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SummaryAfrican populations are the most diverse in the world yet are sorely underrepresented in medical genetics research. Here, we examine the structure of African populations using genetic and comprehensive multigenerational ethnolinguistic data from the Neuropsychiatric Genetics of African Populations-Psychosis study (NeuroGAP-Psychosis) consisting of 900 individuals from Ethiopia, Kenya, South Africa, and Uganda. We find that self-reported language classifications meaningfully tag underlying genetic variation that would be missed with consideration of geography alone, highlighting the importance of culture in shaping genetic diversity. Leveraging our uniquely rich multi-generational ethnolinguistic metadata, we track language transmission through the pedigree, observing the disappearance of several languages in our cohort as well as notable shifts in frequency over three generations. We find suggestive evidence for the rate of language transmission in matrilineal groups having been higher than that for patrilineal ones. We highlight both the diversity of variation within the African continent, as well as how within-Africa variation can be informative for broader variant interpretation; many variants appearing rare elsewhere are common in parts of Africa. The work presented here improves the understanding of the spectrum of genetic variation in African populations and highlights the enormous and complex genetic and ethnolinguistic diversity within Africa.

Acute respiratory distress syndrome (ARDS) is a heterogeneous clinical syndrome. Understanding of the complex pathways involved in lung injury pathogenesis, resolution, and repair has grown considerably in recent decades. Nevertheless, to date, only therapies targeting ventilation-induced lung injury have consistently proven beneficial, and despite these gains, ARDS morbidity and mortality remain high. Many candidate therapies with promise in preclinical studies have been ineffective in human trials, probably at least in part due to clinical and biological heterogeneity that modifies treatment responsiveness in human ARDS. A precision medicine approach to ARDS seeks to better account for this heterogeneity by matching therapies to subgroups of patients that are anticipated to be most likely to benefit, which initially might be identified in part by assessing for heterogeneity of treatment effect in clinical trials. In October 2019, the US National Heart, Lung, and Blood Institute convened a workshop of multidisciplinary experts to explore research opportunities and challenges for accelerating precision medicine in ARDS. Topics of discussion included the rationale and challenges for a precision medicine approach in ARDS, the roles of preclinical ARDS models in precision medicine, essential features of cohort studies to advance precision medicine, and novel approaches to clinical trials to support development and validation of a precision medicine strategy. In this Position Paper, we summarise workshop discussions, recommendations, and unresolved questions for advancing precision medicine in ARDS. Although the workshop took place before the COVID-19 pandemic began, the pandemic has highlighted the urgent need for precision therapies for ARDS as the global scientific community grapples with many of the key concepts, innovations, and challenges discussed at this workshop.

Late detection of critical congenital heart disease (CCHD) is multifactorial and ill defined. We investigated the results of pulse oximetry screening (POS) and points in the care chain that contribute to delayed detection of CCHD. The medical records of 13 infants with delayed detection at a single pediatric cardiac center between 2013 and 2016 were identified and reviewed. Left heart obstructive lesions were the most common diagnosis (n = 8; 62%) and included coarctation of the aorta (n = 6), interrupted aortic arch with ventricular septal defect (n = 1), and critical aortic stenosis (n = 1). Tetralogy of Fallot (TOF) (n = 2), truncus arteriosus (n = 1), pulmonary atresia with ventricular septal defect (n = 1), and total anomalous pulmonary venous drainage (n = 1) made up the remainder of the conditions. Routine prenatal care was reported in most infants (10/13). Infants with late detection had either a true negative POS (10/13 infants) or no POS performed (3/13 infants). At the time of detection, 5/6 (83%) infants with coarctation had normal pulse oximetry values, whereas 6/7 (86%) infants with other CCHD developed abnormal pulse oximetry values. At diagnosis, 11/13 (85%) infants had significant signs or symptoms of clinical deterioration; only 2 infants were completely asymptomatic. Late detection of CCHD is uncommon and multifactorial. Eliminating late detection is dependent upon improving detection on screening obstetrical ultrasounds, enforcement of universal POS, and attention to the neonatal physical exam.

Introduction Progressive supranuclear palsy (PSP) variants other than PSP-Richardson Syndrome (PSP-RS) have been recognized, including PSP with speech and language problems (PSP-SL). Given the reported sleep disruptions in PSP-RS, we investigated sleep abnormalities in PSP-SL. Methods Four sleep-related screening questions were given to the caregivers of 90 patients with PSP-SL (59 suggestive of PSP-SL and 31 possible PSP-SL) and 71 probable PSP-RS (prob. PSP-RS) patients. Results At least one sleep-related disturbance was observed in 35.6% of suggestive of PSP-SL, 38.7% of possible PSP-SL, and 67.6% of prob. PSP-RS, the most common being “unable to fall or stay asleep”. Prob. PSP-RS showed higher frequency of “screaming or talking in sleep”, “acting out dreams”, and “unable to fall or stay asleep” compared to both PSP-SL groups, but did not differ from possible PSP-SL in “excessive daytime sleepiness”. Conclusion Sleep abnormalities are common in PSP-SL, but less frequent than prob.PSP-RS.

Rationale The nutrient sensing mechanistic target of rapamycin complex 1 (mTORC1) and its primary inhibitor, tuberin (TSC2), are cues for the development of cardiac hypertrophy. The phenotype of mTORC1 induced hypertrophy is unknown. Objective To examine the impact of sustained mTORC1 activation on metabolism, function, and structure of the adult heart. Methods and results We developed a mouse model of inducible, cardiac-specific sustained mTORC1 activation (mTORC1iSA) through deletion of Tsc2. Prior to hypertrophy, rates of glucose uptake and oxidation, as well as protein and enzymatic activity of glucose 6-phosphate isomerase (GPI) were decreased, while intracellular levels of glucose 6-phosphate (G6P) were increased. Subsequently, hypertrophy developed. Transcript levels of the fetal gene program and pathways of exercise-induced hypertrophy increased, while hypertrophy did not progress to heart failure. We therefore examined the hearts of wild-type mice subjected to voluntary physical activity and observed early changes in GPI, followed by hypertrophy. Rapamycin prevented these changes in both models. Conclusion Activation of mTORC1 in the adult heart triggers the development of a non-specific form of hypertrophy which is preceded by changes in cardiac glucose metabolism.

We retrospectively analysed overall survival (OS) and potential predictive biomarkers of OS in patients with metastatic melanoma treated with ipilimumab plus nivolumab in a single institution. Electronic medical records of patients with advanced melanoma receiving ≥ 1 dose of a combined ipilimumab plus nivolumab regimen between March 3, 2016 and March 7, 2020 in a single institution, were reviewed. OS was analysed using the Kaplan–Meier method. Sub-group analyses were conducted to examine several endpoints according to relevant clinical, molecular and pathological variables using logistic and Cox models. Forty-four cases were reviewed, 38 (86.4%), of whom had cutaneous melanoma, 21 (47.7%) were BRAF mutant, 21 (47.7%) presented high lactate dehydrogenase (LDH) values, 23 (52.3%) had ≥ 3 disease sites, and 10 (22.7%) patients had brain metastases. The median follow-up was 37.7 months, and the median OS was 21.1 months (95% CI 8.2–NR). In the multivariate analysis, the OS was significantly longer in patients with an Eastern Cooperative Oncology Group (ECOG) score of 0, LDH ≤ upper limit of normal, absence of liver metastases and neutrophil-to-lymphocyte ratio (NLR)

Objective: Major postoperative adverse events (MPAEs) following head and neck surgery are not infrequent and lead to significant morbidity. The objective of this study was to ascertain which factors are most predictive of MPAEs in patients undergoing head and neck surgery. Methods: A cohort study was carried out based on data from patients registered in the National Surgical Quality Improvement Program (NSQIP) from 2006 to 2018. All patients undergoing non-ambulatory head and neck surgery based on Current Procedural Terminology codes were included. Perioperative factors were evaluated to predict MPAEs within 30-days of surgery. Age was classified as both a continuous and categorical variable. Retained factors were classified by attributable fraction and C-statistic. Multivariate regression and supervised machine learning models were used to quantify the contribution of age as a predictor of MPAEs. Results: A total of 43 701 operations were analyzed with 5106 (11.7%) MPAEs. The results of supervised machine learning indicated that prolonged surgeries, anemia, free tissue transfer, weight loss, wound classification, hypoalbuminemia, wound infection, tracheotomy (concurrent with index head and neck surgery), American Society of Anesthesia (ASA) class, and sex as most predictive of MPAEs. On multivariate regression, ASA class (21.3%), hypertension on medication (15.8%), prolonged operative time (15.3%), sex (13.1%), preoperative anemia (12.8%), and free tissue transfer (9%) had the largest attributable fractions associated with MPAEs. Age was independently associated with MPAEs with an attributable fraction ranging from 0.6% to 4.3% with poor predictive ability (C-statistic 0.60). Conclusion: Surgical, comorbid, and frailty-related factors were most predictive of short-term MPAEs following head and neck surgery. Age alone contributed a small attributable fraction and poor prediction of MPAEs. Level of evidence: 3

Study Design: Systematic review. Surgical decompression for degenerative cervical myelopathy (DCM) is associated with perioperative complications, including difficulty or discomfort with swallowing (dysphagia) as well as changes in sound production (dysphonia). This systematic review aims to (1) outline how dysphagia and dysphonia are defined in the literature and (2) assess the quality of definitions using a novel 4-point rating system. Methods: An electronic database search was conducted for studies that reported on dysphagia, dysphonia or other related complications of DCM surgery. Data extracted included study design, surgical details, as well as definitions and rates of surgical complications. A 4-point rating scale was developed to assess the quality of definitions for each complication. Results: Our search yielded 2,673 unique citations, 11 of which met eligibility criteria and were summarized in this review. Defined complications included odynophagia (n = 1), dysphagia (n = 11), dysphonia (n = 2), perioperative swelling complications (n = 2), and soft tissue swelling (n = 3). Rates of dysphagia varied substantially (0.0%-50.0%) depending on whether this complication was patient-reported (4.4%); patient-reported using a modified Swallowing Quality of Life questionnaire (43.1%) or the Bazaz criteria (8.8%-50.0%); or diagnosed using an extensive protocol consisting of clinical assessment, a bedside swallowing test, evaluation by a speech and language pathologist and a modified barium swallowing test/fiberoptic endoscopy (42.9%). The reported incidences of dysphonia also ranged significantly from 0.6% to 38.0%. Conclusion: There is substantial variability in reported rates of dysphagia and dysphonia due to differences in data collection methods, diagnostic strategies, and definitions. Consolidation of nomenclature will improve evaluation of the overall safety of surgery.

STUDY DESIGN Retrospective Cohort. OBJECTIVE Identify patient variables, injury characteristics, and costs associated with operative and non-operative treatment following inter-facility transfer of patients with isolated cervical spine fractures. SUMMARY OF BACKGROUND DATA Patients with isolated cervical spine fractures are subject to inter-facility transfer for surgical assessment, yet are often treated non-operatively. The American College of Surgeons' benchmark rate of "secondary over-triage" is < 50%. Identifying patient and injury characteristics as well as costs associated with treatment following transfer of patients with isolated cervical spine fractures may help reduce rates of secondary over-triage and healthcare expenditures. METHODS Patients transferred to a Level-1 trauma center with isolated cervical spine fractures between January 2015 and September 2020 were identified. Patient demographics, comorbidities, insurance data, injury characteristics, imaging workup, treatment, and financial data were collected for all patients. Multivariable logistic regression models were constructed to identify patient and injury characteristics associated with surgical treatment. RESULTS Nearly 75% of patients were treated non-operatively. Over 97% of transfers were accepted by the general surgery trauma service. Multivariable modeling found that higher BMI, presence of any neurologic deficit including spinal cord or isolated spinal nerve root injuries, current smoking status, or cervical spine MRI obtained post-transfer, were associated with surgical treatment for isolated cervical spine fractures. Among patients with type II dens fractures, increased fracture displacement was associated with surgical treatment. Median charges to patients treated operatively and non-operatively were $380,890 and $90,734, respectively. Median hospital expenditures for patients treated operatively and non-operatively were $55,115 and $12,131, respectively. CONCLUSION A large proportion of patients with isolated cervical spine fractures are subject to over-triage. Injury characteristics are important for determining need for surgical treatment, and therefore inter-facility transfer. Improving communication with spine surgeons when deciding to transfer patients may significantly reduce healthcare costs and resource use.Level of Evidence: 4.

AimsThe aims of this network meta-analysis (NMA) were to examine nonunion rates and functional outcomes following various operative and nonoperative treatments for displaced mid-shaft clavicle fractures.MethodsInitial search strategy incorporated MEDLINE, PubMed, Embase, and the Cochrane Library for relevant randomized controlled trials (RCTs). Four treatment arms were created: nonoperative (NO); intramedullary nailing (IMN); reconstruction plating (RP); and compression/pre-contoured plating (CP). A Bayesian NMA was conducted to compare all treatment options for outcomes of nonunion, malunion, and function using the Disabilities of the Arm Shoulder and Hand (DASH) and Constant-Murley Shoulder Outcome scores.ResultsIn all, 19 RCTs consisting of 1,783 clavicle fractures were included in the NMA. All surgical options demonstrated a significantly lower odds ratio (OR) of nonunion in comparison to nonoperative management: CP versus NO (OR 0.08; 95% confidence interval (CI) 0.04 to 0.17); IMN versus NO (OR 0.07; 95% CI 0.02 to 0.19); RP versus NO (OR 0.07; 95% CI: 0.01 to 0.24). Compression plating was the only treatment to demonstrate significantly lower DASH scores relative to NO at six weeks (mean difference -10.97; 95% CI -20.69 to 1.47).ConclusionSurgical fixation demonstrated a lower risk of nonunion compared to nonoperative management. Compression plating resulted in significantly less disability early after surgery compared to nonoperative management. These results demonstrate possible early improved functional outcomes with compression plating compared to nonoperative treatment. Surgical fixation of mid-shaft clavicle fractures with compression plating may result in quicker return to activity by rendering patients less disabled early after surgery. Cite this article: Bone Jt Open 2021;2(8):646–654.

Objective:To characterize and compare the neuropsychological profiles of patients with primary progressive apraxia of speech (PPAOS) and apraxia of speech with progressive agrammatic aphasia (AOS-PAA).Method:Thirty-nine patients with PPAOS and 49 patients with AOS-PAA underwent formal neurological, speech, language, and neuropsychological evaluations. Cognitive domains assessed included immediate and delayed episodic memory (Wechsler Memory Scale-Third edition; Logical Memory; Visual Reproduction; Rey Auditory Verbal Learning Test), processing speed (Trail Making Test A), executive functioning (Trail Making Test B; Delis-Kaplan Executive Functioning Scale – Sorting), and visuospatial ability (Rey-Osterrieth Complex Figure copy).Results:The PPAOS patients were cognitively average or higher in the domains of immediate and delayed episodic memory, processing speed, executive functioning, and visuospatial ability. Patients with AOS-PAA performed more poorly on tests of immediate and delayed episodic memory and executive functioning compared to those with PPAOS. For every 1 unit increase in aphasia severity (e.g. mild to moderate), performance declined by 1/3 to 1/2 a standard deviation depending on cognitive domain. The degree of decline was stronger within the more verbally mediated domains, but was also notable in less verbally mediated domains.Conclusion:The study provides neuropsychological evidence further supporting the distinction of PPAOS from primary progressive aphasia and should be used to inform future diagnostic criteria. More immediately, it informs prognostication and treatment planning.

OBJECTIVE Degenerative cervical myelopathy (DCM) is among the most common pathologies affecting the spinal cord but its natural history is poorly characterized. The purpose of this study was to investigate functional outcomes in patients with DCM who were managed nonoperatively as well as the utility of quantitative clinical measures and MRI to detect deterioration. METHODS Patients with newly diagnosed DCM or recurrent myelopathic symptoms after previous surgery who were initially managed nonoperatively were included. Retrospective chart reviews were performed to analyze clinical outcomes and anatomical MRI scans for worsening compression or increased signal change. Quantitative neurological assessments were collected prospectively, including modified Japanese Orthopaedic Association (mJOA) score; Quick-DASH; graded redefined assessment of strength, sensation, and prehension–myelopathy version (GRASSP–M: motor, sensory, and dexterity); grip dynamometer; Berg balance scale score; gait stability ratio; and gait variability index. A deterioration of 10% was considered significant (e.g., a 2-point decrease in mJOA score). RESULTS A total of 117 patients were included (95 newly diagnosed, 22 recurrent myelopathy), including 74 mild, 28 moderate, and 15 severe cases. Over a mean follow-up of 2.5 years, 57% (95% CI 46%–67%) of newly diagnosed patients and 73% (95% CI 50%–88%) of patients with recurrent DCM deteriorated neurologically. Deterioration was best detected with grip strength (60%), GRASSP dexterity (60%), and gait stability ratio (50%), whereas the mJOA score had low sensitivity (33%) in 50 patients. A composite score had a sensitivity of 81% and a specificity of 82%. The sensitivity of anatomical MRI was 28% (83 patients). CONCLUSIONS DCM appears to have a poor natural history; however, prospective studies are needed for validation. Serial assessments should include mJOA score, grip strength, dexterity, balance, and gait analysis. The absence of worsening on anatomical MRI or in mJOA scores is not sufficient to determine clinical stability.

Avascular necrosis (AVN) after bunion surgery is an unfortunate complication which can be devastating and painful. We present a case report of gradual medializing transport of the second metatarsal with external fixation to repair a large bone defect caused by AVN affecting >50% of the first metatarsal. The procedure was performed on a 49-year-old female who suffered AVN after failed bunion surgery. At 12-month follow up, first ray position and length were maintained. With respect to the second ray, there were no clinically significant issues. The second digit was mildly elevated but there was no frank instability of the toe or of the Lisfranc complex. The patient was pain free and had returned to her desired daily activities.

Context.— Pathology studies using convolutional neural networks (CNNs) have focused on neoplasms, while studies in inflammatory pathology are rare. We previously demonstrated a CNN that differentiates reactive gastropathy, Helicobacter pylori gastritis (HPG), and normal gastric mucosa. Objective.— To determine whether a CNN can differentiate the following 2 gastric inflammatory patterns: autoimmune gastritis (AG) and HPG. Design.— Gold standard diagnoses were blindly established by 2 gastrointestinal (GI) pathologists. One hundred eighty-seven cases were scanned for analysis by HALO-AI. All levels and tissue fragments per slide were included for analysis. The cases were randomized, 112 (60%; 60 HPG, 52 AG) in the training set and 75 (40%; 40 HPG, 35 AG) in the test set. A HALO-AI correct area distribution (AD) cutoff of 50% or more was required to credit the CNN with the correct diagnosis. The test set was blindly reviewed by pathologists with different levels of GI pathology expertise as follows: 2 GI pathologists, 2 general surgical pathologists, and 2 residents. Each pathologist rendered their preferred diagnosis, HPG or AG. Results.— At the HALO-AI AD percentage cutoff of 50% or more, the CNN results were 100% concordant with the gold standard diagnoses. On average, autoimmune gastritis cases had 84.7% HALO-AI autoimmune gastritis AD and HP cases had 87.3% HALO-AI HP AD. The GI pathologists, general anatomic pathologists, and residents were on average, 100%, 86%, and 57% concordant with the gold standard diagnoses, respectively. Conclusions.— A CNN can distinguish between cases of HPG and autoimmune gastritis with accuracy equal to GI pathologists.

BACKGROUND: A variety of shared care models have been developed, which aim to stratify glaucoma patients according to risk of disease progression. However, there is limited published data on the rate of glaucoma progression in the hospital vs community setting. Here we aimed to compare rates of glaucomatous visual field progression in the Cambridge Community Optometrist Glaucoma Scheme (COGS) and Addenbrooke's Hospital Glaucoma Clinic (AGC). METHODS: A retrospective comparative cohort review was performed. Patients with five or more visual field tests were included. Zeiss Forum software was used to calculate the MD progression rate (dB/year). Loss of sight years (LSY) were also calculated for both COGS and AGC. RESULTS: Overall, 8465 visual field tests from 854 patients were reviewed. In all, 362 eyes from the AGC group and 210 eyes from COGS were included. The MD deterioration rate was significantly lower in the COGS patients compared with the AGC group (-0.1 vs -0.3 dB/year; p

OBJECTIVE To demonstrate the feasibility of implementing a competency-based education (CBE) curriculum within a general surgery residency program and to evaluate its effectiveness in improving resident skill. SUMMARY BACKGROUND DATA Operative skill variability affects residents and practicing surgeons and directly impacts patient outcomes. CBE can decrease this variability by ensuring uniform skill acquisition. We implemented a CBE laparoscopic cholecystectomy (LC) curriculum to improve resident performance and decrease skill variability. METHODS PGY-2 residents completed the curriculum during monthly rotations starting in July 2017. Once simulator proficiency was reached, residents performed elective LCs with a select group of faculty at three hospitals. Performance at curriculum completion was assessed using LC simulation metrics and intraoperative OPRS scores and compared to both baseline and historical controls, comprised of rising PGY-3 s, using a two-sample Wilcoxon rank-sum test. PGY-2 group's performance variability was compared with PGY-3 s using Levene's Robust Test of Equality of Variances; p < 0.05 was considered significant. RESULTS 21 residents each performed 17.52 ± 4.15 consecutive LCs during the monthly rotation. Resident simulated and operative performance increased significantly with dedicated training and reached that of more experienced rising PGY-3 s (n = 7) but with significantly decreased variability in performance (p = 0.04). CONCLUSIONS Completion of a CBE rotation led to significant improvements in PGY-2 residents' LC performance that reached that of PGY-3 s and decreased performance variability. These results support wider implementation of CBE in resident training.

Background: Socioeconomic disadvantages and potential immunocompromise raise particular concerns for people living with HIV (PLWH) and other marginalized communities during the COVID-19 pandemic. In this study, we explored COVID-19 testing and the impact of the pandemic among participants from the Miami Adult Studies on HIV cohort, predominantly composed of lowincome minorities living with and without HIV. Methods: Between July and August 2020, a telephone survey was administered to 299 Miami Adult Studies on HIV participants to assess COVID-19 testing, prevention behaviors, and psychosocial stressors. Health care utilization, antiretroviral adherence, food insecurity, and substance use during the pandemic were compared with those of their last cohort visit (7.8 6 2.9 months earlier). Results: Half of surveyed participants had been tested for COVID-19, 8 had tested positive and 2 had been hospitalized. PLWH (n = 183) were 42% times less likely than HIV-uninfected participants to have been tested. However, after adjustment for age, employment, COVID-19 symptoms, mental health care, and substance use, the effect of HIV status was no longer significant. PLWH were more likely to have seen a health care provider, use face coverings, and avoid public transportation and less likely to be food insecure and drink hazardously. There were significant changes in substance use patterns during the pandemic when compared with those before. Conclusion: PLWH, compared with their HIV-uninfected peers, were more likely to engage in preventive measures and health care during the pandemic, potentially reducing their exposure to COVID-19. There were no reported changes in antiretroviral adherence or health care utilization, but there were changes in substance use;these need to be monitored as this crisis progresses. [ABSTRACT FROM AUTHOR] Copyright of JAIDS: Journal of Acquired Immune Deficiency Syndromes is the property of Lippincott Williams & Wilkins and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Spinal cord injury (SCI) can permanently impair motor and sensory function and has a devastating cost to patients and the United States healthcare system. Stem cell transplantation for treatment of SCI is a new technique aimed at creating biological functional recovery. Operative techniques in stem cell transplantation for SCI are varied. We review various clinical treatment paradigms, surgical techniques and technical considerations important in SCI treatment. The NCBI PubMed database was queried for “SCI” and “stem cell” with a filter placed for “clinical trials”. Thirty-nine articles resulted from the search and 29 were included and evaluated by study authors. A total of 10 articles were excluded (9 not SCI focused or transplantation focused, 1 canine model). Key considerations for stem cell transplantation include method of delivery (intravenous, intrathecal, intramedullary, or excision and engraftment), time course of treatment, number of treatments and time from injury until treatment. There are no phase III clinical trials yet, but decreased time from injury to treatment and a greater number of stem cell injections both seem to increase the chance of functional recovery.

Context Human milk contains hormones that regulate metabolism. Extrauterine growth restriction remains common among preterm infants, but the effect of ingesting milk hormones on preterm infant growth is poorly understood. Objective To quantify associations of longitudinal exposure to leptin, adiponectin, and insulin in milk with physical growth of preterm infants. Design/Methods In 50 preterm neonates (median gestational age 29.4 weeks), we sampled maternal milk on day-of-life 7, 14, 21, and 28 and measured hormone levels in whole milk by ELISA. Milk leptin levels were available for a subset of 18 infants. We calculated milk hormone doses by multiplying the hormone level by the milk volume ingested on each day and estimated the area under the curve (AUC) to reflect longitudinal exposure. We analyzed associations of milk hormone exposure with growth outcomes in generalized estimated equations. Main Outcome Measures Weight gain velocity and z-scores in weight, length, head circumference, and body mass index at 36 weeks’ postmenstrual age (PMA). Results Higher leptin intake was associated with greater weight gain (2.17g/kg/day [95% CI, 1.31, 3.02]) and weight z-score at 36 weeks’ PMA (0.30 [0.08, 0.53] higher z-score per tertile). Higher adiponectin intake was associated with greater length z-score (0.41 [0.13, 0.69]), however, this association was nullified after adjustment of protein and calorie intake. Higher adiponectin was associated with smaller head circumference z-score (−0.36 [−0.64, −0.07]). Insulin was not associated with growth outcomes. Conclusions Milk leptin and adiponectin exposures may affect growth of preterm infants. The long-term effects of milk hormones warrant further investigation.

Although whole food nutrition will likely influence physical health more than any other lifestyle component besides exercise, the use of dietary supplements among men and women continues to be high. Due to this fact, it is imperative that healthcare professionals understand how supplements may impact overall health and wellness of their patients. With the majority of adults taking some form of dietary supplements and many concomitantly taking prescription medications, healthcare providers should be conscientious of adverse effects and interactions that may occur between dietary supplements and prescription drugs. As many consumers are misled by false marketing, healthcare providers should encourage them to be wary of exaggerated claims and direct them to products that are scientifically supported and safe. Continuing education for healthcare providers on dietary supplements is crucial, with new dietary supplement products constantly reaching the markets, in addition to new findings being made through clinical research and case studies. While some dietary supplements provide no meaningful benefit, many dietary supplements have been identified that can be used to ameliorate nutritional deficiencies and reduce the risk of some common health conditions. Others can serve to improve mental and physical performance, while truly enhancing health. This article presents relevant information on dietary supplements that will be useful to the healthcare professional.

No large-scale genome-wide association studies (GWASs) of psychosis have been conducted in Mexico or Latin America to date. Schizophrenia and bipolar disorder in particular have been found to be highly heritable and genetically influenced. However, understanding of the biological basis of psychosis in Latin American populations is limited as previous genomic studies have almost exclusively relied on participants of Northern European ancestry. With the goal of expanding knowledge on the genomic basis of psychotic disorders within the Mexican population, the National Institute of Psychiatry Ramón de la Fuente Muñiz (INPRFM), the Harvard T.H. Chan School of Public Health, and the Broad Institute’s Stanley Center for Psychiatric Research launched the Neuropsychiatric Genetics Research of Psychosis in Mexican Populations (NeuroMex) project to collect and analyze case-control psychosis samples from 5 states across Mexico. This article describes the planned sample collection and GWAS protocol for the NeuroMex study. The 4-year study will span from April 2018 to 2022 and aims to recruit 9,208 participants: 4,604 cases and 4,604 controls. Study sites across Mexico were selected to ensure collected samples capture the genomic diversity within the Mexican population. Blood samples and phenotypic data will be collected during the participant interview process and will contribute to the development of a local biobank in Mexico. DNA extraction will be done locally and genetic analysis will take place at the Broad Institute in Cambridge, MA. We will collect extensive phenotypic information using several clinical scales. All study materials including phenotypic instruments utilized are openly available in Spanish and English. The described study represents a long-term collaboration of a number of institutions from across Mexico and the Boston area, including clinical psychiatrists, clinical researchers, computational biologists, and managers at the 3 collaborating institutions. The development of relevant data management, quality assurance, and analysis plans are the primary considerations in this protocol article. Extensive management and analysis processes were developed for both the phenotypic and genetic data collected. Capacity building, partnerships, and training between and among the collaborating institutions are intrinsic components to this study and its long-term success.

Due to an absence of maternal stress being measured in routine prenatal care by clinicians, prenatal stress has become a serious problem which is associated with poorer obstetric outcomes, as well as worse maternal and infant health. For that reason, the aim of this study was the translation, validation and adaptation of Prenatal Distress Questionnaire Revised (NuPDQ) in a Spanish sample.Three-hundred and seventy-one pregnant women were assessed using the NuPDQ, the Prenatal Distress Questionnaire, Perceived Stress Scale and the Connor-Davidson Resilience Scale. The NuPDQ was translated into Spanish by the backtranslation method and administered to participants.A confirmatory factor analysis revealed the established unidimensional structure to be a poor fit to data with the Spanish version. An exploratory factor analysis suggested a five-factor structure with 14 items. The instrument had good reliability, convergent and discriminant validity psychometric properties.The five-factor 14-item NuPDQ is useful to assess pregnancy-specific stress in Spanish pregnant women. It may be appropriate to use this instrument in order to identify pregnant women with high pregnancy-specific stress to try to prevent negative consequences derived from those high levels.

Objective To provide guidance about management of psoriatic disease during the COVID-19 pandemic. Study Design A task force (TF) of 18 physician voting members with expertise in dermatology, rheumatology, epidemiology, infectious diseases, and critical care was convened. The TF was supplemented by non-voting members which included fellows and National Psoriasis Foundation (NPF) staff. Clinical questions relevant to the psoriatic disease community were informed by questions received by the NPF. A Delphi process was conducted. Results The TF approved 22 guidance statements. The average of the votes was within the category of agreement for all statements. All guidance statements proposed were recommended, 9 with high consensus, 13 with moderate consensus. Limitations The evidence behind many guidance statements is limited in quality. Conclusion These statements provide guidance for the management of patients with psoriatic disease on topics ranging from how the disease and its treatments impact COVID-19 risk and outcome, how medical care can be optimized during the pandemic, what patients should do to lower their risk of getting infected with SARS-CoV-2 and what they should do if they develop COVID-19. The guidance is intended to be a living document that will be updated by the TF as data emerge., Capsule Summary The NPF COVID-19 Task Force produced 22 guidance statements to promote optimal management of psoriatic disease during the pandemic. Shared decision making is recommended as is adherence to evidence-based recommendations when available. The guidance statements will be updated when necessary in accordance with rapidly evolving science of COVID-19.

OBJECTIVE The aim was to analyze the timeline, prevalence, and survival of rapid eye movement (REM) sleep behavior disorder (RBD) in patients who developed alpha-synucleinopathies (Parkinson disease, dementia with Lewy bodies, and Parkinson disease dementia) compared with age- and sex-matched controls in a population-based incident-cohort study. METHODS We used a population-based, 1991 to 2010 incident-cohort study of alpha-synucleinopathies. A movement-disorder specialist reviewed medical records to confirm diagnoses. RBD was diagnosed by reported dream-enactment symptoms or polysomnography. Probable RBD and polysomnographically confirmed RBD were analyzed separately and combined. RESULTS Among the 444 incident cases of alpha-synucleinopathy, 86 were clinically diagnosed with RBD (19.8%), including 30 (35%) by polysomnography and 56 (65%) as probable. The prevalence of idiopathic RBD at alpha-synucleinopathy diagnosis was 3.4%, increasing to 23.8% after 15 years. Cumulative lifetime incidence was 53 times greater in alpha-synucleinopathy patients than in controls (odds ratio [OR] = 53.1, 95% confidence interval [CI]: 13.0-217.2, p

Alzheimer’s disease is characterized by the presence of amyloid-β and tau deposition in the brain, hippocampal atrophy and increased rates of hippocampal atrophy over time. Another protein, TAR DNA binding protein 43 (TDP-43) has been identified in up to 75% of cases of Alzheimer’s disease. TDP-43, tau and amyloid-β have all been linked to hippocampal atrophy. TDP-43 and tau have also been linked to hippocampal atrophy in cases of primary age-related tauopathy, a pathological entity with features that strongly overlap with those of Alzheimer’s disease. At present, it is unclear whether and how TDP-43 and tau are associated with early or late hippocampal atrophy in Alzheimer’s disease and primary age-related tauopathy, whether either protein is also associated with faster rates of atrophy of other brain regions and whether there is evidence for protein-associated acceleration/deceleration of atrophy rates. We therefore aimed to model how these proteins, particularly TDP-43, influence non-linear trajectories of hippocampal and neocortical atrophy in Alzheimer’s disease and primary age-related tauopathy. In this longitudinal retrospective study, 557 autopsied cases with Alzheimer’s disease neuropathological changes with 1638 ante-mortem volumetric head MRI scans spanning 1.0–16.8 years of disease duration prior to death were analysed. TDP-43 and Braak neurofibrillary tangle pathological staging schemes were constructed, and hippocampal and neocortical (inferior temporal and middle frontal) brain volumes determined using longitudinal FreeSurfer. Bayesian bivariate-outcome hierarchical models were utilized to estimate associations between proteins and volume, early rate of atrophy and acceleration in atrophy rates across brain regions. High TDP-43 stage was associated with smaller cross-sectional brain volumes, faster rates of brain atrophy and acceleration of atrophy rates, more than a decade prior to death, with deceleration occurring closer to death. Stronger associations were observed with hippocampus compared to temporal and frontal neocortex. Conversely, low TDP-43 stage was associated with slower early rates but later acceleration. This later acceleration was associated with high Braak neurofibrillary tangle stage. Somewhat similar, but less striking, findings were observed between TDP-43 and neocortical rates. Braak stage appeared to have stronger associations with neocortex compared to TDP-43. The association between TDP-43 and brain atrophy occurred slightly later in time (∼3 years) in cases of primary age-related tauopathy compared to Alzheimer’s disease. The results suggest that TDP-43 and tau have different contributions to acceleration and deceleration of brain atrophy rates over time in both Alzheimer’s disease and primary age-related tauopathy.

CT-guided treatment delivery can improve target localization in mediastinal lymphoma patients treated with "butterfly" intensity-modulated radiotherapy and deep-inspiration breath hold. Although daily CT imaging adds additional radiation exposure, its use may be justified given the greater normal tissue sparing enabled by PTV margin reduction.

Objective The purpose of this case report is to analyze the treatment of a patient with psoriatic arthritis (PsA) using natural medicine. Clinical Features A 73-year-old woman complained of PsA in her second and third digits with gradual onset over a 6-month period. PsA was manifesting as dactylitis with moderate to severe stiffness and edema in her proximal and distal interphalangeal joints and the surrounding soft tissue. A radiographic image revealed narrowing of the proximal and distal interphalangeal joints, mild erosion, and periosteal thickening. Intervention and Outcome Traditional Chinese Medicine-style acupuncture was combined with 500 mg of turmeric curcumin (Curcuma longa root extract) with 3 mg of black pepper extract (Piper nigrum) that was standardized to contain 95% curcuminoids, 425 mg of sarsaparilla root (Smilax officinalis) powdered capsules that were not standardized and 10,000 IU vitamin D3 as cholecalciferol oil capsules once a day. She received 2 acupuncture treatments in combination with the supplements. She experienced an increased range of motion and a reduction in edema and stiffness. She continued to experience a reduction in symptomatology while supplementing with turmeric curcumin, sarsaparilla root, and vitamin D3, which might have helped to control her symptoms. Supplementation with these agents may have helped to maintain the swelling and stiffness at a tolerable level for the past year. Conclusion The natural modalities administered to the patient might have been able to reduce her symptoms of PsA and maintain them at a tolerable level. Acupuncture, turmeric, sarsaparilla root, and vitamin D3 could be viable natural alternatives for the treatment of PsA.

Background Advances in technique and perioperative blood management have improved transfusion rates following unilateral primary total joint arthroplasty and led some centers to change their preoperative blood ordering protocols. The purpose of this study is to determine whether deleting type and screens (T&S) from preoperative order sets was safe for patients undergoing primary total knee (TKA) and total hip arthroplasty (THA) and to identify patients who required allogenic blood transfusion. Methods Prospectively collected data were reviewed to identify any patient with a hemoglobin (Hgb) drawn within 30 days of surgery who received a transfusion following a unilateral primary TKA or THA. Results A total of 1255 patients met inclusion criteria. Of the total, 682 (54%) were TKAs and 573 (46%) were THAs. The mean preoperative Hgb was 11.5 g/dL with an average delta Hgb of 3.6 g/dL on postoperative day 1. No patient required an intraoperative transfusion. Fourteen patients (mean age and body mass index, 67.9 and 29.0) required a transfusion (1.1%) for postoperative blood loss anemia. Of those transfused, 13 (93%) of the patients underwent THA with the mean estimated blood loss of 378.6 mL. The total cost for a patient obtaining a T&S is $191.27. Conclusion In our series, the risk of blood transfusion was rare (1.1%) and occurred only secondary to postoperative blood loss anemia. There were no cases of intraoperative complication requiring urgent or emergent blood transfusion. Removing T&S from standard order sets for patients undergoing primary TKA or THA appears to be a safe and cost-effective practice.

Preventing, treating, and promoting recovery from critical illness due to pulmonary disease are foundational goals of the critical care community and the National Heart, Lung, and Blood Institute. Decades of clinical research in acute respiratory distress syndrome, acute respiratory failure, pneumonia, and sepsis have yielded improvements in supportive care, which have translated into improved patient outcomes. Novel therapeutics have largely failed to translate from promising pre-clinical findings into improved patient outcomes in late-phase clinical trials. Recent advances in personalized medicine, "big data", causal inference using observational data, novel clinical trial designs, pre-clinical disease modeling, and understanding recovery from acute illness promise to transform the methods of pulmonary and critical care clinical research. To assess the current state, research priorities, and future directions for adult pulmonary and critical care research, the NHLBI assembled a multidisciplinary working group of investigators. This working group identified recommendations for future research, including: (1) focusing on understanding the clinical, physiological, and biological underpinnings of heterogeneity in syndromes, diseases, and treatment-response with the goal of developing targeted, personalized interventions; (2) optimizing pre-clinical models by incorporating comorbidities, co-interventions, and organ support; (3) developing and applying novel clinical trial designs; and (4) advancing mechanistic understanding of injury and recovery in order to develop and test interventions targeted at achieving long-term improvements in the lives of patients and families. Specific areas of research are highlighted as especially promising for making advances in pneumonia, acute hypoxemic respiratory failure, and acute respiratory distress syndrome.

Importance: Retinal ganglion cells endure significant metabolic stress with ageing and glaucoma-related stressors. Injured cells require increased energy for repair but maintain capacity to recover function despite periods of functional loss. Nicotinamide, a precursor of redox co-factor and metabolite, NAD + , is low in serum of patients with primary open-angle glaucoma and its supplementation provides robust protection of retinal ganglion cells by targeting mitochondrial health in glaucoma models. However, the potential of nicotinamide to improve retinal ganglion cell function in humans with glaucoma is yet unknown. Objective: To determine whether nicotinamide supplementation taken in conjunction with conventional IOP-lowering therapy leads to early improvement in retinal ganglion cell function in people with glaucoma. Design: Crossover, double-masked, randomized clinical trial conducted between October 2017 to January 2019. Setting: Study participants recruited from two tertiary care centers in Melbourne, Australia. Participants: Adults diagnosed and treated for primary glaucoma. Ninety-four participants assessed for study eligibility. Intervention: Participants randomized to first receive oral placebo or nicotinamide and reviewed six-weekly. Accelerated dosing method utilized; participants commenced 6-week course of 1.5 grams/day followed by 6 weeks of 3.0 grams/day. After 12 weeks, participants crossed over to other intervention for 12 weeks without washout. At each visit, visual function measured using full-field flash electroretinography and white-on-white perimetry. Main outcome measures: Primary endpoint was change in inner retinal function determined a-priori as change in photopic negative response (PhNR) parameters: saturated PhNR amplitude (Vmax), ratio of PhNR/b-wave amplitude (Vmax ratio). Results: Fifty-seven participants (65.5±10.0 years, 39% female) enrolled. PhNR Vmax improved beyond 95% coefficient of repeatability (COR) in 23% of participants following 12 weeks of nicotinamide versus 9% on placebo. Conversely, PhNR Vmax deteriorated in 9% on placebo and 7% on nicotinamide. Overall, Vmax improved by 14.8% [95% CI: 2.8%, 26.9%], (p=0.02) on nicotinamide and 5.2% [-4.2%, 14.6%], (p=0.27) on placebo. Vmax ratio improved on average by 12.6% [5.0%, 20.2%], (p=0.002) following nicotinamide and 3.6% [-3.4%, 10.5%], (p=0.30) on placebo. A concomitant trend for improved visual field mean deviation was observed with 27% improving ≥1dB on nicotinamide and fewer deteriorating ≥1dB (4%) compared to placebo (p=0.02). Moderate correlation was observed between PhNR and visual field change with treatment. Participants demonstrated excellent treatment adherence rates (>94%) and nicotinamide was well tolerated with minimal side effects. Conclusions and Relevance: Nicotinamide supplementation can improve inner retinal function in patients receiving concurrent IOP-lowering glaucoma therapy. Further studies are underway to elucidate the effects of long-term nicotinamide supplementation on glaucoma progression.

Alzheimer’s disease can present clinically with either the typical amnestic phenotype or with atypical phenotypes, such as logopenic progressive aphasia and posterior cortical atrophy. We have recently described longitudinal patterns of flortaucipir PET uptake and grey matter atrophy in the atypical phenotypes, demonstrating a longitudinal regional disconnect between flortaucipir accumulation and brain atrophy. However, it is unclear how these longitudinal patterns differ from typical Alzheimer’s disease, to what degree flortaucipir and atrophy mirror clinical phenotype in Alzheimer’s disease, and whether optimal longitudinal neuroimaging biomarkers would also differ across phenotypes. We aimed to address these unknowns using a cohort of 57 participants diagnosed with Alzheimer’s disease (18 with typical amnestic Alzheimer’s disease, 17 with posterior cortical atrophy and 22 with logopenic progressive aphasia) that had undergone baseline and 1-year follow-up MRI and flortaucipir PET. Typical Alzheimer’s disease participants were selected to be over 65 years old at baseline scan, while no age criterion was used for atypical Alzheimer’s disease participants. Region and voxel-level rates of tau accumulation and atrophy were assessed relative to 49 cognitively unimpaired individuals and among phenotypes. Principal component analysis was implemented to describe variability in baseline tau uptake and rates of accumulation and baseline grey matter volumes and rates of atrophy across phenotypes. The capability of the principal components to discriminate between phenotypes was assessed with logistic regression. The topography of longitudinal tau accumulation and atrophy differed across phenotypes, with key regions of tau accumulation in the frontal and temporal lobes for all phenotypes and key regions of atrophy in the occipitotemporal regions for posterior cortical atrophy, left temporal lobe for logopenic progressive aphasia and medial and lateral temporal lobe for typical Alzheimer’s disease. Principal component analysis identified patterns of variation in baseline and longitudinal measures of tau uptake and volume that were significantly different across phenotypes. Baseline tau uptake mapped better onto clinical phenotype than longitudinal tau and MRI measures. Our study suggests that optimal longitudinal neuroimaging biomarkers for future clinical treatment trials in Alzheimer’s disease are different for MRI and tau-PET and may differ across phenotypes, particularly for MRI. Baseline tau tracer retention showed the highest fidelity to clinical phenotype, supporting the important causal role of tau as a driver of clinical dysfunction in Alzheimer’s disease.

GM1 gangliosidosis (GM1) is a fatal neurodegenerative lysosomal storage disease that occurs most commonly in young children, with no effective treatment available. Long-term follow-up of GM1 cats treated by bilateral thalamic and deep cerebellar nuclei (DCN) injection of adeno-associated virus (AAV)-mediated gene therapy has increased lifespan to 8 years of age, compared with an untreated lifespan of ~8 months. Due to risks associated with cerebellar injection in humans, the lateral ventricle was tested as a replacement route to deliver an AAVrh8 vector expressing feline β-galactosidase (β-gal), the defective enzyme in GM1. Treatment via the thalamus and lateral ventricle corrected storage, myelination, astrogliosis, and neuronal morphology in areas where β-gal was effectively delivered. Oligodendrocyte number increased, but only in areas where myelination was corrected. Reduced AAV and β-gal distribution were noted in the cerebellum with subsequent increases in storage, demyelination, astrogliosis, and neuronal degeneration. These postmortem findings were correlated with endpoint MRI and magnetic resonance spectroscopy (MRS). Compared with the moderate dose with which most cats were treated, a higher AAV dose produced superior survival, currently 6.5 years. Thus, MRI and MRS can predict therapeutic efficacy of AAV gene therapy and non-invasively monitor cellular events within the GM1 brain.

Background Anti-TNF exposure has been linked to demyelination events. We sought to describe the clinical features of demyelination events following anti-TNF treatment and to test whether affected patients were genetically predisposed to multiple sclerosis [MS]. Methods We conducted a case-control study to describe the clinical features of demyelination events following anti-TNF exposure. We compared genetic risk scores [GRS], calculated using carriage of 43 susceptibility loci for MS, in 48 cases with 1219 patients exposed to anti-TNF who did not develop demyelination. Results Overall, 39 [74%] cases were female. The median age [range] of patients at time of demyelination was 41.5 years [20.7–63.2]. The median duration of anti-TNF treatment was 21.3 months [0.5-99.4] and 19 [36%] patients were receiving concomitant immunomodulators. Most patients had central demyelination affecting the brain, spinal cord, or both. Complete recovery was reported in 12 [23%] patients after a median time of 6.8 months [0.1–28.7]. After 33.0 months of follow-up, partial recovery was observed in 29 [55%] patients, relapsing and remitting episodes in nine [17%], progressive symptoms in three [6%]: two [4%] patients were diagnosed with MS. There was no significant difference between MS GRS scores in cases (mean -3.5 × 10–4, standard deviation [SD] 0.0039) and controls [mean -1.1 × 10–3, SD 0.0042] [p = 0.23]. Conclusions Patients who experienced demyelination events following anti-TNF exposure were more likely female, less frequently treated with an immunomodulator, and had a similar genetic risk to anti-TNF exposed controls who did not experience demyelination events. Large prospective studies with pre-treatment neuroimaging are required to identify genetic susceptibility loci.

The meniscus plays a central load bearing role in the knee joint. Unfortunately, meniscus injury is common and can lead to joint degeneration and osteoarthritis. In small animal models, progressive degenerative changes occur with unloading of the meniscus via destabilization of the medial meniscus (DMM). However, few large animal models of DMM exist and the joint-wide initiation of disease has not yet been defined in these models. Thus, the goal of this study was to develop and validate a large-animal model of surgically-induced destabilization of the medial meniscus and to use multi-modal (mechanical, histological, and MRI) and multi-scale (joint to tissue level) quantitative measures to evaluate degeneration in both the meniscus and cartilage. DMM was achieved using an arthroscopic approach in thirteen Yucatan minipigs. One month after DMM, joint contact area decreased and peak pressure increased, indicating altered load transmission as a result of meniscus destabilization. By three months, the joint had adapted to the injury and load transmission patterns were restored to baseline, likely due to the formation and maturation of a fibrovascular scar at the anterior aspect of the meniscus. Despite this, we found a decrease in the indentation modulus of the tibial cartilage and an increase in cartilage histopathology scores at one month compared to Sham operated animals; these deleterious changes persisted through three months. Over this same time course, meniscus remodeling was evident through decreased proteoglycan staining in DMM compared to Sham menisci at both one and three months. These findings support that arthroscopic DMM results in joint degeneration in the Yucatan minipig and provides a new large animal test bed in which to evaluate therapeutics and interventions to treat post-traumatic osteoarthritis (PTOA) that originates from meniscal injury.

Es grande la expectativa que genera en todos los servicios de salud del mundo la rápida expansión del SARS-CoV2 (Coronavirus 2 del Síndrome Respiratorio Agudo y Grave), agente etiológico de la Enfermedad Infecciosa por Coronavirus del año 2019, COVID-19. Por tratarse de una enfermedad emergente es poco lo que se conoce sobre su comportamiento en los humanos, lo que lleva a múltiples interrogantes al momento de tomar decisiones en la práctica clínica. Hasta el momento, las estrategias para enfrentar esta pandemia se basan en la experiencia de los países que han sido epicentro del brote infeccioso y en la evidencia recopilada durante el manejo de otros coronavirus en años anteriores (SARS-CoV en el año 2002 y MERS-CoV en 2012). La falta de información contundente y unificada ha dado lugar a especulaciones y a suposiciones, especialmente relacionadas con la atención del COVID-19 en poblaciones consideradas de alto riesgo, como son los pacientes crónicamente inmunosuprimidos postrasplante. A través de esta revisión narrativa de la literatura, más allá de dar la opinión de los autores, se pretende organizar de manera juiciosa los documentos hasta el momento publicados, y responder, basados en datos reales, cinco de las preguntas más importantes que surgen en el día a día durante el manejo de los pacientes trasplantados.

Durante los primeros meses de la pandemia por SARS-CoV2 (Coronavirus 2 del Síndrome Respiratorio Agudo y Grave), el agente etiológico de la Enfermedad Infecciosa por Coronavirus de 2019 (COVID-19), la actividad de donación y trasplante de órganos en todo el mundo se ha visto claramente afectada. Las principales razones que en este momento motivan el cese parcial o total de los trasplantes son: 1) la carga asistencial que genera el manejo de un potencial donante en la Unidad de Cuidado Intensivo (UCI), 2) el alto riesgo de contagio entre donante y receptor, 3) el riesgo de inmunosuprimir a un paciente en medio de la pandemia y 4) la escases de camas de UCI. A pesar de que el mundo está enfrentando a una enfermedad emergente que merece especial atención, al mismo tiempo continúan prevaleciendo las complicaciones asociadas a las demás enfermedades incluyendo las complicaciones de patologías crónicas en estado terminal. La decisión de continuar con los programas de trasplante se debe basar en el comportamiento local del virus y en la capacidad asistencial de cada una de las instituciones. En Colombia, el comportamiento epidemiológico del SARS-CoV2 varía significativamente entre las diferentes regionales, permitiendo a las instituciones que hasta el momento, presentan poca carga de atención del COVID-19 retomar sus actividades de trasplante. De esta manera se propone un balance entre mantener las medidas de prevención y atención del COVID-19 y continuar ofreciendo los servicios de trasplante, principalmente a los pacientes con alto riesgo de morbi-mortalidad en lista de espera.

Purpose Genetic variations in DNA damage repair (DDR) genes may influence radiation therapy (RT)–induced acute normal tissue toxicity in patients with breast cancer. Identifying an individual or multiple single-nucleotide polymorphisms (SNPs) associated with RT–induced early adverse skin reactions (EASR) is critical for precision medicine in radiation oncology. Methods and Materials At the completion of RT, EASR was assessed using the Oncology Nursing Society scale (0-6) in 416 patients with breast cancer, and Oncology Nursing Society score ≥4 was considered RT-induced EASR. PLINK set-based tests and subsequent individual SNP association analyses were conducted to identify genes and SNPs associated with EASR among the 53 DDR genes and 1968 SNPs. A weighted polygenic risk score (PRS) model was constructed to ascertain the association between the joint effect of risk alleles and EASR. Results The study population consisted of 264 Hispanic whites, 86 blacks or African Americans, 55 non-Hispanic whites, and 11 others. A total of 115 patients (27.6%) developed EASR. Five genes (ATM, CHEK1, ERCC2, RAD51C, and TGFB1) were significantly associated with RT-induced EASR. Nine SNPs within these 5 genes were further identified: ATM rs61915066, CHEK1 rs11220184, RAD51C rs302877, rs405684, TBFB1 rs4803455, rs2241714, and ERCC2 rs60152947, rs10404465, rs1799786. In a multivariable-adjusted PRS model, patients in a higher quartile of PRS were more likely to develop EASR compared with patients in the lowest quartile (ORq2 vs.q1 = 1.94, 95% CI, 0.86-4.39; ORq3 vs.q1 = 3.46, 95% CI, 1.57-7.63; ORq4 vs.q1 = 8.64, 95% CI, 3.92-19.02; and Ptrend Conclusions We newly identified the associations between 9 SNPs in ATM, CHEK1, RAD51C, TGFB1, and ERCC2 and RT-induced EASR. PRS modeling showed its potential in identifying populations at risk. Multiple SNPs in DDR genes may jointly contribute to interindividual variation in RT-induced EASR. Validation in an independent external cohort is required to determine the clinical significance of these predictive biomarkers.

Irrigation during intraventricular endoscopic surgery is critical for visualization, with normal intracranial pressure maintained by balancing fluid ingress and egress. Although irrigation is typically achieved through manual manipulation of inexact stopcocks, the authors have developed a rate-controlled, foot pedal–activated system for precise intraventricular irrigation by using a standard irrigating bipolar electrocautery machine.This study is a retrospective review of patients who underwent endoscopic intraventricular surgery between January 1, 2018, and September 25, 2019, in which this irrigation system was used. Important components of this system include a bipolar module irrigation regulator that is set to a desired rate, a secure connection of the bipolar irrigation tubing to the endoscope, and one or more open egress ports on the endoscope for passive fluid drainage. Nineteen consecutive patients were identified on review (average age ± SD, 4.3 ± 4.1 years). Procedures performed included third ventriculostomies (n = 10); arachnoid/choroid cyst fenestrations/resections (n = 3); biopsy/tumor resection (n = 1); and combined procedures (n = 5). Foot pedal–controlled irrigation provided visualization of all intraventricular structures. A single operator was able to control the endoscope, endoscopic instruments, and irrigation, with assistance as indicated for more complex maneuvers. There were no perioperative complications. Because this setup is easily constructed from a standard irrigating bipolar machine, delivers precise irrigation flow rates, and facilitates a single-surgeon bimanual technique, these data support the utility of foot-controlled irrigation for endoscopic intraventricular surgery.

Background Extensive femoral bone loss poses a challenge in revision total hip arthroplasty (rTHA). Many techniques have been developed to address this problem including fully porous cylindrical stems, impaction bone grafting, and cementation of long stems, which have had varied success. Modular tapered fluted femoral stems (MTFS) show favorable results. We sought to determine the minimum 2-year radiographic and clinical performance of MTFS in rTHA in a population with extensive proximal femoral bone loss. Methods Our clinical database was queried retrospectively for all patients who underwent rTHA with an MTFS. We included patients with Paprosky 3 and 4 femoral bone loss and patients with Vancouver B2 and B3 periprosthetic femur fractures. Patients without 2-year follow-up were invited to return to clinic for X-ray evaluation and to complete clinical questionnaires. We assessed distance of stem subsidence and presence of stem fixation on final X-ray. We recorded all-cause revision and survival of the stem at final follow-up. Results One hundred twenty-nine patients were available for follow-up. Average follow-up time was 3.75 years. One hundred twenty-two stems (95%) remained in place at final follow-up. Median subsidence was 1.4 mm (range 0-21). All-cause revision rate was 16.3% (21 patients). Of the hips revised, 10 were for instability, 6 for infection, 1 for aseptic loosening, and 1 for periprosthetic femur fracture. Three were revised for other reasons. The stem was revised in 7 patients (5.4%), and the most common reason for stem revision was infection (5 patients). The other 2 stems were revised for aseptic loosening in a Paprosky 4 femur and periprosthetic femur fracture. Survival of tapered modular fluted stems with aseptic failure as an endpoint was 98.4%. The mean Hip disability and Osteoarthritis Outcome Score, Joint Replacement score at final follow-up was 73, and mean Veterans Rand 12 item health survey physical and mental scores were 32.8 and 52.2, respectively. Conclusion In patients with Paprosky 3, 4 femoral defects or Vancouver type B2, B3 fractures, modular tapered fluted stems for femoral revision show excellent outcomes at minimum 2-year follow-up.

The development of infections such as urinary tract infections (UTIs) or pneumonia after a traumatic subdural hematoma (tSDH) can worsen patient outcomes and increase healthcare costs. We herein identify clinical parameters that influence the risk of infections after tSDH.This single-institution retrospective cohort study examined the incidence and risk factors for UTI and pneumonia among tSDH patients from 1990 to 2015. Multivariate logistic regression assessed the impact of various demographic and clinical variables on these outcomes.3024 patients with tSDHs were identified (73.1% male); Of those, 208 (6.9%) experienced a UTI and 434 (14.4%) experienced pneumonia. Of the 559 patients (18.5%) who underwent a craniotomy and/or craniectomy for evacuation of a tSDH, 62 (11.1%) experienced a UTI and 222 (39.7%) experienced pneumonia. Risk factors for both pneumonia and UTI included length of stay (LOS) ≥7 days (odds ratio [OR] = 6.0, P0.001; OR = 11.2, P0.001), intensive care unit LOS ≥7 days (OR = 8.1, P0.001; OR = 1.7, P = 0.012), and mechanical ventilation ≥14 days (OR = 3.4, P0.001; OR = 1.8, P = 0.007). Craniotomy/craniectomy increased the risk of pneumonia (OR = 1.4, P = 0.019) but not UTI. Glasgow Coma Scale (GCS) ≥13 was associated with a decreased pneumonia risk (OR = 0.5, P = 0.003), and male gender (OR = 0.5, P0.001) and age60 (OR = 0.6, P0.001) were associated with a decreased UTI risk.Patients with prolonged hospitalizations and/or intensive care unit stays were more likely to experience UTIs and pneumonia. Male gender and younger age were protective against UTI, and higher GCS was protective against pneumonia. These data may aid the identification and treatment of at-risk populations after admission for a tSDH.

Background Revision of monoblock metal-on-metal (MoM) total hip arthroplasty (THA) is associated with high complication rates. Limited revision by conversion to a dual mobility (DM) without acetabular component extraction may mitigate these complications. However, the concern for polyethylene wear and osteolysis remains unsettled. This study investigates the results of DM conversion of monoblock MoM THA compared to formal acetabular revision. Methods One hundred forty-three revisions of monoblock MoM THA were reviewed. Twenty-nine were revisions to a DM construct, and 114 were complete revisions of the acetabular component. Mean patient age was 61, 54% were women. Components used, acetabular cup position, radiographic outcomes, serum metal ion levels, and HOOS Jr clinical outcome scores were investigated. Results At 3.9 years of follow-up (range 2-5), there were 2 revisions (6.9%) in the DM cohort, 1 for instability and another for periprosthetic fracture. Among the formal acetabular revision group there was a 20% major complication rate (23/114) and 16% underwent revision surgery (18/114) for aseptic loosening of the acetabular component (6%), deep infection (6%), dislocation (4%), acetabular fracture (3%), or delayed wound healing (6%). In the DM cohort, there were no radiographic signs of aseptic loosening, component migration, or polyethylene wear. One DM patient had a small posterior metadiaphyseal femur lesion that will require close monitoring. There were no other radiographic signs of osteolysis. There were no clinically significant elevations of serum metal ion levels. HOOS Jr scores were favorable. Conclusion Limited revision with conversion to DM is a viable treatment option for failed monoblock MoM THA with lower complication rates than formal revision. Limited revision to DM appears to be a safe option for revision of monoblock MoM THA with a cup in good position and an internal geometry free of sharp edges or articular surface damage. Longer follow-up is needed to demonstrate any potential wear implications of these articulations.

BACKGROUND: Cryptogenic stroke leading to cerebellar infarction is a rare but serious cause of acute nausea and vomiting. This has the potential of devastating consequences if this occurs in aviators during flight. We present a case of cryptogenic stroke causing incapacitating nausea and vomiting in a U.S. Air Force pilot.CASE REPORT: A 36-yr-old active-duty U.S. Air Force male pilot developed acute onset severe vertigo, nausea, and vomiting during initial descent. Initial computed tomography imaging was normal and his initial assessment yielded a diagnosis of benign paroxysmal positional vertigo. MRI-Brain at 1 mo revealed a small right inferomedial cerebellar infarct. Echocardiography revealed a patent foramen ovale and bilateral atrial enlargement. He made a full neurological recovery and was eventually returned to active flight status with Flying Class IIC waiver.DISCUSSION: Cryptogenic stroke caused by patent foramen ovale (PFO) is uncommon. However, this is increased in patients younger than 50 yr of age. This can lead to an acute incapacitation with varying degrees of dysfunction. There is controversial discussion of treatment options for secondary stroke prevention with PFO. However, there is no significant literature on primary prevention in these patients. A small subset of patients benefit from closure of PFO and most patients benefit from antiplatelet therapy after a stroke occurs. There may also be a significant subset of patients with PFO that may benefit from antiplatelet therapy as a primary prevention of stroke.Lytle ME, Martin BR. Acute cerebellar stroke in a military active-duty pilot. Aerosp Med Hum Perform. 2021; 92(11): 919–923.

Study Design Narrative review. Objective The current review aimed to describe the role of existing techniques and emerging methods of imaging and electrophysiology for the management of degenerative cervical myelopathy (DCM), a common and often progressive condition that causes spinal cord dysfunction and significant morbidity globally. Methods A narrative review was conducted to summarize the existing literature and highlight future directions. Results Anatomical magnetic resonance imaging (MRI) is well established in the literature as the key imaging tool to identify spinal cord compression, disc herniation/bulging, and inbuckling of the ligamentum flavum, thus facilitating surgical planning, while radiographs and computed tomography (CT) provide complimentary information. Electrophysiology techniques are primarily used to rule out competing diagnoses. However, signal change and measures of cord compression on conventional MRI have limited utility to characterize the degree of tissue injury, which may be helpful for diagnosis, prognostication, and repeated assessments to identify deterioration. Early translational studies of quantitative imaging and electrophysiology techniques show potential of these methods to more accurately reflect changes in spinal cord microstructure and function. Conclusion Currently, clinical management of DCM relies heavily on anatomical MRI, with additional contributions from radiographs, CT, and electrophysiology. Novel quantitative assessments of microstructure, perfusion, and function have the potential to transform clinical practice, but require robust validation, automation, and standardization prior to uptake.

The clinical indications and added value of obtaining MRI in the acute phase of spinal cord injury (SCI) remain controversial. This review aims to critically evaluate evidence regarding the role of MRI to influence decision-making and outcomes in acute SCI. A systematic review and meta-analysis were performed according to PRISMA methodology to identify studies that address six key questions (KQs) regarding diagnostic accuracy, frequency of abnormal findings, frequency of altered decision-making, optimal timing, and differences in outcomes related to obtaining an MRI in acute SCI. A total of 32 studies were identified that addressed one or more KQs. MRI showed no adverse events in 156 patients (five studies) and frequently identified cord compression (70%, 12 studies), disc herniation (43%, 16 studies), ligamentous injury (39%, 13 studies), and epidural hematoma (10%, two studies), with good diagnostic accuracy (seven comparative studies) except for fracture detection. MRI findings often altered management, including timing of surgery (78%, three studies), decision to operate (36%, 15 studies), and surgical approach (29%, nine studies). MRI may also be useful to determine the need for instrumentation (100%, one study), which levels to decompress (100%, one study), and if reoperation is needed (34%, two studies). The available literature consistently concluded that MRI was useful prior to surgical treatment (13 studies) and after surgery to assess decompression (two studies), but utility before/after closed reduction of cervical dislocations was unclear (three studies). One study showed improved outcomes with an MRI-based protocol but had a high risk of bias. Heterogeneity was high for most findings (I2 > 0.75). MRI is safe and frequently identifies findings alter clinical management in acute SCI, although direct evidence of its impact on outcomes is lacking. MRI should be performed before and after surgery, when feasible, to facilitate improved clinical decision-making. However, further research is needed to determine its optimal timing, effect on outcomes, cost-effectiveness, and utility before and after closed reduction.

Highlights • Gait and balance impairments correlated to various imaging abnormalities. • Stride length, cadence and balance varied independently in PSP. • PSP phenotype affects the associations between gait and imaging., Progressive supranuclear palsy is a neurodegenerative disorder characterized primarily by tau inclusions and neurodegeneration in the midbrain, basal ganglia, thalamus, premotor and frontal cortex. Neurodegenerative change in progressive supranuclear palsy has been assessed using MRI. Degeneration of white matter tracts is evident with diffusion tensor imaging and PET methods have been used to assess brain metabolism or presence of tau protein deposits. Patients with progressive supranuclear palsy present with a variety of clinical syndromes; however early onset of gait impairments and postural instability are common features. In this study we assessed the relationship between multimodal imaging biomarkers (i.e., MRI atrophy, white matter tracts degeneration, flortaucipir-PET uptake) and laboratory-based measures of gait and balance abnormalities in a cohort of nineteen patients with progressive supranuclear palsy, using univariate and multivariate statistical analyses. The PSP rating scale and its gait midline sub-score were strongly correlated to gait abnormalities but not to postural imbalance. Principal component analysis on gait variables identified velocity, stride length, gait stability ratio, length of gait phases and dynamic stability as the main contributors to the first component, which was associated with diffusion tensor imaging measures in the posterior thalamic radiation, external capsule, superior cerebellar peduncle, superior fronto-occipital fasciculus, body and splenium of the corpus callosum and sagittal stratum, with MRI volumes in frontal and precentral regions and with flortaucipir-PET uptake in the precentral gyrus. The main contributor to the second principal component was cadence, which was higher in patients presenting more abnormalities on mean diffusivity: this unexpected finding might be related to compensatory gait strategies adopted in progressive supranuclear palsy. Postural imbalance was the main contributor to the third principal component, which was related to flortaucipir-PET uptake in the left paracentral lobule and supplementary motor area and white matter disruption in the superior cerebellar peduncle, putamen, pontine crossing tract and corticospinal tract. A partial least square model identified flortaucipir-PET uptake in midbrain, basal ganglia and thalamus as the main correlate of speed and dynamic component of gait in progressive supranuclear palsy. Although causality cannot be established in this analysis, our study sheds light on neurodegeneration of brain regions and white matter tracts that underlies gait and balance impairment in progressive supranuclear palsy.

PROBLEM/CONDITION After the September 11, 2001, terrorist attacks on the United States, approximately 400,000 persons were exposed to toxic contaminants and other factors that increased their risk for certain physical and mental health conditions. Shortly thereafter, both federal and nonfederal funds were provided to support various postdisaster activities, including medical monitoring and treatment. In 2011, as authorized by the James Zadroga 9/11 Health and Compensation Act of 2010, the CDC World Trade Center (WTC) Health Program began providing medical screening, monitoring, and treatment of 9/11-related health conditions for WTC responders (i.e., persons who were involved in rescue, response, recovery, cleanup, and related support activities after the September 11, 2001, terrorist attacks) and affected WTC survivors (i.e., persons who were present in the dust or dust cloud on 9/11 or who worked, lived, or attended school, child care centers, or adult day care centers in the New York City disaster area). REPORTING PERIOD COVERED 2012-2020. DESCRIPTION OF SYSTEM The U.S. Department of Health and Human Services WTC Health Program is administered by the director of CDC's National Institute for Occupational Safety and Health. The WTC Health Program uses a multilayer administrative claims system to process members' authorized program health benefits. Administrative claims data are primarily generated by clinical providers in New York and New Jersey at the Clinical Centers of Excellence and outside those states by clinical providers in the Nationwide Provider Network. This report describes WTC Health Program trends for selected indicators during 2012-2020. RESULTS In 2020, a total of 104,223 members were enrolled in the WTC Health Program, of which 73.4% (n = 76,543) were responders and 26.6% (n = 27,680) were survivors. WTC Health Program members are predominantly male (78.5%). The median age of members was 51 years (interquartile range [IQR]: 44-57) in 2012 and 59 years (IQR: 52-66) in 2020. During 2012-2020, enrollment and number of certifications of WTC-related health conditions increased among members, with the greatest changes observed among survivors. Overall, at enrollment, most WTC Health Program members lived in New York (71.7%), New Jersey (9.3%), and Florida (5.7%). In 2020, the total numbers of cancer and noncancer WTC-related certifications among members were 20,612 and 50,611, respectively. Skin cancer, male genital system cancers, and in situ neoplasms (e.g., skin and breast) are the most common WTC-related certified cancer conditions. The most commonly certified noncancer conditions are in the aerodigestive and mental health categories. The average number of WTC-related certified conditions per certified member is 2.7. In 2020, a total of 40,666 WTC Health Program members received annual monitoring and screening examinations (with an annual average per calendar year of 35,245). In 2020, the total number of WTC Health Program members who received treatment was 41,387 (with an annual average per calendar year of 32,458). INTERPRETATION Since 2011, the WTC Health Program has provided health care for a limited number of 9/11-related health conditions both for responders and survivors of the terrorist attacks. Over the study period, program enrollment and WTC certification increased, particularly among survivors. As the members age, increased use of health services and costs within the WTC Health Program are expected; chronic diseases, comorbidities, and other health-related conditions unrelated to WTC exposures are more common in older populations, which might complicate the clinical management of WTC-related health conditions. PUBLIC HEALTH ACTION Analysis of administrative claims data in the context of WTC research findings can better clarify the health care use patterns of WTC Health Program members. This information guides programmatic decision-making and might also help guide future disaster preparedness and response health care efforts. Strengthening the WTC Health Program health informatics infrastructure is warranted for timely programmatic and research decision-making.

Objective To examine associations of systemic inflammation with growth outcomes at neonatal intensive care unit discharge or transfer among infants with extremely low gestational ages. Study design We studied 850 infants at born at 23-27 weeks of gestation. We defined inflammatory protein elevation as the highest quartile of C-reactive protein (CRP), Interleukin (IL)-6, tumor necrosis factor-∝, or IL-8 on postnatal days 1, 7, and 14. We compared z-scores of weight, length, and head circumference at neonatal intensive care unit discharge or transfer between infants with vs without inflammatory protein elevation, adjusting in linear regression for birth size z-score, sex, gestational age, diet, comorbidities, medications, and length of hospitalization. Results The mean gestational age was 25 weeks (range, 23-27 weeks) and birth weight z-score 0.14 (range, −2.73 to 3.28). Infants with a high CRP on day 7 had lower weights at discharge or transfer (−0.17 z-score; 95% CI, −0.27 to −0.06) than infants without CRP elevation, with similar results on day 14. Infants with CRP elevation on day 14 were also shorter (−0.21 length z-scores; 95% CI, −0.38 to −0.04), and had smaller head circumferences (−0.18 z-scores; 95% CI, −0.33 to −0.04) at discharge or transfer. IL-6 elevation on day 14 was associated with lower weight (−0.12; 95% CI, −0.22 to −0.02); IL-6 elevation on day 7 was associated with shorter length (−0.27; 95% CI, −0.43 to −0.12). Tumor necrosis factor-∝ and IL-8 elevation on day 14 were associated with a lower weight at discharge or transfer. Conclusions Postnatal systemic inflammation may contribute to impaired nutrient accretion during a critical period in development in infants with extremely low gestational ages.