Control of ENaC ubiquitination.

Ubiquitination influences the expression of the epithelial Na+ channel (ENaC). We assessed the mechanisms of selective ubiquitination of the mature, cleaved form of γENaC in both native rodent kidneys and in Fisher Rat Thyroid (FRT) cells expressing the channel heterologously. In both models, singly cleaved and fully cleaved γENaC were both strongly ubiquitinated, implying that the second cleavage releasing an inhibitory peptide was not essential for the process. To see if location of the protein in or near the apical membrane rather than cleavage per se influences ubiquitination we studied mutants of γENaC in which cleavage sites are abolished. These subunits were ubiquitinated only when co-expressed with α and ßENaC, facilitating trafficking through the Golgi apparatus. To test whether reaching the apical surface is necessary we performed in situ surface biotinylation and measured ENaC ubiquitination in the apical membrane of rat kidney. Ubiquitination of cleaved γENaC was similar in whole-kidney and surface fractions, implying that both apical and subapical channels could be modified. In FRT cells, inhibiting clathrin-mediated endocytosis with Dyngo-4a increased both total the ubiquitinated γENaC at the cell surface. Finally, we tested the idea that increased intracellular Na+ could stimulate ubiquitination. Administration of amiloride to block Na+ entry through the channels did not affect ubiquitination of γENaC in either FRT cells or rat kidney. However, presumed large increases in cellular Na+ produced by monensin in FRT cells or acute Na+ repletion in rats increased ubiquitination and decreased overall ENaC expression.

Phase I study targeting newly diagnosed grade 4 astrocytoma with bispecific antibody armed T cells (EGFR BATs) in combination with radiation and temozolomide.

PURPOSE: The purpose of this study was to determine the safety, feasibility, and immunologic responses of treating grade 4 astrocytomas with multiple infusions of anti-CD3 x anti-EGFR bispecific antibody (EGFRBi) armed T cells (EGFR BATs) in combination with radiation and chemotherapy. METHODS: This phase I study used a 3 + 3 dose escalation design to test the safety and feasibility of intravenously infused EGFR BATs in combination with radiation and temozolomide (TMZ) in patients with newly diagnosed grade 4 astrocytomas (AG4). After finding the feasible dose, an expansion cohort with unmethylated O6-methylguanine-DNA methyltransferase (MGMT) tumors received weekly EGFR BATs without TMZ. RESULTS: The highest feasible dose was 80 × 109 EGFR BATs without dose-limiting toxicities (DLTs) in seven patients. We could not escalate the dose because of the limited T-cell expansion. There were no DLTs in the additional cohort of three patients with unmethylated MGMT tumors who received eight weekly infusions of EGFR BATs without TMZ. EGFR BATs infusions induced increases in glioma specific anti-tumor cytotoxicity by peripheral blood mononuclear cells (p < 0.03) and NK cell activity (p < 0.002) ex vivo, and increased serum concentrations of IFN-γ (p < 0.03), IL-2 (p < 0.007), and GM-CSF (p < 0.009). CONCLUSION: Targeting AG4 with EGFR BATs at the maximum feasible dose of 80 × 109, with or without TMZ was safe and induced significant anti-tumor-specific immune responses. These results support further clinical trials to examine the efficacy of this adoptive cell therapy in patients with MGMT-unmethylated GBM. CLINICALTRIALS: gov Identifier: NCT03344250.

Factorial invariance of the Wechsler Intelligence Scale for Children, Fifth Edition, across the UK, US and Australia & New Zealand.

OBJECTIVES: This study examined the factorial invariance of the factor structure of the Wechsler Intelligence Scale for Children, Fifth Edition (WISC-V) across the UK, US and Australia & New Zealand (A&NZ). The factorial equivalence of cognitive assessments should be demonstrated before assuming cross-culture generalizability and interpretations of score comparisons. METHODS: Data were obtained from the UK, US and A&NZ normative standardizations of the WISC-V. The samples consisted of 415 UK, 2200 US and 528 A&NZ children, aged 6-16. Confirmatory factor analysis was applied separately in each sample to establish the baseline model. Next, tests of factorial invariance were undertaken using the recommended hierarchical approach, firstly across the UK and A&NZ samples and then across the UK and US samples. RESULTS: The five-factor first-order scoring model was found to be excellent fit across all three samples independently. Strict factorial invariance of the WISC-V was demonstrated firstly across the UK and A&NZ and secondly the UK and US nationally representative standardization samples. Comparison of latent means found small but significant differences in female children across the UK and A&NZ samples. CONCLUSIONS: Consistent with previous research, these results demonstrate the generality of the WISC-V factor structure across the UK, US and A&NZ. Furthermore, as the WISC-V factor structure aligns with the Cattell-Horn-Carroll (CHC) model of cognitive abilities, the results add further support to the cross-cultural generalizability of the CHC model. Small but significant differences in latent factor scores found across samples support the development and use of local normative data.

How to determine the optimal proximal fusion level for Scheuermann kyphosis.

OBJECTIVE: To determine optimal proximal fusion levels for instrumented spinal fusion for Scheuermann kyphosis. METHODS: We reviewed 86 patients (33 women) who underwent corrective instrumented spinal fusion for Scheuermann kyphosis. All patients had long-cassette upright lateral radiographs taken preoperatively, postoperatively, and at 2 years and the last follow-up. Demographic, radiographic, and surgical parameters were compared between patients with and without PJK. RESULTS: PJK occurred in 28 patients (32%). The mean maximum Cobb angle was 85.8° ± 11.7° preoperatively, 54.8° ± 14.2° postoperatively, and 59.7° ± 16.8° at the last follow-up. Age and sex did not differ between the PJK and non-PJK groups (P > 0.05). The preoperative curve characteristics, fusion levels, and corrective ratio were similar in both groups (P > 0.05). The maximal Cobb angle at 2 years and the last follow-up significantly differed between the 2 groups (P < 0.05). The proportion of patients with the uppermost instrumented vertebra (UIV) at or above the proximal end vertebra (PEV) was similar in both groups (P > 0.05). The proportion of patients with UIV at or above T2 was significantly greater in the non-PJK group (P < 0.05). PJK was significantly associated with a C7 plumb line (C7PL)-sacrum distance ≥ 50 mm (P < 0.05). CONCLUSION: PJK is the main cause of postoperative correction loss. Proper fusion-level selection can reduce PJK occurrence. We recommend having the UIV at T2 or above, especially when the C7PL-sacrum distance ≥ 50 mm.

Assessing the Reproducibility of the Structured Abstracts Generated by ChatGPT and Bard Compared to Human-Written Abstracts in the Field of Spine Surgery: Comparative Analysis.

BACKGROUND: Due to recent advances in artificial intelligence (AI), language model applications can generate logical text output that is difficult to distinguish from human writing. ChatGPT (OpenAI) and Bard (subsequently rebranded as "Gemini"; Google AI) were developed using distinct approaches, but little has been studied about the difference in their capability to generate the abstract. The use of AI to write scientific abstracts in the field of spine surgery is the center of much debate and controversy. OBJECTIVE: The objective of this study is to assess the reproducibility of the structured abstracts generated by ChatGPT and Bard compared to human-written abstracts in the field of spine surgery. METHODS: In total, 60 abstracts dealing with spine sections were randomly selected from 7 reputable journals and used as ChatGPT and Bard input statements to generate abstracts based on supplied paper titles. A total of 174 abstracts, divided into human-written abstracts, ChatGPT-generated abstracts, and Bard-generated abstracts, were evaluated for compliance with the structured format of journal guidelines and consistency of content. The likelihood of plagiarism and AI output was assessed using the iThenticate and ZeroGPT programs, respectively. A total of 8 reviewers in the spinal field evaluated 30 randomly extracted abstracts to determine whether they were produced by AI or human authors. RESULTS: The proportion of abstracts that met journal formatting guidelines was greater among ChatGPT abstracts (34/60, 56.6%) compared with those generated by Bard (6/54, 11.1%; P<.001). However, a higher proportion of Bard abstracts (49/54, 90.7%) had word counts that met journal guidelines compared with ChatGPT abstracts (30/60, 50%; P<.001). The similarity index was significantly lower among ChatGPT-generated abstracts (20.7%) compared with Bard-generated abstracts (32.1%; P<.001). The AI-detection program predicted that 21.7% (13/60) of the human group, 63.3% (38/60) of the ChatGPT group, and 87% (47/54) of the Bard group were possibly generated by AI, with an area under the curve value of 0.863 (P<.001). The mean detection rate by human reviewers was 53.8% (SD 11.2%), achieving a sensitivity of 56.3% and a specificity of 48.4%. A total of 56.3% (63/112) of the actual human-written abstracts and 55.9% (62/128) of AI-generated abstracts were recognized as human-written and AI-generated by human reviewers, respectively. CONCLUSIONS: Both ChatGPT and Bard can be used to help write abstracts, but most AI-generated abstracts are currently considered unethical due to high plagiarism and AI-detection rates. ChatGPT-generated abstracts appear to be superior to Bard-generated abstracts in meeting journal formatting guidelines. Because humans are unable to accurately distinguish abstracts written by humans from those produced by AI programs, it is crucial to exercise special caution and examine the ethical boundaries of using AI programs, including ChatGPT and Bard.

Visual Performance and Sports: A Scoping Review.

Vision is central to success in nearly all sports, and there is an emerging body of research investigating the links between visual abilities and athletic performance. This preregistered scoping review seeks to clarify the topics of study, methodologies used, populations under investigation, researchers, and disciplines driving this field. Systematic searches of English-language articles were conducted in PubMed and Web of Science, with additional literature identified through bibliographic searches. Six hundred sixty-seven articles published between 1976 and 2023 were identified with 547 empirical studies, 58 review articles, 20 commentaries, and 4 meta-analyses, among others. Among the empirical papers, 411 reported on visual assessments and 98 on vision training interventions. The most represented sports included baseball, soccer, basketball, and cricket, with over 150 articles reporting on professional, elite, or Olympic athletes. This scoping review describes the breadth of this emerging field, identifies its strengths and weaknesses, and provides recommendations for future improvement.

Phosphine-Dependent Photoinitiation of Alkyl Thiols under Near-UV Light Facilitates User-Friendly Peptide Desulfurization.

Peptides are steadily gaining importance as pharmaceutical targets, and efficient, green methods for their preparation are critically needed. A key deficiency in the synthetic toolbox is the lack of an industrially viable peptide desulfurization method. Without this tool, the powerful native chemical ligation reaction typically used to assemble polypeptides and proteins remains out of reach for industrial preparation of drug targets. Current desulfurization methods require very large excesses of phosphine reagents and thiol additives or low-abundance metal catalysts. Here, we report a phosphine-only photodesulfurization (POP) using near-UV light that is clean, high-yielding, and requires as little as 1.2 equiv phosphine. The user-friendly reaction gives complete control to the chemist, allowing solvent and reagent selection based on starting material and phosphine solubility. It can be conducted in a range of solvents, including water or buffers, on protected or unprotected peptides, in low or high dilution and on gram scale. Oxidation-prone amino acids, π-bonds, aromatic rings, thio-aminal linkages, thioesters, and glycans are all stable to the POP reaction. We highlight the utility of this approach for desulfurization of industrially relevant targets including cyclic peptides and glucagon-like peptide 1 (GLP-1(7-36)). The method is also compatible with NCL buffer, and we highlight the robustness of the approach through the one-pot disulfide reduction/multidesulfurization of linaclotide, aprotinin, and wheat protein.

High dietary K+ intake inhibits proximal tubule transport.

The impact of chronic dietary K+ loading on proximal tubule (PT) function was measured using free-flow micropuncture along with measurements of overall kidney function, including urine volume, glomerular filtration rate, and absolute and fractional Na+ and K+ excretion in the rat. Feeding animals a diet with 5% KCl [high K+ (HK)] for 7 days reduced glomerular filtration rate by 29%, increased urine volume by 77%, and increased absolute K+ excretion by 202% compared with rats on a 1% KCl [control K+ (CK)] diet. HK did not change absolute Na+ excretion but significantly increased fraction excretion of Na+ (1.40% vs. 0.64%), indicating that fractional Na+ absorption is reduced by HK. PT reabsorption was assessed using free-flow micropuncture in anesthetized animals. At 80% of the accessible length of the PT, measurements of inulin concentration indicated volume reabsorption of 73% and 54% in CK and HK, respectively. At the same site, fractional PT Na+ reabsorption was 66% in CK animals and 37% in HK animals. Fractional PT K+ reabsorption was 66% in CK and 37% in HK. To assess the role of Na+/H+ exchanger isoform 3 (NHE3) in mediating these changes, we measured NHE3 protein expression in total kidney microsomes as well as surface membranes using Western blots. We found no significant changes in protein in either cell fraction. Expression of the Ser552 phosphorylated form of NHE3 was also similar in CK and HK animals. Reduction in PT transport may facilitate K+ excretion and help balance Na+ excretion by shifting Na+ reabsorption from K+-reabsorbing to K+-secreting nephron segments.NEW & NOTEWORTHY In rats fed a diet rich in K+, proximal tubules reabsorbed less fluid, Na+, and K+ compared with those in animals on a control diet. Glomerular filtration rates also decreased, probably due to glomerulotubular feedback. These reductions may help to maintain balance of the two ions simultaneously by shifting Na+ reabsorption to K+-secreting nephron segments.

Furin cleavage of SARS-CoV-2 Spike promotes but is not essential for infection and cell-cell fusion.

Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) infects cells by binding to the host cell receptor ACE2 and undergoing virus-host membrane fusion. Fusion is triggered by the protease TMPRSS2, which processes the viral Spike (S) protein to reveal the fusion peptide. SARS-CoV-2 has evolved a multibasic site at the S1-S2 boundary, which is thought to be cleaved by furin in order to prime S protein for TMPRSS2 processing. Here we show that CRISPR-Cas9 knockout of furin reduces, but does not prevent, the production of infectious SARS-CoV-2 virus. Comparing S processing in furin knockout cells to multibasic site mutants reveals that while loss of furin substantially reduces S1-S2 cleavage it does not prevent it. SARS-CoV-2 S protein also mediates cell-cell fusion, potentially allowing virus to spread virion-independently. We show that loss of furin in either donor or acceptor cells reduces, but does not prevent, TMPRSS2-dependent cell-cell fusion, unlike mutation of the multibasic site that completely prevents syncytia formation. Our results show that while furin promotes both SARS-CoV-2 infectivity and cell-cell spread it is not essential, suggesting furin inhibitors may reduce but not abolish viral spread.

Suitability of Automated Writing Measures for Clinical Trial Outcome in Writer's Cramp.

BACKGROUND: Writer's cramp (WC) dystonia is a rare disease that causes abnormal postures during the writing task. Successful research studies for WC and other forms of dystonia are contingent on identifying sensitive and specific measures that relate to the clinical syndrome and achieve a realistic sample size to power research studies for a rare disease. Although prior studies have used writing kinematics, their diagnostic performance remains unclear. OBJECTIVE: This study aimed to evaluate the diagnostic performance of automated measures that distinguish subjects with WC from healthy volunteers. METHODS: A total of 21 subjects with WC and 22 healthy volunteers performed a sentence-copying assessment on a digital tablet using kinematic and hand recognition softwares. The sensitivity and specificity of automated measures were calculated using a logistic regression model. Power analysis was performed for two clinical research designs using these measures. The test and retest reliability of select automated measures was compared across repeat sentence-copying assessments. Lastly, a correlational analysis with subject- and clinician-rated outcomes was performed to understand the clinical meaning of automated measures. RESULTS: Of the 23 measures analyzed, the measures of word legibility and peak accelerations distinguished subjects with WC from healthy volunteers with high sensitivity and specificity and demonstrated smaller sample sizes suitable for rare disease studies, and the kinematic measures showed high reliability across repeat visits, while both word legibility and peak accelerations measures showed significant correlations with the subject- and clinician-rated outcomes. CONCLUSIONS: Novel automated measures that capture key aspects of the disease and are suitable for use in clinical research studies of WC dystonia were identified. © 2022 International Parkinson and Movement Disorder Society.

The physiology of intraoperative error: using electrokardiograms to understand operator performance during robot-assisted surgery simulations.

BACKGROUND: No platform for objective, synchronous and on-line evaluation of both intraoperative error and surgeon physiology yet exists. Electrokardiogram (EKG) metrics have been associated with cognitive and affective features that are known to impact surgical performance but have not yet been analyzed in conjunction with real-time error signals using objective, real-time methods. METHODS: EKGs and operating console point-of-views (POVs) for fifteen general surgery residents and five non-medically trained participants were captured during three simulated robotic-assisted surgery (RAS) procedures. Time and frequency-domain EKG statistics were extracted from recorded EKGs. Intraoperative errors were detected from operating console POV videos. EKG statistics were synchronized with intraoperative error signals. RESULTS: Relative to personalized baselines, IBI, SDNN and RMSSD decreased 0.15% (S.E. 3.603e-04; P = 3.25e-05), 3.08% (S.E. 1.603e-03; P < 2e-16) and 1.19% (S.E. 2.631e-03; P = 5.66e-06), respectively, during error. Relative LF RMS power decreased 1.44% (S.E. 2.337e-03; P = 8.38e-10), and relative HF RMS power increased 5.51% (S.E. 1.945e-03; P < 2e-16). CONCLUSIONS: Use of a novel, on-line biometric and operating room data capture and analysis platform enabled detection of distinct operator physiological changes during intraoperative errors. Monitoring operator EKG metrics during surgery may help improve patient outcomes through real-time assessments of intraoperative surgical proficiency and perceived difficulty as well as inform personalized surgical skills development.

Adult spinal deformity patients revised for pseudarthrosis have comparable two-year outcomes to those not undergoing any revision surgery.

PURPOSE: This study aimed to evaluate whether adult spinal deformity patients undergoing revision for symptomatic pseudarthrosis have comparable two-year outcomes as patients who do not experience pseudarthrosis. METHODS: Patients whose indexed procedure was revision for pseudarthrosis (pseudo) were compared with patients who underwent a primary procedure and did not have pseudarthrosis by 2Y post-op (non-pseudo). Patients were propensity-matched (PSM) based on baseline (BL) sagittal alignment, specifically C7SVA and CrSVA-Hip. Key outcomes were 2Y PROs (SRS and ODI) and reoperation. All patients had a minimum follow-up period of two years. RESULTS: A total of 224 patients with min 2-year FU were included (pseudo = 42, non-pseudo = 182). Compared to non-pseudo, pseudo-patients were more often female (P = 0.0018) and had worse BL sagittal alignment, including T1PA (P = 0.02], C2-C7 SVA [P = 0.0002], and CrSVA-Hip [P = 0.004]. After 37 PSM pairs were generated, there was no significant difference in demographics, BL and 2Y alignment, or operative/procedural variables. PSM pairs did not report any significantly different PROs at BL. Consistently, at 2Y, there were no significant differences in PROs, including SRS function [3.9(0.2) vs 3.7(0.2), P = 0.44], pain [4.0 (0.2) vs. 3.57 (0.2), P = 0.12], and ODI [25.7 (5.2) vs 27.7 (3.7), P = 0.76]. There were no differences in 1Y (10.8% vs 10.8%, P > 0.99) and 2Y (13.2% vs 15.8%, P = 0.64) reoperation, PJK rate (2.6% vs 10.5%, P = 0.62), or implant failure (2.6% vs 10.5%, P = 0.37). Notably, only 2 patients (5.4%) had recurrent pseudarthrosis following revision. Kaplan-Meier curves indicated that patients undergoing intervention for pseudarthrosis had comparable overall reoperation-free survival (log-rank test, χ2 = 0.1975 and P = 0.66). CONCLUSIONS: Patients undergoing revision for pseudarthrosis have comparable PROs and clinical outcomes as patients who never experienced pseudarthrosis. Recurrence of symptomatic pseudarthrosis was infrequent.

The iliac kickstand screw: anatomic CT analysis of screw trajectory and osseous corridor for screw placement.

INTRODUCTION: The 'kickstand screw-rod' technique has been recently described for correction of coronal malalignment. This technique utilizes powerful 'construct-to-ilium' distraction between a fixed multi-screw thoracic construct and the ilium, facilitated by a novel 'iliac kickstand screw'. The 'iliac kickstand screw' traverses a previously undescribed osseous corridor in the ilium. OBJECTIVE: Using a radiographic CT study, the objective is to describe a large osseous corridor within the ilium to accommodate the novel iliac kickstand screw. METHODS: 50 consecutive patients with pelvic CTs at an academic medical center were queried. Simulated iliac kickstand screw trajectories for the left and right hemipelvis were analyzed with 3D visualization software. Maximal screw lengths and dimensions, and trajectories in the osseous corridor were measured. RESULTS: 50 patients' (31 female, 19 male) pelvic CTs were measured with a total of 100 simulated screws. The mean age was 52.4 years and BMI 28.1 ± 7.9. The average length is 119.7 ± 6.6 mm (range 98.7 - 135.3). The narrowest width (maximum potential screw diameter) is 17.8 ± 2.9 mm (coronal) and 20.8 ± 5.3 mm (sagittal). The starting point to the top of the iliac crest is 66.4 mm lateral to midline, and 15.9° caudal in the sagittal and 6.1° lateral in the coronal planes. CONCLUSIONS: The novel iliac kickstand screw traverses a consistent and large osseous corridor within the ilium. The average simulated screw length is 119.7 mm and maximum potential diameter of 17.8 mm. Starting points relative to the iliac crest are identified.

Development of a preoperative risk score predicting allogeneic red blood cell transfusion in children undergoing spinal fusion.

BACKGROUND: Children undergoing spinal fusion often receive blood products. The goal of this study was to develop a preoperative score to help physicians identify those who are at risk of allogeneic red blood cell (RBC) transfusion. STUDY DESIGN AND METHODS: This retrospective study of children undergoing spinal fusion in the ACS-NSQIP Pediatric database (2016-2019) aimed at identifying risk factors associated with allogeneic RBC transfusion. Univariable logistic regression and multivariable logistic regression were performed using preoperative patient characteristics and aided in the creation of a simplified scoring system. RESULTS: Out of 13,929 total patients, 2990 (21.5%) were transfused. We created a risk score based on 10 independent predictors of transfusion: age, sex, race, weight < 3rd percentile, American Society of Anesthesiologists physical status classification, cardiac risk factors, hematologic disease, preoperative anemia, deformity type, and number of spinal levels to be fused. Patients in both the training and testing cohorts were assigned a score ranging from 0 (lowest risk) to 21 (highest risk). The developed transfusion risk score showed 77% accuracy in distinguishing patients who did not receive a transfusion during or soon after surgery (AUROC 0.7736 [95% CI, 0.7619-0.7852]) in the training cohort and 77% accuracy (AUROC 0.7732 [95% CI, 0.7554-0.7910]) in the testing cohort. DISCUSSION: Our score, based on routinely available preoperative data, accurately estimates the risk of allogeneic RBC transfusion in pediatric patients undergoing spinal fusion. Future studies will inform whether patient blood management interventions targeted to high-risk patients can help reduce the need for transfusion and improve outcomes.

Enhancing Cognitive Restructuring with Concurrent Repetitive Transcranial Magnetic Stimulation: A Transdiagnostic Randomized Controlled Trial.

INTRODUCTION: Emotional dysregulation constitutes a serious public health problem in need of novel transdiagnostic treatments. OBJECTIVE: To this aim, we developed and tested a one-time intervention that integrates behavioral skills training with concurrent repetitive transcranial magnetic stimulation (rTMS). METHODS: Forty-six adults who met criteria for at least one DSM-5 disorder and self-reported low use of cognitive restructuring (CR) were enrolled in a randomized, double-blind, sham-controlled trial that used a between-subjects design. Participants were taught CR and underwent active rTMS applied at 10 Hz over the right (n = 17) or left (n = 14) dorsolateral prefrontal cortex (dlPFC) or sham rTMS (n = 15) while practicing reframing and emotional distancing in response to autobiographical stressors. RESULTS: Those who received active left or active right as opposed to sham rTMS exhibited enhanced regulation (ds = 0.21-0.62) as measured by psychophysiological indices during the intervention (higher high-frequency heart rate variability, lower regulation duration). Those who received active rTMS over the left dlPFC also self-reported reduced distress throughout the intervention (d = 0.30), higher likelihood to use CR, and lower daily distress during the week following the intervention. The procedures were acceptable and feasible with few side effects. CONCLUSIONS: These findings show that engaging frontal circuits simultaneously with cognitive skills training and rTMS may be clinically feasible, well-tolerated and may show promise for the treatment of transdiagnostic emotional dysregulation. Larger follow-up studies are needed to confirm the efficacy of this novel therapeutic approach.

The importance of drug titration in the management of patients with epilepsy.

The variable response to antiseizure medication (ASM) treatment and the numerous drug- and patient-related factors that must be considered when initiating therapy make drug titration to an optimal and tolerable dose an essential component in the pharmacologic treatment of patients with epilepsy. When initiating a new ASM, a "start low, go slow" titration approach is generally recommended and has been shown to reduce the risk of severe idiosyncratic reactions with certain medications and improve tolerability with regard to many frequently occurring central nervous system-related adverse effects (e.g., somnolence, dizziness). Many patients with epilepsy will require medication changes due to lack of efficacy or intolerability of the initial regimen. When this occurs, patients may be switched from one monotherapy to another or receive adjunctive therapy. When transitioning a patient from one ASM to another (referred to as monotherapy conversion or transitional polytherapy), there are several strategies for tapering the baseline ASM depending on the clinical scenario. Regardless of the particular strategy, the goal should be to discontinue the baseline ASM in order to prevent increased toxicity due to drug load. When adding on ASM therapy, flexible titration of the new ASM and adjustment of concomitant ASMs to achieve disease control with the lowest possible drug load (lowest numbers and lowest doses) may help improve tolerability of the add-on therapy. Communication with patients during the initiation of a new therapy may help patients adhere to the titration schedule, allowing them to reach their optimal maintenance dose.

The genetic history of Ice Age Europe.

Modern humans arrived in Europe ~45,000 years ago, but little is known about their genetic composition before the start of farming ~8,500 years ago. Here we analyse genome-wide data from 51 Eurasians from ~45,000-7,000 years ago. Over this time, the proportion of Neanderthal DNA decreased from 3-6% to around 2%, consistent with natural selection against Neanderthal variants in modern humans. Whereas there is no evidence of the earliest modern humans in Europe contributing to the genetic composition of present-day Europeans, all individuals between ~37,000 and ~14,000 years ago descended from a single founder population which forms part of the ancestry of present-day Europeans. An ~35,000-year-old individual from northwest Europe represents an early branch of this founder population which was then displaced across a broad region, before reappearing in southwest Europe at the height of the last Ice Age ~19,000 years ago. During the major warming period after ~14,000 years ago, a genetic component related to present-day Near Easterners became widespread in Europe. These results document how population turnover and migration have been recurring themes of European prehistory.

A novel risk calculator predicting surgical site infection after spinal surgery in patients with cerebral palsy.

AIM: To develop and validate a risk calculator based on preoperative factors to predict the probability of surgical site infection (SSI) in patients with cerebral palsy (CP) undergoing spinal surgery. METHOD: This was a multicenter retrospective cohort study of pediatric patients with CP who underwent spinal fusion. In the development stage, preoperative known factors were collected, and a risk calculator was developed by comparing multiple models and choosing the model with the highest discrimination and calibration abilities. This model was then tested with a separate population in the validation stage. RESULTS: Among the 255 patients in the development stage, risk of SSI was 11%. A final prediction model included non-ambulatory status (odds ratio [OR] 4.0), diaper dependence (OR 2.5), age younger than 12 years (OR 2.5), major coronal curve magnitude greater than 90° (OR 1.3), behavioral disorder/delay (OR 1.3), and revision surgery (OR 1.3) as risk factors. This model had a predictive ability of 73.4% for SSI, along with excellent calibration ability (p = 0.878). Among the 390 patients in the validation stage, risk of SSI was 8.2%. The discrimination of the model in the validation phase was 0.743 and calibration was p = 0.435, indicating 74.3% predictive ability and no difference between predicted and observed values. INTERPRETATION: This study provides a risk calculator to identify the risk of SSI after spine surgery for patients with CP. This will allow us to enhance decision-making and patient care while providing valid hospital comparisons, public reporting mechanisms, and reimbursement determinations.

Can weather help explain 'why now?': The potential role of hourly temperature as a stroke trigger.

BACKGROUND: While evidence suggests that daily ambient temperature exposure influences stroke risk, little is known about the potential triggering role of ultra short-term temperature. METHODS: We examined the association between hourly temperature and ischemic and hemorrhagic stroke, separately, and identified any relevant lags of exposure among adult New York State residents from 2000 to 2015. Cases were identified via ICD-9 codes from the New York Department of Health Statewide Planning and Reearch Cooperative System. We estimated ambient temperature up to 36 h prior to estimated stroke onset based on patient residential ZIP Code. We applied a time-stratified case-crossover study design; control periods were matched to case periods by year, month, day of week, and hour of day. Additionally, we assessed effect modification by leading stroke risk factors hypertension and atrial fibrillation. RESULTS: We observed 578,181 ischemic and 164,755 hemorrhagic strokes. Among ischemic and hemorrhagic strokes respectively, the mean (standard deviation; SD) patient age was 71.8 (14.6) and 66.8 (17.4) years, with 55% and 49% female. Temperature ranged from -29.5 °C to 39.2 °C, with mean (SD) 10.9 °C (10.3 °C). We found linear relationships for both stroke types. Higher temperature was associated with ischemic stroke over the 7 h following exposure; a 10 °C increase over 7 h was associated with 5.1% (95% Confidence Interval [CI]: 3.8, 6.4%) increase in hourly stroke rate. In contrast, temperature was negatively associated with hemorrhagic stroke over 5 h, with a 5-h cumulative association of -6.2% (95% CI: 8.6, -3.7%). We observed suggestive evidence of a larger association with hemorrhagic stroke among patients with hypertension and a smaller association with ischemic stroke among those with atrial fibrillation. CONCLUSION: Hourly temperature was positively associated with ischemic stroke and negatively associated with hemorrhagic stroke. Our results suggest that ultra short-term weather influences stroke risk and hypertension may confer vulnerability.

A national analysis on complications and readmissions for adult cerebral palsy patients undergoing primary spinal fusion surgery.

STUDY DESIGN: Retrospective National Database Study. OBJECTIVE: Surgical intervention with spinal fusion is often indicated in cerebral palsy (CP) patients with progressive scoliosis. The purpose of this study was to utilize the National Readmission Database to determine the national estimates of complication rates, 90-day readmission rates, and costs associated with spinal fusion in adult patients with CP. METHODS: The 2012-2015 NRD databases were queried for all adult (age ≥ 19 years) patients diagnosed with CP (ICD-9: 333.71, 343.0-4, and 343.8-9) undergoing spinal fusion (ICD-9: 81.00-08). RESULTS: 1166 adult patients with CP (42.7% female) underwent spinal fusion surgery between 2012 and 2015. 153 (13.1%) were readmitted within 90 days following the primary surgery, with a mean 33.8 ± 26.5 days. Mean hospital charge of the primary admission was $141,416 ± $157,359 and $167,081 ± $145,416 for the non-readmitted and readmitted patients, respectively (p = 0.06). The mean 90-day readmission charge was $72,479 ± $104,100. Most common complications with the primary admission included UTIs (no readmission vs. readmission: 7.6% vs. 4.8%; p = 0.18), respiratory (6.9% vs. 5.6%; p = 0.62), implant (3.8% vs. 6.0%; p = 0.21), and paralytic ileus (3.6% vs. 3.2%; p = 0.858). Multivariate analyses demonstrated the following as independent predictors for 90-day readmission: comorbid anemia (OR: 2.8; 95% CI: 1.6-4.9; p < 0.001), coagulopathy (2.9, 1.1-8.0, 0.037), perioperative blood transfusion (2.0, 1.1-3.8, 0.026), wound complication (6.4, 1.3-31.6, 0.023), and transfer to short-term hospital versus routine disposition (4.9, 1.0-23.3, 0.045). CONCLUSION: Quality improvement efforts should be aimed at reducing rates of infection related complications as this was the most common reason for short-term complications and unplanned readmission following surgery.