Plasma VEGFA and PGF impact longitudinal tau and cognition in preclinical Alzheimer's disease.

Vascular dysfunction is increasingly recognized as an important contributor to the pathogenesis of Alzheimer's disease. Alterations in vascular endothelial growth factor (VEGF) pathways have been implicated as potential mechanisms. However, the specific impact of VEGF proteins in preclinical Alzheimer's disease and their relationships with other Alzheimer's disease and vascular pathologies during this critical early period remain to be elucidated. We included 317 older adults from the Harvard Aging Brain Study, a cohort of individuals who were cognitively unimpaired at baseline and followed longitudinally for up to 12 years. Baseline VEGF family protein levels (VEGFA, VEGFC, VEGFD, PGF and FLT1) were measured in fasting plasma using high-sensitivity immunoassays. Using linear mixed effects models, we examined the interactive effects of baseline plasma VEGF proteins and amyloid PET burden (Pittsburgh Compound-B) on longitudinal cognition (Preclinical Alzheimer Cognitive Composite-5). We further investigated if effects on cognition were mediated by early neocortical tau accumulation (flortaucipir PET burden in the inferior temporal cortex) or hippocampal atrophy. Lastly, we examined the impact of adjusting for baseline cardiovascular risk score or white matter hyperintensity volume. Baseline plasma VEGFA and PGF each showed a significant interaction with amyloid burden on prospective cognitive decline. Specifically, low VEGFA and high PGF were associated with greater cognitive decline in individuals with elevated amyloid, i.e. those on the Alzheimer's disease continuum. Concordantly, low VEGFA and high PGF were associated with accelerated longitudinal tau accumulation in those with elevated amyloid. Moderated mediation analyses confirmed that accelerated tau accumulation fully mediated the effects of low VEGFA and partially mediated (31%) the effects of high PGF on faster amyloid-related cognitive decline. The effects of VEGFA and PGF on tau and cognition remained significant after adjusting for cardiovascular risk score or white matter hyperintensity volume. There were concordant but non-significant associations with longitudinal hippocampal atrophy. Together, our findings implicate low VEGFA and high PGF in accelerating early neocortical tau pathology and cognitive decline in preclinical Alzheimer's disease. Additionally, our results underscore the potential of these minimally-invasive plasma biomarkers to inform the risk of Alzheimer's disease progression in the preclinical population. Importantly, VEGFA and PGF appear to capture distinct effects from vascular risks and cerebrovascular injury. This highlights their potential as new therapeutic targets, in combination with anti-amyloid and traditional vascular risk reduction therapies, to slow the trajectory of preclinical Alzheimer's disease and delay or prevent the onset of cognitive decline.

Effect of Early vs Late Inguinal Hernia Repair on Serious Adverse Event Rates in Preterm Infants: A Randomized Clinical Trial.

Importance: Inguinal hernia repair in preterm infants is common and is associated with considerable morbidity. Whether the inguinal hernia should be repaired prior to or after discharge from the neonatal intensive care unit is controversial. Objective: To evaluate the safety of early vs late surgical repair for preterm infants with an inguinal hernia. Design, Setting, and Participants: A multicenter randomized clinical trial including preterm infants with inguinal hernia diagnosed during initial hospitalization was conducted between September 2013 and April 2021 at 39 US hospitals. Follow-up was completed on January 3, 2023. Interventions: In the early repair strategy, infants underwent inguinal hernia repair before neonatal intensive care unit discharge. In the late repair strategy, hernia repair was planned after discharge from the neonatal intensive care unit and when the infants were older than 55 weeks' postmenstrual age. Main Outcomes and Measures: The primary outcome was occurrence of any prespecified serious adverse event during the 10-month observation period (determined by a blinded adjudication committee). The secondary outcomes included the total number of days in the hospital during the 10-month observation period. Results: Among the 338 randomized infants (172 in the early repair group and 166 in the late repair group), 320 underwent operative repair (86% were male; 2% were Asian, 30% were Black, 16% were Hispanic, 59% were White, and race and ethnicity were unknown in 9% and 4%, respectively; the mean gestational age at birth was 26.6 weeks [SD, 2.8 weeks]; the mean postnatal age at enrollment was 12 weeks [SD, 5 weeks]). Among 308 infants (91%) with complete data (159 in the early repair group and 149 in the late repair group), 44 (28%) in the early repair group vs 27 (18%) in the late repair group had at least 1 serious adverse event (risk difference, -7.9% [95% credible interval, -16.9% to 0%]; 97% bayesian posterior probability of benefit with late repair). The median number of days in the hospital during the 10-month observation period was 19.0 days (IQR, 9.8 to 35.0 days) in the early repair group vs 16.0 days (IQR, 7.0 to 38.0 days) in the late repair group (82% posterior probability of benefit with late repair). In the prespecified subgroup analyses, the probability that late repair reduced the number of infants with at least 1 serious adverse event was higher in infants with a gestational age younger than 28 weeks and in those with bronchopulmonary dysplasia (99% probability of benefit in each subgroup). Conclusions and Relevance: Among preterm infants with inguinal hernia, the late repair strategy resulted in fewer infants having at least 1 serious adverse event. These findings support delaying inguinal hernia repair until after initial discharge from the neonatal intensive care unit. Trial Registration: ClinicalTrials.gov Identifier: NCT01678638.

Protocolized management of pediatric complicated appendicitis leads to improved outcomes.

PURPOSE: We aimed to evaluate a complicated appendicitis clinical practice guideline at our institution. METHODS: Records were compared before and after protocol implementation. We standardized an ED consult pathway, antibiotic use and need for early appendectomy (EA) versus interval appendectomy (IA). We evaluated demographics, clinical characteristics, and outcomes. Subgroup analysis was performed to compare patients with small abscess treated with IA pre-protocol versus similar patients treated by EA post-protocol. RESULTS: In total 246 patients were reviewed (Pre-protocol = 152, Post-protocol = 94). Pre-protocol early appendectomy rate was 51% versus 82% on post-protocol patients. There were no differences in demographics. Post-protocol the use of preoperative imaging significantly decreased (Pre 92% vs. 56%, p = 0.0001), as well as the use of discharge antibiotics (Pre 93% vs. Post 27%, p = 0.0001) with no change in abscess rate. Overall, post-protocol patients had fewer total CT scans performed (Pre 40% vs. Post 28%, p = 0.03) and decreased total length of stay (Pre 7.7 vs. Post 6.5 days, p = 0.049). On subgroup analysis, post-protocol EA with no or small abscess had lower median number of admissions, decreased total LOS (Pre IA 9 days vs. Post EA 5 days, p = 0.00001) and fewer complications (Pre IA 42% vs. EA 22%, p = 0.022). CONCLUSION: The establishment of a standardized pediatric complicated appendicitis protocol may lead to improved outcomes and resource utilization. Patients presenting with no or small abscess may be the least likely to benefit from interval appendectomy. LEVEL OF EVIDENCE: Level III.

Plasma IL-12/IFN-γ axis predicts cognitive trajectories in cognitively unimpaired older adults.

INTRODUCTION: Immune dysregulation is implicated in neurodegeneration and altered cytokine levels are seen in people with dementia. However, whether cytokine levels are predictive of cognitive decline in cognitively unimpaired (CU) elderly, especially in the setting of elevated amyloid beta (Aß), remains unclear. METHODS: We measured nine cytokines in the baseline plasma of 298 longitudinally followed CU elderly and assessed whether these measures were associated with cognitive decline, alone or synergistically with Aß. We next examined associations between cytokine levels and neuroimaging biomarkers of Aß/tau/neurodegeneration. RESULTS: Higher IL-12p70 was associated with slower cognitive decline in the setting of higher Aß (false discovery rate [FDR] = 0.0023), whereas higher IFN-γ was associated with slower cognitive decline independent of Aß (FDR = 0.013). Higher IL-12p70 was associated with less tau and neurodegeneration in participants with higher Aß. DISCUSSION: Immune dysregulation is implicated in early-stage cognitive decline, and greater IL-12/IFN-γ axis activation may be protective against cognitive decline and early-stage AD progression.

Screening Laboratory Testing in Asymptomatic Minor Pediatric Blunt Trauma Leads to Unnecessary Needle Sticks.

OBJECTIVE: Screening blood work after minor injuries is common in pediatric trauma. The risk of missed injuries versus diagnostic necessity in an asymptomatic patient remains an ongoing debate. We evaluated the clinical utility of screening blood work in carefully selected asymptomatic children after minor trauma. METHODS: Patients seen at a level 1 pediatric center with "minor trauma" for blunt trauma between 2010 and 2015 were retrospectively reviewed. Exclusion criteria were age <4 of >18 years, a Glasgow Coma Scale score of <15, penetrating trauma, nonaccidental trauma, hemodynamic instability, abdominal findings (pain, distension, bruising, tenderness), hematuria, pelvic/femur fracture, multiple fractures, and operative intervention. Data abstraction included demographics, blood work, interventions, and disposition. RESULT: A total of 1308 patients were treated during the study period. Four hundred thirty-three (33%) met inclusion criteria. Mean ± SD age was 12.7 ± 4 years (range, 4-18 years), and 59% were male. Seventy-eight percent were discharged home from the emergency department. All patients had blood work. Twenty-eight percent had at least one abnormal laboratory value. The most common abnormal blood work was leukocytosis (16%). Thirty percent had an intervention, and none prompted by abnormal blood work. One patient had an intra-abdominal finding (psoas hematoma). CONCLUSION: When appropriately selected, screening laboratory testing in asymptomatic minor pediatric blunt trauma patients leads to unnecessary needle sticks without significant advantage.

Imaging for acute appendicitis at nonpediatric centers exposes children to excess radiation.

BACKGROUND: Radiation exposure is the reason for the decreased utilization of computed tomography (CT) in pediatric centers (PCs). We sought to compare the radiation dose exposure of CT imaging performed at outside hospitals (OH) versus PC in pediatric patients with acute appendicitis (AA). MATERIAL AND METHODS: A retrospective review of all patients managed at our PC for AA from January 2011 to March 2016 was performed. Patients who had CT imaging for AA at OH were compared to those who underwent CT for appendicitis at our PC. Radiation dosing was compared using the dose index (CTDI [mGY]) and dose length product (DLP [mGYcm]). Independent t-test samples were used to compare means for radiation dose. RESULTS: 379 patients met inclusion criteria. There were 59.4% (225) patients imaged at our PC and 40.6% (154) patients were transferred from an OH. When performed at OH, 6.5% of CTs were considered inadequate as they were done without intravenous contrast compared to 1.3% in our PC. Mean CTDI was 6.9 at our PC and 11.8 at OH (P < 0.0001). Mean DLP at PC was 296.2 versus 456.8 at OH (P < 0.0001). An excess radiation dose of 4.9 mGY and 160.5 mGYcm was noted when CT scan was performed at OH versus PC. CONCLUSIONS: Using DLP as a gauge of radiation exposure, CT imaging performed at OH has a 44% higher radiation rate relative to the exposure at PC. In cases of suspected AA at a facility without pediatric surgeons, early transfer to PC prior to imaging is advocated.

Optimal timing of cholecystectomy in children with gallstone pancreatitis.

BACKGROUND: Little data exist regarding the recurrence of pancreatitis in pediatric patients with gallstone pancreatitis awaiting cholecystectomy. This study evaluates the recurrence rate of pancreatitis after acute gallstone pancreatitis based on the timing of cholecystectomy in pediatric patients. MATERIALS AND METHODS: A retrospective chart review of all patients admitted with gallstone pancreatitis from 2007 to 2015 was performed. Children were divided into the following five groups. Group 1 had surgery during the index admission. Group 2 had surgery within 2 wk of discharge. Group 3 had surgery between 2 and 6 wk postdischarge. Group 4 had surgery 6 wk after discharge, and group 5 patients had no surgery. The recurrence rates of pancreatitis were calculated for all groups. RESULTS: Forty-eight patients with gallstone pancreatitis were identified in this study. The 19 patients in group 1 had no recurrence of their pancreatitis. Of the remaining 29 patients, nine (31%) had recurrence of pancreatitis or required readmission for abdominal pain prior to their cholecystectomy. In group 2, two of the eight patients (25%) had recurrent pancreatitis. In group 3, three of eight patients (37.5%) developed recurrent pancreatitis. In group 4, three of five patients (60%), and in group 5, one of eight. No children in group 5 had demonstrable gallstones at presentation, only sludge in their gallbladder. CONCLUSIONS: Cholecystectomy during the index admission is associated with no recurrence or readmission for pancreatitis. Therefore, we recommend that cholecystectomy be performed after resolution of an episode of gallstone pancreatitis during index admission.

Utility of hospital admission for pediatric intussusceptions.

PURPOSE: The standard practice in pediatric patients diagnosed with intussusception has been reduction via enema and admission for a period of nil per os and observation. Little data exists to support this practice. The objective of this study was to examine whether post-reduction admission to hospital is required. METHODS: A retrospective chart review was performed on all patients aged 0-18 years old with intussusception over a span of 20 years. Study included children treated for intussusception on first encounter with enema and subsequently admitted for observation. Study excluded those readmitted for recurrence after 48 h, patients whose intussusception did not reduce on first try, those lost to follow-up, and those who went to the operating room. Early recurrence was defined as recurrence within 48 h post-reduction. RESULTS: Out of 171 patients admitted, only one experienced an early recurrence (0.6 %). Median length of stay for all patients was 2 days. Average cost incurred per day for intussusception admission was $404. CONCLUSION: Intussusception in a child that is successfully reduced via enema has a low recurrence rate and is usually followed by prompt resolution of symptoms. An abbreviated period of observation in the emergency department post-reduction may result in healthcare savings.

Holocord syringomyelia secondary to tethered spinal cord associated with anterior sacral meningocele and tailgut cyst: case report and review of literature.

BACKGROUND AND IMPORTANCE: Anterior sacral meningoceles are lesions that are uncommonly reported and can be associated with other pathology including presacral masses, tethered spinal cord, and syringomyelia. Tethered spinal cord and syringomyelia can result in neurologic deficits, while large meningoceles and presacral masses can have gastroenterologic, urologic, reproductive, and oncologic consequences. CLINICAL PRESENTATION: The authors report a case of a 14-year-old girl with an anterior sacral meningocele, tailgut cyst, and tethered cord with holocord syringomyelia who presented with a tethered cord syndrome, manifested by constipation, urinary retention, bilateral lower extremity weakness, and sensory deficits. After extensive radiographic and urodynamic workups were performed, the patient was treated by the neurosurgery and pediatric surgery teams with a posterior sagittal approach for cord detethering, resection of an intradural cystic mass, resection of the anterior sacral meningocele, and resection of the adjacent presacral mass. After surgical treatment, motor weakness and sensory deficits were resolved, though urinary symptoms persisted. The syrinx resolved after detethering alone. Pathology of the intradural cystic mass and the presacral mass inferior to the anterior sacral meningocele were consistent with tailgut cyst. CONCLUSION: The patient's clinical and surgical management are discussed, and a literature review related to anterior sacral meningoceles and their related pathologies is presented. An interdisciplinary approach is required for the best treatment of this constellation of findings.

Comparison of Climate Impact, Clinical Outcome, and Cost-Efficiency of Pediatric Transumbilical Laparoscopic Assisted Appendectomy vs Standard 3-Port Laparoscopic Appendectomy.

BACKGROUND: Healthcare is responsible for 8.5% of US greenhouse gas emissions. These impacts must be mitigated while maintaining clinical excellence. This study compares clinical outcomes, cost-efficiency, and climate impact of trans-umbilical laparoscopic assisted appendectomy (TULAA) versus 3-port laparoscopic appendectomy (LA). STUDY DESIGN: Institutional Review Board approval was obtained. Appendectomies performed between Jan 1, 2020 and December 31, 2022 at a tertiary children's hospital were reviewed. Data abstracted included clinical characteristics, operative approach and findings, supplies and equipment utilized, and complications. For analysis TULAA was combined with cases converted to LA (TULAA+C). To determine a surgical site infection (SSI) increase of ≤ 2.5%, a minimum sample size of 479 patients per group was needed to achieve a power of 80%. A composite supply list for each approach was determined by averaging supplies from cases reviewed. The composite was used to calculate cost-efficiency and climate impact. Life cycle assessment was used to determine the carbon footprint (according to ISO 14067) of supplies and equipment. RESULTS: Analysis was performed on 1,611 appendectomies: 497 LA and 1,114 TULAA+C (932 TULAA, 182 converted). Except for BMI, there were no clinically significant differences between groups. SSI did not increase with TULAA+C (n=15, 1.3%) versus LA (n=6, 1.2%), p=0.81. TULAA+C ($369.21/case) was more cost efficient than LA ($879.30/case) and TULAA+C (24.8 kg CO2e) produced fewer emissions than LA (27.4 kg CO2e). CONCLUSIONS: While patient safety and excellent clinical outcomes must remain the top priority in healthcare, the current environmental crisis demands consideration of climate impacts. When clinical non-inferiority can be demonstrated, treatment options with a fewer greenhouse gas emissions should be chosen.

Environmental Impact of Traveling to the Annual American Pediatric Surgical Association Meeting.

PURPOSE: Research has demonstrated negative environmental impacts from in-person conferences. Nonetheless, there are benefits to in-person meetings. The 2023 American Pediatric Surgical Association (APSA) meeting was mostly attended in-person. To understand the environmental impact, this study quantifies the travel emissions generated from that meeting. METHODS: The 2023 APSA meeting was held in Orlando, FL. Using a de-identified list of attendees, the distance between the attendee's home city and Orlando was determined. If ≤ 200 miles, it was assumed the attendee drove. If > 200 miles, the distance between the closest airport and Orlando International Airport was determined. Travel emissions factors represent emissions per person-mile traveled. The Environmental Protection Agency (EPA) Greenhouse Gas Inventory emissions factors for carbon dioxide (CO2), methane (CH4), and nitrous oxide (N2O) were multiplied by travel distances to determine the emissions generated from each attendee. These were aggregated to determine the total meeting travel emissions. The EPA Greenhouse Gas Equivalencies Calculator was used to convert the emissions to a relatable outcome. RESULTS: There were 757 in-person and 135 virtual attendees. Fifty attendees drove and 707 attendees flew. This generated 267,279 kg CO2, 1222 gm CH4, and 8486 gm N2O; equivalent to the emissions generated from the average annual use of 60 gasoline-powered passenger vehicles in the United States. CONCLUSION: Based on attendance to the 2023 APSA meeting, there is a preference for meeting in-person, though the associated environmental cost should be recognized. Based on these results, APSA should consider strategies to mitigate the environmental impact of its annual meeting. LEVELS OF EVIDENCE: N/A.

γ-Secretase activity, clinical features, and biomarkers of autosomal dominant Alzheimer's disease: cross-sectional and longitudinal analysis of the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS).

BACKGROUND: Genetic variants that cause autosomal dominant Alzheimer's disease are highly penetrant but vary substantially regarding age at symptom onset (AAO), rates of cognitive decline, and biomarker changes. Most pathogenic variants that cause autosomal dominant Alzheimer's disease are in presenilin 1 (PSEN1), which encodes the catalytic core of γ-secretase, an enzyme complex that is crucial in production of amyloid ß. We aimed to investigate whether the heterogeneity in AAO and biomarker trajectories in carriers of PSEN1 pathogenic variants could be predicted on the basis of the effects of individual PSEN1 variants on γ-secretase activity and amyloid ß production. METHODS: For this cross-sectional and longitudinal analysis, we used data from participants enrolled in the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS) via the DIAN-OBS data freeze version 15 (data collected between Feb 29, 2008, and June 30, 2020). The data freeze included data from 20 study sites in research institutions, universities, hospitals, and clinics across Europe, North and South America, Asia, and Oceania. We included individuals with PSEN1 pathogenic variants for whom relevant genetic, clinical, imaging, and CSF data were available. PSEN1 pathogenic variants were characterised via genetically modified PSEN1 and PSEN2 double-knockout human embryonic kidney 293T cells and immunoassays for Aß37, Aß38, Aß40, Aß42, and Aß43. A summary measure of γ-secretase activity (γ-secretase composite [GSC]) was calculated for each variant and compared with clinical history-derived AAO using correlation analyses. We used linear mixed-effect models to assess associations between GSC scores and multimodal-biomarker and clinical data from DIAN-OBS. We used separate models to assess associations with Clinical Dementia Rating Sum of Boxes (CDR-SB), Mini-Mental State Examination (MMSE), and Wechsler Memory Scale-Revised (WMS-R) Logical Memory Delayed Recall, [11C]Pittsburgh compound B (PiB)-PET and brain glucose metabolism using [18F] fluorodeoxyglucose (FDG)-PET, CSF Aß42-to-Aß40 ratio (Aß42/40), CSF log10 (phosphorylated tau 181), CSF log10 (phosphorylated tau 217), and MRI-based hippocampal volume. FINDINGS: Data were included from 190 people carrying PSEN1 pathogenic variants, among whom median age was 39·0 years (IQR 32·0 to 48·0) and AAO was 44·5 years (40·6 to 51·4). 109 (57%) of 190 carriers were female and 81 (43%) were male. Lower GSC values (ie, lower γ-secretase activity than wild-type PSEN1) were associated with earlier AAO (r=0·58; p<0·0001). GSC was associated with MMSE (ß=0·08, SE 0·03; p=0·0043), CDR-SB (-0·05, 0·02; p=0·0027), and WMS-R Logical Memory Delayed Recall scores (0·09, 0·02; p=0·0006). Lower GSC values were associated with faster increase in PiB-PET signal (p=0·0054), more rapid decreases in hippocampal volume (4·19, 0·77; p<0·0001), MMSE (0·02, 0·01; p=0·0020), and WMS-R Logical Memory Delayed Recall (0·004, 0·001; p=0·0003). INTERPRETATION: Our findings suggest that clinical heterogeneity in people with autosomal dominant Alzheimer's disease can be at least partly explained by different effects of PSEN1 variants on γ-secretase activity and amyloid ß production. They support targeting γ-secretase as a therapeutic approach and suggest that cell-based models could be used to improve prediction of symptom onset. FUNDING: US National Institute on Aging, Alzheimer's Association, German Center for Neurodegenerative Diseases, Raul Carrea Institute for Neurological Research, Japan Agency for Medical Research and Development, Korea Health Industry Development Institute, South Korean Ministry of Health and Welfare, South Korean Ministry of Science and ICT, and Spanish Institute of Health Carlos III.

Face Name Associative Memory Exam and biomarker status in the ARMADA study: Advancing reliable measurement in Alzheimer's disease and cognitive aging.

The Face Name Associative Memory Exam (FNAME) was introduced into the NIH Toolbox as part of the ARMADA study and establishes normative data for diverse participants, ages 64 to 85+, and proposes cutoff scores between biomarker positive versus negative (+/-) groups. The FNAME was administered to 257 participants across the clinical spectrum with 122 having amyloid biomarkers. Linear regression explored the association between demographics and FNAME and between amyloid (+/-) groups. Receiver operating characteristic curves (ROC) identified performance thresholds that best discriminated between biomarker (+/-) individuals. Lower FNAME scores occurred in males, older ages, Black/African Americans, Hispanics, and biomarker-positive participants. ROC analyses demonstrated acceptable accuracy (0.73 to 0.77) but only when combined with clinical status. The diagnostic discrimination of amyloid positivity was acceptable but not excellent, suggesting the FNAME may be a better screening indicator of clinical status rather than amyloid deposition in cognitively normal individuals. Normative data are provided.

Associations of the Harvard Automated Phone Task and Alzheimer's Disease Pathology in Cognitively Normal Older Adults: Preliminary Findings.

BACKGROUND: Detecting clinically meaningful changes in instrumental activities of daily living (IADL) at the earliest stages of Alzheimer's disease (AD) is critical. OBJECTIVE: The objective of this exploratory study was to examine the cross-sectional relationship between a performance-based IADL test, the Harvard Automated Phone Task (APT), and cerebral tau and amyloid burden in cognitively normal (CN) older adults. METHODS: Seventy-seven CN participants underwent flortaucipir tau and Pittsburgh Compound B amyloid PET. IADL were assessed using the three Harvard APT tasks: prescription refill (APT-Script), health insurance company call (APT-PCP), and bank transaction (APT-Bank). Linear regression models were used to determine associations between each APT task and entorhinal cortex, inferior temporal, or precuneus tau with or without an interaction with amyloid. RESULTS: Significant associations were found between APT-Bank task rate and interaction between amyloid and entorhinal cortex tau, and APT-PCP task and interactions between amyloid and inferior temporal and precuneus tau. No significant associations were found between the APT tasks and tau or amyloid alone. CONCLUSION: Our preliminary findings suggest an association between a simulated real-life IADL test and interactions of amyloid and several regions of early tau accumulation in CN older adults. However, some analyses were underpowered due to the small number of participants with elevated amyloid, and findings should be interpreted with caution. Future studies will further explore these associations cross-sectionally and longitudinally in order to determine whether the Harvard APT can serve as a reliable IADL outcome measure for preclinical AD prevention trials and ultimately in the clinic setting.

Etiology of White Matter Hyperintensities in Autosomal Dominant and Sporadic Alzheimer Disease.

Importance: Increased white matter hyperintensity (WMH) volume is a common magnetic resonance imaging (MRI) finding in both autosomal dominant Alzheimer disease (ADAD) and late-onset Alzheimer disease (LOAD), but it remains unclear whether increased WMH along the AD continuum is reflective of AD-intrinsic processes or secondary to elevated systemic vascular risk factors. Objective: To estimate the associations of neurodegeneration and parenchymal and vessel amyloidosis with WMH accumulation and investigate whether systemic vascular risk is associated with WMH beyond these AD-intrinsic processes. Design, Setting, and Participants: This cohort study used data from 3 longitudinal cohort studies conducted in tertiary and community-based medical centers-the Dominantly Inherited Alzheimer Network (DIAN; February 2010 to March 2020), the Alzheimer's Disease Neuroimaging Initiative (ADNI; July 2007 to September 2021), and the Harvard Aging Brain Study (HABS; September 2010 to December 2019). Main Outcome and Measures: The main outcomes were the independent associations of neurodegeneration (decreases in gray matter volume), parenchymal amyloidosis (assessed by amyloid positron emission tomography), and vessel amyloidosis (evidenced by cerebral microbleeds [CMBs]) with cross-sectional and longitudinal WMH. Results: Data from 3960 MRI sessions among 1141 participants were included: 252 pathogenic variant carriers from DIAN (mean [SD] age, 38.4 [11.2] years; 137 [54%] female), 571 older adults from ADNI (mean [SD] age, 72.8 [7.3] years; 274 [48%] female), and 318 older adults from HABS (mean [SD] age, 72.4 [7.6] years; 194 [61%] female). Longitudinal increases in WMH volume were greater in individuals with CMBs compared with those without (DIAN: t = 3.2 [P = .001]; ADNI: t = 2.7 [P = .008]), associated with longitudinal decreases in gray matter volume (DIAN: t = -3.1 [P = .002]; ADNI: t = -5.6 [P < .001]; HABS: t = -2.2 [P = .03]), greater in older individuals (DIAN: t = 6.8 [P < .001]; ADNI: t = 9.1 [P < .001]; HABS: t = 5.4 [P < .001]), and not associated with systemic vascular risk (DIAN: t = 0.7 [P = .40]; ADNI: t = 0.6 [P = .50]; HABS: t = 1.8 [P = .06]) in individuals with ADAD and LOAD after accounting for age, gray matter volume, CMB presence, and amyloid burden. In older adults without CMBs at baseline, greater WMH volume was associated with CMB development during longitudinal follow-up (Cox proportional hazards regression model hazard ratio, 2.63; 95% CI, 1.72-4.03; P < .001). Conclusions and Relevance: The findings suggest that increased WMH volume in AD is associated with neurodegeneration and parenchymal and vessel amyloidosis but not with elevated systemic vascular risk. Additionally, increased WMH volume may represent an early sign of vessel amyloidosis preceding the emergence of CMBs.

Location of pathogenic variants in PSEN1 impacts progression of cognitive, clinical, and neurodegenerative measures in autosomal-dominant Alzheimer's disease.

Although pathogenic variants in PSEN1 leading to autosomal-dominant Alzheimer disease (ADAD) are highly penetrant, substantial interindividual variability in the rates of cognitive decline and biomarker change are observed in ADAD. We hypothesized that this interindividual variability may be associated with the location of the pathogenic variant within PSEN1. PSEN1 pathogenic variant carriers participating in the Dominantly Inherited Alzheimer Network (DIAN) observational study were grouped based on whether the underlying variant affects a transmembrane (TM) or cytoplasmic (CY) protein domain within PSEN1. CY and TM carriers and variant non-carriers (NC) who completed clinical evaluation, multimodal neuroimaging, and lumbar puncture for collection of cerebrospinal fluid (CSF) as part of their participation in DIAN were included in this study. Linear mixed effects models were used to determine differences in clinical, cognitive, and biomarker measures between the NC, TM, and CY groups. While both the CY and TM groups were found to have similarly elevated Aß compared to NC, TM carriers had greater cognitive impairment, smaller hippocampal volume, and elevated phosphorylated tau levels across the spectrum of pre-symptomatic and symptomatic phases of disease as compared to CY, using both cross-sectional and longitudinal data. As distinct portions of PSEN1 are differentially involved in APP processing by γ-secretase and the generation of toxic ß-amyloid species, these results have important implications for understanding the pathobiology of ADAD and accounting for a substantial portion of the interindividual heterogeneity in ongoing ADAD clinical trials.

Analysis of the genealogy process in forensic genetic genealogy.

The genealogy process is typically the most time-consuming part of-and a limiting factor in the success of-forensic genetic genealogy, which is a new approach to solving violent crimes and identifying human remains. We formulate a stochastic dynamic program that-given the list of matches and their genetic distances to the unknown target-chooses the best decision at each point in time: which match to investigate (i.e., find its ancestors and look for most recent common ancestors between the match and the target), which set of potential most recent common ancestors to descend from (i.e., find its descendants, with the goal of identifying a marriage between the maternal and paternal sides of the target's family tree), or whether to terminate the investigation. The objective is to maximize the probability of finding the target minus a cost associated with the expected size of the final family tree. We estimate the parameters of our model using data from 17 cases (eight solved, nine unsolved) from the DNA Doe Project. We assess the Proposed Strategy using simulated versions of the 17 DNA Doe Project cases, and compare it to a Benchmark Strategy that ranks matches by their genetic distance to the target and only descends from known common ancestors between a pair of matches. The Proposed Strategy solves cases ≈10 - fold faster than the Benchmark Strategy, and does so by aggressively descending from a set of potential most recent common ancestors between the target and a match even when this set has a low probability of containing the correct most recent common ancestor. Our analysis provides a mathematical foundation for improving the genealogy process in forensic genetic genealogy.

Pneumomediastinum: A Rare Presentation of Inflicted Injuries in Infants.

Reports of incidental pneumomediastinum in infants secondary to inflicted trauma are limited. A retrospective review of infants with pneumomediastinum and history of inflicted trauma was performed. A comprehensive literature review was performed. Three infants presented with pneumomediastinum associated with inflicted trauma. Mean age was 4.6 weeks. All patients underwent diagnostic studies, as well as a standardized evaluation for nonaccidental trauma. All patients with pneumomediastinum were resolved at follow-up. Review of the literature identified other cases with similar presentations with related oropharyngeal injuries. Spontaneous pneumomediastinum in previously healthy infants may be associated with inflicted injuries. Clinicians should be aware of the possibility of an oropharyngeal perforation related to this presentation.

To Button or Not to Button? Primary Gastrostomy Tubes Offer No Significant Advantage Over Buttons.

Purpose: Outcomes between primary gastrostomy tubes and buttons (G-tube and G-button) have not been established in pediatric patients. We hypothesized that primary G-tube have decreased complications when compared to G-button. Methods: A retrospective review of surgically placed gastrostomy devices from 2010 to 2017 was performed. Data collected included demographics, outcomes and 90-day complications. We divided the patients into primary G-tube and primary G-button. Results: Of 265 patients, 142 (53.6%) were male. Median age and weight at the time of surgery were 7 months (interquartile range [IQR], 2-44 months) and 6.70 kg (IQR, 3.98-14.15 kg), respectively. Among the groups, G-tube had 80 patients (30.2%) while G-button 185 patients (69.8%). There were 153 patients with at least one overall complication within 90 days postoperative. There was no significant difference in overall complications between groups (G-tube 63.8% vs. G-button 55.7%, p=0.192). More importantly, there were no significant differences in major complications among the groups, G-tube vs. G-button (5% vs. 4%; p=0.455). Conclusion: Primary G-tube offers no significant advantage in overall, minor or major complications when compared to primary G-button.

Variant-dependent heterogeneity in amyloid ß burden in autosomal dominant Alzheimer's disease: cross-sectional and longitudinal analyses of an observational study.

BACKGROUND: Insights gained from studying individuals with autosomal dominant Alzheimer's disease have broadly influenced mechanistic hypotheses, biomarker development, and clinical trials in both sporadic and dominantly inherited Alzheimer's disease. Although pathogenic variants causing autosomal dominant Alzheimer's disease are highly penetrant, there is substantial heterogeneity in levels of amyloid ß (Aß) between individuals. We aimed to examine whether this heterogeneity is related to disease progression and to investigate the association with mutation location within PSEN1, PSEN2, or APP. METHODS: We did cross-sectional and longitudinal analyses of data from the Dominantly Inherited Alzheimer's Network (DIAN) observational study, which enrols individuals from families affected by autosomal dominant Alzheimer's disease. 340 participants in the DIAN study who were aged 18 years or older, had a history of autosomal dominant Alzheimer's disease in their family, and who were enrolled between September, 2008, and June, 2019, were included in our analysis. 206 participants were carriers of pathogenic mutations in PSEN1, PSEN2, or APP, and 134 were non-carriers. 62 unique pathogenic variants were identified in the cohort and were grouped in two ways. First, we sorted variants in PSEN1, PSEN2, or APP by the affected protein domain. Second, we divided PSEN1 variants according to position before or after codon 200. We examined variant-dependent variability in Aß biomarkers, specifically Pittsburgh-Compound-B PET (PiB-PET) signal, levels of CSF Aß1-42 (Aß42), and levels of Aß1-40 (Aß40). FINDINGS: Cortical and striatal PiB-PET signal showed striking variant-dependent variability using both grouping approaches (p<0·0001), despite similar progression on the clinical dementia rating (p>0·7), and CSF Aß42 levels (codon-based grouping: p=0·49; domain-based grouping: p=0·095). Longitudinal PiB-PET signal also varied across codon-based groups, mirroring cross-sectional analyses. INTERPRETATION: Autosomal dominant Alzheimer's disease pathogenic variants showed highly differential temporal and regional patterns of PiB-PET signal, despite similar functional progression. These findings suggest that although increased PiB-PET signal is generally seen in autosomal dominant Alzheimer's disease, higher levels of PiB-PET signal at an individual level might not reflect more severe or more advanced disease. Our results have high relevance for ongoing clinical trials in autosomal dominant Alzheimer's disease, including those using Aß PET as a surrogate marker of disease progression. Additionally, and pertinent to both sporadic and autosomal dominant Alzheimer's disease, our results suggest that CSF and PET measures of Aß levels are not interchangeable and might reflect different Aß-driven pathobiological processes. FUNDING: National Institute on Aging, Doris Duke Charitable Foundation, German Center for Neurodegenerative Diseases, Japanese Agency for Medical Research and Development.