Factor XI as a new target for prevention of thromboembolism in cardiovascular disease: a meta-analysis of randomized controlled trials.

Anticoagulant therapy is a mainstay in the management of patients with cardiovascular disease. The use of conventional anticoagulants carries potential side effects, mainly bleeding. Drugs targeting Factor XI (FXI) have been investigated in randomized controlled trials as a new option with more favorable outcomes. A comprehensive literature search was conducted to identify relevant studies comparing FXI inhibitors to placebo or standard therapy. The primary outcomes were incidence of all bleeding events, major bleeding, and thromboembolism. Secondary outcomes included incidence of all adverse events (AE), serious AE, and all-cause mortality. A total of 11 studies involving 10,536 patients were included. FXI inhibitors were associated with a trend toward reduction of bleeding events and incidence of thromboembolism compared to the control group (placebo/standard therapy). There was no statistically significant difference between both groups in terms of adverse events and all-cause mortality. When compared to enoxaparin, FXI inhibitors significantly reduced the risk of bleeding events (RR = 0.42, 95% CI: 0.23-0.76, P = 0.004) and thromboembolism (RR = 0.59, 95% CI: 0.44-0.77, P = 0.001). On the other hand, when compared to DOACs, FXI inhibitors were associated with a significant reduction in bleeding events but not thromboembolism. Whereas, compared to placebo, FXI inhibitors did not increase the risk of bleeding events, adverse events, or all-cause mortality (P > 0.05). FXI inhibitors could be a safer and more potent option for prevention of thromboembolism than conventional therapy.

Medical Masks Versus N95 Respirators for Preventing COVID-19 Among Health Care Workers : A Randomized Trial.

BACKGROUND: It is uncertain if medical masks offer similar protection against COVID-19 compared with N95 respirators. OBJECTIVE: To determine whether medical masks are noninferior to N95 respirators to prevent COVID-19 in health care workers providing routine care. DESIGN: Multicenter, randomized, noninferiority trial. (ClinicalTrials.gov: NCT04296643). SETTING: 29 health care facilities in Canada, Israel, Pakistan, and Egypt from 4 May 2020 to 29 March 2022. PARTICIPANTS: 1009 health care workers who provided direct care to patients with suspected or confirmed COVID-19. INTERVENTION: Use of medical masks versus fit-tested N95 respirators for 10 weeks, plus universal masking, which was the policy implemented at each site. MEASUREMENTS: The primary outcome was confirmed COVID-19 on reverse transcriptase polymerase chain reaction (RT-PCR) test. RESULTS: In the intention-to-treat analysis, RT-PCR-confirmed COVID-19 occurred in 52 of 497 (10.46%) participants in the medical mask group versus 47 of 507 (9.27%) in the N95 respirator group (hazard ratio [HR], 1.14 [95% CI, 0.77 to 1.69]). An unplanned subgroup analysis by country found that in the medical mask group versus the N95 respirator group RT-PCR-confirmed COVID-19 occurred in 8 of 131 (6.11%) versus 3 of 135 (2.22%) in Canada (HR, 2.83 [CI, 0.75 to 10.72]), 6 of 17 (35.29%) versus 4 of 17 (23.53%) in Israel (HR, 1.54 [CI, 0.43 to 5.49]), 3 of 92 (3.26%) versus 2 of 94 (2.13%) in Pakistan (HR, 1.50 [CI, 0.25 to 8.98]), and 35 of 257 (13.62%) versus 38 of 261 (14.56%) in Egypt (HR, 0.95 [CI, 0.60 to 1.50]). There were 47 (10.8%) adverse events related to the intervention reported in the medical mask group and 59 (13.6%) in the N95 respirator group. LIMITATION: Potential acquisition of SARS-CoV-2 through household and community exposure, heterogeneity between countries, uncertainty in the estimates of effect, differences in self-reported adherence, differences in baseline antibodies, and between-country differences in circulating variants and vaccination. CONCLUSION: Among health care workers who provided routine care to patients with COVID-19, the overall estimates rule out a doubling in hazard of RT-PCR-confirmed COVID-19 for medical masks when compared with HRs of RT-PCR-confirmed COVID-19 for N95 respirators. The subgroup results varied by country, and the overall estimates may not be applicable to individual countries because of treatment effect heterogeneity. PRIMARY FUNDING SOURCE: Canadian Institutes of Health Research, World Health Organization, and Juravinski Research Institute.

Remdesivir for the treatment of patients in hospital with COVID-19 in Canada: a randomized controlled trial.

BACKGROUND: The role of remdesivir in the treatment of patients in hospital with COVID-19 remains ill defined in a global context. The World Health Organization Solidarity randomized controlled trial (RCT) evaluated remdesivir in patients across many countries, with Canada enrolling patients using an expanded data collection format in the Canadian Treatments for COVID-19 (CATCO) trial. We report on the Canadian findings, with additional demographics, characteristics and clinical outcomes, to explore the potential for differential effects across different health care systems. METHODS: We performed an open-label, pragmatic RCT in Canadian hospitals, in conjunction with the Solidarity trial. We randomized patients to 10 days of remdesivir (200 mg intravenously [IV] on day 0, followed by 100 mg IV daily), plus standard care, or standard care alone. The primary outcome was in-hospital mortality. Secondary outcomes included changes in clinical severity, oxygen- and ventilator-free days (at 28 d), incidence of new oxygen or mechanical ventilation use, duration of hospital stay, and adverse event rates. We performed a priori subgroup analyses according to duration of symptoms before enrolment, age, sex and severity of symptoms on presentation. RESULTS: Across 52 Canadian hospitals, we randomized 1282 patients between Aug. 14, 2020, and Apr. 1, 2021, to remdesivir (n = 634) or standard of care (n = 648). Of these, 15 withdrew consent or were still in hospital, for a total sample of 1267 patients. Among patients assigned to receive remdesivir, in-hospital mortality was 18.7%, compared with 22.6% in the standard-of-care arm (relative risk [RR] 0.83 (95% confidence interval [CI] 0.67 to 1.03), and 60-day mortality was 24.8% and 28.2%, respectively (95% CI 0.72 to 1.07). For patients not mechanically ventilated at baseline, the need for mechanical ventilation was 8.0% in those assigned remdesivir, and 15.0% in those receiving standard of care (RR 0.53, 95% CI 0.38 to 0.75). Mean oxygen-free and ventilator-free days at day 28 were 15.9 (± standard deviation [SD] 10.5) and 21.4 (± SD 11.3) in those receiving remdesivir and 14.2 (± SD 11) and 19.5 (± SD 12.3) in those receiving standard of care (p = 0.006 and 0.007, respectively). There was no difference in safety events of new dialysis, change in creatinine, or new hepatic dysfunction between the 2 groups. INTERPRETATION: Remdesivir, when compared with standard of care, has a modest but significant effect on outcomes important to patients and health systems, such as the need for mechanical ventilation. Trial registration: ClinicalTrials.gov, no. NCT04330690.

Segmental Imaging of the Trochlear Nerve: Anatomic and Pathologic Considerations.

BACKGROUND: The trochlear nerve (the fourth cranial nerve) is the only cranial nerve that arises from the dorsal aspect of the midbrain. The nerve has a lengthy course making it highly susceptible to injury. It is also the smallest cranial nerve and is often difficult to identify on neuroimaging. EVIDENCE ACQUISITION: High-resolution 3-dimensional skull base MRI allows for submillimeter isotropic acquisition and is optimal for cranial nerve evaluation. In this text, the detailed anatomy of the fourth cranial nerve applicable to imaging will be reviewed. RESULTS: Detailed anatomic knowledge of each segment of the trochlear nerve is necessary in patients with trochlear nerve palsy. A systematic approach to identification and assessment of each trochlear nerve segment is essential. Pathologic cases are provided for each segment. CONCLUSIONS: A segmental approach to high-resolution 3-dimensional MRI for the study of the trochlear nerve is suggested.

Reactivation of Rate Remapping in CA3.

UNLABELLED: The hippocampus is thought to contribute to episodic memory by creating, storing, and reactivating patterns that are unique to each experience, including different experiences that happen at the same location. Hippocampus can combine spatial and contextual/episodic information using a dual coding scheme known as "global" and "rate" remapping. Global remapping selects which set of neurons can activate at a given location. Rate remapping readjusts the firing rates of this set depending on current experience, thus expressing experience-unique patterns at each location. But can the experience-unique component be retrieved spontaneously? Whereas reactivation of recent, spatially selective patterns in hippocampus is well established, it is never perfect, raising the issue of whether the experiential component might be absent. This question is key to the hypothesis that hippocampus can assist memory consolidation by reactivating and broadcasting experience-specific "index codes" to neocortex. In CA3, global remapping exhibits attractor-like dynamics, whereas rate remapping apparently does not, leading to the hypothesis that only the former can be retrieved associatively and casting doubt on the general consolidation hypothesis. Therefore, we studied whether the rate component is reactivated spontaneously during sleep. We conducted neural ensemble recordings from CA3 while rats ran on a circular track in different directions (in different sessions) and while they slept. It was shown previously that the two directions of running result in strong rate remapping. During sleep, the most recent rate distribution was reactivated preferentially. Therefore, CA3 can retrieve patterns spontaneously that are unique to both the location and the content of recent experience. SIGNIFICANCE STATEMENT: The hippocampus is required for memory of events and their spatial contexts. The primary correlate of hippocampal activity is location in space, but multiple memories can occur in the same location. To be useful for distinguishing these memories, the hippocampus must be able, not only to express, but also to retrieve both spatial and nonspatial information about events. Whether it can retrieve nonspatial information has been challenged recently. We exposed rats to two different experiences (running in different directions) in the same locations and showed that even the nonspatial components of hippocampal cell firing are reactivated spontaneously during sleep, supporting the conclusion that both types of information about a recent experience can be retrieved.

Long-term recordings improve the detection of weak excitatory-excitatory connections in rat prefrontal cortex.

Characterization of synaptic connectivity is essential to understanding neural circuit dynamics. For extracellularly recorded spike trains, indirect evidence for connectivity can be inferred from short-latency peaks in the correlogram between two neurons. Despite their predominance in cortex, however, significant interactions between excitatory neurons (E) have been hard to detect because of their intrinsic weakness. By taking advantage of long duration recordings, up to 25 h, from rat prefrontal cortex, we found that 7.6% of the recorded pyramidal neurons are connected. This corresponds to ∼70% of the local E-E connection probability that has been reported by paired intracellular recordings (11.6%). This value is significantly higher than previous reports from extracellular recordings, but still a substantial underestimate. Our analysis showed that long recording times and strict significance thresholds are necessary to detect weak connections while avoiding false-positive results, but will likely still leave many excitatory connections undetected. In addition, we found that hyper-reciprocity of connections in prefrontal cortex that was shown previously by paired intracellular recordings was only present in short-distance, but not in long distance (∼300 micrometers or more) interactions. As hyper-reciprocity is restricted to local clusters, it might be a minicolumnar effect. Given the current surge of interest in very high-density neural spike recording (e.g., NIH BRAIN Project) it is of paramount importance that we have statistically reliable methods for estimating connectivity from cross-correlation analysis available. We provide an important step in this direction.

Strengthening the skin with topical delivery of keratinocyte growth factor-1 using a novel DNA plasmid.

Fragile skin, susceptible to decubitus ulcers and incidental trauma, is a problem particularly for the elderly and for those with spinal cord injury. Here, we present a simple approach to strengthen the skin by the topical delivery of keratinocyte growth factor-1 (KGF-1) DNA. In initial feasibility studies with the novel minimalized, antibiotic-free DNA expression vector, NTC8385-VA1, the reporter genes luciferase and enhanced green fluorescent protein were delivered. Transfection was documented when luciferase expression significantly increased after transfection. Microscopic imaging of enhanced green fluorescent protein-transfected skin showed green fluorescence in hair follicles, hair shafts, and dermal and superficial epithelial cells. With KGF-1 transfection, KGF-1 mRNA level and protein production were documented with quantitative reverse transcriptase-polymerase chain reaction and immunohistochemistry, respectively. Epithelial thickness of the transfected skin in the KGF group was significantly increased compared with the control vector group (26 ± 2 versus 16 ± 4 µm) at 48 hours (P = 0.045). Dermal thickness tended to be increased in the KGF group (255 ± 36 versus 162 ± 16 µm) at 120 hours (P = 0.057). Biomechanical assessment showed that the KGF-1-treated skin was significantly stronger than control vector-transfected skin. These findings indicate that topically delivered KGF-1 DNA plasmid can increase epithelial thickness and strength, demonstrating the potential of this approach to restore compromised skin.

(3R,4S)-3-Methyl-4-phenyl-2-[(R)-1-phenyl-eth-yl]-3,4-di-hydro-isoquinolin-2-ium tetra-fluorido-borate.

The title salt, C24H24N(+)·BF4 (-), is one of two possible dias-tereoisomers having a different configuration of the asymmetric centre in the α-phenyl-ethyl substituent, whose absolute configuration was established to be R. The two phenyl substituents of the cation have a cofacial orientation, albeit with a long centroid-centroid separation of 4.129 (3) Å. The crystal structure exhibits numerous C-H⋯F contacts between counter-ions, with the tetra-fluorido-borate anion surrounded by five iminium cations.

Evaluating the Efficacy of Interatrial Shunt Devices in Heart Failure With Preserved Ejection Fraction: A Systematic Review and Meta-Analysis.

Heart failure with preserved ejection fraction (HFpEF) is a prevalent and challenging condition with limited therapeutic options. This meta-analysis aims to assess the feasibility and effectiveness of interatrial shunt devices (IASD) in the treatment of HFpEF, focusing on key hemodynamic parameters and clinical outcomes. Six clinical trials, encompassing 324 patients, were included in this analysis. The results showed a significant reduction in pulmonary capillary wedge pressure (PCWP) at rest after IASD implantation, with a mean difference of 1.55 mm Hg. PCWP during exercise also exhibited a decrease, indicating improved exercise tolerance. However, there was an increase in mean right atrial pressure following IASD implantation. These findings suggest that IASD implementation can effectively lower left atrial pressure, a critical target in HFpEF management. This results in substantial clinical improvements, including enhanced New York Heart Association class, quality of life, and 6-minute walk distance. Echocardiographic assessments revealed a reduction in left ventricular end-diastolic volume index and stable right ventricular changes. The meta-analysis underscores the potential benefits of IASD in ameliorating the symptoms and clinical outcomes of HFpEF patients. The increase in mean right atrial pressure warrants further investigation into its effects on right heart function. Additionally, this analysis emphasizes the need for larger, randomized clinical trials to validate these findings and determine optimal patient selection criteria. IASD implantation holds promise as a therapeutic option for HFpEF, offering the potential to improve the quality of life and functional status of affected patients. However, further research is imperative to confirm its efficacy relative to existing treatments and to address concerns regarding its impact on right heart function. This meta-analysis contributes to a deeper understanding of IASD's role in HFpEF management.

Efficacy and safety of restrictive versus liberal blood transfusion strategies in acute myocardial infarction and anemia: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Blood transfusion strategies in patients with acute myocardial infarction (AMI) and anemia are yet to be conclusively identified. Thus, we aim to assess the efficacy and safety of restrictive versus liberal blood transfusion strategies for AMI and anemia. METHODS: A systematic review and meta-analysis of randomized controlled trials (RCTs) retrieved from PubMed, web of science, SCOPUS, EMBASE, and Cochrane Central Register of Controlled Trials were performed through November 2023. We used RevMan V. 5.4 to pool dichotomous data using risk ratio (RR) and continuous data using mean difference (MD) with a 95% confidence interval (CI). (PROSPERO): ID: CRD42023490692. RESULTS: We included four RCTs with 4.325 patients. There was no significant difference between both groups regarding MACE whether at 30 days (RR: 0.93 with 95% CI [0.57-1.51], P  = 0.76) or ≥ six months (RR: 1.17 with 95% CI [0.95-1.45], P  = 0.14), all-cause mortality at 30 days (RR: 1.16 with 95% CI [0.95-1.40], P  = 0.14) or ≥ six months (RR: 1.16 with 95% CI [0.88-1.53], P  = 0.28). However, the liberal strategy was significantly associated with increased hemoglobin level change (MD: -1.44 with 95% CI [-1.68 to -1.20], P  < 0.00001). However, the restrictive strategy was significantly associated with a lower incidence of acute lung injury (RR: 0.11 with 95% CI [0.02-0.60], P  = 0.01). CONCLUSION: There was no significant difference between the restrictive blood transfusion strategy and the liberal blood transfusion strategy regarding the clinical outcomes. However, restrictive blood transfusion strategy was significantly associated with a lower incidence of acute lung injury than liberal blood transfusion strategy.

Initial institutional experience using a robotic arm-enabled 4K 3D exoscope in neurosurgical operations.

The extracorporeal telescope (exoscope) presents a novel digital camera system as a versatile alternative to traditional optical microscopy for microsurgery and minimally invasive neurosurgical operations. Recent innovations in exoscope technology offer 4K-definition multiscreen outputs, pneumatic robot arms, 3-dimensional depth perception, and greater illumination, focus, and magnification powers for enhanced intraoperative visualization. The authors present their initial institutional experience using a robotic arm-enabled 4K 3D exoscope in a variety of cranial and spinal neurosurgical operations, namely Chiari decompression, microvascular decompression for trigeminal neuralgia, anterior cervical discectomy, and lumbar decompressions. The video can be found here: https://stream.cadmore.media/r10.3171/2023.10.FOCVID23150.

Long QT syndrome unmasked in an adult subject presenting with excited delirium.

BACKGROUND: Excited delirium is increasingly recognized as a risk factor for sudden death, though the specific pathophysiology of these deaths is typically unclear. OBJECTIVES: We describe a survivor of excited delirium that displayed a transient severe prolongation of the QT interval, suggesting unmasking of long QT syndrome as a possible mechanism of sudden death. CASE REPORT: A 30-year-old man was arrested by police for violent assaultive behavior. Officers at the scene noted confusion, nonsensical speech, sweating, and bizarre agitated behavior; he was transported to the Emergency Department for medical evaluation of possible excited delirium. His initial electrocardiogram revealed a markedly prolonged corrected QT interval of over 600 ms. Intravenous hydration and sodium bicarbonate were administered, with normalization of the QT; he was admitted and recovered uneventfully. CONCLUSIONS: We discuss the possible association between long QT syndrome and unexplained sudden deaths seen with excited delirium. Sodium bicarbonate may be considered when long QT syndrome is identified during or after agitated delirium, though its routine use cannot be recommended based on a case report.

Syndrome of Inappropriate Antidiuretic Hormone Secretion as a Presentation of Untreated Parkinson's Disease.

Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is the most common electrolyte disorder associated with neurological conditions. Parkinson's disease (PD) has not been known to be causative of SIADH. We present the case of a 71-year-old male patient with diabetes type II (T2DM) and hypothyroidism admitted with progressive confusion, slow speech, and severe fatigue for one week, accompanied by sluggish body movements for a few months. A neurological exam revealed mild arm rigidity, bradykinesia, resting tremors, and stiff gait. The exam was otherwise normal. Initial blood work showed hypo-osmolar hyponatremia (Na 122 mEq/L, serum osmolarity (Osm) 275 mOsm/kg, and urine Osm 672 mOsm/Kg). CT chest showed localized infiltrate. The initial diagnosis was SIADH secondary to pulmonary process, most probably pneumonia. After starting him on a fluid restriction of 1.5 L/day and urea 15 mg BID, sodium improved gradually to 133 mEq/L on discharge. Urine osmolality continued to be elevated ranging between 700 and 800 mOsm/Kg. An active pulmonary process was ruled out by a pulmonologist. Parkinsonism was diagnosed four weeks after discharge by Neurology who started carbidopa/levodopa. As extrapyramidal symptoms improved, urine osmolality improved as well to 400 mOsm/Kg. Sodium level was maintained between 135 and 137 while urea treatment was stopped and fluid restrictions removed. New-onset SIADH was thought to be secondary to Parkinson's disease. Parkinson's disease treatment (carbidopa/levodopa) is known to cause SIADH. In this case, the treatment itself and a dose increase led to improvement in sodium levels and urine osmolality concomitantly with the improvement of the patient's extrapyramidal symptoms.

Hyaluronan Inhibition as a Therapeutic Target for Diabetic Kidney Disease: What Is Next?

Diabetic kidney disease (DKD) is the leading cause of CKD and ESKD in the United States and worldwide. Pharmacotherapy and lifestyle modifications for glycemia, dyslipidemia, and BP control have shown success in slowing the progression of DKD. Traditional treatments, such as angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and more recently the use of sodium-glucose cotransporter 2 inhibitors, nonsteroidal selective mineralocorticoid receptor antagonists, such as finerenone, and glucagon-like peptide 1 receptor agonists, have led to added benefits on various outcomes. However, significant residual risk for DKD progression remains despite the current standard-of-care approaches. Arteriolar hyalinosis (AH) is among the key findings seen on kidney biopsies of patients with DKD. It results from the excessive accumulation of hyaluronan (HA) in the arterioles. AH has not been targeted specifically by any of the therapeutic methods currently being used. We discuss in this manuscript the potential use of a selective therapy targeting AH and the increased total renal HA deposits using a HA synthesis inhibitor in DKD.

The Safety and Efficacy of Human Umbilical Cord-Derived Mesenchymal Stem Cells in Patients With Heart Failure and Myocardial Infarction: A Meta-Analysis of Clinical Trials.

Evidence from preclinical and clinical studies suggests that human umbilical cord-derived mesenchymal stromal cells (HUC-MSCs) may be useful in treating heart failure and acute myocardial infarction (MI). However, the effects of stem cell therapy on patients with heart failure remain the subject of ongoing controversy, and the safety and effectiveness of HUC-MSCs therapy have not yet been proven. To date, there has been no systematic overview and meta-analysis of clinical studies using HUC-MSCs therapy for heart failure and MI. The purpose of this study is to assess the safety and efficacy of HUC-MSC therapy versus a placebo in patients with heart failure and MI. While preparing this systematic review and meta-analysis, we adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A computer literature search of PubMed was performed. We considered randomized controlled trials (RCTs) that reported data on the safety and efficacy of HUC-MSC transplantation in patients with heart failure and MI. Two investigators independently searched the literature, extracted data, and rated the quality of the included research. Pooled data were analyzed using the fixed-effect model or the random-effect model in Review Manager 5.3. The Cochrane risk of bias tool was used to assess the bias of included studies. The primary outcome was ejection fraction (EF), whereas the secondary outcomes were readmission and mortality rates. Three RCTs (201 patients) were included in this meta-analysis. The overall effect did not favor either of the two groups in terms of risk of readmission (risk ratio = 0.5, 95% confidence interval (CI) = 0.22-1.15, p = 0.10) as well as mortality rate (risk ratio = 0.44, 95% CI = 0.14-1.44, p = 0.18). However, there was an improvement in EF in patients who received HUC-MSCs compared to placebo after 12 months of transplantation (mean difference (MD) = 3.21, 95% CI = 2.91-3.51, p < 0.00001). At the six-month follow-up period, there was no significant improvement in EF (MD = 1.30, 95% CI = -1.94-4.54), p = 0.43), indicating that the duration of follow-up can shape the response to therapy. Our findings indicate that HUC-MSC transplantation can improve EF but has no meaningful effect on readmission or mortality rates. Existing evidence is insufficient to confirm the efficacy of HUC-MSCs for broader therapeutic applications. Therefore, additional double-blind RCTs with larger sample sizes are required.

An Overview of Diabetes Mellitus in Egypt and the Significance of Integrating Preventive Cardiology in Diabetes Management.

In Egypt, diabetes mellitus (DM) is a significant public health concern, and the disease is considered a modern pandemic throughout the world. The incidence of diabetes is steadily climbing, which is causing grave concern. As a result, it is essential to take into consideration the risk factors that are pervasive in Egyptian society and have led to the worsening of this problem. These risk factors include sedentary lifestyles, obesity, hepatitis C infections, pesticides, smoking, and bad cultural habits. In this review, we aim to demonstrate the possible solutions to fight diabetes mellitus and overcome its serious health and socioeconomic burdens in Egypt. A multidisciplinary, team-based approach is highly recommended in diabetes management. Primary care physicians, endocrinologists, nephrologists, and preventive cardiologists all play a crucial role in providing the highest possible level of care to diabetic patients by collaborating closely with one another. The assessment of cardiovascular risk and the prevention of life-threatening cardiovascular events, common among diabetic patients, warrant the introduction of preventive cardiology, a new and significant concept in diabetes care that demands adoption. The integration of preventive cardiology into the treatment of diabetic patients is expected to significantly cut down the morbidity and mortality rates associated with diabetes mellitus and provide them with a better quality of life.

Fostering reproducibility and generalizability in machine learning for clinical prediction modeling in spine surgery.

As the use of machine learning algorithms in the development of clinical prediction models has increased, researchers are becoming more aware of the deleterious effects that stem from the lack of reporting standards. One of the most obvious consequences is the insufficient reproducibility found in current prediction models. In an attempt to characterize methods to improve reproducibility and to allow for better clinical performance, we utilize a previously proposed taxonomy that separates reproducibility into 3 components: technical, statistical, and conceptual reproducibility. By following this framework, we discuss common errors that lead to poor reproducibility, highlight the importance of generalizability when evaluating a ML model's performance, and provide suggestions to optimize generalizability to ensure adequate performance. These efforts are a necessity before such models are applied to patient care.

Vertebral bone quality score predicts fragility fractures independently of bone mineral density.

BACKGROUND: Current evidence suggests that dual-energy x-ray absorptiometry (DXA) scans, the conventional method defining osteoporosis, is underutilized and, when used, may underestimate patient risk for skeletal fragility. It has recently been suggested that other imaging modalities may better estimate bone quality, such as the magnetic resonance imaging (MRI)-based vertebral bone quality (VBQ) score which also may assess vertebral compression fracture risk in patients with spine metastases. PURPOSE: To evaluate whether VBQ score is predictive of fragility fractures in a population with pre-existing low bone density and at high-risk for fracture. STUDY DESIGN/SETTING: Retrospective single-center cohort. PATIENT SAMPLE: Patients followed at a metabolic bone clinic for osteopenia and/or osteoporosis. OUTCOME MEASURES: Radiographically-documented new-onset fragility fracture. METHODS: Patients with a DXA and MRI scans at the time of consultation and ≥2-year follow-up were included. Details were gathered about patient demographics, health history, current medication use, and serological studies of kidney function and bone turnover. For each patient, VBQ score was calculated using T1-weighted lumbar MRI images. Univariable and multivariable analyses were used to identify the independent predictors of a new fragility fracture. To support the construct validity of VBQ, patient VBQ scores were compared to those in a cohort of 45 healthy adults. RESULTS: Seventy-two (39.1%) study participants suffered fragility fractures, the occurrence of which was associated with higher VBQ score (3.50 vs. 3.01; p<.001), chronic glucocorticoid use (30.6% vs. 15.2%; p=.014), and a history of prior fragility fracture (36.1% vs. 21.4%; p=.030). Mean VBQ score across all patients in the study cohort was significantly higher than the mean VBQ score in the healthy controls (p<.001). In multivariable analysis, new-onset fracture was independently associated with history of prior fracture (OR=6.94; 95% confidence interval [2.48-19.40]; p<.001), higher VBQ score (OR=2.40 per point; [1.30-4.44]; p=.003), higher body mass index (OR=1.09 per kg/m²; [1.01-1.17]; p=.03), and chronic glucocorticoid use (OR=2.89; [1.03-8.17]; p=0.043). Notably, DXA bone mineral density (BMD) was not found to be significantly predictive of new-onset fractures in the multivariable analysis (p=.081). CONCLUSIONS: Here we demonstrate the novel, MRI-derived VBQ score is both an independent predictor of fragility fracture in at-risk patients and a superior predictor of fracture risk than DXA-measured BMD. Given the frequency with which MRIs are obtained by patients undergoing spine surgery consultation, we believe the VBQ score could be a valuable tool for estimating bone quality in order to optimize the management of these patients.

Assessment of Sleep, K-Complexes, and Sleep Spindles in a T21 Light-Dark Cycle.

Circadian rhythm misalignment has a deleterious impact on the brain and the body. In rats, exposure to a 21-hour day length impairs hippocampal dependent memory. Sleep, and particularly K-complexes and sleep spindles in the cortex, have been hypothesized to be involved in memory consolidation. Altered K-complexes, sleep spindles, or interaction between the cortex and hippocampus could be a mechanism for the memory consolidation failure but has yet to be assessed in any circadian misalignment paradigm. In the current study, continuous local field potential recordings from five rats were used to assess the changes in aspects of behavior and sleep, including wheel running activity, quiet wakefulness, motionless sleep, slow wave sleep, REM sleep, K-complexes and sleep spindles, in rats exposed to six consecutive days of a T21 light-dark cycle (L9:D12). Except for a temporal redistribution of sleep and activity during the T21, there were no changes in period, or total amount for any aspect of sleep or activity. These data suggest that the memory impairment elicited from 6 days of T21 exposure is likely not due to changes in sleep architecture. It remains possible that hippocampal plasticity is affected by experiencing light when subjective circadian phase is calling for dark. However, if there is a reduction in hippocampal plasticity, changes in sleep appear not to be driving this effect.

Memory reactivation in rat medial prefrontal cortex occurs in a subtype of cortical UP state during slow-wave sleep.

Interaction between hippocampal sharp-wave ripples (SWRs) and UP states, possibly by coordinated reactivation of memory traces, is conjectured to play an important role in memory consolidation. Recently, it was reported that SWRs were differentiated into multiple subtypes. However, whether cortical UP states can also be classified into subtypes is not known. Here, we analysed neural ensemble activity from the medial prefrontal cortex from rats trained to run a spatial sequence-memory task. Application of the hidden Markov model (HMM) with three states to epochs of UP-DOWN oscillations identified DOWN states and two subtypes of UP state (UP-1 and UP-2). The two UP subtypes were distinguished by differences in duration, with UP-1 having a longer duration than UP-2, as well as differences in the speed of population vector (PV) decorrelation, with UP-1 decorrelating more slowly than UP-2. Reactivation of recent memory sequences predominantly occurred in UP-2. Short-duration reactivating UP states were dominated by UP-2 whereas long-duration ones exhibit transitions from UP-1 to UP-2. Thus, recent memory reactivation, if it occurred within long-duration UP states, typically was preceded by a period of slow PV evolution not related to recent experience, and which we speculate may be related to previously encoded information. If that is the case, then the transition from UP-1 to UP-2 subtypes may help gradual integration of recent experience with pre-existing cortical memories by interleaving the two in the same UP state. This article is part of the Theo Murphy meeting issue 'Memory reactivation: replaying events past, present and future'.