Exploratory Cohort Research Articles

Referral for publicly funded aged care services in Indigenous populations: An exploratory cohort study of ethnic variation in Aotearoa New Zealand.

ObjectivesAs people age, they are more likely to require support to maintain activities of daily living. Referral for formal assessment of need (assessed using the ‘international Resident Assessment Instrument’ [interRAI]) is the first step to access publicly funded services in Aotearoa New Zealand (NZ). It is unclear whether ethnic access inequities present in other areas of the NZ health system occur in this referral process. This exploratory research aimed to explore ethnic variation in referrals for interRAI assessment, and associated factors.MethodsA retrospective cohort study of all new referrals for aged care services for those 55‐plus, received in 2018 by Waitematā District Health Board (WDHB), was conducted. The primary outcome was referral outcome (assessment and no assessment). Secondary outcomes included time from referral to assessment, reason for referral, mortality and, in the assessed cohort, assessment outcome.ResultsNew referrals (n = 3263) were ethnically representative of the general older adult population in WDHB. Māori were younger and more likely to be referred for higher‐level care needs than non‐Māori, non‐Pasifika (NMNP) (p = 0.03). There was no significant difference in referral outcome, time to assessment or mortality between ethnicities. NMNP were more likely to access lower‐level care services than Māori or Pasifika older adults (p = 0.002).ConclusionsEthnicity was not associated with aged care service assessment access once people were referred for publicly funded services, nor was it associated with time to assessment or mortality in this exploratory study. Māori had higher care needs than NMNP at the time of referral.

Identifying Immunological and Clinical Predictors of COVID-19 Severity and Sequelae by Mathematical Modeling.

Since its emergence as a pandemic in March 2020, coronavirus disease (COVID-19) outcome has been explored via several predictive models, using specific clinical or biochemical parameters. In the current study, we developed an integrative non-linear predictive model of COVID-19 outcome, using clinical, biochemical, immunological, and radiological data of patients with different disease severities. Initially, the immunological signature of the disease was investigated through transcriptomics analysis of nasopharyngeal swab samples of patients with different COVID-19 severity versus control subjects (exploratory cohort, n=61), identifying significant differential expression of several cytokines. Accordingly, 24 cytokines were validated using a multiplex assay in the serum of COVID-19 patients and control subjects (validation cohort, n=77). Predictors of severity were Interleukin (IL)-10, Programmed Death-Ligand-1 (PDL-1), Tumor necrosis factors-α, absolute neutrophil count, C-reactive protein, lactate dehydrogenase, blood urea nitrogen, and ferritin; with high predictive efficacy (AUC=0.93 and 0.98 using ROC analysis of the predictive capacity of cytokines and biochemical markers, respectively). Increased IL-6 and granzyme B were found to predict liver injury in COVID-19 patients, whereas interferon-gamma (IFN-γ), IL-1 receptor-a (IL-1Ra) and PD-L1 were predictors of remarkable radiological findings. The model revealed consistent elevation of IL-15 and IL-10 in severe cases. Combining basic biochemical and radiological investigations with a limited number of curated cytokines will likely attain accurate predictive value in COVID-19. The model-derived cytokines highlight critical pathways in the pathophysiology of the COVID-19 with insight towards potential therapeutic targets. Our modeling methodology can be implemented using new datasets to identify key players and predict outcomes in new variants of COVID-19.

Benzodiazepine Sedation and Postoperative Neurological Deficits after Awake Craniotomy for Brain Tumor - An Exploratory Retrospective Cohort Study.

An awake craniotomy is a common neurosurgical procedure for excising brain tumor(s) located near or in eloquent areas. The use of benzodiazepine (BZD) for sedation in some patients with neuropathological conditions (e.g., stroke, brain tumors) has been previously linked with re-appearance of neurological deficits including limb incoordination, ataxia, and motor weakness, resulting in complications for the patient along with procedural challenges. Whether or not these findings can be extrapolated to patients undergoing brain tumor resection is largely unknown. The current work primarily sought to compare neurological outcome(s) in the immediate postoperative period between BZD-free and BZD-based sedation techniques in patients undergoing awake craniotomy. Using a database composed of awake craniotomies conducted within a single center and by a single surgeon, patients were retrospectively classified based on midazolam administration into BZD-free sedation (n=125) and BZD-based sedation (n=416) groups. Patients from each group were matched based on age, sex, tumor location, tumor grade, preoperative neurological deficits, non-operative BZD use, and Karnofsky Performance Scale scores, resulting in 108 patients within each group. Postoperative neurological deficits were recorded. Logistic regression analyses were conducted comparing postoperative neurological deficits between the matched groups. Postoperative neurological deficits were more prevalent within the BZD-based sedation group compared to the BZD-free sedation group (adjusted odds ratio (aOR)=1.903, 95% CI=1.018-3.560, p=0.044). In addition, subgroup analysis of the matched cohort showed a relationship between preoperative neurological symptoms and postoperative neurological deficits in the BZD-based sedation group (aOR=3.756, 95% CI=1.390-10.147, p=0.009). Our findings support the notion that the increased incidence of postoperative neurological deficits with BZD sedation may in part be related to the unmasking of preoperative neurological deficits. Further studies are required to confirm this phenomenon.

Associations of Intellectual Disability with Cardiopulmonary Resuscitation and Endotracheal Intubation at End of Life.

Background: Little is known about end-of-life intensive care provided to patients with intellectual disabilities (ID). Objectives: To identify differences in receipt of end-of-life cardiopulmonary resuscitation (CPR) and endotracheal intubation among adult patients with and without ID and examine whether do-not-resuscitate orders (DNRs) mediate associations between ID and CPR. Design: Exploratory matched cohort study using medical records of inpatient decedents treated between 2012 and 2018. Results: Patients with ID (n = 37) more frequently received CPR (37.8% vs. 21.6%) and intubation (78.4% vs. 47.8%) than patients without ID (n = 74). In multivariable models, ID was associated with receiving CPR (relative risk [RR] = 2.92, 95% confidence interval = 1.26-6.78, p = 0.012), but not intubation. Patients with ID less frequently had a DNR placed (67.6% vs. 91.9%), mediating associations between ID and CPR. Conclusions: In this pilot study, ID was associated with increased likelihood of receiving end-of-life CPR, likely due to lower utilization of DNRs among patients with ID. Further research is needed to confirm these results.

The association of 5-year therapeutic responsiveness with long-term renal outcome in IgA nephropathy.

Immunoglobulin A nephropathy (IgAN) is the most common type of primary glomerulonephritis. Since most patients have a relatively benign renal prognosis, long-term follow-up is required. During such a long course of disease, relapse of IgAN is occasionally observed after upper respiratory tract infection or without any trigger. However, little is known about the impact of relapse on long-term renal outcomes. In this retrospective cohort study of biopsy-proven primary IgAN, we analyzed the association of 5-year therapeutic responsiveness (relapse) with the subsequent development of end-stage kidney disease (ESKD) using a 5-year landmark analysis (Cox model) and explored predictors of relapse from histological and clinical data at baseline. Among 563 patients from the exploratory cohort, most relapses (13.7%) occurred within 5years after treatment. Using 5-year landmark analysis, among 470 patients, 79 developed ESKD during a median follow-up period of 155months. Even after adjustment for clinicopathological relevant confounders, hazard ratios (95% confidence intervals) in the relapse and non-responder groups compared with the remission group were 2.86 (1.41-5.79) and 2.74 (1.48-5.11), respectively. Among 250 patients who achieved remission within 5years, proteinuria, eGFR, mesangial hypercellularity, endocapillary hypercellularity, segmental sclerosis, and crescent, but not interstitial fibrosis/tubular atrophy, were independent predictors of 5-year relapse in multivariable logistic regression analysis, CONCLUSIONS: Both relapsers and non-responders had similarly strong association with ESKD in patients with IgAN. We also confirmed the predictors of relapse 5years after renal biopsy, which may guide the treatment strategies for patients with IgAN who occasionally relapse after remission.

Relationship Between Circulating MicroRNAs and Left Ventricular Hypertrophy in Hypertensive Patients.

ObjectiveLeft ventricular hypertrophy (LVH) is a common complication of hypertension and microRNAs (miRNAs) are considered to play an important role in cardiac hypertrophy development. This study evaluated the relationship between circulating miRNAs and LVH in hypertensive patients.MethodsTwo cohorts [exploratory (n = 42) and validation (n = 297)] of hypertensive patients were evaluated by clinical, laboratory and echocardiography analysis. The serum expression of 754 miRNAs in the exploratory cohort and 6 miRNAs in the validation cohort was evaluated by the TaqMan OpenArray® system and quantitative polymerase chain reaction, respectively.ResultsAmong the 754 analyzed miRNAs, ten miRNAs (miR-30a-5p, miR-let7c, miR-92a, miR-451, miR-145-5p, miR-185, miR-338, miR-296, miR-375, and miR-10) had differential expression between individuals with and without LVH in the exploratory cohort. Results of multivariable regression analysis adjusted for confounding variables showed that three miRNAs (miR-145-5p, miR-451, and miR-let7c) were independently associated with LVH and left ventricular mass index in the validation cohort. Functional enrichment analysis demonstrated that these three miRNAs can regulate various genes and pathways related to cardiac remodeling. Furthermore, in vitro experiments using cardiac myocytes demonstrated that miR-145-5p mimic transfection up-regulated the expression of brain and atrial natriuretic peptide genes, which are markers of cardiac hypertrophy, while anti-miR-145-5p transfection abrogated the expression of these genes in response to norepinephrine stimulus.ConclusionsOur data demonstrated that circulating levels of several miRNAs, in particular miR-145-5p, miR-451, and let7c, were associated with LVH in hypertensive patients, indicating that these miRNAS may be potential circulating biomarkers or involved in hypertension-induced LV remodeling.

Real-World Crash Circumstances Among Newly Licensed Adolescent Drivers With and Without Attention-Deficit/Hyperactivity Disorder

PurposeAdolescents with attention-deficit/hyperactivity disorder (ADHD) have 30%–40% higher crash rates. However, we still do not understand which factors underlie heightened crash risk and if crash circumstances differ for drivers with ADHD. We compared prevalences of crash responsibility, driver actions, and crash types among adolescent and young adult drivers with and without ADHD who crashed within 48 months of licensure. MethodsIn this exploratory retrospective cohort study, we identified patients of Children's Hospital of Philadelphia's (CHOP) New Jersey (NJ) primary care locations who were born between 1987 and 2000, NJ residents, had their last CHOP visit ≥ age 12 years, and acquired a driver's license. We linked CHOP electronic health records to NJ's licensing and crash databases. ADHD diagnosis was based on International Classification of Diseases, Ninth Revision, Clinical Modification/International Classification of Diseases, Tenth Revision, Clinical Modification codes. Prevalence ratios were estimated using generalized estimating equation log-binomial regression. ResultsWe identified 934 drivers with ADHD in 1,308 crashes and 5,158 drivers without ADHD in 6,676 crashes. Within 48 months postlicensure, drivers with ADHD were more likely to be at fault for their crash (prevalence ratio: 1.09 [1.05–1.14]) and noted as inattentive (1.15 [1.07–1.23]). With the exception that drivers with ADHD were less likely to crash while making a left/U-turn, we did not find substantial differences in crash types by diagnosis. Analyses also suggest females with ADHD may have a higher risk of colliding with a nonmotor vehicle and crashing due to unsafe speed than females without ADHD. DiscussionThe results suggest crash circumstances do not widely differ for drivers with and without ADHD but highlight several factors that may be particularly challenging for young drivers with ADHD.

The impact of an intensive care unit admission on the health status of relatives of intensive care survivors: A prospective cohort study in primary care

Background Relatives of intensive care unit (ICU) survivors may suffer from various symptoms after ICU admittance of their relative, known as post-intensive care syndrome-family (PICS-F). Studies regarding PICS-F have been performed but its impact in primary care is unknown. Objectives To explore health problems of relatives of ICU survivors in primary care. Methods This is an exploratory prospective cohort study in which we combined data from two hospitals and a primary care research network in the Netherlands. ICU survivors who had been admitted between January 2005 and July 2017 were identified and matched by sex and age with up to four chronically ill (e.g. COPD, cardiovascular disease) patients. In both groups, relatives living in the same household were identified and included in this study. Primary outcome was the number of new episodes of care (International Classification of Primary Care-2) for up to five years. Hazard ratios (HRs) for the total number of new episodes were calculated. Results Relatives of ICU survivors (n = 267, mean age 38.1 years, 41.0% male) had significantly more new care episodes compared to the reference group (n = 705, mean age 36.3 years, 41.1% male) 1–2 years (median 0.11 vs. 0.08, HR 1.26; 95% confidence interval (CI) 1.03–1.54) and 2–5 years (median 0.18 vs. 0.13, HR 1.28; 95%CI 1.06–1.56) after ICU discharge. No differences were found in the period before ICU admission. Conclusion Relatives of ICU survivors present more morbidity in primary care than relatives of chronically ill patients up to five years after ICU discharge.

Analysis of physical activity and plasma levels of soluble CD40 and CD40L in older people with gastrointestinal tract cancer.

Regular physical activity prevents and treats cancer patients by assisting and improving the immune system. Co-stimulatory molecules that activate the immune system have been studied in cancer, such as immune checkpoint molecules of the CD40/CD40L pathway. This study aimed to characterize plasma levels of soluble CD40 (sCD40) and CD40 ligand (sCD40L) in older people with gastrointestinal tract (GIT) cancer and associate results with physical activity. This prospective and exploratory cohort study was performed with 24 older people with GIT cancer and 23 healthy elderly individuals as controls. Physical activity level was classified as active or sedentary according to the International Physical Activity Questionnaire-Short Form (IPAQ-SF). Plasma levels of sCD40 and sCD40L were determined using Enzyme-Linked Immunosorbent Assay. Plasma levels of sCD40 were higher, while sCD40L were lower (p=0.0171) in older people with GIT cancer than controls (p=0.0038). Regarding physical activity, active older people with GIT cancer presented lower plasma levels of sCD40 and sCD40L than those sedentary with GIT cancer (p=0.0228 and p=0.0236), respectively. Our findings suggest that GIT cancer stimulates the immune system in older people, elevates levels of sCD40, and reduces levels of sCD40L. Physical activity may be a protective factor for the immune system of these patients since it acts on sCD40/sCD40L pathway.

Validation of a Wound Tool for Assessment of Surgical Wounds in Infants.

Wound assessment is a critical part of the care of hospitalized infants in neonatal intensive care. Early recognition and initiation of appropriate treatment of wounds are imperative to facilitate wound healing and avoid complications such as secondary infection and wound dehiscence. There are, however, no validated tools for assessing surgical wounds in infants. The aim of this study was to develop and interrogate a tool for the assessment of surgical wounds. Specific aims for the tool included interrater reliability (give a consistent and dependable result independent of user) and test criterion validity (give an accurate assessment of the wound compared with an expert). This was an exploratory cohort study involving a structured wound tool applied by nursing staff to 40 surgical wounds. The wounds were also assessed by wound experts (a pediatric wound care nurse and a pediatric surgeon). Comparisons were made to elucidate estimates of reliability and validity. The wound tool demonstrated interrater reliability with intraclass correlation coefficient of 0.775 (95% CI, 0.665-0.862) as well as criterion validity with rank correlation coefficient of 0.55 (95% CI, 0.34-0.76) to 0.71 (95% CI, 0.53-0.88). To obtain 100% sensitivity to distinguish mild from moderate-severe wounds, a low cutoff score was needed. Wound assessment continues to be a subjective exercise, even with the utilization of a tool. Additional research is needed for strategies to support the assessment of surgical wounds in infants. Such tools are needed for future research, particularly when multiple institutions are involved.

A Cell Cycle-Related 13-mRNA Signature to Predict Prognosis in Hepatocellular Carcinoma.

We aimed to propose a cell cycle-related multi/mRNA signature (CCS) for prognosis prediction and uncover new tumor-driver genes for hepatocellular carcinoma (HCC). Cell cycle-related gene sets and HCC samples with mRNA-Seq data were retrieved from public sources. The genes differentially expressed in HCCs relative to normal peritumoral tissues were extracted through statistical analysis. The CCS was constructed by Cox regression analyses. Predictive capacity and clinical practicality of the signature were evaluated and validated. The expression of the function-unknown genes in the CCS was determined by RT-qPCR. Candidate gene TICRR was selected for subsequent validation through functional experiments. A cell cycle-related 13-mRNA signature was generated from the exploratory cohort [The Cancer Genome Atlas (TCGA), n = 371)]. HCC cases were classified as high- vs. low-risk groups per overall survival (OS) [hazard ratio (HR) = 2.699]. Significantly, the CCS exhibited great predictive value for prognosis in three independent cohorts, particularly in GSE76427 cohort [area under the curve (AUC) = 0.835/0.822/0.808/0.821/0.826 at 1/2/3/4/5 years]. The nomogram constructed by integrating clinicopathological features with the CCS indicated high accuracy and practicability. Significant enrichment of tumorigenesis-associated pathways was observed in the high-risk patients by Gene Set Enrichment Analysis (GSEA). RT-qPCR revealed that TICRR was overexpressed in HCC samples. Increased TICRR expression implied poor prognosis in HCC patients. Furthermore, depletion of TICRR in HCC cells decreased cell proliferation and the G1/S transition. In conclusion, the established 13-CCS had efficacy in prognostic prediction of HCC patients. Additionally, TICRR was demonstrated as a tumor-driver gene for this deadly disease.

Tolerance induction through non-avoidance to prevent persistent food allergy (TINA) in children and adults with peanut or tree nut allergy: rationale, study design and methods of a randomized controlled trial and observational cohort study

BackgroundPeanuts (PN) and tree nuts (TN) are among the most frequent elicitors of food allergy and can lead to life-threatening reactions. The current advice for allergic patients is to strictly avoid the offending food independently of their individual threshold level, whereas sensitized patients without allergic symptoms should frequently consume the food to avoid (re-)development of food allergy. The aim of this trial is to investigate (I) whether the consumption of low allergen amounts below the individual threshold may support natural tolerance development and (II) to what extent regular allergen consumption in sensitized but tolerant subjects prevents the (re-)development of PN or TN allergy.MethodsThe TINA trial consisting of (part I) a randomized, controlled, open, parallel group, single-center, superiority trial (RCT), and (part II) a prospective observational exploratory cohort study. Children and adults (age 1–67 years) with suspected or known primary PN and/or TN allergy will undergo an oral food challenge (OFC) to determine their clinical reactivity and individual threshold. In the RCT, 120 PN or TN allergic patients who tolerate ≥100 mg of food protein will be randomized (1:1 ratio) to consumption of products with low amounts of PN or TN on a regular basis or strict avoidance for 1 year. The consumption group will start with 1/100 of their individual threshold, increasing the protein amount to 1/50 and 1/10 after 4 and 8 months, respectively. The primary endpoint is the clinical tolerance to PN or TN after 1 year assessed by OFC. In the cohort study, 120 subjects sensitized to PN and/or TN but tolerant are advised to regularly consume the food and observed for 1 year. The primary endpoint is the maintenance of clinical tolerance to PN and/or TN after 1 year assessed by challenging with the former tolerated cumulative dose.DiscussionThis clinical trial will help to determine the impact of allergen consumption versus avoidance on natural tolerance development and whether the current dietary advice for PN or TN allergic patients with higher threshold levels is still valid.Trial registrationGerman Clinical Trials Register; ID: DRKS00016764 (RCT), DRKS00020467 (cohort study). Registered on 15 January 2020, http://www.drks.de.

Cannabidiol (CBD) in the Self-Treatment of Depression-Exploratory Study and a New Phenomenon of Concern for Psychiatrists.

Cannabis sativa, whose flowers are also known as marijuana or marihuana, is a recreational plant that contains many chemicals that are constantly being studied by scientists around the world. One of these substances is cannabidiol (CBD), which has gained widespread popularity on the internet as a cure for mental health problems, leading many people to use CBD to self-treat depression and anxiety. This article presents an exploratory cohort study (n = 90) of a group of people aged 16–69 using CBD to self-heal depression symptoms. The survey included basic sociodemographic questionnaire and validated Hospital Depression and Anxiety Scale. And was distributed via the Internet. The results were statistically analyzed. High school degree was the most commonly held education (46%), large city was the most popular place of living (33%) and majority of the respondents have a full-time job (53%). Only 19% of the respondents consult their doctor or pharmacists about taking CBD. On the group of psychiatric patients, only 49% of respondents tell their psychiatrist about using the compound. Psychiatrists should be aware of CBD use in their patients during their daily practice, as CBD use can be found within people from all walks of life, and due to public interest, there is a need for education and research on the efficacy and safety of CBD use for mental disorders.

Association of Type of Oral Anticoagulant Dispensed With Adverse Clinical Outcomes in Patients Extending Anticoagulation Therapy Beyond 90 Days After Hospitalization for Venous Thromboembolism

Guidelines for managing venous thromboembolism (VTE) recommend at least 90 days of therapy with oral anticoagulants. Limited evidence exists about the optimal drug for continuing therapy beyond 90 days. To compare having prescriptions dispensed for apixaban, rivaroxaban, or warfarin after an initial 90 days of anticoagulation therapy for the outcomes of hospitalization for recurrent VTE, major bleeding, and death. This exploratory retrospective cohort study used data from fee-for-service Medicare (2009-2017) and from 2 commercial health insurance (2004-2018) databases and included 64 642 adults who initiated oral anticoagulation following hospitalization discharge for VTE and continued treatment beyond 90 days. Apixaban, rivaroxaban, or warfarin prescribed after an initial 90-day treatment for VTE. Primary outcomes included hospitalization for recurrent VTE and hospitalization for major bleeding. Analyses were adjusted using propensity score weighting. Patients were followed up from the end of the initial 90-day treatment episode until treatment cessation, outcome, death, disenrollment, or end of available data. Weighted Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% CIs. The study included 9167 patients prescribed apixaban (mean [SD] age, 71 [14] years; 5491 [59.9%] women), 12 468 patients prescribed rivaroxaban (mean [SD] age, 69 [14] years; 7067 [56.7%] women), and 43 007 patients prescribed warfarin (mean [SD] age, 70 [15] years; 25 404 [59.1%] women). The median (IQR) follow-up was 109 (59-228) days for recurrent VTE and 108 (58-226) days for major bleeding outcome. After propensity score weighting, the incidence rate of hospitalization for recurrent VTE was significantly lower for apixaban compared with warfarin (9.8 vs 13.5 per 1000 person-years; HR, 0.69 [95% CI, 0.49-0.99]), but the incidence rates were not significantly different between apixaban and rivaroxaban (9.8 vs 11.6 per 1000 person-years; HR, 0.80 [95% CI, 0.53-1.19]) or rivaroxaban and warfarin (HR, 0.87 [95% CI, 0.65-1.16]). Rates of hospitalization for major bleeding were 44.4 per 1000 person-years for apixaban, 50.0 per 1000 person-years for rivaroxaban, and 47.1 per 1000 person-years for warfarin, yielding HRs of 0.92 (95% CI, 0.78-1.09) for apixaban vs warfarin, 0.86 (95% CI, 0.71-1.04) for apixaban vs rivaroxaban, and 1.07 (95% CI, 0.93-1.24) for rivaroxaban vs warfarin. In this exploratory analysis of patients prescribed extended-duration oral anticoagulation therapy after hospitalization for VTE, prescription dispenses for apixaban beyond 90 days, compared with warfarin beyond 90 days, were significantly associated with a modestly lower rate of hospitalization for recurrent VTE, but no significant difference in rate of hospitalization for major bleeding. There were no significant differences for comparisons of apixaban vs rivaroxaban or rivaroxaban vs warfarin.

Preoperative Chemoradiotherapy plus Nivolumab before Surgery in Patients with Microsatellite Stable and Microsatellite Instability-High Locally Advanced Rectal Cancer.

Preoperative chemoradiotherapy (CRT) and surgical resection are the standard treatment for locally advanced rectal cancer (LARC). Combining immune checkpoint inhibitors with radiation suggests a promising approach for enhancing efficacy. We investigated the efficacy of CRT followed by nivolumab and surgery in patients with LARC. In phase I, we investigated the feasibility of sequentially combined CRT, 5 cycles of nivolumab, and radical surgery. In phase II, patients with microsatellite stable (MSS) and microsatellite instability-high (MSI-H) LARC were evaluated. Three patients in phase I received full courses of CRT and nivolumab without dose modification; the schedule was recommended for phase II. A pathologic complete response (pCR) was centrally confirmed in 30% [11/37; 90% confidence interval (CI), 18%-44%] and 60% (3/5) of the MSS and exploratory MSI-H cohorts, respectively. While immune-related severe adverse events were observed in 3 patients, no treatment-related deaths were observed. In 38 patients with MSS who underwent surgery, pCR rates of 75% (6/8) and 17% (5/30; P = 0.004, Fisher exact test) were observed in those with programmed cell death ligand 1 (PD-L1) tumor proportion score ≥1% and <1%, respectively; IHC staining was performed using pre-CRT samples. In 24 patients with MSS, pre-CRT samples were analyzed by flow cytometry; pCR rates of 78% (7/9) and 13% (2/15; P = 0.003, Fisher exact test) were observed for CD8+ T cell/effector regulatory T cell (CD8/eTreg) ratios of ≥2.5 and <2.5, respectively, in tumor-infiltrating lymphocytes. CRT followed by consolidation nivolumab could increase pCR. PD-L1 expression and an elevated CD8/eTreg ratio were positive predictors in patients with MSS LARC.

The clinical and molecular cardiometabolic fingerprint of an exploratory psoriatic arthritis cohort is associated with the disease activity and differentially modulated by methotrexate and apremilast.

Objectives(1) To evaluate clinical and molecular cardiovascular disease (CVD) signs and their relationship with psoriatic arthritis (PsA) features and (2) to identify a clinical patient profile susceptible to benefit from methotrexate (MTX) and/or apremilast regarding CVD risk.MethodsThis cross‐sectional study included 100 patients with PsA and 100 age‐matched healthy donors. In addition, an exploratory cohort of 45 biologically naïve patients treated for 6 months with apremilast, MTX or combined therapy according to routine clinical practice was recruited. Extensive clinical and metabolic profiles were obtained. Ninety‐nine surrogate CVD‐related molecules were analysed in plasma and peripheral blood mononuclear cells (PBMCs). Hard cluster analysis was performed to identify the clinical and molecular phenotypes. Mechanistic studies were performed on adipocytes.ResultsCardiometabolic comorbidities were associated with disease activity and long‐term inflammatory status. Thirty‐five CVD‐related proteins were altered in the plasma and PBMCs of PsA patients and were associated with the key clinical features of the disease. Plasma levels of some of the CVD‐related molecules might distinguish insulin‐resistant patients (MMP‐3, CD163, FABP‐4), high disease activity (GAL‐3 and FABP‐4) and poor therapy outcomes (CD‐163, LTBR and CNTN‐1). Hard cluster analysis identified two phenotypes of patients according to the rates of cardiometabolic comorbidities with distinctive clinical and molecular responses to each treatment.Conclusions(1) Novel CVD‐related proteins associated with clinical features could be emerging therapeutic targets in the context of PsA and (2) the pleiotropic action of apremilast could make it an excellent choice for the management of PsA patients with high CVD risk, targeting metabolic alterations and CVD‐related molecules.

Amyloid processing in COVID-19-associated neurological syndromes.

SARS‐CoV‐2 infection can damage the nervous system with multiple neurological manifestations described. However, there is limited understanding of the mechanisms underlying COVID‐19 neurological injury. This is a cross‐sectional exploratory prospective biomarker cohort study of 21 patients with COVID‐19 neurological syndromes (Guillain–Barre Syndrome [GBS], encephalitis, encephalopathy, acute disseminated encephalomyelitis [ADEM], intracranial hypertension, and central pain syndrome) and 23 healthy COVID‐19 negative controls. We measured cerebrospinal fluid (CSF) and serum biomarkers of amyloid processing, neuronal injury (neurofilament light), astrocyte activation (GFAp), and neuroinflammation (tissue necrosis factor [TNF] ɑ, interleukin [IL]‐6, IL‐1β, IL‐8). Patients with COVID‐19 neurological syndromes had significantly reduced CSF soluble amyloid precursor protein (sAPP)‐ɑ (p = 0.004) and sAPPβ (p = 0.03) as well as amyloid β (Aβ) 40 (p = 5.2 × 10−8), Aβ42 (p = 3.5 × 10−7), and Aβ42/Aβ40 ratio (p = 0.005) compared to controls. Patients with COVID‐19 neurological syndromes showed significantly increased neurofilament light (NfL, p = 0.001) and this negatively correlated with sAPPɑ and sAPPβ. Conversely, GFAp was significantly reduced in COVID‐19 neurological syndromes (p = 0.0001) and this positively correlated with sAPPɑ and sAPPβ. COVID‐19 neurological patients also displayed significantly increased CSF proinflammatory cytokines and these negatively correlated with sAPPɑ and sAPPβ. A sensitivity analysis of COVID‐19‐associated GBS revealed a non‐significant trend toward greater impairment of amyloid processing in COVID‐19 central than peripheral neurological syndromes. This pilot study raises the possibility that patients with COVID‐19‐associated neurological syndromes exhibit impaired amyloid processing. Altered amyloid processing was linked to neuronal injury and neuroinflammation but reduced astrocyte activation.

Early modulation of Angiopoietin-2 plasma levels predicts benefit from regorafenib in patients with metastatic colorectal cancer

BackgroundNo biomarkers are currently available to predict the efficacy of trifluridine/tipiracil (FTD/TPI) in chemorefractory metastatic colorectal cancer. The multicohort REGOLAND study aims at exploring and validating circulating markers potentially able to predict benefit from regorafenib in this setting. Material and methodsIn the retrospective ‘regorafenib exploratory cohort’, including 105 patients treated with regorafenib, baseline (d1) plasma levels of angiogenesis-related biomarkers and their early modulation after 15 days (d15) of treatment were investigated for correlation with clinical outcome. Based on a pre-specified statistical hypothesis, main retrospective findings were prospectively challenged in the ‘regorafenib validation cohort’, including 100 patients treated with regorafenib. Prospectively validated putative biomarkers were then assessed in the control ‘FTD/TPI cohort’, including 93 patients treated with FTD/TPI. ResultsIn the ‘regorafenib exploratory cohort’, the early (d15) increase of Angiopoietin-2 (Ang-2) was associated with longer progression-free survival (HR:0.57 [95%CI:0.38–0.88], P = 0.004) and a trend towards longer OS (HR:0.74 [95%CI:0.48–1.14], P = 0.165), than the early decrease. Similar results were prospectively confirmed in the ‘regorafenib validation cohort’ (HR for progression-free survival:0.72 [95%CI:0.48–1.08], P = 0.095; HR for OS:0.77 [95%CI:0.51–1.16], P = 0.204). No predictive impact was shown for the early modulation of Ang-2 in the ‘FTD/TPI cohort’. High baseline Ang-2 levels predict poor prognosis in all the investigated cohorts, independently of other clinical prognostic variables. ConclusionsThe early modulation of circulating Ang-2 predicts the efficacy of regorafenib. Baseline Ang-2 plasma levels are an independent prognostic biomarker in chemorefractory metastatic colorectal cancer.

Dialectical Behavior Therapy for Emotional and Mindless Eating After Bariatric Surgery: a Prospective Exploratory Cohort Study.

To assess the effect of dialectical behavior therapy (DBT) on emotional and mindless eating and, consequently, body mass index (BMI) loss, in patients who have undergone bariatric surgery. A prospective exploratory cohort study was conducted with two groups of patients who had undergone bariatric surgery: the DBT group received DBT group skills training sessions, while the control group received no intervention. Outcome measurements included BMI and scores of the Emotional Eating Scale (EES) and Mindful Eating Questionnaire (MEQ). The study included 36 women: 18 in each group. In the DBT group, the interval from surgery was 11.17 ± 7.12months, and in the control group 10.89 ± 5.74. Laparoscopic sleeve gastrectomy was done in 88.9% and 83.3% of patients in the DBT and control groups respectively. The rest underwent Roux-en-Y gastric bypass. The DBT group showed significant changes in overall and subscale scores of the EES and MEQ and BMI in kg/m2 after 6months of follow-up. BMI in kg/m2 changed from mean ± SD 35.45 ± 6.17 to 28.47 ± 4.28 in the DBT group, in control 35.88 ± 5.07 to 31.56 ± 3.71. The excess weight loss percentage (EWL%) in the DBT was mean ± SD 75.3 ± 17.9 and in the control was 63.6 ± 14.5. In the DBT group, the EES score and MEQ score changed from mean ± SD 45.06 ± 20.19 to 20.50 ± 13.40 and 11.52 ± 2.02 to 15.87 ± 1.92, respectively. The control group showed no significant change in scores. DBT skills training can reduce emotional eating, increase mindful eating, and facilitate weight loss after bariatric surgery.

Maternal expectations about breastfeeding: a prospective observational study of pre-partum and post-partum evaluation

Introduction: Breastfeeding is one of the main experiences that occur in the relationship between mother and baby. As stated in the Child Health Manual, breastfeeding is much more than nurturing the child, it is a process that involves deep interaction between mother and child. The view or psychological reading of the pregnant mother about the act of breastfeeding her baby and the socio-cultural image of the mother/woman who breastfeeds impact the sphere of the future personality of the newborn. Objectives: to map the set of intervening factors that interfere in the breastfeeding process, taking into account the expectations conceived by the pregnant woman before breastfeeding, in addition to the analysis of the positive and negative experiences of nursing mothers during breastfeeding in the postpartum period. Methods: an exploratory and descriptive cohort study, using qualitative and quantitative variables resulting from a questionnaire applied to 35 pregnant women during pregnant women and subsequently interviewed with them in postpartum situations. Results: Regarding the age group, the highest concentration of age was between 26 and 33 years old, but there was the participation of women in the extremes of reproductive life; the association between the time of pregnancy and the search for content/guidance on breastfeeding, most participants were between the 20th and 30th week of the pregnancy period, when they sought information on the subject; to the level of education and information on when breastfeeding should be started, among the 19 pregnant women who had higher education, 17 said it should be started during the baby's first hour of life and 02 said it should be after the first hour; among the 15 participants who had completed high school, 14 responded that it should be in the first hour and only 01 responded after the first hour, and 01 participants who reported having completed elementary school, responded that breastfeeding should be started after the first hour of life. of the baby; when asked if they were breastfed and if they had breastfed previously, 04 pregnant women answered that they had not received breast milk and of these, 03 had already breastfed children before the current pregnancy, among the 31 participants who had been breastfed, 27 said they had not yet breastfed and 04 informed that who had already lived the experience with other children. When approached in the puerperium, the most frequent findings were: 14 reported having received professional help; 13 intended to breastfeed exclusively until the 6th month; 15 had already started formula milk; 17 intended to continue breastfeeding after the baby was six months old and 09 were unable to latch on. Conclusion: Breastfeeding is shown to be one of the biggest factors of doubt and insecurity for pregnant women who enter the puerperium in search of humanized and comprehensive care. Thus, the participation of the health professional becomes essential for the success of breastfeeding and the effective dissemination of concrete and assertive knowledge, both prepartum and postpartum.