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In aircraft panel assembly, the interference fit unevenly distributed along the axial direction of the rivet holes leads to an uneven stress–strain field around the rivet holes. The uneven stress–strain fields of single rivets, when accumulated through multiple rivets, result in overall bending and twisting deformation, severely impacting the assembly coordination quality of the panel. This study introduces a numerical model using a single row of multiple rivets to explore cumulative deformation during both sequential and changing order riveting. The results show that the deformation in sequential riveting is mainly bending-oriented towards the driven head side, with the maximum displacement exhibiting a fluctuating accumulation trend as the number of rivets increase. In contrast, a changing riveting order can lead to a reduction in deformation accumulation. To reveal the technological mechanism behind deformation accumulation during the riveting process, a model correlating to the residual stress field was established. It was indicated that the continuous increase in the maximum equivalent bending moment in the axial section is the primary factor leading to deformation accumulation. Based on this finding, a pre-bending suppression method aimed at reducing the local maximum equivalent bending moment was proposed. Numerical calculations and experimental results showed that the maximum displacement of the specimen was reduced by 73.27%, proving that this method can effectively suppress the cumulative increase in deformation.

Analytical modeling of the squeezing force for aircraft wings and fuselage panels in the existing literature usually assumes uniform deformation of the rivets, while in reality, the deformation of the rivets is non-uniform. To achieve high-quality squeezing force modeling, this paper introduces Coulomb’s friction and four critical adjustments to the original equation: the non-uniform rivet/sheet interference along the sheet’s hole axial ordinate; the barreling effect when calculating the driven head’s volume; the spring-back of the driven head’s dimensions; the modified height of the driven head; and the modified sheet-hole expanded diameter considering the convex structure of the driven head. The calculated values of the proposed new model demonstrate an improved level of accuracy, particularly under squeeze ratios commonly encountered in the aerospace industry.

Abstract Background Galactose-deficient IgA1 (Gd-IgA1) has an increased tendency to form immunocomplexes with IgG in the serum, contributing to IgAN pathogenesis by accumulating in the glomerular mesangium. Several studies showed that glomerular IgG deposition in IgAN is an important cause of mesangial proliferation and glomerular damage. This study aims to determine the association of the positivity of IgG and the intensity of IgG staining with a poor renal prognosis. Methods A total of 943 IgAN patients were included in the study. Glomerular IgG staining negative and positive patients were compared using Oxford classification scores, histopathological evaluations, proteinuria, eGFR, albumin, blood pressures. IgG positive patients were classified as (+), (++), (+++) based on their staining intensity, and the association with the prognostic criteria was also evaluated. Results 81% (n = 764) of the patients were detected as IgG negative, while 19% (n = 179) were positive. Age, gender, body mass index, blood pressure, proteinuria, eGFR, uric acid values were similar in IgG positive and negative patients who underwent biopsy (p > 0.05). Intensity of glomerular IgG positivity was not found to be associated with diastolic and systolic blood pressure, urea, uric acid, age, eGFR, albumin, proteinuria (p > 0.05 for all, r = − 0.084, r = − 0.102, r = − 0.006, r = 0.062, r = 0.014, r = − 0.044, r = − 0.061, r = − 0.066, r = 0.150, respectively). There was no difference for histopathological findings between IgG (+), IgG (++), IgG (+++) groups (for all, p > 0.05). Conclusion Glomerular IgG negativity and positivity detected by routine IFM in IgAN patients is not associated with poor renal prognostic risk factors.

Introduction:Secondary hyperparathyroidism is considered an unconventional risk factor of vascular calcification in hemodialysis patients (HPs). An important factor of vascular calcification is vitamin D receptor activator used in the treatment of secondary hyperparathyroidism. This study aimed to investigate the change in pulse wave velocity (PWV) and fibroblast growth factor-23 (FGF-23), Klotho, and 25-hydroxyvitamin D [25(OH)D] levels as a result of 1-year treatment with paricalcitol or calcitriol among patients undergoing chronic dialysis.Methods:Eighty HPs were included in the study, and PWV measurements were obtained at the beginning and after 1 year of treatment. Serum Klotho and 25(OH)D levels were evaluated at the end of 1-year treatment with paricalcitol or calcitriol.Results:At the end of 1 year, FGF-23 levels in the paricalcitol group were significantly lower than those in the calcitriol group. Klotho and 25(OH)D levels were significantly higher in the paricalcitol group. The PWV at the beginning of the study was statistically similar between the two groups; in contrast, PWV at 1 year was significantly lower in the paricalcitol group than in the calcitriol group (p=0.002). When the PWV change was considered as the dependent variable, the most powerful determinant in multiple regression analysis was the FGF-23 level.Conclusion:In HPs, paricalcitol has a protective effect against vascular calcification compared with calcitriol treatment, owing to its positive effects on both parathyroid hormone and calcium-phosphorus balance. Therefore, paricalcitol should be the first choice in the treatment of secondary hyperparathyroidism.

Abstract Background We aimed to present the demographic characteristics, clinical presentation, and outcomes of our multicenter cohort of adult KTx recipients with COVID-19. Methods We conducted a multicenter, retrospective study using data of patients hospitalized for COVID-19 collected from 34 centers in Turkey. Demographic characteristics, clinical findings, laboratory parameters (hemogram, CRP, AST, ALT, LDH, and ferritin) at admission and follow-up, and treatment strategies were reviewed. Predictors of poor clinical outcomes were analyzed. The primary outcomes were in-hospital mortality and the need for ICU admission. The secondary outcome was composite in-hospital mortality and/or ICU admission. Results One hundred nine patients (male/female: 63/46, mean age: 48.4 ± 12.4 years) were included in the study. Acute kidney injury (AKI) developed in 46 (42.2%) patients, and 4 (3.7%) of the patients required renal replacement therapy (RRT). A total of 22 (20.2%) patients were admitted in the ICU, and 19 (17.4%) patients required invasive mechanical ventilation. 14 (12.8%) of the patients died. Patients who were admitted in the ICU were significantly older (age over 60 years) (38.1% vs 14.9%, p = 0.016). 23 (21.1%) patients reached to composite outcome and these patients were significantly older (age over 60 years) (39.1% vs. 13.9%; p = 0.004), and had lower serum albumin (3.4 g/dl [2.9–3.8] vs. 3.8 g/dl [3.5–4.1], p = 0.002), higher serum ferritin (679 μg/L [184–2260] vs. 331 μg/L [128–839], p = 0.048), and lower lymphocyte counts (700/μl [460–950] vs. 860 /μl [545–1385], p = 0.018). Multivariable analysis identified presence of ischemic heart disease and initial serum creatinine levels as independent risk factors for mortality, whereas age over 60 years and initial serum creatinine levels were independently associated with ICU admission. On analysis for predicting secondary outcome, age above 60 and initial lymphocyte count were found to be independent variables in multivariable analysis. Conclusion Over the age of 60, ischemic heart disease, lymphopenia, poor graft function were independent risk factors for severe COVID-19 in this patient group. Whereas presence of ischemic heart disease and poor graft function were independently associated with mortality.

Abstract Background Maintenance hemodialysis (MHD) patients are at increased risk for coronavirus disease 2019 (COVID-19). The aim of this study was to describe clinical, laboratory, and radiologic characteristics and determinants of mortality in a large group of MHD patients hospitalized for COVID-19. Methods This multicenter, retrospective, observational study collected data from 47 nephrology clinics in Turkey. Baseline clinical, laboratory and radiological characteristics, and COVID-19 treatments during hospitalization, need for intensive care and mechanical ventilation were recorded. The main study outcome was in-hospital mortality and the determinants were analyzed by Cox regression survival analysis. Results Of 567 MHD patients, 93 (16.3%) patients died, 134 (23.6%) patients admitted to intensive care unit (ICU) and 91 of the ones in ICU (67.9%) needed mechanical ventilation. Patients who died were older (median age, 66 [57–74] vs. 63 [52–71] years, p = 0.019), had more congestive heart failure (34.9% versus 20.7%, p = 0.004) and chronic obstructive pulmonary disease (23.6% versus 12.7%, p = 0.008) compared to the discharged patients. Most patients (89.6%) had radiological manifestations compatible with COVID-19 pulmonary involvement. Median platelet (166 × 103 per mm3 versus 192 × 103 per mm3, p = 0.011) and lymphocyte (800 per mm3 versus 1000 per mm3, p

Abstract Background The largest data on the epidemiology of primary glomerular diseases (PGDs) are obtained from the databases of countries or centers. Here, we present the extended results of the Primary Glomerular Diseases Study of the Turkish Society of Nephrology Glomerular Diseases (TSN-GOLD) Working Group. Methods Data of patients who underwent renal biopsy and received the diagnosis of PGD were recorded in the database prepared for the study. A total of 4399 patients from 47 centers were evaluated between May 2009 and May 2019. The data obtained at the time of kidney biopsy were analyzed. After the exclusion of patients without light microscopy and immunofluorescence microscopy findings, a total of 3875 patients were included in the study. Results The mean age was 41.5 ± 14.9 years. 1690 patients were female (43.6%) and 2185 (56.3%) were male. Nephrotic syndrome was the most common biopsy indication (51.7%). This was followed by asymptomatic urinary abnormalities (18.3%) and nephritic syndrome (17.8%). The most common PGD was IgA nephropathy (25.7%) followed by membranous nephropathy (25.6%) and focal segmental glomerulosclerosis (21.9%). The mean total number of glomeruli per biopsy was 17 ± 10. The mean baseline systolic blood pressure was 130 ± 20 mmHg and diastolic blood pressure was 81 ± 12 mmHg. The median proteinuria, serum creatinine, estimated GFR, and mean albumin values were 3300 (IQR: 1467–6307) mg/day, 1.0 (IQR: 0.7–1.6) mg/dL, 82.9 (IQR: 47.0–113.0) mL/min and 3.2 ± 0.9 g/dL, respectively. Conclusions The distribution of PGDs in Turkey has become similar to that in other European countries. IgA nephropathy diagnosed via renal biopsy has become more prevalent compared to membranous nephropathy.

We aimed to evaluate the effect of a combination of natural products on parameters related to inflammation, endothelial dysfunction, and oxidative stress in a cohort of familial Mediterranean fever (FMF) patients with Serum Amyloid A amyloidosis, in a non-randomized, 24-week open-label interventional study. Morinda citrifolia (anti-atherosclerotic-AAL), omega-3 (anti-inflammatory-AIC), and extract with Alaskan blueberry (antioxidant-AOL) were given to patients with FMF-related biopsy-proven AA amyloidosis. Patients were >18 years and had proteinuria (>3500 mg/day) but a normal estimated glomerular filtration rate (eGFR). Arterial flow-mediated dilatation (FMD), carotid intima media thickness (CIMT), and serum biomarkers asymmetric dimethylarginine (ADMA), high sensitivity C-reactive protein (hs-CRP), pentraxin (PTX3), malondialdehyde (MDA), Cu/Zn-superoxide dismutase (Cu/Zn-SOD), and glutathione peroxidase (GSH-Px) were studied at baseline and after 24 weeks of treatment. A total of 67 FMF-related amyloidosis patients (52 male (77.6%); median age 36 years (range 21–66)) were enrolled. At the end of a 24-week treatment period with AAL, AIC, and AOL combination therapy, ADMA, MDA, PTX3, hsCRP, cholesterol, and proteinuria were significantly decreased compared to baseline, while CuZn-SOD, GSH-Px, and FMD levels were significantly increased. Changes in inflammatory markers PTX3, and hsCRP were negatively correlated with FMD change, and positively correlated with decreases in proteinuria, ADMA, MDA, cholesterol, and CIMT. Treatment with AAL, AIC and AOL combination for 24 weeks were significantly associated with reduction in inflammatory markers, improved endothelial functions, and oxidative state. Efficient control of these three mechanisms can have long term cardiovascular and renal benefits for patients with AA amyloidosis.

Cardiovascular disease (CVD) remains underestimated in familial Mediterranean fever-associated AA amyloidosis (FMF-AA). We aimed to compare early markers of endothelial dysfunction and atherosclerosis in FMF-AA with a homozygous M694V mutation (Group 1 = 76 patients) in the Mediterranean fever (MEFV) gene and in patients with other genotypes (Group 2 = 93 patients). Measures of increased risk for future CVD events and endothelial dysfunction, including flow-mediated dilatation (FMD), pentraxin-3 (PTX3), and carotid intima-media thickness (cIMT), and fibroblast growth factor 23 (FGF23) as a marker of atherosclerotic vascular disease were compared between groups. The frequency of clinical FMF manifestations did not differ between the two groups apart from arthritis (76.3% in Group 1 and 59.1% in Group 2, p < 0.05). FMD was significantly lower in Group 1 when compared with Group 2 (MD [95% CI]: −0.6 [(−0.89)–(−0.31)]). cIMT, FGF23, and PTX3 levels were higher in Group 1 (cIMT MD [95% CI]: 0.12 [0.08–0.16]; FGF23 MD [95% CI]: 12.8 [5.9–19.6]; PTX3 MD [95% CI]: 13.3 [8.9–17.5]). In patients with FMF-AA, M694V homozygosity is associated with lower FMD values and higher cIMT, FGF23, and PTX3 levels, suggesting increased CVD risk profiles. These data suggest that a genotype–phenotype association exists in terms of endothelial dysfunction and atherosclerosis in patients with FMF-AA.

Abstract Background Autologous grafting, despite some disadvantages, is still considered the gold standard for reconstruction of maxillofacial bone defects. The aim of this study was to evaluate bone regeneration using bone marrow-derived mesenchymal stromal cells (MSCs) in a clinical trial, a less invasive approach than autologous bone grafting. This comprehensive clinical trial included subjects with severe mandibular ridge resorption. Methods The study included 11 subjects aged 52–79 years with severe mandibular ridge resorption. Bone marrow cells were aspirated from the posterior iliac crest and plastic adherent cells were expanded in culture medium containing human platelet lysate. The MSCs and biphasic calcium phosphate granules as scaffolds were inserted subperiosteally onto the resorbed alveolar ridge. After 4–6 months of healing, new bone formation was assessed clinically and radiographically, as were safety and feasibility. Bone at the implant site was biopsied for micro-computed topography and histological analyses and dental implants were placed in the newly regenerated bone. Functional outcomes and patient satisfaction were assessed after 12 months. Results The bone marrow cells, expanded in vitro and inserted into the defect together with biphasic calcium phosphate granules, induced significant new bone formation. The regenerated bone volume was adequate for dental implant installation. Healing was uneventful, without adverse events. The patients were satisfied with the esthetic and functional outcomes. No side effects were observed. Conclusions The results of this comprehensive clinical trial in human subjects confirm that MSCs can successfully induce significant formation of new bone, with no untoward sequelae. Hence, this novel augmentation procedure warrants further investigation and may form the basis of a valid treatment protocol, challenging the current gold standard. Trial registration EudraCT, 2012-003139-50. Registered on 21 August 2013. ClinicalTrials.gov, NCT 02751125. Registered on 26 April 2016.

Purpose. We aimed to investigate the factors influencing hemoglobin variability with inflammatory and nutritional parameters and its associations with all-cause mortality among hemodialysis patients. Methods. One hundred and sixty-nine patients during the entire 12 months were enrolled into the study. Fasting plasma glucose, creatinine, calcium, phosphorus, alkaline phosphatase, parathyroid hormone (PTH), C-reactive protein (CRP), serum iron, serum iron-binding capacity, and transferrin saturation were analyzed. We defined six groups: low, target range, high, low-amplitude fluctuation with low hemoglobin levels, low-amplitude fluctuation with high hemoglobin levels, and high-amplitude fluctuation. Body mass index (BMI), malnutrition-inflammation score (MIS), and Charlson Comorbidity Index were evaluated. Results. Hemoglobin variability was significantly correlated with age, platelet count, and number of hospitalization instances and inversely correlated with erythropoietin dose per body surface area. The coefficient of variation of hemoglobin showed a correlation with MIS and ferritin. The absolute level of hemoglobin showed a negative correlation between PTH, CRP, MIS, number of hospitalization instances and a positive correlation with albumin and BMI. High, low, and target-range groups showed survival advantage compared to the other three groups. In regression analysis, age, CRP levels, MIS, and BMI were the predictors of mortality. Conclusion. Inflammation and duration of anemia were the major predictors of hemoglobin variability. High-amplitude fluctuation predicts high mortality; on the contrary low-amplitude fluctuations is related to better survival. MIS was independently associated with mortality. This trial is registered with NCT03454906.

To determine the effect of hyperuricemia and allopurinol therapy on renal functions in chronic kidney disease (CKD) stage 3-4, we studied 96 patients in stage 3-4 CKD (57% male, age 65.3 ± 12.4 years). The mean estimated glomerular filtration rate (GFR) was 44.62 ± 14.38 iriL/ min/1.73 m 2 . The study patients were divided into non-allopurinol users (n = 47) and those using allopurinol (n = 49) in the last 12 months. Serum uric acid (UA) and C-reactive protein levels decreased after allopurinol therapy (P = 0.00 and P = 0.04, respectively), but no change was observed in the control group during the study period. In the allopurinol group, the mean GFR increased 3.3 ±1.2 mL/min/1.73 m 2 /year, while it decreased 1.3 ± 0.6 mL/min/1.73 m 2 in the control group during the follow-up period (P = 0.04); the patients in the allopurinol group exhibited lower levels of serum potassium, serum low-density lipoprotein (LDL) and renal resistance index (RRI) (P-values were

Background. New-onset diabetes after transplantation (NODAT) is associated with decreased graft survival and an increased risk for cardiovascular disease. The objective of this study was to evaluate the risk factors for development of NODAT and its’ relationship with arterial stiffness and left ventricular mass index (LVMI) in kidney transplant recipients. Methods. 159 kidney transplant recipients were selected from our transplantation center who underwent renal transplantation between years 2007 and 2010. Results. Among 159 patients, 57 (32.2%) patients were with NODAT who were significantly older than patients without diabetes (P: 0.0001). Patients with NODAT had significantly higher pulse wave velocity (PWv) (P: 0.033) and left ventricular mass index LVMI (P: 0.001) compared to patients without NODAT. Further analysis was done according to LVMI as follows: LVMI > 130 g/m2 (n: 57) and LVMI ≤ 130 g/m2 (n: 102). We observed higher office systolic and diastolic BP, serum trygliceride, glucose, creatinine, age, and HbA1c (P: 0.0001) levels in patients with LVMI > 130 g/m2. Linear regression analysis revealed that HbA1c was the major determinant of LVMI (P: 0.026, β: 0.361). Conclusions. HbA1c is the major determinant of LVMI, so strict control of serum glucose levels is essential for preventing cardiovascular disease in patients with NODAT.

Objective. Increased viscosity may increase the risk of thrombosis or thromboembolic events. Recombinant human erythropoietin (rHuEPO) is the key stone treatment in anemic ESRD patients with the thrombotic limiting side effect. We evaluated the influence of clinical and laboratory findings on plasma viscosity in MHD patients in the present study. Method. After applying exclusion criteria 84 eligible MHD patients were included (30 female, age: years). Results. Patients with high viscosity had longer MHD history, calcium × phosphorus product, and higher rHuEPO requirement (356.4 versus 204.2 U/kg/week, : 0.006). rHuEPO hyporesponsiveness was also more common in hyperviscosity group. According to HD duration, no rHuEPO group had the longest and the low rHuEPO dosage group had the shortest duration. Despite similar Hb levels, 68% of patients in high rHuEPO dosage group; and 38.7% of patients in low rHuEPO dosage group had higher plasma viscosity (: 0.001). Patients with hyperviscosity had higher rHuEPO/Hb levels (: 0.021). Binary logistic regression analyses revealed that rHuEPO hyporesponsiveness was the major determinant of hyperviscosity. Conclusion. We suggest that the hyperviscous state of the hemodialysis patients may arise from the inflammatory situation of long term HD, the calcium-phosphorus mineral abnormalities, rHuEPO hyporesponsiveness, and related high dosage requirements.

The article focuses on the result of the study which investigates the pros and cons of conventional glycaemic control method against targeting intensive glycaemic control in patients with type 2 diabetes in a randomised clinical trials.It states that the mortality rate of patients did not seem to lessen in the targeting intensive control compared with the conventional control. Sponsors of the study were also mentioned such as the Rigshospitalet in Denmark and the Copenhagen Trial Unit.

Purpose: Obesity surgery and polycystic ovary syndrome (PCOS) are both associated with increased risk of intrauterine growth restriction. We investigated whether offspring of mothers with PCOS who underwent obesity surgery had an increased risk of deviating birth anthropometrics compared to offspring of mothers without PCOS., Methods: In this observational study, data from two study databases (BAROBS and PregMet2) were supplemented with data from patient's records from secondary and tertiary hospitals. In total, 162 offspring born to mothers with PCOS (n = 48) and without PCOS (n = 114) were included. Forty-nine offspring were born prior to, and 113 after obesity surgery., Results: Mean ± SD birthweight (BW), birth length (BL), and head circumference (HC) before and after surgery for offspring born to mothers with PCOS were 3987 ± 495 g vs 3396 ± 526 g (P = 0.001), 52.2 ± 1.6 cm vs 50.1 ± 2.2 cm (P = 0.010), and 36.3 ± 1.97 cm vs 35.3 ± 1.66 cm (P = 0.183), respectively. In the non-PCOS group BW, BL and HC before and after were 3859 ± 603 g vs 3490 ± 538 g (P = 0.001), 51.3 ± 2.0 cm vs 49.9 ± 2.5 cm (P = 0.013), and 36.4 ± 2.0 cm vs 35.3 ± 1.8 cm (P = 0.016), respectively. Post-surgery, we found no difference in z-score BW, (∆-0.08, P = 0.677), BL (∆0.21, P = 0.184), and HC (∆0.14, P = 0.476) between children of PCOS and non-PCOS mothers., Comclusion: Babies born after obesity surgery were smaller and shorter in both the PCOS and non-PCOS group. Post-surgery anthropometrics were similar in babies born to mothers with and without PCOS., (© 2024. The Author(s).)

Introduction: Newborn resuscitation algorithms emphasize that resuscitation is time-critical, and all algorithm steps are related to the time of birth. Infrared thermal video has the potential to capture events in the delivery room, such as birth, cord clamping, and resuscitative interventions, while upholding the privacy of patients and healthcare providers., Objectives: The objectives of this concept study were to (i) investigate the technical feasibility of using thermal video in the delivery room to detect birth and cord clamping, and (ii) evaluate the accuracy of manual real-time registrations of the time of birth and cord clamping by comparing it with the accuracy of registrations abstracted from thermal videos., Methods: An observational study with data collected at Stavanger University Hospital, Norway, from September 2022 to August 2023. The time of birth and cord clamping were manually registered on a portable tablet by healthcare providers. Thermal cameras were placed in the delivery rooms and operating theatre to capture births. Videos were retrospectively reviewed to determine the time of birth and cord clamping., Results: Participation consent was obtained from 306 mothers, of which 195 births occurred in delivery rooms or an operating theatre with a thermal camera installed. We excluded 12 videos in which no births occurred. Births were detectable in all 183 (100%) thermal videos evaluated. There was a median (quartiles) of 1.8 (0.7, 5.4) s deviation in the manual registrations of the times of births relative to those abstracted from thermal videos. Cord clamping was detectable in 173 of the 183 (95%) thermal videos, with a median of 18.3 (3.3, 108) s deviation in the manual registrations of the times of cord clampings relative to those abstracted from thermal videos., Conclusion: Recognizing the time of birth and cord clamping from thermal videos is technically feasible and provides a method for determining when resuscitative events occur., Competing Interests: Authors SB, AJ, and ØM-B were employed by Laerdal Medical AS. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Kolstad, García-Torres, Brunner, Johannessen, Foglia, Ersdal, Meinich-Bache and Rettedal.)

Purpose: Biallelic pathogenic variants in the gene encoding the ATP-binding cassette transporter ABCA4 are the leading cause of irreversible vision loss in inherited retinal dystrophies (IRDs). Interpretation of ABCA4 variants is challenging, due to cis-modifying and hypomorphic variants. We have previously detected 10 missense variants of unknown significance (VUS) in patients with suspected ABCA4-retinal dystrophies (ABCA4-RDs) in Norway. In this study, we functionally characterized the VUS to aid interpretation of the variants and to determine if they are associated with the disease., Methods: The ABCA4 VUS were expressed in HEK293T cells and the ABCA4 expression level and ATPase activity were determined and correlated with the patients' phenotype. The functional data further used for reclassification of the VUS following the American College of Medical Genetics and Genomics (ACMG) guidelines., Results: Of the 10 VUSs, 2 variants, Cys205Phe and Asn415Thr, were categorized as functionally severe. The age at presentation in the 2 patients carrying these variants was divergent and seemed to be driven by the patients' second pathogenic variants Gly1961Glu and c.5461-10T>C, respectively. Three variants, Val643Gly, Pro799Leu, and Val1433Ile were categorized as functionally moderate, and were found in patients with intermediate/late age at presentation. The remaining five variants were categorized as functionally normal/mild. Based on our data, c.614G>T p.(Cys205Phe), c.1244A>C p.(Asn415Thr), and c.2396C>T p.(Pro799Leu) were reclassified to (likely) pathogenic, while 4 of the functionally normal/mild variants could be reclassified to likely benign., Conclusions: Functional analyses of ABCA4 variants are a helpful tool in variant classification and enable us to better predict the disease severity in patients with ABCA4-RDs.

We aimed to provide a detailed phenotypic description of status epilepticus (SE) in a large cohort of patients with POLG disease and identify prognostic biomarkers to improve the management of this life-threatening condition. In a multinational, retrospective study with data on patients with POLG disease from seven European countries, we identified those who had SE. The age of SE onset, accompanying clinical, laboratory, imaging and genetic findings were analysed. One hundred and ninety-five patients with genetically confirmed POLG disease were recruited, of whom 67% (130/194) had epilepsy. SE was identified in 77% (97/126), with a median age of SE onset of 7 years. SE was the presenting symptom of the disease in 43% (40/93) of those with SE, while 57% (53/93) developed SE during the disease course. Convulsive SE was reported in 97% (91/94) followed by epilepsia partialis continua in 67% (56/84). Liver impairment 78% (74/95), ataxia 69% (60/87), stroke-like episodes 57% (50/88), were the major comorbidities. In the majority (66%; 57/86) with SE this became refractory or super-refractory. The presence of seizures was associated with significantly higher mortality compared to those without (P ≤ 0.001). The median time from SE debut to death was 5 months. SE is a major clinical feature of POLG disease in early and juvenile to adult-onset disease and can be the presenting feature or arise as part of a multisystem disease. It is associated with high morbidity and mortality, with the majority of patients with SE going on to develop refractory or super-refractory SE., (© 2024. The Author(s).)

As an important genus in Orchidaceae, Cymbidium has rich ecological diversity and significant economic value. DNA binding with one zinc finger (Dof) proteins are pivotal plant-specific transcription factors that play crucial roles in the growth, development, and stress response of plants. Although the Dof genes have been identified and functionally analyzed in numerous plants, exploration in Orchidaceae remains limited. We conducted a thorough analysis of the Dof gene family in Cymbidium goeringii , C. ensifolium , and C. sinensis . In total, 91 Dof genes (27 CgDof s, 34 CeDof s, 30 CsDof s) were identified, and Dof genes were divided into five groups (I-V) based on phylogenetic analysis. All Dof proteins have motif 1 and motif 2 conserved domains and over half of the genes contained introns. Chromosomal localization and collinearity analysis of Dof genes revealed their evolutionary relationships and potential gene duplication events. Analysis of cis -elements in CgDof s, CeDof s, and CsDof s promoters showed that light-responsive cis -elements were the most common, followed by hormone-responsive elements, plant growth-related elements, and abiotic stress response elements. Dof proteins in three Cymbidium species primarily exhibit a random coil structure, while homology modeling exhibited significant similarity. In addition, RT-qPCR analysis showed that the expression levels of nine CgDofs changed greatly under heat stress. CgDof03 , CgDof22 , CgDof27 , CgDof08 , and CgDof23 showed varying degrees of upregulation. Most upregulated genes under heat stress belong to group I, indicating that the Dof genes in group I have great potential for high-temperature resistance. In conclusion, our study systematically demonstrated the molecular characteristics of Dof genes in different Cymbidium species, preliminarily revealed the patterns of heat stress, and provided a reference for further exploration of stress breeding in orchids.

Purpose: Congenital hyperinsulinism (CHI) is a rare, monogenic disease characterized by excessive insulin secretion. We aimed to evaluate all probands with suspected CHI in Norway registered over the past two decades., Methods: The study included 98 probands. Clinical data were cumulated from medical records. All probands were screened for variants in the genes ABCC8 and KCNJ11. Other CHI-related genes were Sanger-sequenced as indicated by the patients' phenotype (N=75) or analyzed by next-generation sequencing employing a panel of 30 CHI-related genes (N=23)., Results: Twenty-one probands (21%) received a diagnosis other than CHI, the most common being idiopathic ketotic hypoglycemia (9%) or syndromic hyperinsulinism (4%). In the final cohort of 77 CHI probands, genetic findings were revealed in 46 (60%). ABCC8 variants were most common (N=40) and five novel variants were identified. One proband harbored both the pathogenic GCK variant p.(Ala456Val) and the ABCC8 variant p.(Gly505Cys). Although most ABCC8 variants caused immediate disease onset with severe hypoglycemia and were diazoxide-unresponsive, eight probands had a heterozygous, apparently dominant variant with milder phenotype. Two probands had pathogenic variants in GLUD1, whereas variants in HADH, HNF4A, KCNJ11, and HK1 were identified in one proband each, the latter being non-coding. Neurologic sequelae were reported in 53% of the CHI probands. Of non-surgically treated probands, 43% had spontaneous resolution. The minimum birth prevalence of CHI in Norway is 1:19,400 live births., Main Conclusions: Individuals with disease-causing ABCC8 variants dominated our cohort. Patients with known genetic etiology had earlier and more severe disease-onset than genetically unsolved patients., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Purpose: The aim was to describe the frequency of bradycardia 12 years after Roux-en-Y gastric bypass (RYGB), relations to weight loss, patient characteristics, and the clinical impact., Materials and Methods: The BAROPS study is a prospective observational study of patients who had follow-up > 10 years after RYGB. Patients with heart rate (HR) ≤ 50 bpm were compared to patients with HR > 50 bpm., Results: After a mean observation period of 12 years, 32 of 546 patients (6%) had a HR ≤ 50 with a mean HR of 47.0 (2.8) bpm. The comparator group (192 patients) had a mean HR of 66.4 (10.2) bpm (p < 0.001). A higher proportion of the bradycardic vs. non-bradycardic patients (18.8% vs. 7.8% at baseline (p = 0.05) and 18.8% vs. 5.2% at end of study (p = 0.006)) used beta-blockers. Both groups had a significant reduction in heart rate from pre-surgery to end of observation. Percent total weight loss from baseline was negatively related to heart rate (p < 0.001), and smoking was positively related to heart rate (p = 0.014). Change in BMI from pre-surgery (p < 0.001) and hypertension at pre-surgery (p = 0.006) were significant predictors of change in heart rate. The only predictor of HR ≤ 50 was the use of beta-blockers (p = 0.010). There were no difference in bradycardia-related symptoms., Conclusion: Six percent of patients had HR ≤ 50 bpm 12 years after RYGB, but there was no increased bradycardia-related symptoms in these patients. RYGB induced a significant reduction in HR, and heart rate and changes in heart rate 12 years after RYGB were related to the amount of weight loss., (© 2024. The Author(s).)

Objective: To investigate the prevalence and natural history of POLG disease in the Norwegian population., Methods: A national, population-based, retrospective study using demographic, clinical, and genetic data of patients with genetically confirmed POLG disease. The patients were diagnosed between 2002 and 2022, and were included into the Norwegian POLG Patient Registry. Patients were stratified according to age at disease onset (early <12 years, juvenile to adult 12-40 years, late ≥40 years) and resident region., Results: Ninety-one patients were included. The point prevalence of POLG disease was 1:149,253. Birth prevalence was 1:48,780. Median age at clinical onset was 16 years (range: 2 months to 70 years). Onset occurred early in 35% (32 out of 91), juvenile-adult in 55% (50 out of 91) and late in 10% (9 out of 91). A distinct seasonal pattern in disease onset was observed, with 57% (52 out of 91) presenting between May and August. Forty-five patients (49%) had acute exacerbations that required intensive care, and this affected 72% of those in the early-onset group. The mortality rate was 54% (49 out of 91), with a median time from disease onset to death of 3 years (range: 1 month to 36 years)., Interpretation: We provide the point prevalence and birth prevalence of POLG disease in the first nationwide study in which epidemiological and clinical data were integrated. Seasonal variations in clinical onset may offer valuable insights into disease mechanisms and modifying factors. The findings from this study are crucial for quantifying the disease burden, and contribute to evidence-based healthcare planning., (© 2024 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Purpose: Coronavirus disease 2019 (COVID-19) placed a significant strain on nursing homes, leading to numerous outbreaks and high mortality rates. This situation created considerable stress and challenges for residents, their physicians and nurses, as well as family caregivers. By understanding these challenges, we can gain new insights and learn valuable lessons. Thus, the purpose of this study is to examine the treatment and care provided to nursing home residents with COVID-19, as experienced by physicians, nurses, and family caregivers., Participants and Methods: This study is a secondary analysis of 35 interviews with physicians, nurses, and family caregivers, each with personal experience caring for nursing home residents diagnosed with COVID-19. The interviews took place from December 2020 to April 2021. We analyzed the transcriptions based on Braun and Clarke's reflexive thematic analysis model and followed a qualitative descriptive design as outlined by Sandelowski., Findings: The analysis produced three themes: 1) Balancing medical treatment, 2) The need for increased systematic monitoring of vital functions, and 3) Determining the treatment level for nursing home residents. These themes were explored through the unique perspectives of the three participant groups: physicians, nurses, and family caregivers. The findings revealed several challenges related to treatment and care for nursing home residents diagnosed with COVID-19. This applied both to relief of symptoms, monitoring of vital functions, assessment of treatment level and use of advance care planning., Conclusion: Drawing from the experiences of physicians, nurses, and family caregivers, there should be a unified plan at the municipal or national level for competency development in nursing homes to prepare for future crises like pandemics or epidemics. Additionally, the safe engagement of family caregivers and relatives should be given priority., Competing Interests: PhD funding for Anita Nilsen and open access funding was provided by Molde University College. The authors report no other conflicts of interest in this work., (© 2024 Nilsen et al.)

Objective: To determine the prevalence of bradycardia in the first minute after birth and association with positive pressure ventilation (PPV)., Method: A population-based cross-sectional study was conducted from June 2019 to December 2021 at Stavanger University Hospital, Norway. Parents consented to participation during pregnancy, and newborns ≥28 weeks' gestation were included at birth. Heart rate (HR) was captured immediately after birth and continuously for the first minute(s). Time of birth was registered on a tablet. Provision of PPV was captured using video., Results: Of 4876 included newborns, 164 (3.4%) did not breathe (two-thirds) or breathed ineffectively (one-third) and received PPV at birth. HR in the first minute had a wide distribution. The prevalence of first measured HR <100 and <60 beats/minute at median 16 s was 16.3% and 0.6%, respectively. HR increased in most cases. At 60 s, 3.7% had HR <100 beats/minute, of which 82% did not require PPV. In total, 25% of newborns had some registered HR <100 beats/minute during the first minute, of which 95% did not require PPV. Among newborns who received PPV, 76% and 62% had HR ≥100 beats/minute at 60 s and at start PPV, respectively., Conclusion: Bradycardia with HR <100 bpm in the first minute of life was frequent, but mostly self-resolved. Among the 4% of newborns that remained bradycardic at 60 s, only 20% received PPV. Two-thirds of resuscitated newborns had HR ≥100 beats/minute at start PPV. None of the ventilated newborns were breathing adequately at start PPV., Trial Registration Number: NCT03849781., Competing Interests: Competing interests: JE is a Laerdal Medical employee. SR had an unconditional research grant from Laerdal. The other authors have no conflicts of interest to disclose., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The GRAS gene family, responsible for encoding transcription factors, serves pivotal functions in plant development, growth, and responses to stress. The exploration of the GRAS gene family within the Orchidaceae has been comparatively limited, despite its identification and functional description in various plant species. This study aimed to conduct a thorough examination of the GRAS gene family in Cymbidum goeringii , focusing on its physicochemical attributes, phylogenetic associations, gene structure, cis-acting elements, and expression profiles under heat stress. The results show that a total of 54 CgGRAS s were pinpointed from the genome repository and categorized into ten subfamilies via phylogenetic associations. Assessment of gene sequence and structure disclosed the prevalent existence of the VHIID domain in most CgGRAS s, with around 57.41% (31/54) CgGRAS s lacking introns. The Ka/Ks ratios of all CgGRAS s were below one, indicating purifying selection across all CgGRASs . Examination of cis-acting elements unveiled the presence of numerous elements linked to light response, plant hormone signaling, and stress responsiveness. Furthermore, CgGRAS5 contained the highest quantity of cis-acting elements linked to stress response. Experimental results from RT-qPCR demonstrated notable variations in the expression levels of eight CgGRAS s after heat stress conditions, particularly within the LAS, HAM, and SCL4/7 subfamilies. In conclusion, this study revealed the expression pattern of CgGRAS s under heat stress, providing reference for further exploration into the roles of CgGRAS transcription factors in stress adaptation.

Analytical modeling of the squeezing force for aircraft wings and fuselage panels in the existing literature usually assumes uniform deformation of the rivets, while in reality, the deformation of the rivets is non-uniform. To achieve high-quality squeezing force modeling, this paper introduces Coulomb's friction and four critical adjustments to the original equation: the non-uniform rivet/sheet interference along the sheet's hole axial ordinate; the barreling effect when calculating the driven head's volume; the spring-back of the driven head's dimensions; the modified height of the driven head; and the modified sheet-hole expanded diameter considering the convex structure of the driven head. The calculated values of the proposed new model demonstrate an improved level of accuracy, particularly under squeeze ratios commonly encountered in the aerospace industry.

Extant Old World camels (genus Camelus) contributed to the economic and cultural exchanges between the East and West for thousands of years. 1 , 2 Although many remains have been unearthed, 3 , 4 , 5 we know neither whether the prevalent hybridization observed between extant Camelus species 2 , 6 , 7 also occurred between extinct lineages and the ancestors of extant Camelus species nor why some populations became extinct while others survived. To investigate these questions, we generated paleogenomic and stable isotope data from an extinct two-humped camel species, Camelus knoblochi. We find that in the mitochondrial phylogeny, all C. knoblochi form a paraphyletic group that nests within the diversity of modern, wild two-humped camels (Camelus ferus). In contrast, they are clearly distinguished from both wild and domesticated (Camelus bactrianus) two-humped camels on the nuclear level. Moreover, the divergence pattern of the three camel species approximates a trifurcation, because the most common topology is only slightly more frequent than the two other possible topologies. This mito-nuclear phylogenetic discordance likely arose due to interspecific gene flow between all three species, suggesting that interspecific hybridization is not exclusive to modern camels but a recurrent phenomenon throughout the evolutionary history of the genus Camelus. These results suggest that the genomic complexity of Old World camels' evolutionary history is underestimated when considering data from only modern species. Finally, we find that C. knoblochi populations began declining prior to the last glacial maximum and, by integrating palaeoecological evidence and stable isotope data, suggest that this was likely due to failure to adapt to a changing environment., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: The primary objective of this study was to evaluate the effect of a low-carbohydrate diet (LCD) compared with a control diet on pain in female patients with lipedema. The secondary objectives were to compare the impact of the two diets on quality of life (QoL) and investigate potential associations of changes in pain with changes in body weight, body composition, and ketosis., Methods: Adult female patients with lipedema and obesity were randomized to either the LCD or control diet (energy prescription: 1200 kcal/day) for 8 weeks. Body weight and body composition, pain (Brief Pain Inventory measured pain), and QoL (RAND 36-Item Health Survey [RAND-36], Impact of Weight on Quality of Life [IWQOL]-Lite, and Lymphoedema Quality of Life [LYMQOL]) were measured at baseline and at postintervention., Results: A total of 70 female patients (age, mean [SD], 47 [11] years; BMI 37 [5] kg/m 2 ) were included. The LCD group had greater weight loss (-2.8 kg; 95% CI: -4.1 to -1.0; p < 0.001) and larger reduction in pain now (-1.1; 95% CI: -1.9 to -0.3; p = 0.009) compared with the control group. No association was found between changes in pain now and weight loss. Both groups experienced improvements in several QoL dimensions., Conclusions: Diet-induced weight loss in women with lipedema can improve QoL. An energy-restricted LCD seems to be superior to a standard control diet in reducing pain., (© 2024 The Authors. Obesity published by Wiley Periodicals LLC on behalf of The Obesity Society.)

Precise regulation of gene expression is important for correct neurodevelopment. 9q34.3 deletions affecting the EHMT1 gene result in a syndromic neurodevelopmental disorder named Kleefstra syndrome. In contrast, duplications of the 9q34.3 locus encompassing EHMT1 have been suggested to cause developmental disorders, but only limited information has been available. We have identified 15 individuals from 10 unrelated families, with 9q34.3 duplications <1.5 Mb in size, encompassing EHMT1 entirely. Clinical features included mild developmental delay, mild intellectual disability or learning problems, autism spectrum disorder, and behavior problems. The individuals did not consistently display dysmorphic features, congenital anomalies, or growth abnormalities. DNA methylation analysis revealed a weak DNAm profile for the cases with 9q34.3 duplication encompassing EHMT1, which could segregate the majority of the affected cases from controls. This study shows that individuals with 9q34.3 duplications including EHMT1 gene present with mild non-syndromic neurodevelopmental disorders and DNA methylation changes different from Kleefstra syndrome., (© 2024 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.)

Molybdenum cofactor deficiency classically presents in neonates with intractable seizures; however, milder cases generally present before age 2 years with developmental delays and may go undiagnosed. Early diagnosis, and safe, US Food and Drug Administration-approved substrate replacement are critical to preserve neurologic function. This article discusses 2 children who presented with late-onset molybdenum cofactor deficiency type A.

The TIFY gene family (formerly known as the zinc finger proteins expressed in inflorescence meristem (ZIM) family) not only functions in plant defense responses but also are widely involved in regulating plant growth and development. However, the identification and functional analysis of TIFY proteins remain unexplored in Orchidaceae. Here, we identified 19 putative TIFY genes in the Phalaenopsis aphrodite genome. The phylogenetic tree classified them into four subfamilies: 14 members from JAZ, 3 members from ZML, and 1 each from PPD and TIFY. Sequence analysis revealed that all Phalaenopsis TIFY proteins contained a TIFY domain. Exon-intron analysis showed that the intron number and length of Phalaenopsis TIFY genes varied, whereas the same subfamily and subgroup genes had similar exon or intron numbers and distributions. The most abundant cis -elements in the promoter regions of the 19 TIFY genes were associated with light responsiveness, followed by MeJA and ABA, indicating their potential regulation by light and phytohormones. The 13 candidate TIFY genes screened from the transcriptome data exhibited two types of expression trends, suggesting their different roles in cell proliferation and cell expansion of floral organ growth during Phalaenopsis flower opening. Overall, this study serves as a background for investigating the underlying roles of TIFY genes in floral organ growth in Phalaenopsis .

To decipher the interactions between various components of the tumor microenvironment (TME) and tumor cells in a preserved spatial context, a multiparametric approach is essential. In this pursuit, imaging mass cytometry (IMC) emerges as a valuable tool, capable of concurrently analyzing up to 40 parameters at subcellular resolution. In this study, a set of antibodies was selected to spatially resolve multiple cell types and TME elements, including a comprehensive panel targeted at dissecting the heterogeneity of cancer-associated fibroblasts (CAF), a pivotal TME component. This antibody panel was standardized and optimized using formalin-fixed paraffin-embedded tissue (FFPE) samples from different organs/lesions known to express the markers of interest. The final composition of the antibody panel was determined based on the performance of conjugated antibodies in both immunohistochemistry (IHC) and IMC. Tissue images were segmented employing the Steinbock framework. Unsupervised clustering of single-cell data was carried out using a bioinformatics pipeline developed in R program. This paper provides a detailed description of the staining procedure and analysis workflow. Subsequently, the panel underwent validation on clinical FFPE samples from head and neck squamous cell carcinoma (HNSCC). The panel and bioinformatics pipeline established here proved to be robust in characterizing different TME components of HNSCC while maintaining a high degree of spatial detail. The platform we describe shows promise for understanding the clinical implications of TMA heterogeneity in large patient cohorts with FFPE tissues available in diagnostic biobanks worldwide., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Harsh Nitin Dongre reports financial support was provided by 10.13039/501100005416Research Council of Norway, Norway. Daniela Elena Costea reports financial support was provided by Western Norway Regional Health Authority, Norway. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

The Homeodomain-Leucine Zipper (HD-ZIP) transcription factors play a pivotal role in governing various aspects of plant growth, development, and responses to abiotic stress. Despite the well-established importance of HD-ZIPs in many plants, their functions in Acoraceae, the basal lineage of monocots, remain largely unexplored. Using recently published whole-genome data, we identified 137 putative HD-ZIPs in two Acoraceae species, Acorus gramineus and Acorus calamus . These HD-ZIP genes were further classified into four subfamilies (I, II, III, IV) based on phylogenetic and conserved motif analyses, showcasing notable variations in exon-intron patterns among different subfamilies. Two microRNAs, miR165/166 , were found to specifically target HD-ZIP III genes with highly conserved binding sites. Most cis -acting elements identified in the promoter regions of Acoraceae HD-ZIPs are involved in modulating light and phytohormone responsiveness. Furthermore, our study revealed an independent duplication event in Ac. calamus and a one-to-multiple correspondence between HD-ZIP genes of Ac. calamus and Ac. gramineus. Expression profiles obtained from qRT-PCR demonstrated that HD-ZIP I genes are strongly induced by salinity stress, while HD-ZIP II members have contrasting stress responses in two species. HD-ZIP III and IV genes show greater sensitivity in stress-bearing roots. Taken together, these findings contribute valuable insights into the roles of HD-ZIP genes in stress adaptation and plant resilience in basal monocots, illuminating their multifaceted roles in plant growth, development, and response to abiotic stress., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhang, Zhao, Huang, Zhang, He, Yin, Lan, Liu and Ma.)

Objectives: To evaluate the use of newborn resuscitation timelines to assess the incidence, sequence, timing, duration of and response to resuscitative interventions., Methods: A population-based observational study conducted June 2019-November 2021 at Stavanger University Hospital, Norway. Parents consented to participation antenatally. Newborns ≥28 weeks' gestation receiving positive pressure ventilation (PPV) at birth were enrolled. Time of birth was registered. Dry-electrode electrocardiogram was applied as soon as possible after birth and used to measure heart rate continuously during resuscitation. Newborn resuscitation timelines were generated from analysis of video recordings., Results: Of 7466 newborns ≥28 weeks' gestation, 289 (3.9%) received PPV. Of these, 182 had the resuscitation captured on video, and were included. Two-thirds were apnoeic, and one-third were breathing ineffectively at the commencement of PPV. PPV was started at median (quartiles) 72 (44, 141) seconds after birth and continued for 135 (68, 236) seconds. The ventilation fraction, defined as the proportion of time from first to last inflation during which PPV was provided, was 85%. Interruption in ventilation was most frequently caused by mask repositioning and auscultation. Suctioning was performed in 35% of newborns, in 95% of cases after the initiation of PPV. PPV was commenced within 60 s of birth in 49% of apnoeic and 12% of ineffectively breathing newborns, respectively., Conclusions: Newborn resuscitation timelines can graphically present accurate, time-sensitive and complex data from resuscitations synchronised in time. Timelines can be used to enhance understanding of resuscitation events in data-guided quality improvement initiatives., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Joar Eilevstjønn is a Laerdal Medical employee. Siren Rettedal and Hanne Pike had unconditional research grants from Laerdal Foundation, Stavanger, Norway [grant numbers 5007, 2023-0087]. The other authors have no conflicts of interest to disclose. The funder had no role in the design and conduct of the study.]., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)