Clinical perspectives on sampling and processing approaches for the management of infection in diabetic foot ulceration: A qualitative study.

Diabetic foot ulcers (DFUs) often become infected and are treated with antimicrobials, with samples collected to inform care. Swab samples are easier than tissue sampling but report fewer organisms. Compared with culture and sensitivity (C&S) methods, molecular microbiology identifies more organisms. Clinician perspectives on sampling and processing are unknown. We explored clinician perspectives on DFU sampling-tissue samples/wound swabs-and on processing techniques, culture and sensitivity or molecular techniques. The latter provides information on organisms which have not survived transport to the laboratory for culture. We solicited feedback on molecular microbiology reports. Qualitative study using semi-structured interview, with analysis using a Framework approach. CODIFI2 clinicians from UK DFU clinics. Seven consultants agreed to take part. They reported, overall, a preference for tissue samples over swabbing. Clinicians were not confident replacing C&S with molecular microbiology as the approach to reporting was unfamiliar. The study was small and did not recruit any podiatrists or nurses, who may have discipline-specific attitudes or perspectives on DFU care. Both sampling approaches appear to be used by clinicians. Molecular microbiology reports would not be, at present, suitable for replacement of traditional culture and sensitivity.

Therapeutic Patterns and Clinical Outcomes in Limited Disease Small Cell Lung Cancer: A Decade of Analysis at a Tertiary Cancer Center.

In this study, we investigated the outcomes and factors influencing treatment efficacy in 93 patients with limited disease small cell lung cancer (LD-SCLC), with a median age of 64 years. We focused on the impact of chemotherapy regimens, prophylactic cranial irradiation (PCI), and patient-related variables. The median follow-up for OS was 17.3 months. We observed a statistically significant difference in PFS between LD-SCLC patients treated with cisplatin and etoposide (EP) and those treated with carboplatin and etoposide (CP) (PFS: EP 13.63 months vs. CP 6.54 months, p < 0.01). Patients treated with EP had better overall survival (OS) than CP-treated patients (OS: EP 26.9 months vs. CP 16.16 months, p < 0.01). Concomitant chemotherapy was associated with improved PFS (p = 0.003) and OS (p = 0.002). Patients receiving PCI showed superior OS (p = 0.05) and a trend towards improved PFS (p = 0.057). Female gender was associated with better OS (p = 0.025). Most patients had an ECOG performance status of 0 (71%). This real-world study underscores the importance of multidisciplinary LD-SCLC management, emphasizing the roles of chemotherapy, radiotherapy, and PCI. These findings inform personalized treatment strategies and emphasize the need for prospective trials to validate these results and optimize LD-SCLC treatment.

Long-Term Comparative Efficacy and Safety of Risdiplam and Nusinersen in Children with Type 1 Spinal Muscular Atrophy.

INTRODUCTION: Spinal muscular atrophy (SMA) is a severe genetic neuromuscular disease characterized by a loss of motor neurons and progressive muscle weakness. Children with untreated type 1 SMA never sit independently and require increasing levels of ventilatory support as the disease progresses. Without intervention, and lacking ventilatory support, death typically occurs before the age of 2 years. There are currently no head-to-head trials comparing available treatments in SMA. Indirect treatment comparisons are therefore needed to provide information on the relative efficacy and safety of SMA treatments for healthcare decision-making. METHODS: The long-term efficacy and safety of risdiplam versus nusinersen in children with type 1 SMA was evaluated using indirect treatment comparison methodology to adjust for differences between population baseline characteristics, to reduce any potential bias in the comparative analysis. An unanchored matching-adjusted indirect comparison was conducted using risdiplam data from 58 children in FIREFISH (NCT02913482) and published aggregate nusinersen data from 81 children obtained from the ENDEAR (NCT02193074) and SHINE (NCT02594124) clinical trials with at least 36 months of follow-up. RESULTS: Children with type 1 SMA treated with risdiplam had a 78% reduction in the rate of death, an 81% reduction in the rate of death or permanent ventilation, and a 57% reduction in the rate of serious adverse events compared with children treated with nusinersen. Children treated with risdiplam also had a 45% higher rate of achieving a Hammersmith Infant Neurological Examination, Module 2 motor milestone response and a 186% higher rate of achieving a ≥ 4-point improvement in Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders compared with children treated with nusinersen. CONCLUSION: Long-term data supported risdiplam as a superior alternative to nusinersen in children with type 1 SMA. Video abstract available for this article. Video abstract (MP4 184542 KB).

Risdiplam and nusinersen are two approved treatments for patients with type 1 spinal muscular atrophy (SMA). There are currently no head-to-head trials that compare the outcomes of these treatments in patients. This study conducted a statistical comparison of the efficacy and safety of risdiplam and nusinersen in children with type 1 SMA who received treatment for at least 36 months. Risdiplam data were collected from 58 children who participated in the FIREFISH trial (NCT02913482). Published combined data were collected from 81 children treated with nusinersen who participated in the ENDEAR (NCT02193074) and SHINE (NCT02594124) trials. Outcomes from the two studies were compared using matching-adjusted indirect comparison (MAIC) methodology. MAIC adjusts for differences in baseline characteristics between patients in two trials to make the populations more similar and reduce bias in the comparison. Results suggested that children with type 1 SMA treated with risdiplam had a 78% reduction in the rate of death and an 81% reduction in the rate of death or permanent ventilation compared with children treated with nusinersen. With risdiplam, children also had a higher rate of achieving motor function responses, and a longer time to the first serious adverse event compared with children treated with nusinersen. These results support risdiplam as a superior alternative to nusinersen in children with type 1 SMA over 36 months of follow-up. Access to long-term data beyond 36 months would allow for additional indirect comparisons between SMA treatments. These comparisons are key to guiding treatment decision-making in the absence of head-to-head trials.

Fulminant Heterotopic Ossification of the Lower Extremity After Gunshot Injury and Blunt Trauma: A Case Report.

Traumatic heterotopic ossification (HO) of the lower extremity is relatively rare but is of major importance in clinical practice. They are defined as posttraumatic abnormal formations of bone within soft tissue outside of the skeletal system. This article describes the clinical case of a 31-year-old male patient who suffered 2 traumatic events within 12 months-a gunshot wound in the lumbar spine/gluteal region followed by a severe traumatic brain injury with intracranial hemorrhage in a traffic accident as a pedestrian. Clinically, the patient was bedridden because of complete stiffening of the lumbar spine, both hip joints, and the left knee joint. After preoperative diagnosis, 3 surgical ablations of the HO were performed on both the hip joints and the left knee joint. In addition, physiotherapeutic exercise, postoperative nonsteroidal anti-inflammatory drug administration (25 mg of indomethazine for 6 weeks, 3 times a day), and perioperative radiation with 7 Gy for each operation were advised. After 4 years of follow-up, the patient showed significant improvement. In HO treatment, prophylactic local radiotherapy (pre- and postoperative radiation with a local single dose of 7 Gy) and postoperative administration of nonsteroidal anti-inflammatory drugs are often recommended. For therapeutic purposes, surgical resection is still indicated for pronounced cases.

Total Muscle Area and Visceral Adipose Tissue Measurements for Frailty Assessment in TAVR Patients.

Background: Transcatheter aortic valve replacement (TAVR) is a treatment option for severe aortic valve stenosis. Pre-TAVR assessments, extending beyond anatomy, include evaluating frailty. Potential frailty parameters in pre-TAVR computed tomography (CT) scans are not fully explored but could contribute to a comprehensive frailty assessment. The primary objective was to investigate the impact of total muscle area (TMA) and visceral adipose tissue (VAT) as frailty parameters on 5-year all-cause mortality in patients undergoing TAVR. Methods: Between 01/2017 and 12/2018, consecutive TAVR patients undergoing CT scans enabling TMA and VAT measurements were included. Results: A total of 500 patients qualified for combined TMA and VAT analysis. Age was not associated with a higher risk of 5-year mortality (HR 1.02, 95% CI: 0.998-1.049; p = 0.069). Body surface area normalized TMA (nTMA) was significantly associated with 5-year, all-cause mortality (HR 0.927, 95% CI: 0.927-0.997; p = 0.033), while VAT had no effect (HR 1.002, 95% CI: 0.99-1.015; p = 0.7). The effect of nTMA on 5-year, all-cause mortality was gender dependent: the protective effect of higher nTMA was found in male patients (pinteraction: sex × nTMA = 0.007). Conclusions: Normalized total muscle area derived from a routine CT scan before transcatheter aortic valve replacement complements frailty assessment in patients undergoing TAVR.

Validation of the brain health index in the European Prevention of Alzheimer's Dementia cohort.

Background: Brain Health Index (BHI) assimilates various MRI sequences, giving a quantitative measure of brain health. To date, BHI validation has been cross-sectional and limited to selected populations. Further large-scale validation and assessment of temporal change is required to understand its clinical utility. Aim: Assess 1) relationships between variables associated with cognitive decline and BHI 2) associations between BHI and measures of cognition and 3) longitudinal changes in BHI and relationship with cognitive function. Methods: BHI computation involved Gaussian mixture-model cluster analysis of T1, T2, T2*, and T2 FLAIR MRI data from participants within the European Prevention of Alzheimer's Dementia (EPAD) cohort. Group differences (gender- and health-based) were evaluated using independent samples Welch's t-tests. Relationships between BHI, age and cognitive tests used linear regression. Longitudinal analysis (12/24 months) utilised mixed linear regression models to examine BHI changes, and paired BHI/cognition associations. Results: Data from N = 1496 predominantly Caucasian participants (50-88 years old, 43.32% male) were used. BHI scores were lower in those with diabetes (p < 0.001, d = 0.419), hypertension (p < 0.001, d = 0.375), hypercholesterolemia (p < 0.001, d = 0.193) and stroke (p < 0.05, d = 0.512). APOE was not significantly related to BHI scores. After correction for age, cross-sectional BHI scores were significantly associated with all measures of cognitive function in males, but only the Four Mountains Test (4MT) in females. Longitudinal change in BHI and cognition were not consistently related. Conclusions: BHI is a valid marker of cognitive decline and relatively stable over 1-2 year follow-up periods. Further work should assess temporal changes over a longer duration and determine relationships between BHI and cognition in more diverse populations.

Professional Social Media Use Among Orthopedic and Trauma Surgeons in Germany: Cross-Sectional Questionnaire-Based Study.

BACKGROUND: Social media (SM) has been recognized as a professional communication tool in the field of orthopedic and trauma surgery that can enhance communication with patients and peers, and increase the visibility of research and offered services. The specific purposes of professional SM use and the benefits and concerns among orthopedic and trauma surgeons, however, remain unexplored. OBJECTIVE: This study aims to demonstrate the specific uses of different SM platforms among orthopedic and trauma surgeons in Germany as well as the advantages and concerns. METHODS: A web-based questionnaire was developed on the use of SM in a professional context by considering the current literature and the authors' topics of interest. The final questionnaire consisted of 33 questions and was distributed among German orthopedic and trauma surgeons via the mail distributor of the Berufsverband für Orthopädie und Unfallchirurgie (Professional Association of Orthopaedic Surgeons in Germany). The study was conducted between June and July 2022. A subgroup analysis was performed for sex (male vs female), age (<60 years vs ≥60 years), and type of workplace (practice vs hospital). RESULTS: A total of 208 participants answered the questionnaire (male: n=166, 79.8%; younger than 60 years: n=146, 70.2%). In total, all of the participants stated that they use SM for professional purposes. In contrast, the stated specific uses of SM were low. Overall, the most used platforms were employment-oriented SM, messenger apps, and Facebook. Instagram emerged as a popular choice among female participants and participants working in hospital settings. The highest specific use of SM was for professional networking, followed by receiving and sharing health-related information. The lowest specific use was for education and the acquisition of patients. Conventional websites occupied a dominating position, exceeding the use of SM across all specific uses. The key benefit of SM was professional networking. Under 50% of the participants stated that SM could be used to enhance communication with their patients, keep up-to-date, or increase their professional visibility. In total, 65.5% (112/171) of participants stated that SM use was time-consuming, 43.9% (76/173) stated that they lacked application knowledge, and 45.1% (78/173) stated that they did not know what content to post. Additionally, 52.9% (91/172) mentioned medicolegal concerns. CONCLUSIONS: Overall, SM did not seem to be used actively in the professional context among orthopedic and trauma surgeons in Germany. The stated advantages were low, while the stated concerns were high. Adequate education and information material are needed to elucidate the possible professional applications of SM and to address legal concerns.

Allopurinol and blood pressure variability following ischemic stroke and transient ischemic attack: a secondary analysis of XILO-FIST.

Blood Pressure Variability (BPV) is associated with cardiovascular risk and serum uric acid level. We investigated whether BPV was lowered by allopurinol and whether it was related to neuroimaging markers of cerebral small vessel disease (CSVD) and cognition. We used data from a randomised, double-blind, placebo-controlled trial of two years allopurinol treatment after recent ischemic stroke or transient ischemic attack. Visit-to-visit BPV was assessed using brachial blood pressure (BP) recordings. Short-term BPV was assessed using ambulatory BP monitoring (ABPM) performed at 4 weeks and 2 years. Brain MRI was performed at baseline and 2 years. BPV measures were compared between the allopurinol and placebo groups, and with CSVD and cognition. 409 participants (205 allopurinol; 204 placebo) were included in the visit-to-visit BPV analyses. There were no significant differences found between placebo and allopurinol groups for any measure of visit-to-visit BPV. 196 participants were included in analyses of short-term BPV at week 4. Two measures were reduced by allopurinol: the standard deviation (SD) of systolic BP (by 1.30 mmHg (95% confidence interval (CI) 0.18-2.42, p = 0.023)); and the average real variability (ARV) of systolic BP (by 1.31 mmHg (95% CI 0.31-2.32, p = 0.011)). There were no differences in other measures at week 4 or in any measure at 2 years, and BPV was not associated with CSVD or cognition. Allopurinol treatment did not affect visit-to-visit BPV in people with recent ischemic stroke or TIA. Two BPV measures were reduced at week 4 by allopurinol but not at 2 years.

Second Order Splitting Dynamics with Vanishing Damping for Additively Structured Monotone Inclusions.

In the framework of a real Hilbert space, we address the problem of finding the zeros of the sum of a maximally monotone operator A and a cocoercive operator B. We study the asymptotic behaviour of the trajectories generated by a second order equation with vanishing damping, attached to this problem, and governed by a time-dependent forward-backward-type operator. This is a splitting system, as it only requires forward evaluations of B and backward evaluations of A. A proper tuning of the system parameters ensures the weak convergence of the trajectories to the set of zeros of A+B, as well as fast convergence of the velocities towards zero. A particular case of our system allows to derive fast convergence rates for the problem of minimizing the sum of a proper, convex and lower semicontinuous function and a smooth and convex function with Lipschitz continuous gradient. We illustrate the theoretical outcomes by numerical experiments.

The impact of varying levels of residual disease following cytoreductive surgery on survival outcomes in patients with ovarian cancer: a meta-analysis.

BACKGROUND: Residual disease following cytoreductive surgery in patients with ovarian cancer has been associated with poorer survival outcomes compared with no residual disease. We performed a meta-analysis to assess the impact of varying levels of residual disease status on survival outcomes in patients with ovarian cancer who have undergone primary cytoreductive surgery or interval cytoreductive surgery in the setting of new therapies for this disease. METHODS: Medline, Embase, and Cochrane databases (January 2011 - July 2020) and grey literature, bibliographic and key conference proceedings, were searched for eligible studies. Fixed and random-effects meta-analyses compared progression and survival by residual disease level across studies. Heterogeneity between comparisons was explored via type of surgery, disease stage, and type of adjuvant chemotherapy. RESULTS: Of 2832 database and 16 supplementary search articles screened, 50 studies were selected; most were observational studies. The meta-analysis showed that median progression-free survival and overall survival decreased progressively with increasing residual disease (residual disease categories of 0 cm, > 0-1 cm and > 1 cm). Compared with no residual disease, hazard ratios (HR) for disease progression increased with increasing residual disease category (1.75 [95% confidence interval: 1.42, 2.16] for residual disease > 0-1 cm and 2.14 [1.34, 3.39] for residual disease > 1 cm), and also for reduced survival (HR versus no residual disease, 1.75 [ 1.62, 1.90] for residual disease > 0-1 cm and 2.32 [1.97, 2.72] for residual disease > 1 cm). All comparisons were significant (p < 0.05). Subgroup analyses showed an association between residual disease and disease progression/reduced survival irrespective of type of surgery, disease stage, or type of adjuvant chemotherapy. CONCLUSIONS: This meta-analysis provided an update on the impact of residual disease following primary or interval cytoreductive surgery, and demonstrated that residual disease was still highly predictive of progression-free survival and overall survival in adults with ovarian cancer despite changes in ovarian cancer therapy over the last decade. Higher numerical categories of residual disease were associated with reduced survival than lower categories.

Factores que influyen en la supervivencia de pacientes con diálisis en El Salvador / Influencing Factors in the Survival of Dialysis Patients in El Salvador

Introducción. La enfermedad renal crónica es responsable de aproximadamente 2,4 millones de defunciones a nivel mundial. La supervivencia a los cinco años después de iniciar diálisis se encuentra entre un 39 a 60 % dependiendo del país. Objetivo. Describir la situación epidemiológica de los pacientes con diálisis y analizar los factores que influyen en la supervivencia de pacientes a cinco años de iniciar tratamiento sustitutivo renal en El Salvador. Metodología. Estudio de cohorte retrospectivo de los pacientes incluidos en el Registro Nacional de Diálisis y Trasplante Renal desde enero de 2016 hasta febrero de 2023. El seguimiento se comenzó al inicio de la diálisis, el evento de interés fue la muerte del paciente. Se utilizó el método de Kaplan-Meier para determinar la supervivencia al año y a los cinco años y la regresión de Cox con el modelo de Royston-Parmar para analizar los factores que influyen sobre la supervivencia a los cinco años. Resultados. El estudio incluyó 7088 pacientes, la supervivencia a uno y cinco años fue del 79,5 % (IC 95 %: 78,6-80,5) y 50,6 % (IC 95 %: 49,1-52,1) respectivamente. La regresión de Cox para la edad de inicio de tratamiento resultó en un hazard ratio de 1,02 (IC 95 %: 1,01-1,02), mientras que para el oficio de ser agricultor el hazard ratio fue 1,1 (IC 95 %: 1,01-1,18) y para la etiología hipertensiva el hazard ratio fue de 0,7 (IC 95 %: 0,64-0,78). Conclusión. La edad de inicio de tratamiento y el ser agricultor están asociados con una menor supervivencia a cinco años en pacientes con diálisis

Introduction. The chronic kidney disease is responsible for approximately 2.4 million deaths worldwide, in El Salvador during 2019 death rate was 72.9 for 100 000 habitants, five year survival in patients after starting dialysis was between 39 and 60 % depending on the country. Objective. Analyze the factors that influence the five years survival in patients after starting renal replacement therapy in El Salvador. Methodology. It is a retrospective cohort study from patients included in dialysis and renal replacement therapy national registry from January 2016 to February 2023, the start point for the following was the initiation of dialysis, the event of interest was patient ́s death, the Kaplan-Meier method was used to determine one year and five year survival; and Cox regression with Royston-Parmar model was used to analyze the factors that influence survival. Results. The study included 7088 patients, one and five-years survival was 79.5 % (CI 95 %: 78.6-80.5) and 50.6 % (CI 95 %: 49.1-52.1) respectively. The Cox regression for age of treatment initiation resulted in a hazard ratio of 1.02 (CI 95 %: 1.01-1.02), while for farmers, the hazard ratio was 1.09 (CI 95 %: 1.00-1.18), for hypertensive etiology the hazard ratio was 0.7 (CI 95 %: 0.64-0.78). Conclusion. Data suggest that age of treatment initiation, and jobs related to agriculture were associated with less five year survival in dialysis patients.

And Yet It Moves: Clinical Outcomes and Motion Management in Stereotactic Body Radiation Therapy (SBRT) of Centrally Located Non-Small Cell Lung Cancer (NSCLC): Shedding Light on the Internal Organ at Risk Volume (IRV) Concept.

The internal organ at risk volume (IRV) concept might improve toxicity profiles in stereotactic body radiation therapy (SBRT) for non-small cell lung cancer (NSCLC). We studied (1) clinical aspects in central vs. peripheral tumors, (2) the IRV concept in central tumors, (3) organ motion, and (4) associated normal tissue complication probabilities (NTCPs). We analyzed patients who received SBRT for NSCLC (clinical aspects, n = 78; motion management, n = 35). We found lower biologically effective doses, larger planning target volume sizes, higher lung doses, and worse locoregional control for central vs. peripheral tumors. Organ motion was greater in males and tall patients (bronchial tree), whereas volume changes were lower in patients with a high body mass index (BMI) (esophagus). Applying the IRV concept (retrospectively, without new optimization), we found an absolute increase of >10% in NTCPs for the bronchial tree in three patients. This study emphasizes the need to optimize methods to balance dose escalation with toxicities in central tumors. There is evidence that organ motion/volume changes could be more pronounced in males and tall patients, and less pronounced in patients with higher BMI. Since recent studies have made efforts to further subclassify central tumors to refine treatment, the IRV concept should be considered for optimal risk assessment.

Outpatient paracentesis for the management of ovarian hyperstimulation syndrome: study protocol for the STOP-OHSS randomised controlled trial.

INTRODUCTION: Ovarian hyperstimulation syndrome (OHSS) is the most significant short-term complication of pharmacological ovarian stimulation. Symptoms range from mild abdominal discomfort to rare complications such as renal failure, thromboembolism and respiratory distress syndrome.Currently, clinical practice typically involves monitoring the patient until the condition becomes severe, at which point they are admitted to hospital, where drainage of ascitic fluid (paracentesis) may take place. Preliminary studies have indicated that earlier outpatient paracentesis may reduce the progression of OHSS and prevent hospitalisation in women. METHODS AND ANALYSIS: This UK, multicentre, pragmatic, two-arm, parallel-group, adaptive (group sequential with one interim analysis), open-label, superiority, confirmatory, group sequential, individually randomised controlled trial, with internal pilot will assess the clinical and cost-effectiveness and safety of outpatient paracentesis versus conservative management (usual care) for moderate or severe OHSS. 224 women from 20 National Health Service and private fertility units will be randomised (1:1) and followed up for up to 13.5 months. The primary outcome is the rate of OHSS related hospital admission of at least 24 hours within 28 days postrandomisation. The primary analysis will be an intention to treat with difference in hospitalisation rates as measure of treatment effect. Secondary outcomes include time to resolution of symptoms, patient satisfaction, adverse events and cost-effectiveness. A qualitative substudy will facilitate the feasibility of recruitment. Participant recruitment commenced in June 2022. ETHICS AND DISSEMINATION: London-Southeast Research Ethics Committee approved the protocol (reference: 22/LO/0015). Findings will be submitted to peer-reviewed journals and abstracts to relevant national and international conferences, as well as being disseminated to trial participants and patient groups. TRIAL REGISTRATION NUMBER: ISRCTN71978064.

Outcomes of Multimodal Treatment in Elderly Patients with Localized Non-Small Lung Cancer from a Radiation Oncology Point of View: Special Focus on Low-Dose Cisplatin.

Identification of the optimal treatment strategy is challenging in elderly with localized non-small cell lung cancer (NSCLC). Concurrent chemotherapy with low-dose cisplatin represents an option for elderly. Outcomes (1) in elderly (≥70 years, n = 158) vs. younger patients (n = 188) and (2), independently of age, in definitive radiochemotherapy, with low-dose cisplatin (n = 125) vs. cisplatin/vinorelbine (n = 76) were studied. Elderly included more males, had a lower Karnofsky index, more comorbidities, and lower stages. Low-dose cisplatin patients (vs. cisplatin/vinorelbine) had higher age, more comorbidities, and lower stages. We observed reduced dermatitis and dysphagia and increased anemia and thrombocytopenia in elderly vs. younger patients, without increased ≥grade 3 toxicities. Low-dose cisplatin was less toxic than cisplatin/vinorelbine. Survival outcomes were lower in elderly vs. younger and comparable between low-dose cisplatin and cisplatin/vinorelbine. In elderly, gender, Karnofsky index, stage, and multimodal treatment (including additional surgery/systemic therapy) were identified as prognostic factors. In conclusion, we found evidence for an acceptable toxicity profile and the need for improvement of outcomes in elderly with localized NSCLC. Multimodal strategies (including additional surgery/systemic treatment) showed favorable outcomes and should be reasonably considered in elderly who are deemed fit enough. Low-dose cisplatin should be discussed on an individual basis due to favorable toxicity and outcomes.

Thalamic connectivity topography in newborns with spina bifida: association with neurological functional level but not developmental outcome at 2 years.

Spina bifida affects spinal cord and cerebral development, leading to motor and cognitive delay. We investigated whether there are associations between thalamocortical connectivity topography, neurological function, and developmental outcomes in open spina bifida. Diffusion tensor MRI was used to assess thalamocortical connectivity in 44 newborns with open spina bifida who underwent prenatal surgical repair. We quantified the volume of clusters formed based on the strongest probabilistic connectivity to the frontal, parietal, and temporal cortex. Developmental outcomes were assessed using the Bayley III Scales, while the functional level of the lesion was assessed by neurological examination at 2 years of age. Higher functional level was associated with smaller thalamo-parietal, while lower functional level was associated with smaller thalamo-temporal connectivity clusters (Bonferroni-corrected P < 0.05). Lower functional levels were associated with weaker thalamic temporal connectivity, particularly in the ventrolateral and ventral anterior nuclei. No associations were found between thalamocortical connectivity and developmental outcomes. Our findings suggest that altered thalamocortical circuitry development in open spina bifida may contribute to impaired lower extremity function, impacting motor function and independent ambulation. We hypothesize that the neurologic function might not merely be caused by the spinal cord lesion, but further impacted by the disruption of cerebral neuronal circuitry.

Checkpoint Inhibitor-Associated Autoimmune Diabetes Mellitus Is Characterized by C-peptide Loss and Pancreatic Atrophy.

OBJECTIVE: To conduct a multicenter case series characterizing the clinical characteristics at presentation and pancreatic volume changes of patients with checkpoint inhibitor-associated autoimmune diabetes (CIADM). RESEARCH DESIGN AND METHODS: Electronic medical records were reviewed with 36 consecutive patients identified with CIADM, as defined by (1) previous immune checkpoint inhibitor (ICI) therapy, (2) new-onset hyperglycemia (blood glucose level ≥ 11.1 mmol/L and/or glycosylated hemoglobin ≥ 6.5%), and (3) insulin deficiency [C-peptide <0.4 nmol/L or diabetic ketoacidosis (DKA)] within 1 month of presentation. Pancreatic volume was available and measured using computed tomography volumetry for 17 patients with CIADM and 3 sets of control patients: 7 with ICI-related pancreatitis, 13 with asymptomatic ICI-related lipase elevation, and 11 ICI-treated controls for comparison. RESULTS: All patients had either anti-programmed cell death protein 1 or anti-programmed cell death ligand 1 therapy. Median time from ICI commencement to CIADM diagnosis was 15 weeks. At presentation, 25 (69%) had DKA, 27 (84%) had low C-peptide, and, by 1 month, 100% had low C-peptide. Traditional type 1 diabetes autoantibodies were positive in 15/35 (43%). Lipase was elevated in 13/27 (48%) at presentation. In 4 patients with longitudinal lipase testing, elevated levels peaked 1 month prior to CIADM diagnosis. Pancreatic volume was lower pre-ICI in CIADM patients compared with controls and demonstrated a mean decline of 41% from pretreatment to 6 months post-CIADM diagnosis. CONCLUSION: Pronounced biochemical and radiologic changes occur during CIADM pathogenesis. Rapid loss of C-peptide is a distinct characteristic that can be used to aid diagnosis as autoantibodies are often negative.

Detrusor nerve radiofrequency ablation (DENERA): Experimental study of safety and efficacy in an ovine model.

PURPOSE: The subtrigonal perivesical nerve plexus contains a large proportion of the bladder's innervation. A transurethral radiofrequency ablation approach has successfully denervated this region to alleviate overactive bladder symptoms, with some urothelial heat injury. We report a novel transvaginal RFA device (DENERA) and assess its feasibility and efficacy in denervating the perivesical nerve plexus of in vivo sheep. METHODS: In 14 adult female in vivo sheep, pulsed radiofrequency energy was applied transvaginally for three cycles of 4 min, maintaining the tissue temperature at 45°C, with 30 s of rest between each cycle. The control group (n = 4) was sacrificed without ablation, and various groups were sacrificed 1 week (n = 3), 4 weeks (n = 4), and 12 weeks (n = 3) after ablation. The bladder subtrigones were harvested then analyzed with H&E, S100, and TH immunostaining to quantify their neural density and neural vacuolization. RESULTS: The ablation procedure increased the neural vacuolization the most at 1 week and decreased the neural density the most at 4 weeks, with both variables displaying a significant change followed by a slight rebound towards baseline at 12 weeks. The H&E analysis showed that the needles penetrated deep into the subtrigonal detrusor muscle. The sheep recovered from the procedure with no complications or damage in the bladder wall or urothelium. CONCLUSIONS: This study shows that one DENERA treatment can cause subtrigonal denervation with some rebound afterwards and no complications. DENERA may become a promising OAB treatment option that can ablate the perivesical plexus without harming the urothelium.

Tendencias actuales en la preparación física del futbolista: una revisión documental

La preparación física en el fútbol es crucial para el rendimiento físico, por lo que es necesario estar al tanto de las últimas tendencias sobre los enfoques utilizados a fin de identificar las mejores prácticas y las áreas que requieren perfeccionarse. El objetivo de la investigación consistió en desarrollar una revisión exhaustiva de las tendencias actuales en la preparación física del futbolista profesional. Esta investigación fue de tipo teórica, se aplicó la técnica de revisión documental y el instrumento matriz de registro. Los pasos que se siguieron fueron la búsqueda y selección de artículos relevantes de preparación física, extracción de información, validación de fuentes, organización de hallazgos, identificación de patrones y síntesis narrativa. La investigación reveló las tendencias en la preparación física de los futbolistas y resaltó la importancia de la personalización, la planificación estratégica, el enfoque integral del entrenamiento y la alimentación adecuada. El estudio generó nuevas perspectivas en el campo de la preparación física, permitió una comprensión más completa y actualizada de las tendencias y prácticas en este ámbito, lo que sirve como base para futuras investigaciones y cubre brechas de conocimiento en el campo de la preparación física del futbolista profesional.

A preparação física no futebol é crucial para o desempenho físico, por isso é necessário estar atento às últimas tendências nas abordagens utilizadas para identificar as melhores práticas e áreas que necessitam de melhorias. O objetivo da pesquisa foi desenvolver uma revisão exaustiva das tendências atuais na preparação física de jogadores de futebol profissionais. Esta pesquisa teve caráter teórico, foram aplicadas a técnica de revisão documental e o instrumento matriz de registro. As etapas seguidas foram a busca e seleção de artigos relevantes sobre preparação física, extração de informações, validação de fontes, organização de achados, identificação de padrões e síntese narrativa. A investigação revelou tendências na preparação física dos jogadores de futebol e destacou a importância da personalização, do planeamento estratégico, de uma abordagem abrangente ao treino e de uma alimentação adequada. jogador profissional.

Physical preparation in soccer is crucial for physical performance, so it is necessary to be aware of the latest trends in the approaches used in order to identify best practices and areas that require improvement. The objective of the research was to develop an exhaustive review of current trends in the physical preparation of professional soccer player. This research was theoretical, the documentary review technique and the registration matrix instrument were applied. The steps followed were the search and selection of relevant articles on physical preparation, information extraction, validation of sources, organization of findings, identification of patterns and narrative synthesis. The research revealed trends in the physical preparation of foot players and highlighted the importance of personalization, strategic planning, a comprehensive approach to training and proper nutrition. The study generated new perspectives in the field of physical preparation, allowed a more complete and updated understanding of the trends and practices in this area, which serves as a basis for future research and covers knowledge gaps, in the field of physical preparation of the professional soccer player.

PET imaging of focused-ultrasound enhanced delivery of AAVs into the murine brain.

Rationale: Despite recent advances in the use of adeno-associated viruses (AAVs) as potential vehicles for genetic intervention of central and peripheral nervous system-associated disorders, gene therapy for the treatment of neuropathology in adults has not been approved to date. The currently FDA-approved AAV-vector based gene therapies rely on naturally occurring serotypes, such as AAV2 or AAV9, which display limited or no transport across the blood-brain barrier (BBB) if systemically administered. Recently developed engineered AAV variants have shown broad brain transduction and reduced off-target liver toxicity in non-human primates (NHPs). However, these vectors lack spatial selectivity for targeted gene delivery, a potentially critical limitation for delivering therapeutic doses in defined areas of the brain. The use of microbubbles, in conjunction with focused ultrasound (FUS), can enhance regional brain AAV transduction, but methods to assess transduction in vivo are needed. Methods: In a murine model, we combined positron emission tomography (PET) and optical imaging of reporter gene payloads to non-invasively assess the spatial distribution and transduction efficiency of systemically administered AAV9 after FUS and microbubble treatment. Capsid and reporter probe accumulation are reported as percent injected dose per cubic centimeter (%ID/cc) for in vivo PET quantification, whereas results for ex vivo assays are reported as percent injected dose per gram (%ID/g). Results: In a study spanning accumulation and transduction, mean AAV9 accumulation within the brain was 0.29 %ID/cc without FUS, whereas in the insonified region of interest of FUS-treated mice, the spatial mean and maximum reached ~2.3 %ID/cc and 4.3 %ID/cc, respectively. Transgene expression assessed in vivo by PET reporter gene imaging employing the pyruvate kinase M2 (PKM2)/[18F]DASA-10 reporter system increased up to 10-fold in the FUS-treated regions, as compared to mice receiving AAVs without FUS. Systemic injection of AAV9 packaging the EF1A-PKM2 transgene followed by FUS in one hemisphere resulted in 1) an average 102-fold increase in PKM2 mRNA concentration compared to mice treated with AAVs only and 2) a 12.5-fold increase in the insonified compared to the contralateral hemisphere of FUS-treated mice. Conclusion: Combining microbubbles with US-guided treatment facilitated a multi-hour BBB disruption and stable AAV transduction in targeted areas of the murine brain. This unique platform has the potential to provide insight and aid in the translation of AAV-based therapies for the treatment of neuropathologies.