Activity-dependent p25 generation regulates synaptic plasticity and Aß-induced cognitive impairment.

Cyclin-dependent kinase 5 regulates numerous neuronal functions with its activator, p35. Under neurotoxic conditions, p35 undergoes proteolytic cleavage to liberate p25, which has been implicated in various neurodegenerative diseases. Here, we show that p25 is generated following neuronal activity under physiological conditions in a GluN2B- and CaMKIIα-dependent manner. Moreover, we developed a knockin mouse model in which endogenous p35 is replaced with a calpain-resistant mutant p35 (Δp35KI) to prevent p25 generation. The Δp35KI mice exhibit impaired long-term depression and defective memory extinction, likely mediated through persistent GluA1 phosphorylation at Ser845. Finally, crossing the Δp35KI mice with the 5XFAD mouse model of Alzheimer's disease (AD) resulted in an amelioration of ß-amyloid (Aß)-induced synaptic depression and cognitive impairment. Together, these results reveal a physiological role of p25 production in synaptic plasticity and memory and provide new insights into the function of p25 in Aß-associated neurotoxicity and AD-like pathology.

Programmable RNA sensing for cell monitoring and manipulation.

RNA is a central and universal mediator of genetic information underlying the diversity of cell types and cell states, which together shape tissue organization and organismal function across species and lifespans. Despite numerous advances in RNA sequencing technologies and the massive accumulation of transcriptome datasets across the life sciences1,2, the dearth of technologies that use RNAs to observe and manipulate cell types remains a bottleneck in biology and medicine. Here we describe CellREADR (Cell access through RNA sensing by Endogenous ADAR), a programmable RNA-sensing technology that leverages RNA editing mediated by ADAR to couple the detection of cell-defining RNAs with the translation of effector proteins. Viral delivery of CellREADR conferred specific cell-type access in mouse and rat brains and in ex vivo human brain tissues. Furthermore, CellREADR enabled the recording and control of specific types of neurons in behaving mice. CellREADR thus highlights the potential for RNA-based monitoring and editing of animal cells in ways that are specific, versatile, simple and generalizable across organ systems and species, with wide applications in biology, biotechnology and programmable RNA medicine.

The Role of Sleep in Cardiovascular Disease.

PURPOSE OF REVIEW: Sleep is an important component of cardiovascular (CV) health. This review summarizes the complex relationship between sleep and CV disease (CVD). Additionally, we describe the data supporting the treatment of sleep disturbances in preventing and treating CVD. RECENT FINDINGS: Recent guidelines recommend screening for obstructive sleep apnea in patients with atrial fibrillation. New data continues to demonstrate the importance of sleep quality and duration for CV health. There is a complex bidirectional relationship between sleep health and CVD. Sleep disturbances have systemic effects that contribute to the development of CVD, including hypertension, coronary artery disease, heart failure, and arrhythmias. Additionally, CVD contributes to the development of sleep disturbances. However, more data are needed to support the role of screening for and treatment of sleep disorders for the prevention of CVD.

Altered bile acid and coproporphyrin-I disposition in patients with autosomal dominant polycystic kidney disease.

AIMS: Serum, liver and urinary bile acids are increased, and hepatic transport protein levels are decreased in a non-clinical model of polycystic kidney disease. Similar changes in patients with autosomal dominant polycystic kidney disease (ADPKD) may predispose them to drug-induced liver injury (DILI) and hepatic drug-drug interactions (DDIs). Systemic coproporphyrin-I (CP-I), an endogenous biomarker for hepatic OATP1B function and MRP2 substrate, is used to evaluate OATP1B-mediated DDI risk in humans. In this clinical observational cohort-comparison study, bile acid profiles and CP-I concentrations in healthy volunteers and patients with ADPKD were compared. METHODS: Serum and urine samples from healthy volunteers (n = 16) and patients with ADPKD (n = 8) were collected. Serum bile acids, and serum and urine CP-I concentrations, were quantified by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). RESULTS: Patients with ADPKD exhibited increased serum concentrations of total (1.3-fold) and taurine-conjugated (2.8-fold) bile acids compared to healthy volunteers. Specifically, serum concentrations of six bile acids known to be more hydrophobic/hepatotoxic (glycochenodeoxycholate, taurochenodeoxycholate, taurodeoxycholate, lithocholate, glycolithocholate and taurolithocholate) were increased (1.5-, 2.9-, 2.8-, 1.6-, 1.7- and 2.7-fold, respectively) in patients with ADPKD. Furthermore, serum CP-I concentrations were elevated and the renal clearance of CP-I was reduced in patients with ADPKD compared to healthy volunteers. CONCLUSIONS: Increased exposure to bile acids may increase susceptibility to DILI in some patients with ADPKD. Furthermore, the observed increase in serum CP-I concentrations could be attributed, in part, to impaired OATP1B function in patients with ADPKD, which could increase the risk of DDIs involving OATP1B substrates compared to healthy volunteers.

Stronger together: learner reactions on a team-based, interprofessional first death simulation experience.

Patient death is a common experience that may be traumatic for health care providers. Although current rates of burnout are high, evidence supports that interprofessional coping can improve clinician mental health. While health care simulation affords learners freedom of safety to participate in a variety of educational experiences, current application of simulation during patient death is limited to professional duties, without explicitly addressing learner emotional well-being. We designed a patient death simulation scenario within a supportive and reflective interprofessional environment to teach foundational coping and well-being strategies to preclinical nursing, medical, and pharmacy students. Sixty-one students participated in this team-based, First Death simulation experience. Debriefings were analyzed using qualitative inductive content analysis methodology. Students reacted to being part of an interprofessional team after having participated in simulation about the death of a patient as described by five categories: emotional awareness, communication insight, feeling stronger together, with role curiosity, and through reflections on support. Findings suggested that simulation is an effective teaching modality for mentoring interprofessional students on humanistic well-being strategies. Furthermore, the experience fostered reactions transcending interprofessional competencies, which are transferrable to future clinical practice.

Pore residues of transient receptor potential channels canonical 1 and 4 heteromer determine channel properties.

Transient receptor potential channels canonical 1 and 4 (TRPC1 and TRPC4) are proteins belonging to the same TRPC channel family, and the two are known to form a heterotetrameric channel. TRPC4 can form a homotetrameric, nonselective cation channel by itself, but the involvement of the TRPC1 subunit changes several major characteristics of the channel. In this study, we focused on the pore region (selectivity filter, pore helix, and S6 helix) of TRPC1 and TRPC4 as a determinant of the identity and characteristics of a heteromeric TRPC1/4 channel: decreased calcium permeability of the channel and outward-rectifying current-voltage (I-V) curve. Mutants and chimeras of the pore residues were created, and their currents were recorded using whole cell patch clamp. The lower gate mutants of TRPC4 exhibited diminished calcium permeability as measured by GCaMP6 fluorescence. Also, chimeric channels substituting the pore region of TRPC1 to TRPC4 were made to locate the pore region that is critical in the production of an outward-rectifying I-V curve characteristic of TRPC1/4 heteromeric channels.NEW & NOTEWORTHY Heteromer research has been a challenging field due to lack of structural studies. Using chimeras and single mutants, we present evidence that the pore region of TRPC1/4 heteromer contributes to determining the channel's characteristics such as calcium permeability, I-V curve, and conductance.

A comparison of deprivation indices and application to transplant populations.

The choice of deprivation index can influence conclusions drawn regarding the extent of deprivation within a community and the identification of the most deprived communities in the United States. This study aimed to determine the degree of correlation among deprivation indices commonly used to characterize transplant populations. We used a retrospective cohort consisting of adults listed for liver or kidney transplants between 2008 and 2018 to compare 4 deprivation indices: neighborhood deprivation index, social deprivation index (SDI), area deprivation index, and social vulnerability index. Pairwise correlation between deprivation indices by transplant referral regions was measured using Spearman correlations of population-weighted medians and upper quartiles. In total, 52 individual variables were used among the 4 deprivation indices with 25% overlap. For both organs, the correlation between the population-weighted 75th percentile of the deprivation indices by transplant referral region was highest between SDI and social vulnerability index (liver and kidney, 0.93) and lowest between area deprivation index and SDI (liver, 0.19 and kidney, 0.15). The choice of deprivation index affects the applicability of research findings across studies examining the relationship between social risk and clinical outcomes. Appropriate application of these measures to transplant populations requires careful index selection based on the intended use and included variable relevance.

Effectiveness and feasibility of three types of parent reminders to increase adolescent human papillomavirus (HPV) vaccination.

Parent reminders have produced modest improvements in human papillomavirus (HPV) vaccination among adolescents. However, little prior research has compared the effectiveness and feasibility of different HPV reminder types in resource-limited settings. We conducted a quasi-experimental study (2016-2017) to evaluate the effectiveness of three parent reminder types (mailed letters, robocalls, text messages) on next-dose HPV vaccine receipt among 12-year-olds in a large Federally Qualified Health Center in Los Angeles County. Six clinics were matched into three pairs: randomly assigning one clinic within each pair to intervention and control. Intervention clinics were randomly assigned to deliver one of the three parent reminder types. We calculated rates of next-dose vaccine receipt and assessed intervention effects using logistic regression models. We calculated the proportion of each type of reminder successfully delivered as a feasibility measure. The study sample comprised 877 12-year-olds due for an HPV vaccine dose (47% female, >85% Latino). At 4-month follow-up, 23% of intervention patients received an HPV vaccine dose compared to only 12% of control patients. Overall, receipt of any reminder increased rates of the next-needed HPV vaccine compared to usual care (p = 0.046). Significant improvements were observed for text reminders (p = 0.036) and boys (p = 0.006). Robocalls were the least feasible reminder type. Text message reminders are feasible and effective for promoting HPV vaccination. Future research is needed to assess the effectiveness and feasibility of reminders compared to other vaccine promotion strategies.

Allostatic load and incident heart failure in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study.

BACKGROUND: Allostatic load (AL) is the physiologic "wear and tear" on the body from stress. Yet, despite stress being implicated in the development heart failure (HF), it is unknown whether AL is associated with incident HF events. METHODS: We examined 16,765 participants without HF at baseline from the REasons for Geographic and Racial Differences in Stroke (REGARDS) cohort. The main exposure was AL score quartile. AL was determined according to 11 physiologic parameters, whereby each parameter was assigned points (0-3) based on quartiles within the sample, and points were summed to create a total AL score ranging from 0-33. The outcome was incident HF event. We examined the association between AL quartile (Q1-Q4) and incident HF events using Cox proportional hazards models, adjusted for demographics, socioeconomic factors, and lifestyle. RESULTS: The mean age was 64 ± 9.6 years, 61.5% were women, and 38.7% were Black participants. Over a median follow up of 11.4 years, we observed 750 incident HF events (635 HF hospitalizations and 115 HF deaths). Compared to the lowest AL quartile (Q1), the fully adjusted hazards of an incident HF event increased in a graded fashion: Q2 HR 1.49 95% CI 1.12-1.98; Q3 HR 2.47 95% CI 1.89-3.23; Q4 HR 4.28 95% CI 3.28-5.59. The HRs for incident HF event in the fully adjusted model that also adjusted for CAD were attenuated, but remained significant and increased in a similar, graded fashion by AL quartile. There was a significant age interaction (p-for-interaction < 0.001), whereby the associations were observed across each age stratum, but the HRs were highest among those aged < 65 years. CONCLUSION: AL was associated with incident HF events, suggesting that AL could be an important risk factor and potential target for future interventions to prevent HF.

High-Impact Chronic Pain Transition in Lumbar Surgery Recipients.

OBJECTIVE: High-impact chronic pain (HICP) is a term that characterizes the presence of a severe and troubling pain-related condition. To date, the prevalence of HICP in lumbar spine surgery recipients and their HICP transitions from before to after surgery are unexplored. The purpose was to define HICP prevalence, transition types, and outcomes in lumbar spine surgery recipients and to identify predictors of HICP outcomes. METHODS: In total, 43,536 lumbar surgery recipients were evaluated for HICP transition. Lumbar spine surgery recipients were categorized as having HICP preoperatively and at 3 months after surgery if they exhibited chronic and severe pain and at least one major activity limitation. Four HICP transition groups (Stable Low Pain, Transition from HICP, Transition to HICP, and Stable High Pain) were categorized and evaluated for outcomes. Multivariate multinomial modeling was used to predict HICP transition categorization. RESULTS: In this sample, 15.1% of individuals exhibited HICP preoperatively; this value declined to 5.1% at 3 months after surgery. Those with HICP at baseline and 3 months had more comorbidities and worse overall outcomes. Biological, psychological, and social factors predicted HICP transition or Stable High Pain; some of the strongest involved social factors of 2 or more to transition to HICP (OR = 1.43; 95% CI = 1.21-1.68), and baseline report of pain/disability (OR = 3.84; 95% CI = 3.20-4.61) and psychological comorbidity (OR = 1.78; 95% CI = 1.48-2.12) to Stable Stable High Pain. CONCLUSION: The percentage of individuals with HICP preoperatively (15.1%) was low, which further diminished over a 3-month period (5.1%). Postoperative HICP groups had higher levels of comorbidities and worse baseline outcomes scores. Transition to and maintenance of HICP status was predicted by biological, psychological, and social factors.

Safety and comparative efficacy of initiating low-molecular-weight heparin within 24 hours of injury or surgery for venous thromboembolism prophylaxis in patients with spinal cord injury: a prospective TRACK-SCI registry study.

OBJECTIVE: Venous thromboembolism (VTE) following traumatic spinal cord injury (SCI) is a significant clinical concern. This study sought to determine the incidence of VTE and hemorrhagic complications among patients with SCI who received low-molecular-weight heparin (LMWH) within 24 hours of injury or surgery and identify variables that predict VTE using the prospective Transforming Research and Clinical Knowledge in SCI (TRACK-SCI) database. METHODS: The TRACK-SCI database was queried for individuals with traumatic SCI from 2015 to 2022. Primary outcomes of interest included rates of VTE (including deep vein thrombosis [DVT] and pulmonary embolism [PE]) and in-hospital hemorrhagic complications that occurred after LWMH administration. Secondary outcomes included intensive care unit and hospital length of stay, discharge location type, and in-hospital mortality. RESULTS: The study cohort consisted of 162 patients with SCI. Fifteen of the 162 patients withdrew from the study, leading to loss of data for certain variables for these patients. One hundred thirty patients (87.8%) underwent decompression and/or fusion surgery for SCI. DVT occurred in 11 (7.4%) of 148 patients, PE in 9 (6.1%) of 148, and any VTE in 18 (12.2%) of 148 patients. The analysis showed that admission lower-extremity motor score (p = 0.0408), injury at the thoracic level (p = 0.0086), admission American Spinal Injury Association grade (p = 0.0070), and younger age (p = 0.0372) were significantly associated with VTE. There were 3 instances of postoperative spine surgery-related bleeding (2.4%) in the 127 patients who had spine surgery with bleeding complication data available, with one requiring return to surgery (0.8%). Thirteen (8.8%) of 147 patients had a bleeding complication not related to spine surgery. There were 2 gastrointestinal bleeds associated with nasogastric tube placement, 3 cases of postoperative non-spine-related surgery bleeding, and 8 cases of other bleeding complications (5.4%) not related to any surgery. CONCLUSIONS: Initiation of LMWH within 24 hours was associated with a low rate of spine surgery-related bleeding. Bleeding complications unrelated to SCI surgery still occur with LMWH administration. Because neurosurgical intervention is typically the limiting factor in initializing chemical DVT prophylaxis, many of these bleeding complications would have likely occurred regardless of the protocol.

Minimally invasive versus open transforaminal lumbar interbody fusion for grade I lumbar spondylolisthesis: 5-year follow-up from the prospective multicenter Quality Outcomes Database registry.

OBJECTIVE: Minimally invasive transforaminal lumbar interbody fusion (MI-TLIF) has been used to treat degenerative lumbar spondylolisthesis and is associated with expedited recovery, reduced operative blood loss, and shorter hospitalizations compared to those with traditional open TLIF. However, the impact of MI-TLIF on long-term patient-reported outcomes (PROs) is less clear. Here, the authors compare the outcomes of MI-TLIF to those of traditional open TLIF for grade I degenerative lumbar spondylolisthesis at 60 months postoperatively. METHODS: The authors utilized the prospective Quality Outcomes Database registry and queried for patients with grade I degenerative lumbar spondylolisthesis who had undergone single-segment surgery via an MI or open TLIF method. PROs were compared 60 months postoperatively. The primary outcome was the Oswestry Disability Index (ODI). The secondary outcomes included the numeric rating scale (NRS) for back pain (NRS-BP), NRS for leg pain (NRS-LP), EQ-5D, North American Spine Society (NASS) satisfaction, and cumulative reoperation rate. Multivariable models were constructed to assess the impact of MI-TLIF on PROs, adjusting for variables reaching p < 0.20 on univariable analyses and respective baseline PRO values. RESULTS: The study included 297 patients, 72 (24.2%) of whom had undergone MI-TLIF and 225 (75.8%) of whom had undergone open TLIF. The 60-month follow-up rates were similar for the two cohorts (86.1% vs 75.6%, respectively; p = 0.06). Patients did not differ significantly at baseline for ODI, NRS-BP, NRS-LP, or EQ-5D (p > 0.05 for all). Perioperatively, MI-TLIF was associated with less blood loss (108.8 ± 85.6 vs 299.6 ± 242.2 ml, p < 0.001) and longer operations (228.2 ± 111.5 vs 189.6 ± 66.5 minutes, p < 0.001) but had similar lengths of hospitalizations (MI-TLIF 2.9 ± 1.8 vs open TLIF 3.3 ± 1.6 days, p = 0.08). Discharge disposition to home or home health was similar (MI-TLIF 93.1% vs open TLIF 91.1%, p = 0.60). Both cohorts improved significantly from baseline for the 60-month ODI, NRS-BP, NRS-LP, and EQ-5D (p < 0.001 for all comparisons). In adjusted analyses, MI-TLIF, compared to open TLIF, was associated with similar 60-month ODI, ODI change, odds of reaching ODI minimum clinically important difference, NRS-BP, NRS-BP change, NRS-LP, NRS-LP change, EQ-5D, EQ-5D change, and NASS satisfaction (adjusted p > 0.05 for all). The 60-month reoperation rates did not differ significantly (MI-TLIF 5.6% vs open TLIF 11.6%, p = 0.14). CONCLUSIONS: For symptomatic, single-level grade I degenerative lumbar spondylolisthesis, MI-TLIF was associated with decreased blood loss perioperatively, but there was no difference in 60-month outcomes for disability, back pain, leg pain, quality of life, or satisfaction between MI and open TLIF. There was no difference in cumulative reoperation rates between the two procedures. These results suggest that in appropriately selected patients, either procedure may be employed depending on patient and surgeon preferences.

Which supervised machine learning algorithm can best predict achievement of minimum clinically important difference in neck pain after surgery in patients with cervical myelopathy? A QOD study.

OBJECTIVE: The purpose of this study was to evaluate the performance of different supervised machine learning algorithms to predict achievement of minimum clinically important difference (MCID) in neck pain after surgery in patients with cervical spondylotic myelopathy (CSM). METHODS: This was a retrospective analysis of the prospective Quality Outcomes Database CSM cohort. The data set was divided into an 80% training and a 20% test set. Various supervised learning algorithms (including logistic regression, support vector machine, decision tree, random forest, extra trees, gaussian naïve Bayes, k-nearest neighbors, multilayer perceptron, and extreme gradient boosted trees) were evaluated on their performance to predict achievement of MCID in neck pain at 3 and 24 months after surgery, given a set of predicting baseline features. Model performance was assessed with accuracy, F1 score, area under the receiver operating characteristic curve, precision, recall/sensitivity, and specificity. RESULTS: In total, 535 patients (46.9%) achieved MCID for neck pain at 3 months and 569 patients (49.9%) achieved it at 24 months. In each follow-up cohort, 501 patients (93.6%) were satisfied at 3 months after surgery and 569 patients (100%) were satisfied at 24 months after surgery. Of the supervised machine learning algorithms tested, logistic regression demonstrated the best accuracy (3 months: 0.76 ± 0.031, 24 months: 0.773 ± 0.044), followed by F1 score (3 months: 0.759 ± 0.019, 24 months: 0.777 ± 0.039) and area under the receiver operating characteristic curve (3 months: 0.762 ± 0.027, 24 months: 0.773 ± 0.043) at predicting achievement of MCID for neck pain at both follow-up time points, with fair performance. The best precision was also demonstrated by logistic regression at 3 (0.724 ± 0.058) and 24 (0.780 ± 0.097) months. The best recall/sensitivity was demonstrated by multilayer perceptron at 3 months (0.841 ± 0.094) and by extra trees at 24 months (0.817 ± 0.115). Highest specificity was shown by support vector machine at 3 months (0.952 ± 0.013) and by logistic regression at 24 months (0.747 ± 0.18). CONCLUSIONS: Appropriate selection of models for studies should be based on the strengths of each model and the aims of the studies. For maximally predicting true achievement of MCID in neck pain, of all the predictions in this balanced data set the appropriate metric for the authors' study was precision. For both short- and long-term follow-ups, logistic regression demonstrated the highest precision of all models tested. Logistic regression performed consistently the best of all models tested and remains a powerful model for clinical classification tasks.

Improving Image Classification of Knee Radiographs: An Automated Image Labeling Approach.

Large numbers of radiographic images are available in musculoskeletal radiology practices which could be used for training of deep learning models for diagnosis of knee abnormalities. However, those images do not typically contain readily available labels due to limitations of human annotations. The purpose of our study was to develop an automated labeling approach that improves the image classification model to distinguish normal knee images from those with abnormalities or prior arthroplasty. The automated labeler was trained on a small set of labeled data to automatically label a much larger set of unlabeled data, further improving the image classification performance for knee radiographic diagnosis. We used BioBERT and EfficientNet as the feature extraction backbone of the labeler and imaging model, respectively. We developed our approach using 7382 patients and validated it on a separate set of 637 patients. The final image classification model, trained using both manually labeled and pseudo-labeled data, had the higher weighted average AUC (WA-AUC 0.903) value and higher AUC values among all classes (normal AUC 0.894; abnormal AUC 0.896, arthroplasty AUC 0.990) compared to the baseline model (WA-AUC = 0.857; normal AUC 0.842; abnormal AUC 0.848, arthroplasty AUC 0.987), trained using only manually labeled data. Statistical tests show that the improvement is significant on normal (p value < 0.002), abnormal (p value < 0.001), and WA-AUC (p value = 0.001). Our findings demonstrated that the proposed automated labeling approach significantly improves the performance of image classification for radiographic knee diagnosis, allowing for facilitating patient care and curation of large knee datasets.

A scoping review of inequities in access to organ transplant in the United States.

BACKGROUND: Organ transplant is the preferred treatment for end-stage organ disease, yet the majority of patients with end-stage organ disease are never placed on the transplant waiting list. Limited access to the transplant waiting list combined with the scarcity of the organ pool result in over 100,000 deaths annually in the United States. Patients face unique barriers to referral and acceptance for organ transplant based on social determinants of health, and patients from disenfranchised groups suffer from disproportionately lower rates of transplantation. Our objective was to review the literature describing disparities in access to organ transplantation based on social determinants of health to integrate the existing knowledge and guide future research. METHODS: We conducted a scoping review of the literature reporting disparities in access to heart, lung, liver, pancreas and kidney transplantation based on social determinants of health (race, income, education, geography, insurance status, health literacy and engagement). Included studies were categorized based on steps along the transplant care continuum: referral for transplant, transplant evaluation and selection, living donor identification/evaluation, and waitlist outcomes. RESULTS: Our search generated 16,643 studies, of which 227 were included in our final review. Of these, 34 focused on disparities in referral for transplantation among patients with chronic organ disease, 82 on transplant selection processes, 50 on living donors, and 61 on waitlist management. In total, 15 studies involved the thoracic organs (heart, lung), 209 involved the abdominal organs (kidney, liver, pancreas), and three involved multiple organs. Racial and ethnic minorities, women, and patients in lower socioeconomic status groups were less likely to be referred, evaluated, and added to the waiting list for organ transplant. The quality of the data describing these disparities across the transplant literature was variable and overwhelmingly focused on kidney transplant. CONCLUSIONS: This review contextualizes the quality of the data, identifies seminal work by organ, and reports gaps in the literature where future research on disparities in organ transplantation should focus. Future work should investigate the association of social determinants of health with access to the organ transplant waiting list, with a focus on prospective analyses that assess interventions to improve health equity.

Educational and economic returns to cognitive ability in low- and middle-income countries: A systematic review.

There is growing interest to use early cognitive ability to predict schooling and employment outcomes in low- and middle-income countries (LMICs). Rather than using educational attainment and school enrollment as predictors of future economic growth or of improving an individual's earning potential, mounting evidence suggests that cognitive ability may be a better predictor. The relationship between cognitive ability, education, and employment are essential to predict future development in LMICs. We performed a systematic literature review and meta-analysis of the evidence regarding the relationship between cognitive ability and educational outcomes, and between cognitive ability and economic outcomes across LMICs. We searched peer-reviewed studies since 2000 that quantitatively measured these relationships. Based on an initial search of 3,766 records, we identified 14 studies, including 8 studies that examined the cognition-education link and 8 studies that assessed cognition-employment returns in LMICs. Identified studies showed that higher cognitive ability increased the probability of school enrollment, academic achievement, and educational attainment across LMICs. A meta-analysis of returns to wages from cognitive ability suggested that a standard deviation increase in cognitive test scores was associated with a 4.5% (95% CI 2.6%-9.6%) increase in wages. Investments into early cognitive development could play a critical role in improving educational and economic outcomes in LMICs. Further research should focus particularly in low-income countries with the least evidence, and examine the impact on education and economic outcomes by cognitive domains to provide more robust evidence for policy makers to take action.

Implication of auditory confounding in interpreting somatosensory and motor responses in low-intensity focused transcranial ultrasound stimulation.

Low-intensity transcranial focused ultrasound (LI-tFUS) stimulation is a noninvasive neuromodulation tool that demonstrates high target localization accuracy and depth penetration. It has been shown to modulate activities in the primary motor and somatosensory cortex. Previous studies in animals as well as in humans, illustrated in the recently published paper in Brain Stimulation by Braun et al. [Braun V, Blackmore J, Cleveland RO, Butler CR. Brain Stimul 13: 1527-1534, 2020], acknowledged the possibility of indirect stimulation of the peripheral auditory pathway that could confound the somatosensory and motor responses observed with LI-tFUS stimulation. Here, we discuss the implications and interpretations of auditory confounding in the context of neuromodulation.

The Impact of the 2017 Kidney Allocation Policy Change on Simultaneous Liver-Kidney Utilization and Outcomes.

Historically in the United States, kidneys for simultaneous liver-kidney transplantation (SLKT) candidates were allocated with livers, prioritizing SLKT recipients over much of the kidney waiting list. A 2017 change in policy delineated renal function criteria for SLKT and implemented a safety net for kidney-after-liver transplantation. We compared the use and outcomes of SLKT and kidney-after-liver transplant with the 2017 policy. United Network for Organ Sharing Standard Transplant Analysis and Research files were used to identify adults who received liver transplantations (LT) from August 10, 2007 to August 10, 2012; from August 11, 2012 to August 10, 2017; and from August 11, 2017 to June 12, 2019. LT recipients with end-stage renal disease (ESRD) were defined by dialysis requirement or estimated glomerular filtration rate <25. We evaluated outcomes and center-level, regional, and national practice before and after the policy change. Nonparametric cumulative incidence of kidney-after-liver listing and transplant were modeled by era. A total of 6332 patients received SLKTs during the study period; fewer patients with glomerular filtration rate (GFR) ≥50 mL/min underwent SLKT over time (5.8%, 4.8%, 3.0%; P = 0.01 ). There was also less variability in GFR at transplant after policy implementation on center and regional levels. We then evaluated LT-alone (LTA) recipients with ESRD (n = 5408 from 2012-2017; n = 2321 after the policy). Listing for a kidney within a year of LT increased from 2.9% before the policy change to 8.8% after the policy change, and the rate of kidney transplantation within 1 year increased from 0.7% to 4% (P < 0.001). After the policy change, there was no difference in patient survival rates between SLKT and LTA among patients with ESRD. Implementation of the 2017 SLKT policy change resulted in reduced variability in SLKT recipient kidney function and increased access to deceased donor kidney transplantation for LTA recipients with kidney disease without negatively affecting outcomes.

Reducing Underdiagnosis of Hirschsprung-Associated Enterocolitis: A Novel Scoring System.

BACKGROUND: Hirschsprung-Associated Enterocolitis (HAEC) is a life-threatening and difficult to diagnose complication of Hirschsprung Disease (HSCR). The goal of this study was to evaluate existing HAEC scoring systems and develop a new scoring system. METHODS: Retrospective, multi-institutional data collection was performed. For each patient, all encounters were analyzed. Data included demographics, symptomatology, laboratory and radiographic findings, and treatments received. A "true" diagnosis of HAEC was defined as receipt of treatment with rectal irrigations, antibiotics, and bowel rest. The Pastor and Frykman scoring systems were evaluated for sensitivity/specificity and univariate and multivariate logistic regression performed to create a new scoring system. RESULTS: Four centers worldwide provided data on 200 patients with 1450 encounters and 369 HAEC episodes. Fifty-seven percent of patients experienced one or more episodes of HAEC. Long-segment colonic disease was associated with a higher risk of HAEC on univariate analysis (OR 1.92, 95% CI 1.43-2.57). Six variables were significantly associated with HAEC on multivariate analysis. Using published diagnostic cutoffs, sensitivity/specificity for existing systems were found to be 38.2%/96% for Pastor's and 56.4%/86.9% for Frykman's score. A new scoring system with a sensitivity/specificity of 67.8%/87.9% was created by stepwise multivariate analysis. The new score outperformed the existing scores by decreasing underdiagnosis in this patient cohort. CONCLUSIONS: Existing scoring systems perform poorly in identifying episodes of HAEC, resulting in significant underdiagnosis. The proposed scoring system may be better at identifying those underdiagnosed in the clinical setting. Head-to-head comparison of HAEC scoring systems using prospective data collection may be beneficial to achieve standardization in the field.

Pseudarthrosis rate following anterior cervical discectomy with fusion using an allograft cellular bone matrix: a multi-institutional analysis.

OBJECTIVE: The use of osteobiologics, engineered materials designed to promote bone healing by enhancing bone growth, is becoming increasingly common for spinal fusion procedures, but the efficacy of some of these products is unclear. The authors performed a retrospective, multi-institutional study to investigate the clinical and radiographic characteristics of patients undergoing single-level anterior cervical discectomy with fusion performed using the osteobiologic agent Osteocel, an allograft mesenchymal stem cell matrix. METHODS: The medical records across 3 medical centers and 12 spine surgeons were retrospectively queried for patients undergoing single-level anterior cervical discectomy and fusion (ACDF) with the use of Osteocel. Pseudarthrosis was determined based on CT or radiographic imaging of the cervical spine. Patients were determined to have radiographic pseudarthrosis if they met any of the following criteria: 1) lack of bridging bone on CT obtained > 300 days postoperatively, 2) evidence of instrumentation failure, or 3) motion across the index level as seen on flexion-extension cervical spine radiographs. Univariate and multivariate analyses were then performed to identify independent preoperative or perioperative predictors of pseudarthrosis in this population. RESULTS: A total of 326 patients met the inclusion criteria; 43 (13.2%) patients met criteria for pseudarthrosis, of whom 15 (34.9%) underwent revision surgery. There were no significant differences between patients with and those without pseudarthrosis, respectively, for patient age (54.1 vs 53.8 years), sex (34.9% vs 47.4% male), race, prior cervical spine surgery (37.2% vs 33.6%), tobacco abuse (16.3% vs 14.5%), chronic kidney disease (2.3% vs 2.8%), and diabetes (18.6% vs 14.5%) (p > 0.05). Presence of osteopenia or osteoporosis (16.3% vs 3.5%) was associated with pseudarthrosis (p < 0.001). Implant type was also significantly associated with pseudarthrosis, with a 16.4% rate of pseudarthrosis for patients with polyetherethereketone (PEEK) implants versus 8.4% for patients with allograft implants (p = 0.04). Average lengths of follow-up were 27.6 and 23.8 months for patients with and those without pseudarthrosis, respectively. Multivariate analysis demonstrated osteopenia or osteoporosis (OR 4.97, 95% CI 1.51-16.4, p < 0.01) and usage of PEEK implant (OR 2.24, 95% CI 1.04-4.83, p = 0.04) as independent predictors of pseudarthrosis. CONCLUSIONS: In patients who underwent single-level ACDF, rates of pseudarthrosis associated with the use of the osteobiologic agent Osteocel are higher than the literature-reported rates associated with the use of alternative osteobiologics. This is especially true when Osteocel is combined with a PEEK implant.