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BackgroundStudies involving organ transplant recipients (OTRs) are often limited to the variables collected in the national Scientific Registry of Transplant Recipients database. Electronic health records contain additional variables that can augment this data source if OTRs can be identified accurately. ObjectiveThe aim of this study was to develop phenotyping algorithms to identify OTRs from electronic health records. MethodsWe used Vanderbilt’s deidentified version of its electronic health record database, which contains nearly 3 million subjects, to develop algorithms to identify OTRs. We identified all 19,817 individuals with at least one International Classification of Diseases (ICD) or Current Procedural Terminology (CPT) code for organ transplantation. We performed a chart review on 1350 randomly selected individuals to determine the transplant status. We constructed machine learning models to calculate positive predictive values and sensitivity for combinations of codes by using classification and regression trees, random forest, and extreme gradient boosting algorithms. ResultsOf the 1350 reviewed patient charts, 827 were organ transplant recipients while 511 had no record of a transplant, and 12 were equivocal. Most patients with only 1 or 2 transplant codes did not have a transplant. The most common reasons for being labeled a nontransplant patient were the lack of data (229/511, 44.8%) or the patient being evaluated for an organ transplant (174/511, 34.1%). All 3 machine learning algorithms identified OTRs with overall >90% positive predictive value and >88% sensitivity. ConclusionsElectronic health records linked to biobanks are increasingly used to conduct large-scale studies but have not been well-utilized in organ transplantation research. We present rigorously evaluated methods for phenotyping OTRs from electronic health records that will enable the use of the full spectrum of clinical data in transplant research. Using several different machine learning algorithms, we were able to identify transplant cases with high accuracy by using only ICD and CPT codes.

Accurate measurement of Alzheimer's disease (AD) pathology in older adults without significant clinical impairment is critical to assessing intervention strategies aimed at slowing AD-related cognitive decline. The U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (POINTER) is a 2-year randomized controlled trial to evaluate the effect of multicomponent risk reduction strategies in older adults (60-79 years) who are cognitively unimpaired but at increased risk for cognitive decline/dementia due to factors such as cardiovascular disease and family history. The POINTER Imaging ancillary study is collecting tau-PET ([18F]MK6240), beta-amyloid (Aβ)-PET ([18F]florbetaben [FBB]) and MRI data to evaluate neuroimaging biomarkers of AD and cerebrovascular pathophysiology in this at-risk sample. Here 481 participants (70.0±5.0; 66% F) with baseline MK6240, FBB and structural MRI scans were included. PET scans were coregistered to the structural MRI which was used to create FreeSurfer-defined reference regions and target regions of interest (ROIs). We also created off-target signal (OTS) ROIs to examine the magnitude and distribution of MK6240 OTS across the brain as well as relationships between OTS and age, sex, and race. OTS was unimodally distributed, highly correlated across OTS ROIs and related to younger age and sex but not race. Aiming to identify an optimal processing approach for MK6240 that would reduce the influence of OTS, we compared our previously validated MRI-guided standard PET processing and 6 alternative approaches. The alternate approaches included combinations of reference region erosion and meningeal OTS masking before spatial smoothing as well as partial volume correction. To compare processing approaches we examined relationships between target ROIs (entorhinal cortex (ERC), hippocampus or a temporal meta-ROI (MetaROI)) SUVR and age, sex, race, Aβ and a general cognitive status measure, the Modified Telephone Interview for Cognitive Status (TICSm). Overall, the processing approaches performed similarly, and none showed a meaningful improvement over standard processing. Across processing approaches we observed previously reported relationships with MK6240 target ROIs including positive associations with age, an Aβ+> Aβ- effect and negative associations with cognition. In sum, we demonstrated that different methods for minimizing effects of OTS, which is highly correlated across the brain within subject, produced no substantive change in our performance metrics. This is likely because OTS contaminates both reference and target regions and this contamination largely cancels out in SUVR data. Caution should be used when efforts to reduce OTS focus on target or reference regions in isolation as this may exacerbate OTS contamination in SUVR data.

BackgroundThe association of cognitive function with symptoms of psychological distress during the coronavirus disease 2019 (COVID-19) pandemic or adherence to COVID-19 protective health behaviors is not well-understood.MethodsWe examined 2 890 older women from the Women's Health Initiative cohort. Prepandemic (ie, within 12 months prior to pandemic onset) and peripandemic global cognitive function scores were assessed with the modified Telephone Interview for Cognitive Status (TICS-m). Anxiety, stress, and depressive symptom severity during the pandemic were assessed using validated questionnaires. We examined adherence to protective behaviors that included safe hygiene, social distancing, mask wearing, and staying home. Multivariable models were adjusted for age, race, ethnicity, education, region of residence, alcohol intake, and comorbidities.ResultsEvery 5-point lower prepandemic TICS-m score was associated with 0.33-point mean higher (95% confidence interval [CI], 0.20, 0.45) perceived stress and 0.20-point mean higher (95% CI, 0.07, 0.32) depressive symptom severity during the pandemic. Higher depressive symptom severity, but not anxiety or perceived stress, was associated with a 0.69-point (95% CI, -1.13, -0.25) mean decline in TICS-m from the prepandemic to peripandemic period. Every 5-point lower peripandemic TICS-m score was associated with 12% lower odds ratio (OR, 0.88; 95% CI, 0.80, 0.97) of practicing safe hygiene.ConclusionsAmong older women, we observed that: (a) lower prepandemic global cognitive function was associated with higher stress and depressive symptom severity during the pandemic; (b) higher depressive symptom severity during the pandemic was associated with cognitive decline; and (c) lower global cognitive function during the pandemic was associated with lower odds of practicing safe hygiene.

Receptor tyrosine kinase (RTK)-RAS signalling through the downstream mitogen-activated protein kinase (MAPK) cascade regulates cell proliferation and survival. The SHOC2-MRAS-PP1C holophosphatase complex functions as a key regulator of RTK-RAS signalling by removing an inhibitory phosphorylation event on the RAF family of proteins to potentiate MAPK signalling1. SHOC2 forms a ternary complex with MRAS and PP1C, and human germline gain-of-function mutations in this complex result in congenital RASopathy syndromes2-5. However, the structure and assembly of this complex are poorly understood. Here we use cryo-electron microscopy to resolve the structure of the SHOC2-MRAS-PP1C complex. We define the biophysical principles of holoenzyme interactions, elucidate the assembly order of the complex, and systematically interrogate the functional consequence of nearly all of the possible missense variants of SHOC2 through deep mutational scanning. We show that SHOC2 binds PP1C and MRAS through the concave surface of the leucine-rich repeat region and further engages PP1C through the N-terminal disordered region that contains a cryptic RVXF motif. Complex formation is initially mediated by interactions between SHOC2 and PP1C and is stabilized by the binding of GTP-loaded MRAS. These observations explain how mutant versions of SHOC2 in RASopathies and cancer stabilize the interactions of complex members to enhance holophosphatase activity. Together, this integrative structure-function model comprehensively defines key binding interactions within the SHOC2-MRAS-PP1C holophosphatase complex and will inform therapeutic development .

The WHI (Womens Health Initiative) enrolled 161,808 racially and ethnically diverse postmenopausal women, ages 50-79 years, from 1993 to 1998 at 40 clinical centers across the United States. In its clinical trial component, WHI evaluated 3 randomized interventions (menopausal hormone therapy; diet modification; and calcium/vitamin D supplementation) for the primary prevention of major chronic diseases, including cardiovascular disease, in older women. In the WHI observational study, numerous clinical, behavioral, and social factors have been evaluated as predictors of incident chronic disease and mortality. Although the original interventions have been completed, the WHI data and biomarker resources continue to be leveraged and expanded through ancillary studies to yield novel insights regarding cardiovascular disease prevention and healthy aging in women.

[This corrects the article DOI: 10.3389/fphys.2021.645342.].

IntroductionEffective strategies to recruit older adults with mild cognitive impairment (MCI) into nonpharmacological intervention trials are lacking.MethodsRecruitment for EXERT, a multisite randomized controlled 18-month trial examining the effects of aerobic exercise on cognitive trajectory in adults with amnestic MCI, involved a diverse portfolio of strategies to enroll 296 participants.ResultsRecruitment occurred September 2016 through March 2020 and was initially slow. After mass mailings of 490,323 age- and geo-targeted infographic postcards and brochures, recruitment rates increased substantially, peaking at 16 randomizations/month in early 2020. Mass mailings accounted for 52% of randomized participants, whereas 25% were recruited from memory clinic rosters, electronic health records, and national and local registries. Other sources included news broadcasts, public service announcements (PSA), local advertising, and community presentations.DiscussionAge- and geo-targeted mass mailing of infographic materials was the most effective approach in recruiting older adults with amnestic MCI into an 18-month exercise trial.

Vascular risk factors (e.g., obesity and hypertension) are associated with cerebral small vessel disease, Alzheimers disease (AD) pathology, and dementia. Reduced perfusion may reflect the impaired ability of blood vessels to regulate blood flow in reaction to varying circumstances such as hypercapnia (increased end-tidal partial pressures of CO2). It has been shown that cerebrovascular reactivity (CVR) measured with blood-oxygen-level-dependent (BOLD) MRI is correlated with cognitive performance and alterations of CVR may be an indicator of vascular disfunction leading to cognitive decline. However, the underlying mechanism of CVR alterations in BOLD signal may not be straight-forward because BOLD signal is affected by multiple physiological parameters, such as cerebral blood flow (CBF), cerebral blood volume, and oxygen metabolism. Arterial spin labeling (ASL) MRI quantitatively measures blood flow in the brain providing images of local CBF. Therefore, in this study, we measured CBF and its changes using a dynamic ASL technique during a hypercapnia challenge and tested if CBF or CVR was related to cognitive performance using the Mini-mental state examination (MMSE) score. Seventy-eight participants underwent cognitive testing and MRI including ASL during a hypercapnia challenge with a RespirAct computer-controlled gas blender, targeting 10 mmHg higher end-tidal CO2 level than the baseline while end-tidal O2 level was maintained. Pseudo-continuous ASL (PCASL) was collected during a 2-min baseline and a 2-min hypercapnic period. CVR was obtained by calculating a percent change of CBF per the end-tidal CO2 elevation in mmHg between the baseline and the hypercapnic challenge. Multivariate regression analyses demonstrated that baseline resting CBF has no significant relationship with MMSE, while lower CVR in the whole brain gray matter (β = 0.689, p = 0.005) and white matter (β = 0.578, p = 0.016) are related to lower MMSE score. In addition, region of interest (ROI) based analysis showed positive relationships between MMSE score and CVR in 26 out of 122 gray matter ROIs.

Background: Modification of the surgical technique to a 2-incision technique with skin bridge from the traditional lazy S (LS) incision, as well as use of prophylactic incisional negative-pressure wound therapy (iNPWT), are theorized to reduce the risk of surgical site infection (SSI) after inguinal lymph node dissection (ILND). We sought to investigate the role of a perioperative ILND bundle on adverse events after ILND and lymph node harvest. Methods: We performed a retrospective review of patients who underwent ILND before and after implementation of the ILND bundle (September 2016) at 1 centre in southeastern Ontario between 2013 and 2018. The ILND bundle included a skin bridge incision, running subcuticular skin closure and NPWT. Previously, an LS incision was used, with stapled skin closure and conventional dressing. Development of SSI was the primary outcome, and dehiscence and seroma and hematoma formation were secondary outcomes. We estimated the associations using multivariable logistic regression. Results: Thirty-four ILNDs in 33 patients were included, 15 in the LS incision group and 19 in the perioperative bundle group. The baseline demographic characteristics of the 2 groups were similar. The perioperative bundle was associated with a reduction in the SSI rate (11 [73%] v. 6 [32%], p = 0.02) and elimination of wound dehiscence (0 [0%] v. 5 [33%], p = 0.006). On multivariable logistic regression, it was associated with a 5.9-fold reduction in the SSI rate (odds ratio 0.17, 95% confidence interval 0.03-0.74). Conclusion: The results suggest a decrease in SSI rates with use of a perioperative bundle compared to the LS incision and a standard dressing. Randomized controlled trials are required to better understand the associations among the skin bridge incision, iNPWT and SSI. Contexte : Les infections du site operatoire (ISO) sont courantes apres un curage gan gli on naire inguinal (CGI). L'ISO apres l'intervention est associee a une reduction de la qualite de vie et a des retards dans le traitement oncologique adjuvant. Le remplacement de la technique d'incision de Blair modifee par la technique a double incision avec pont cutane en association avec la therapie par pression negative en prophylaxie pour le traitement des plaies entrainerait theoriquement une reduction du risque d'ISO a la suite d'un CGI. Methodes : Une etude retrospective a compare les patients ayant subi un CGI entre 2013 et 2018, soit avant ou apres la mise en place du protocole de CGI en septembre 2016. Ce protocole incluait l'incision avec pont cutane, le surjet intradermique et l'application de la therapie par pression negative pour le traitement des plaies. Avant la mise en place de ce protocole, l'intervention consistait en une incision de Blair modi fee suivie d'une suture cutanee par agrafes chirurgicales et de l'application d'un panse ment classique. La comparaison de la frequence des ISO constituait le parametre principal. Les apparitions de dehiscences, de seromes, et d'hematomes etaient les parametres secondaires. Les associations ont ete estimees a l'aide d'un rapport de cotes (RC) etabli au moyen d'un modele de regression logistique multivariee. Resultats : Trente-quatre CGI realises sur 33 patients durant la periode de l'etude ont ete inclus (n = 15 pour les CGI realises avant la mise en place du protocole [incision de Blair modifee] et n = 19 pour les CGI realises apres sa mise en place). Les 2 cohortes etaient similaires sur le plan demographique. La mise en place du protocole a ete associee a une reduction des ISO (31,6 % c. 73,3 %, p = 0,016) et a une elimination des dehiscences de la plaie (0 % c. 33,3 %, p = 0,006). La regression logistique multivariee a permis de montrer que l'application du protocole etait associee a une reduction des ISO d'un facteur de 5,9 (RC 0,17, intervalle de confance de 95 % 0,03-0,74, p = 0,024). Conclusion : Cette etude de cohorte retrospective monocentrique semble indiquer que l'application d'un protocole perioperatoire permet de reduire la frequence des ISO, comparativement au recours a une incision de Blair modifee et a un pansement classique., Inguinal lymph node dissection (ILND) is considered in nodal metastases of penile cancer, vulvar cancer, and cutaneous cancers of the trunk and lower extremities. (1,2) The most common use of [...]