients; no cardiac symptoms developed during the follow-up. In three patients, cardiac radiotracer uptake was found at enrollment; other laboratory/instrumental abnormal findings occurred later and cardiac symptoms developed during the follow-up period. Two patients had a negative 99mTc-DPD scan at enrollment and showed cardiac uptake in the following scans. Increased mean left-ventricular (LV) wall thickness was found 3 years after positive scintigraphy; NT-proBNP increased later in one patient. These patients developed cardiac symptoms during the follow-up period. CONCLUSIONS: 99mTc-DPD scan detects cardiac involvement in subjects with TTR gene mutation earlier than ECG, echocardiography and biochemical markers, occurring some years before the fulfillment of current diagnostic criteria for cardiac amyloidosis. A positive 99mTc-DPD scan predicts cardiac symptoms onset.

'Colouring' wipes phenomenon: a peculiar skin pigmentation induced by ascorbic acid observed during lockdown.

During the SARS-CoV-2 (COVID-19) pandemic, an unusual outbreak of yellow-brown pigmentation on the skin of children was reported. Because of the restrictions on movement promulgated during the lockdown, most consultancies were performed using teledermatology. Data concerning personal care products and application of topical substances were collected, which revealed use of the same brand of wipes for all patients. A liquid chromatography-mass spectrometry analysis was performed to compare the components of the wipes before and after the observation of the pigmentation, in order to detect the responsible substance. This analysis revealed a level about 10-fold higher than normal of ascorbic acid and its oxidation products (dehydroascorbic acid and L-threonic acid) in the wipes associated with the pigmentation. These 'colouring wipes' represent a peculiar but harmless phenomenon that highlights the importance of careful questioning about personal care products used by patients.

Short communication: Seroprevalence of paratuberculosis in Italian water buffaloes (Bubalus bubalis) in the region of Campania.

Paratuberculosis is a chronic enteric disease affecting virtually all ruminants, but only anecdotal information is currently available about the occurrence of this disease in water buffaloes (Bubalus bubalis). We carried out a survey study aimed at determining the prevalence of paratuberculosis in 2 provinces in the region of Campania, Italy, where about half of all Italian buffaloes are reared. From May 2017 to December 2018, we collected 201,175 individual serum samples from 995 buffalo herds. The sera were collected from animals over 24 mo old and were tested using a commercial ELISA test. The herd-level apparent prevalence result was 54.7%, and the animal-level apparent prevalence was 1.8%. The herd-level true prevalence was estimated using a Bayesian approach, demonstrating a high herd-level prevalence of paratuberculosis in water buffaloes from the Campania area. These findings suggest that the urgent adoption of paratuberculosis herd-control programs for water buffaloes in this area would be beneficial.

Decarbonizing the energy supply one pandemic at a time.

This study explores different energy consumption vectors during the first year of the COVID-19 pandemic in Portugal. Most of the workforce started working from home and resource consumption significantly shifted towards the domestic sector. The ensuing confinement protocols caused a shift in everyday life, which in turn significantly altered the energy supply and demand landscape. This event, although catastrophic in terms of loss of human life and economic development, can provide us with valuable data to study the potential of new strategies to achieve EU 2050 Energy goals. It was investigated whether the pandemic has opened a path and provided us with a partial answer to decarbonization in the form of home office practices as a possible energy efficiency measure. The present study shows that, in Portugal, there was a 15.7% reduction of primary energy consumption (accounting for electricity, natural gas and transport fuels) compared to 2019. The data suggest that actions targeting reduced mobility, such as home office practices and the decentralization of the workforce, could be a relevant energy efficiency measure.

The rebel thyroid of a revolutionary First Lady.

Nadezda Krupskaya, the revolutionary Russian and Lenin's wife, was affected by Graves' disease and many photos and portraits, including the painting of 1933 by Ivan Vladimirovich Kosmin, highlight evident goiter and exoftalmos. To treat Graves' disease, Krupskaya underwent to surgery performed by Theodor Kocher, considered the father of the modern thyroid surgery.

Responses of monogenean species to variations in abiotic parameters in tilapiculture.

Fish farming is becoming an increasingly popular agricultural activity, and water quality in these environments is a major concern. Fish parasites, such as monogeneans, respond to changes in abiotic conditions, either with an increase or decrease in population. This study aimed to identify gill monogeneans and analyse their relationships with abiotic factors during the ontogenetic development of Nile tilapia over the fish culture cycle in Mato Grosso do Sul, Brazil. Fish were sampled monthly for eight months, and a total of 200 fish were collected. The physical and chemical water parameters were measured and correlated with the abundance of each monogenean species. Over the fish culture cycle, the physical and chemical parameters fluctuated, and the water quality decreased. The parasites found included Cichlidogyrus tilapiae, Cichlidogyrus thurstonae, Cichlidogyrus sclerosus, Cichlidogyrus halli and Scutogyrus longicornis. The abundances of all species showed significant differences during ontogenetic development (body size) and C. tilapiae, C. sclerosus, C. thurstonae and S. longicornis were correlated with changes in abiotic conditions. However, C. halli was not significantly correlated with any of the evaluated physical or chemical parameters. Understanding how different monogenean species respond to changes in the physical and chemical parameters of water during a production cycle can prevent peaks in abundance and subsequent sanitary problems.

Surveillance of patients with differentiated thyroid cancer and indeterminate response: a longitudinal study on basal thyroglobulin trend.

PURPOSE: This is a longitudinal study of retrospective data aimed at verifying whether repeated measurements of serum non-stimulated thyroglobulin (Tg) allow the prediction of persistent disease in patients with differentiated thyroid cancer (DTC) and indeterminate response. METHODS: We examined 145 DTC patients with indeterminate response to therapy followed up for a median time of 68 months. Tg measurements and neck ultrasound (US) were performed every 6-12 months. The changes over time of repeated measurements of basal Tg were analyzed through the multilevel linear regression. RESULTS: Seventy (48.3%) out of 145 patients spontaneously achieved an excellent response, while persistent indeterminate response was observed in 62 (42.7%) patients. The remaining 13 (9.0%) patients had progression: 3/13 with biochemical disease and 10/13 with structural disease. Tg steadily increased in patients with progressive disease (mean percentage change + 27.1% at each follow-up visit), while Tg decreased in patients without any evidence of progression (mean percentage change - 8.8%). This different trend between the two groups was not related to either different values of median TSH at baseline (0.32 vs 0.28 mIU/l, respectively) or to different trend of TSH during follow-up (p = 0.76). Basal Tg values did not increase in three out of ten patients with structural disease that was identified by neck US. CONCLUSIONS: The importance of the study is that, in DTC patients with indeterminate response, rising values of unstimulated Tg, independently from the basal levels, may be useful to identify patients with progressive disease. These results are also useful to avoid unnecessary TSH stimulation.

Early Clinical Experience with Double Ring Implantation for Aortic and Mitral Valve Repair.

Reconstruction of cardiac valves is associated with reduced mortality, including in multiple valve surgery. However, multiple valve repair is still considered a challenge, even with established techniques. Recently, internal aortic ring annuloplasty has been introduced and could simplify multiple valve reconstruction. This study reports early results with double ring aortic and mitral valve repair. Three patients with bivalvular degenerative regurgitation were managed with combined aortic and mitral valve repair using double rings. Mean (±SD) age was 41 ± 21 years, preoperative left ventricular end-diastolic volume was 119 ± 53 mL/m2, and ejection fraction was 0.50 ± 0.07. Mean aortic ring diameter was 21 mm, and mitral rings averaged 32 mm. No operative mortalities or major complications were observed. No valve-related events occurred. Postoperative echo showed complete resolution of mitral and aortic regurgitation. Postoperative left ventricular end-diastolic volume decreased to 98 ± 10 mL/m2; no left ventricular outflow tract obstruction or significant transvalvular gradients were observed. Postoperative cardiac CTs showed an optimal three-dimensional configuration of aortic and mitral annuloplasty devices. This initial series demonstrated the feasibility and safety of combined aortic and mitral repair with double rings. Clinical and hemodynamic results were promising. Increasing application and more clinical experience with combined aortic and mitral double ring repair seems indicated.

Prediction of Gait without Physical Assistance after Inpatient Rehabilitation in Severe Subacute Stroke Subjects.

BACKGROUND: Gait recovery is one of the main therapeutic goals of the rehabilitation for patients after a stroke. OBJECTIVE: This study is aimed at describing the frequency of achievement of gait without physical assistance in poststroke subacute patients by the time of discharge from a rehabilitation hospitalized program. Secondarily, our goal is to identify gait without physical assistance predictors in this same population based on the admission's clinical and demographic conditions. METHODS: Data from 185 first unilateral hemispheric stroke patients that need physical assistance to walk at admission were analyzed. The sample was dichotomized into gait with physical assistance and gait without physical assistance to calculate the frequency of achievement of gait without assistance at discharge. Multivariate logistic modeling was applied to identify prognostic factors for regaining gait without physical assistance. RESULTS: Gait without assistance was achieved in 50.27% of the subjects. Five variables were identified for the prediction model: age (Odds ratio [OR] = .87, 95% confidence interval [CI] = .83-.92), gender (OR = .37, 95% CI = .14-.94), time between stroke and hospitalization (OR = .96, 95% CI = .94-.99), initial Berg Balance (OR = 1.52, 95% CI = 1.23-1.88), and initial lower limb Fugl Meyer (OR = 1.17, 95% CI = 1.07-1.27). CONCLUSIONS: Although discharge planning is complex, achievement of gait without physical assistance is undoubtedly a landmark to decide on hospitalization discharge. Half of this sample was able to walk without physical assistance at hospitalization discharge. Five clinical and demographic conditions at admission were found predictors of gait without physical assistance at inpatient discharge.

Cardiovascular diseases may play a negative role in the prognosis of amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: Only a few studies have considered the role of comorbidities in the prognosis of amyotrophic lateral sclerosis (ALS) and have provided conflicting results. METHODS: Our multicentre, retrospective study included patients diagnosed from 1 January 2009 to 31 December 2013 in 13 referral centres for ALS located in 10 Italian regions. Neurologists at these centres collected a detailed phenotypic profile and follow-up data until death in an electronic database. Comorbidities at diagnosis were recorded by main categories and single medical diagnosis, with the aim of investigating their role in ALS prognosis. RESULTS: A total of 2354 incident cases were collected, with a median survival time from onset to death/tracheostomy of 43 months. According to univariate analysis, together with well-known clinical prognostic factors (age at onset, diagnostic delay, site of onset, phenotype, Revised El Escorial Criteria and body mass index at diagnosis), the presence of dementia, hypertension, heart disease, chronic obstructive pulmonary disease, haematological and psychiatric diseases was associated with worse survival. In multivariate analysis, age at onset, diagnostic delay, phenotypes, body mass index at diagnosis, Revised El Escorial Criteria, dementia, hypertension, heart diseases (atrial fibrillation and heart failure) and haematological diseases (disorders of thrombosis and haemostasis) were independent prognostic factors of survival in ALS. CONCLUSIONS: Our large, multicentre study demonstrated that, together with the known clinical factors that are known to be prognostic for ALS survival, hypertension and heart diseases (i.e. atrial fibrillation and heart failure) as well as haematological diseases are independently associated with a shorter survival. Our findings suggest some mechanisms that are possibly involved in disease progression, giving new interesting clues that may be of value for clinical practice and ALS comorbidity management.

Ancient DNA reveals temporal population structure within the South-Central Andes area.

OBJECTIVES: The main aim of this work was to contribute to the knowledge of pre-Hispanic genetic variation and population structure among the South-central Andes Area by studying individuals from Quebrada de Humahuaca, North-western (NW) Argentina. MATERIALS AND METHODS: We analyzed 15 autosomal STRs in 19 individuals from several archaeological sites in Quebrada de Humahuaca, belonging to the Regional Developments Period (900-1430 AD). Compiling autosomal, mitochondrial, and Y-chromosome data, we evaluated population structure and differentiation among eight South-central Andean groups from the current territories of NW Argentina and Peru. RESULTS: Autosomal data revealed a structuring of the analyzed populations into two clusters which seemed to represent different temporalities in the Andean pre-Hispanic history: pre-Inca and Inca. All pre-Inca samples fell into the same cluster despite being from the two different territories of NW Argentina and Peru. Also, they were systematically differentiated from the Peruvian Inca group. These results were mostly confirmed by mitochondrial and Y-chromosome analyses. We mainly found a clearly different haplotype composition between clusters. DISCUSSION: Population structure in South America has been mostly studied on current native groups, mainly showing a west-to-east differentiation between the Andean and lowland regions. Here we demonstrated that genetic population differentiation preceded the European contact and might have been more complex than thought, being found within the South-central Andes Area. Moreover, divergence among temporally different populations might be reflecting socio-political changes occurred in the evermore complex pre-Hispanic Andean societies.