High-Frequency 10-kHz Spinal Cord Stimulation Provides Long-term (24-Month) Improvements in Diabetes-Related Pain and Quality of Life for Patients with Painful Diabetic Neuropathy.

BACKGROUND: The SENZA-PDN study evaluated high-frequency 10-kHz spinal cord stimulation (SCS) for the treatment of painful diabetic neuropathy (PDN). Over 24 months, 10-kHz SCS provided sustained pain relief and improved health-related quality of life. This report presents additional outcomes from the SENZA-PDN study, focusing on diabetes-related pain and quality of life outcomes. METHODS: The SENZA-PDN study randomized 216 participants with refractory PDN to receive either conventional medical management (CMM) or 10-kHz SCS plus CMM (10-kHz SCS + CMM), allowing crossover after six months if pain relief was insufficient. Postimplantation assessments at 24 months were completed by 142 participants with a permanent 10-kHz SCS implant, comprising 84 initial and 58 crossover recipients. Measures included the Brief Pain Inventory for Diabetic Peripheral Neuropathy (BPI-DPN), Diabetes-Related Quality of Life (DQOL), Global Assessment of Functioning (GAF), and treatment satisfaction. RESULTS: Over 24 months, 10-kHz SCS treatment significantly reduced pain severity by 66.9% (P < .001; BPI-DPN) and pain interference with mood and daily activities by 65.8% (P < .001; BPI-DPN). Significant improvements were also observed in overall DQOL score (P < .001) and GAF score (P < .001), and 91.5% of participants reported satisfaction with treatment. CONCLUSIONS: High-frequency 10-kHz SCS significantly decreased pain severity and provided additional clinically meaningful improvements in DQOL and overall functioning for patients with PDN. The robust and sustained benefits over 24 months, coupled with high participant satisfaction, highlight that 10-kHz SCS is an efficacious and comprehensive therapy for patients with PDN.

Global remodeling of ADP-ribosylation by PARP1 suppresses influenza A virus infection.

ADP-ribosylation is a highly dynamic and fully reversible post-translational modification performed by poly(ADP-ribose) polymerases (PARPs) that modulates protein function, abundance, localization and turnover. Here we show that influenza A virus infection causes a rapid and dramatic upregulation of global ADP-ribosylation that inhibits viral replication. Mass spectrometry defined for the first time the global ADP-ribosylome during infection, creating an infection-specific profile with almost 4,300 modification sites on ~1,080 host proteins, as well as over 100 modification sites on viral proteins. Our data indicate that the global increase likely reflects a change in the form of ADP-ribosylation rather than modification of new targets. Functional assays demonstrated that modification of the viral replication machinery antagonizes its activity and further revealed that the anti-viral activity of PARPs and ADP-ribosylation is counteracted by the influenza A virus protein NS1, assigning a new activity to the primary viral antagonist of innate immunity. We identified PARP1 as the enzyme producing the majority of poly(ADP-ribose) present during infection. Influenza A virus replicated faster in cells lacking PARP1, linking PARP1 and ADP-ribosylation to the anti-viral phenotype. Together, these data establish ADP-ribosylation as an anti-viral innate immune-like response to viral infection antagonized by a previously unknown activity of NS1.

NCCN Guidelines® Insights: Bladder Cancer, Version 3.2024.

Bladder cancer, the sixth most common cancer in the United States, is most commonly of the urothelial carcinoma histologic subtype. The clinical spectrum of bladder cancer is divided into 3 categories that differ in prognosis, management, and therapeutic aims: (1) non-muscle-invasive bladder cancer (NMIBC); (2) muscle invasive, nonmetastatic disease; and (3) metastatic bladder cancer. These NCCN Guidelines Insights detail recent updates to the NCCN Guidelines for Bladder Cancer, including changes in the fifth edition of the WHO Classification of Tumours: Urinary and Male Genital Tumours and how the NCCN Guidelines aligned with these updates; new and emerging treatment options for bacillus Calmette-Guérin (BCG)-unresponsive NMIBC; and updates to systemic therapy recommendations for advanced or metastatic disease.

Testing retrogenesis and physiological explanations for tract-wise white matter aging: links to developmental order, fibre calibre, and vascularization.

To understand the consistently observed spatial distribution of white-matter (WM) aging, developmentally driven theories termed "retrogenesis" have gained traction, positing that the order of WM tract development predicts the order of declines. Regions that develop first are expected to deteriorate the last, i.e. "last-in-first-out". Alternatively, regions which develop most rapidly may also decline most rapidly in aging, or "gains-predict-loss". The validity of such theories remains uncertain, in part due to lack of clarity on the definition of developmental order. Importantly, our recent findings suggest that WM aging is also associated with physiological parameters such as perfusion, which may be linked to fibre metabolic need, which in turn varies with fibre size. Here we address the extent to which the degree of WM aging is determined by development trajectory (i.e. retrogenesis) and/or by physiological state. We obtained microstructural and perfusion measures using data from the Human Connectome Project in Aging (HCP-A), complemented by a meta-analysis involving maps of fibre calibre and macrovascular volume. Our results suggest that (1) while tracts that appear last or finish myelinating first in development display the slowest aging, the pattern of aging is not fully explained by retrogenesis; in fact, time courses of tract emergence and myelination give rise to opposite associations with WM decline; (2) tracts that appear earlier also have higher mean axon calibre and are also associated with lower degrees of WM microstructural aging; (3) such tracts also tend to exhibit relatively sustained CBF with a higher rate of lengthening of the arterial transit times (ATT), suggestive of collateral blood supply. These findings were also sex dependent in a tract-specific manner. Future work will investigate whether these are ultimately influenced by each tract's metabolic demand and the role of macrovascular collateral flow.

Family ideals in an era of low fertility.

Taking stock of individuals' perceived family ideals is particularly important in the current moment given unprecedented fertility declines and the diversification of households in advanced industrial societies. Study participants in urban China, Japan, South Korea, Singapore, the United States, Italy, Spain, and Norway were asked to evaluate vignettes describing families whose characteristics vary on ten dimensions. In contrast to previous studies that focused on a single dimension, such as fertility ideals or gender roles, this holistic vignette approach identifies the relative importance of each dimension. Multilevel regression analysis reveals both expected and unexpected findings. Parenthood remains a positive ideal, but the number of children does not matter once other family dimensions are considered, a potentially important finding in light of conventional wisdom regarding the two-children ideal. When evaluating families with at least one child, respondents tend to positively evaluate more traditional arrangements, including valuing marriage relative to cohabitation and, particularly, divorce. Also, in addition to financial resources, good communication between immediate and extended family members, as well as maintaining respect in the larger community, are highly salient attributes of an ideal family. Notwithstanding some important cross-national differences, egalitarian gender roles and avoiding work-family conflict are also valued positively. Overall, even as the study reveals some notable variations between societies, respondents across countries identify similar components of an ideal family.

The impact on clinical outcomes after 1 year of implementation of an artificial intelligence solution for the detection of intracranial hemorrhage.

BACKGROUND: To assess the effect of a commercial artificial intelligence (AI) solution implementation in the emergency department on clinical outcomes in a single level 1 trauma center. METHODS: A retrospective cohort study for two time periods-pre-AI (1.1.2017-1.1.2018) and post-AI (1.1.2019-1.1.2020)-in a level 1 trauma center was performed. The ICH algorithm was applied to 587 consecutive patients with a confirmed diagnosis of ICH on head CT upon admission to the emergency department. Study variables included demographics, patient outcomes, and imaging data. Participants admitted to the emergency department during the same time periods for other acute diagnoses (ischemic stroke (IS) and myocardial infarction (MI)) served as control groups. Primary outcomes were 30- and 120-day all-cause mortality. The secondary outcome was morbidity based on Modified Rankin Scale for Neurologic Disability (mRS) at discharge. RESULTS: Five hundred eighty-seven participants (289 pre-AI-age 71 ± 1, 169 men; 298 post-AI-age 69 ± 1, 187 men) with ICH were eligible for the analyzed period. Demographics, comorbidities, Emergency Severity Score, type of ICH, and length of stay were not significantly different between the two time periods. The 30- and 120-day all-cause mortality were significantly reduced in the post-AI group when compared to the pre-AI group (27.7% vs 17.5%; p = 0.004 and 31.8% vs 21.7%; p = 0.017, respectively). Modified Rankin Scale (mRS) at discharge was significantly reduced post-AI implementation (3.2 vs 2.8; p = 0.044). CONCLUSION: The added value of this study emphasizes the introduction of artificial intelligence (AI) computer-aided triage and prioritization software in an emergent care setting that demonstrated a significant reduction in a 30- and 120-day all-cause mortality and morbidity for patients diagnosed with intracranial hemorrhage (ICH). Along with mortality rates, the AI software was associated with a significant reduction in the Modified Ranking Scale (mRs).

Long-term efficacy of high-frequency (10 kHz) spinal cord stimulation for the treatment of painful diabetic neuropathy: 24-Month results of a randomized controlled trial.

AIMS: To evaluate the long-term efficacy of high-frequency (10 kHz) spinal cord stimulation (SCS) for treating refractory painful diabetic neuropathy (PDN). METHODS: The SENZA-PDN study was a prospective, multicenter, randomized controlled trial that compared conventional medical management (CMM) alone with 10 kHz SCS plus CMM (10 kHz SCS+CMM) in 216 patients with refractory PDN. After 6 months, participants with insufficient pain relief could cross over to the other treatment. In total, 142 patients with a 10 kHz SCS system were followed for 24 months, including 84 initial 10 kHz SCS+CMM recipients and 58 crossovers from CMM alone. Assessments included pain intensity, health-related quality of life (HRQoL), sleep, and neurological function. Investigators assessed neurological function via sensory, reflex, and motor tests. They identified a clinically meaningful improvement relative to the baseline assessment if there was a significant persistent improvement in neurological function that impacted the participant's well-being and was attributable to a neurological finding. RESULTS: At 24 months, 10 kHz SCS reduced pain by a mean of 79.9% compared to baseline, with 90.1% of participants experiencing ≥50% pain relief. Participants had significantly improved HRQoL and sleep, and 65.7% demonstrated clinically meaningful neurological improvement. Five (3.2%) SCS systems were explanted due to infection. CONCLUSIONS: Over 24 months, 10 kHz SCS provided durable pain relief and significant improvements in HRQoL and sleep. Furthermore, the majority of participants demonstrated neurological improvement. These long-term data support 10 kHz SCS as a safe and highly effective therapy for PDN. TRIAL REGISTRATION: ClincalTrials.gov Identifier, NCT03228420.

Localization and Laparoscopic Excision of Gastric Heterotopic Pancreas in a Child by Endoscopic SPOT® Tattooing.

Heterotopic pancreas (HP) is defined as pancreatic tissue lacking vascular or anatomic connection with the normal pancreas. Surgical resection is often indicated for symptomatic gastric HP. However, intraoperative identification of gastric HP is often difficult during laparoscopic surgery. Herein, we describe a patient with gastric HP, which was marked with SPOT® dye (GI Supply, Camp Hill, PA, USA). The dye was seen clearly laparoscopically facilitating total excision of the lesion. The final pathology report confirmed the presence of heterotopic pancreatic tissue including pancreatic acini, small pancreatic ducts tissue with islets of Langerhans in the deep gastric submucosal area. There were no postoperative complications, and the patient was symptom-free. To the best of our knowledge, this was the first case report in the literature in which endoscopic tattooing of gastric HP before laparoscopic resection was performed. This method of localization was simple and reliable in children.

Intraoperative OK-432 pleurodesis for preventing recurrence of primary spontaneous pneumothorax in children and adolescents: a single-center experience.

BACKGROUND: Primary spontaneous pneumothorax (PSP) commonly occurs in lean, tall, male children and adolescents. To reduce recurrence rates of PSP, chemical pleurodesis could be helpful for patients undergoing video-assisted thoracoscopic surgery (VATS) wedge bullectomy. The efficacy and safety of intraoperative OK-432 (Picibanil) pleurodesis on preventing the recurrence of PSP in pediatric patients remain unclear. METHODS: It is a retrospective observational study in a single center, between 2014 and 2020, enrolled 48 (8 females) pediatric PSP patients with persistent air leakage at the mean age of 16.3 ± 1.1 years to receive VATS wedge bullectomy and pleural abrasion. Twenty patients received additional intraoperative OK-432 pleurodesis. The clinical characteristics of patients, surgical outcomes, and recurrence rates were analyzed. RESULTS: The OK-432 group had longer operation time (118.6 ± 35.6 vs. 96.5 ± 23.3 min; p < 0.05) and higher proportion of postoperative fever (75.0% vs. 28.5%; p = 0.015) than the standard group. No serious adverse events were noted and other surgical outcomes in the two groups were comparable. After a mean follow-up period of 18.1 ± 19.1 months, the OK-432 group had a lower recurrence rate compared with the standard group (5% vs. 28.6%; p < 0.05, odds ratio 0.13, 95% confidence interval: 0.01-1.15), but it had no significant difference in statistics on the Kaplan-Meier curves (log-rank p = 0.105). CONCLUSION: It was the first study that focused on the addition of intraoperative OK-432 pleurodesis for PSP with persistent air leakage in children and adolescents receiving VATS. It demonstrated the efficacy with a low recurrence rate and short-term safety as a single-center experience. LEVEL OF EVIDENCE: Retrospective review, therapeutic study, Level III.

Highly aneuploid non-small cell lung cancer shows enhanced responsiveness to concurrent radiation and immune checkpoint blockade.

Over 500 clinical trials are investigating combination radiotherapy and immune checkpoint blockade (ICB) as cancer treatments; however, the majority of trials have found no positive interaction. Here we perform a comprehensive molecular analysis of a randomized phase I clinical trial of patients with non-small cell lung cancer (NSCLC) treated with concurrent or sequential ablative radiotherapy and ICB. We show that concurrent treatment is superior to sequential treatment in augmenting local and distant tumor responses and in improving overall survival in a subset of patients with immunologically cold, highly aneuploid tumors, but not in those with less aneuploid tumors. In addition, radiotherapy alone decreases intratumoral cytotoxic T cell and adaptive immune signatures, whereas radiotherapy and ICB upregulates key immune pathways. Our findings challenge the prevailing paradigm that local ablative radiotherapy beneficially stimulates the immune response. We propose the use of tumor aneuploidy as a biomarker and therapeutic target in personalizing treatment approaches for patients with NSCLC treated with radiotherapy and ICB.

Preimplantation genetic testing for aneuploidy in patients with low embryo numbers: benefit or harm?

PURPOSE: We sought to explore the utility of preimplantation genetic testing for aneuploidy (PGT-A) in a poor prognosis group of women with few embryos available for transfer. METHODS: This was a retrospective matched cohort study examining records for first or second-cycle IVF patients with 1 to 3 blastocysts. The study group comprised 130 patients who underwent PGT-A on all embryos. The control group included 130 patients matched by age, BMI, and blastocyst number and quality who did not undergo PGT-A during the same time period. RESULTS: The live birth rate (LBR) per embryo transfer (ET) were similar in the PGT-A and control groups, and the spontaneous abortion (SAB) rate was the same (23%). However, we found a significantly higher LBR per oocyte retrieval in the control group vs the PGT-A group (43% vs 20%, respectively) likely due to the many no-euploid cycles in the PGT-A group. In a subgroup analysis for age, the similar LBR per ET persisted in women < 38. However, in older women, there was a trend to a higher LBR per ET in the PGT-A group (43%) vs the control group (22%) but a higher LBR per oocyte retrieval in the control group (31%) vs the PGT-A group (13%). CONCLUSIONS: Overall, we observed a significant increase in LBR per oocyte retrieval in women in the control group compared to women undergoing PGT-A, and no difference in SAB rate. Our data suggests that PGT-A has no benefit in a subpopulation of women with few embryos and may cause harm.

High-Frequency 10-kHz Spinal Cord Stimulation Improves Health-Related Quality of Life in Patients With Refractory Painful Diabetic Neuropathy: 12-Month Results From a Randomized Controlled Trial.

Objective: To evaluate high-frequency (10-kHz) spinal cord stimulation (SCS) treatment in refractory painful diabetic neuropathy. Patients and Methods: A prospective, multicenter randomized controlled trial was conducted between Aug 28, 2017 and March 16, 2021, comparing conventional medical management (CMM) with 10-kHz SCS+CMM. The participants had hemoglobin A1c level of less than or equal to 10% and pain greater than or equal to 5 of 10 cm on visual analog scale, with painful diabetic neuropathy symptoms 12 months or more refractory to gabapentinoids and at least 1 other analgesic class. Assessments included measures of pain, neurologic function, and health-related quality of life (HRQoL) over 12 months with optional crossover at 6 months. Results: The participants were randomized 1:1 to CMM (n=103) or 10-kHz SCS+CMM (n=113). At 6 months, 77 of 95 (81%) CMM group participants opted for crossover, whereas none of the 10-kHz SCS group participants did so. At 12 months, the mean pain relief from baseline among participants implanted with 10-kHz SCS was 74.3% (95% CI, 70.1-78.5), and 121 of 142 (85%) participants were treatment responders (≥50% pain relief). Treatment with 10-kHz SCS improved HRQoL, including a mean improvement in the EuroQol 5-dimensional questionnaire index score of 0.136 (95% CI, 0.104-0.169). The participants also reported significantly less pain interference with sleep, mood, and daily activities. At 12 months, 131 of 142 (92%) participants were "satisfied" or "very satisfied" with the 10-kHz SCS treatment. Conclusion: The 10-kHz SCS treatment resulted in substantial pain relief and improvement in overall HRQoL 2.5- to 4.5-fold higher than the minimal clinically important difference. The outcomes were durable over 12 months and support 10-kHz SCS treatment in patients with refractory painful diabetic neuropathy. Trial registration: clincaltrials.gov Identifier: NCT03228420.

National Canadian Survey on the Management of Noneuploid Embryos.

OBJECTIVE: To comprehensively describe current preimplantation genetic testing for aneuploidy (PGT-A) practices and management of non-euploid embryos in Canada. METHODS: This was a cross-sectional study utilizing an online survey distributed by email to all medical directors of fertility clinics with independent in vitro fertilization (IVF) embryology laboratories. The survey was designed to determine practice patterns regarding PGT-A usage; PGT-A reference laboratory, platform, and thresholds for classifying embryos; and management of embryos classified as mosaic, inconclusive, or aneuploid. RESULTS: Twenty-five medical directors (69%) participated in the survey. The majority of clinics (91%) offered PGT-A screening, with 45% of clinics offering PGT-A as routine screening. The majority of clinics (90%) that offered PGT-A received mosaicism data; 61% of these clinics had transferred mosaic embryos, and 94% would transfer mosaic embryos. Clinics that performed ≥1000 IVF cycles annually were more likely to have transferred mosaic embryos (100% vs. 45.5%; P = 0.043). The mean percentage of IVF cycles using PGT-A was lower in clinics that had transferred mosaic embryos (12.3% vs. 30.4%; P = 0.033). Only 1 clinic had transferred an aneuploid embryo, but 2 other clinics would consider this option. The majority of clinics (61%) that receive mosaicism data would recommend noninvasive prenatal testing (NIPT) following mosaic embryo transfer, with 22% of clinics indicating that this would be the only genetic test offered. CONCLUSION: We report significant practice variation in PGT-A and management of non-euploid embryos across Canada and highlight areas where consensus should be encouraged.

A Clinically Optimal Protocol for the Imaging of Enteric Tubes: On the Basis of Radiologist Interpreted Diagnostic Utility and Radiation Dose Reduction.

RATIONALE AND OBJECTIVES: The purpose of this study was to develop and evaluate a patient thickness-based protocol specifically for the confirmation of enteric tube placements in bedside abdominal radiographs. Protocol techniques were set to maintain image quality while minimizing patient dose. MATERIALS AND METHODS: A total of 226 pre-intervention radiographs were obtained to serve as a baseline cohort for comparison. After the implementation of a thickness-based protocol, a total of 229 radiographs were obtained as part of an intervention cohort. Radiographs were randomized and graded for diagnostic quality by seven expert radiologists based on a standardized conspicuity scale (grades: 0 non-diagnostic to 3+). Basic patient demographics, body mass index, ventilatory status, and enteric tube type were recorded and subgroup analyses were performed. Effective dose was estimated for both cohorts. RESULTS: The dedicated thickness-based protocol resulted in a significant reduction in effective dose of 80% (p-value < 0.01). There was no significant difference in diagnostic quality between the two cohorts with 209 (92.5%) diagnostic radiographs in the baseline and 221 (96.5%) diagnostic radiographs in the thickness-based protocol (p-value 0.06). CONCLUSION: A protocol optimized for the confirmation of enteric tube placements was developed. This protocol results in lower patient effective dose, without sacrificing diagnostic accuracy. The technique chart is provided for reference. The protocol development process outlined in this work could be readily generalized to other imaging clinical tasks.