Category: Nevin Manimala

Clin Epigenetics. 2023 Jan 4;15(1):1. doi: 10.1186/s13148-022-01394-5.

ABSTRACT

Depression is a multifactorial disorder representing a significant public health burden. Previous studies have linked multiple single nucleotide polymorphisms with depressive phenotypes and suicidal behavior. MAD1L1 is a mitosis metaphase checkpoint protein that has been linked to depression in GWAS. Using a longitudinal EWAS approach in an adolescent cohort at two time points (n = 216 and n = 154), we identified differentially methylated sites that were associated with depression-related genetic variants in MAD1L1. Three methylation loci (cg02825527, cg18302629, and cg19624444) were consistently hypomethylated in the minor allele carriers, being cross-dependent on several SNPs. We further investigated whether DNA methylation at these CpGs is associated with depressive psychiatric phenotypes in independent cohorts. The first site (cg02825527) was hypomethylated in blood (exp(β) = 84.521, p value ~ 0.003) in participants with severe suicide attempts (n = 88). The same locus showed increased methylation in glial cells (exp(β) = 0.041, p value ~ 0.004) in the validation cohort, involving 29 depressed patients and 29 controls, and showed a trend for association with suicide (n = 40, p value ~ 0.089) and trend for association with depression treatment (n = 377, p value ~ 0.075). The second CpG (cg18302629) was significantly hypomethylated in depressed participants (exp(β) = 56.374, p value ~ 0.023) in glial cells, but did not show associations in the discovery cohorts. The last methylation site (cg19624444) was hypomethylated in the whole blood of severe suicide attempters; however, this association was at the borderline for statistical significance (p value ~ 0.061). This locus, however, showed a strong association with depression treatment in the validation cohort (exp(β) = 2.237, p value ~ 0.003) with 377 participants. The direction of associations between psychiatric phenotypes appeared to be different in the whole blood in comparison with brain samples for cg02825527 and cg19624444. The association analysis between methylation at cg18302629 and cg19624444 and MAD1L1 transcript levels in CD¹⁴⁺ cells shows a potential link between methylation at these CpGs and MAD1L1 expression. This study suggests evidence that methylation at MAD1L1 is important for psychiatric health as supported by several independent cohorts.

PMID:36600305 | DOI:10.1186/s13148-022-01394-5

World J Emerg Surg. 2023 Jan 4;18(1):2. doi: 10.1186/s13017-022-00472-6.

ABSTRACT

BACKGROUND: A structured approach involves systematic management of trauma patients. We aim to conduct an overview of reviews about the clinical efficacy and safety of structured approach (i.e., primary and secondary survey) by guideline checklist compared to non-structured approach (i.e. clinical examination); moreover, routine screening whole-body computer tomography (WBCT) was compared to non-routine WBCT in patients with suspected major trauma.

METHODS: We systematically searched MEDLINE (PubMed), EMBASE and Cochrane Database of Systematic Reviews up to 3 May 2022. Systematic reviews (SRs) that investigated the use of a structured approach compared to a non-structured approach were eligible. Two authors independently extracted data, managed the overlapping of primary studies belonging to the included SRs and calculated the corrected covered area (CCA). The certainty of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology.

RESULTS: We included nine SRs investigating two comparisons in stable trauma patients: structured approach vs non-structured approach (n = 1) and routine WBCT vs non-routine WBCT (n = 8). The overlap of included primary studies was generally high across outcomes (CCA ranged between 20.85 and 42.86%) with some discrepancies in the directions of effects across reviews. The application of a structured approach by checklist may improve adherence to guidelines (e.g. Advanced Trauma Life Support) during resuscitation and might lead to a reduction in mortality among severely injured patients as compared to clinical examination (Adjusted OR 0.51; 95% CI 0.30-0.89; p = 0.018; low certainty of evidence). The use of routine WBCT seems to offer little to no effects in reducing mortality and time spent in emergency room or department, whereas non-routine WBCT seems to offer little to no effects in reducing radiation dose, intensive care unit length of stay (LOS) and hospital LOS (low-to-moderate certainty of evidence).

CONCLUSIONS: The application of structured approach by checklist during trauma resuscitation may improve patient- and process-related outcomes. Including non-routine WBCT seems to offer the best trade-offs between benefits and harm. Clinicians should consider these findings in the light of their clinical context, the volume of patients in their facilities, the need for time management, and costs.

PMID:36600301 | DOI:10.1186/s13017-022-00472-6

Arch Public Health. 2023 Jan 4;81(1):2. doi: 10.1186/s13690-022-01022-x.

ABSTRACT

BACKGROUND: Reinforcing self-efficacy in patients is important in person-centered care; therefore, reliable and valid measures of a person’s self-efficacy is of clinical relevance. A questionnaire suitable for self-efficacy and patient engagement that is not limited to a particular condition is the Self-efficacy to Manage Chronic Disease (SEMCD). This study aims to evaluate the measurement properties of a Swedish translation of the SEMCD with a Rasch analysis.

METHODS: The translation and cultural adaptation of the SEMCD was performed according to the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) recommendations. Self-reported data was collected from two cohorts: patients with pituitary tumors (n = 86) and patients on sick leave due to common mental disorders (n = 209). Measurement properties were evaluated with a Rasch analysis in RUMM2030.

RESULTS: The original six-item SEMCD did not fit to a unidimensional scale. Two items, item 5 and item 6, deviated both statistically and conceptually and were removed. A four-item solution, the SEMCD-4 with collapsed thresholds for mid-range response options, showed good targeting and unidimensionality, no item misfit, and a reliability of 0.83.

CONCLUSION: In a Swedish context with a mix of patients with pituitary tumors or common mental disorders, SEMCD-4 showed satisfactory measurement properties. Thus, SEMCD-4 could be used to identify patient self-efficacy in long-term illnesses. This knowledge about patient self-efficacy may be of importance to tailor person-centered support based on each patient´s resources, needs and goals.

PMID:36600298 | DOI:10.1186/s13690-022-01022-x

BMC Med. 2023 Jan 5;21(1):9. doi: 10.1186/s12916-022-02703-8.

ABSTRACT

BACKGROUND: Understanding the relationship between chronic pain conditions and suicidal behavior-suicide attempt, other intentional self-harm, and death by suicide-is imperative for suicide prevention efforts. Although chronic pain conditions are associated with suicidal behaviors, these associations might be attributed to unmeasured confounding or mediated via pain comorbidity.

METHODS: We linked a population-based Swedish twin study (N=17,148 twins) with 10 years of longitudinal, nationwide records of suicidal behavior from health and mortality registers through 2016. To investigate whether pain comorbidity versus specific pain conditions were more important for later suicidal behavior, we modeled a general factor of pain and two independent specific pain factors (measuring pain-related somatic symptoms and neck-shoulder pain, respectively) based on 9 self-reported chronic pain conditions. To examine whether the pain-suicidal behavior associations were attributable to familial confounding, we applied a co-twin control model.

RESULTS: Individuals scoring one standard deviation above the mean on the general pain factor had a 51% higher risk of experiencing suicidal behavior (odds ratio (OR), 1.51; 95% confidence interval (CI), 1.34-1.72). The specific factor of somatic pain was also associated with increased risk for suicidal behavior (OR, 1.80; 95% CI, 1.45-2.22]). However, after adjustment for familial confounding, the associations were greatly attenuated and not statistically significant within monozygotic twin pairs (general pain factor OR, 0.89; 95% CI, 0.59-1.33; somatic pain factor OR, 1.02; 95% CI, 0.49-2.11) CONCLUSION: Clinicians might benefit from measuring not only specific types of pain, but also pain comorbidity; however, treating pain might not necessarily reduce future suicidal behavior, as the associations appeared attributable to familial confounding.

PMID:36600296 | DOI:10.1186/s12916-022-02703-8

BMC Med. 2023 Jan 4;21(1):3. doi: 10.1186/s12916-022-02693-7.

ABSTRACT

BACKGROUND: Approximately 10% of stage I colorectal cancer (CRC) patients experience unfavorable clinical outcomes after surgery. However, little is known about the subset of stage I patients who are predisposed to high risk of recurrence or death. Previous evidence was limited by small sample sizes and lack of validation.

METHODS: We aimed to identify early indicators and develop a risk stratification model to inform prognosis of stage I patients by employing two large prospective cohorts. Prognostic factors for stage II tumors, including T stage, number of nodes examined, preoperative carcinoma embryonic antigen (CEA), lymphovascular invasion, perineural invasion (PNI), and tumor grade were investigated in the discovery cohort, and significant findings were further validated in the other cohort. We adopted disease-free survival (DFS) as the primary outcome for maximum statistical power and recurrence rate and overall survival (OS) as secondary outcomes. Hazard ratios (HRs) were estimated from Cox proportional hazard models, which were subsequently utilized to develop a multivariable model to predict DFS. Predictive performance was assessed in relation to discrimination, calibration and net benefit.

RESULTS: A total of 728 and 413 patients were included for discovery and validation. Overall, 6.7% and 4.1% of the patients developed recurrences during follow-up. We identified consistent significant effects of PNI and higher preoperative CEA on inferior DFS in both the discovery (PNI: HR = 4.26, 95% CI: 1.70-10.67, p = 0.002; CEA: HR = 1.46, 95% CI: 1.13-1.87, p = 0.003) and the validation analysis (PNI: HR = 3.31, 95% CI: 1.01-10.89, p = 0.049; CEA: HR = 1.58, 95% CI: 1.10-2.28, p = 0.014). They were also significantly associated with recurrence rate. Age at diagnosis was a prominent determinant of OS. A prediction model on DFS using Age at diagnosis, CEA, PNI, and number of LYmph nodes examined (ACEPLY) showed significant discriminative performance (C-index: 0.69, 95% CI:0.60-0.77) in the external validation cohort. Decision curve analysis demonstrated added clinical benefit of applying the model for risk stratification.

CONCLUSIONS: PNI and preoperative CEA are useful indicators for inferior survival outcomes of stage I CRC. Identification of stage I patients at high risk of recurrence is feasible using the ACEPLY model, although the predictive performance is yet to be improved.

PMID:36600277 | DOI:10.1186/s12916-022-02693-7

JMIR Public Health Surveill. 2022 Dec 16. doi: 10.2196/43049. Online ahead of print.

ABSTRACT

BACKGROUND: The impact of the COVID-19 pandemic on mental health in general practice remains uncertain. Several studies showed an increase in terms of mental health problems during the pandemic. In Belgium, especially during the first waves of the pandemic, access to general practice was limited. Specifically, it is unclear how this impacted not only the registration of mental health problems itself, but also the care for patients with an existing mental health problem.

OBJECTIVE: To know the impact of the COVID-19 pandemic on 1) the incidence of newly registered mental health problems and 2) the provision of care for patients with mental health problems in general practice, both using a pre-COVID baseline.

METHODS: Pre-pandemic volume of provided care (care provision) for patients with mental health problems was compared to that in 2020 and 2021 by using INTEGO, a Belgian general practice morbidity registry. Care provision was defined as the total number of new registrations in a patient’s electronic medical record. Regression models evaluated the association of demographic factors and care provision in patients with mental health problems, both before and during the pandemic.

RESULTS: During the COVID-19 pandemic as compared to pre-COVID, the incidence of registered mental health problems showed a fluctuating course, with a sharp drop in registrations during the first wave. Registrations for depression and anxiety increased, whereas the incidence of registered eating disorders, substance abuse and personality problems decreased. During the five COVID-19 waves, the overall incidence of registered mental health problems dropped during the wave and rose again when measures were relaxed. A relative rise of 8.7% and 40% in volume of provided care, specifically for patients with mental health problems, was seen during the first and second year of the COVID-19 pandemic. Care provision for patients with mental health problems was higher: in older patients, males, patients living in center cities (centrumsteden), patients with lower socioeconomic status (SES), native Belgians and patients with acute rather than mental health problems. Compared to pre-pandemic care provision, a reduction of 10% was observed in people with a low SES.

CONCLUSIONS: This study showed 1) a relative overall increase in the registrations of mental health problems in general practice and 2) an increase in care provision for patients with mental health problems in the first two years of the COVID-19 pandemic. Low SES remained a determining factor for more care provision, but care provision dropped significantly in people with mental health problems with a low SES. Our findings suggest that the pandemic in Belgium was also largely a ‘syndemic’, affecting different layers of the population disproportionately.

PMID:36599160 | DOI:10.2196/43049

J Speech Lang Hear Res. 2023 Jan 4:1-18. doi: 10.1044/2022_JSLHR-21-00541. Online ahead of print.

ABSTRACT

PURPOSE: This research aimed to identify reliable tasks discriminating French-speaking adolescents with developmental language disorder (DLD) from their peers with typical language (TL) and to assess which linguistic domains represent areas of particular weakness in DLD. Unlike English, morphosyntax has not been identified as a special area of weakness when compared with lexicosemantics in French preschoolers with DLD. Since there is evidence that subject-verb number agreement is consolidated in later childhood, one might expect morphosyntax to be a particular weakness and marker of French DLD only in (pre)adolescence.

METHOD: We administered 20 subtasks that assessed linguistic and phonological working memory skills of two groups: 17 adolescents clinically identified as having DLD (M = 14.1 years) and 20 (pre)teens with TL (M = 12.2 years). Using robust statistics that are less affected by outliers, we selected the most discriminating subtasks between our groups, calculated their optimal cutoff score, and derived diagnostic accuracy statistics. We combined these subtasks in a multivariable model to identify which subtasks contributed the most to the identification of DLD.

RESULTS: Seven subtasks were selected as discriminating between our groups, and three showed outstanding diagnostic accuracy: Recalling Sentences, a multiword task assessing lexicosemantic skills, and a subject-verb number agreement production task. When combined, we found that the latter contributed the most to our multivariable model.

CONCLUSION: This study provides evidence that the most relevant markers to identify DLD in French teenagers are tasks assessing lexicosemantics and morphosyntactic domains, and that morphosyntax should be considered an important area of weakness in French-speaking teenagers with DLD.

SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.21753932.

PMID:36599157 | DOI:10.1044/2022_JSLHR-21-00541

J Chin Med Assoc. 2023 Jan 4. doi: 10.1097/JCMA.0000000000000874. Online ahead of print.

NO ABSTRACT

PMID:36599146 | DOI:10.1097/JCMA.0000000000000874

J Clin Oncol. 2023 Jan 4:JCO2201096. doi: 10.1200/JCO.22.01096. Online ahead of print.

ABSTRACT

PURPOSE: To report clinical and treatment characteristics, remission and failure patterns, and risk factors for local failure (LF) from the EMBRACE-I study.

MATERIALS AND METHODS: EMBRACE-I was a prospective, observational, multicenter cohort study on magnetic resonance imaging-based image-guided adaptive brachytherapy (MR-IGABT) in locally advanced cervical cancer. Treatment consisted of external beam radiotherapy, concurrent chemotherapy, and MR-IGABT. LF was defined as progressive or recurrent disease in the cervix, uterus, parametria, pelvic wall, or vagina. Competing risk analysis was used to estimate local tumor control (LC) and Cox proportional regression models for multivariable analysis and dose-response analysis.

RESULTS: One thousand three hundred eighteen patients with a median follow-up of 52 months were available for this analysis. Eighty-one patients had persistent disease 3 months after end of treatment. Of those, 60 patients achieved LC at 6-9 months without further treatment, whereas 21 patients had progressive disease. In addition, 77 patients developed a local recurrence after complete remission comprising a total number of 98 LFs. LFs were located inside the MR-IGABT target volumes in 90% of patients with LF. In multivariable analysis, histology, minimal dose to 90% of high-risk clinical target volume (CTV_HR), maximum tumor dimension, CTV_HR > 45 cm³, overall treatment time, tumor necrosis on magnetic resonance imaging at diagnosis, uterine corpus infiltration at diagnosis and at MR-IGABT, and mesorectal infiltration at MR-IGABT had significant impact on LF. Dose-response analysis showed that a minimal dose to 90% of 85 Gy to the CTV_HR led to 95% (95% CI, 94 to 97) LC 3 years postintervention for squamous cell in comparison to 86% (95% CI, 81 to 90) for adeno/adenosquamous carcinoma histology.

CONCLUSION: The present study demonstrates the safety and validity of the GYN GEC-ESTRO/ICRU-89 target concept and provides large-scale evidence for dose prescription and new risk factors for LF in MR-IGABT in locally advanced cervical cancer.

PMID:36599120 | DOI:10.1200/JCO.22.01096

Dis Colon Rectum. 2023 Jan 4. doi: 10.1097/DCR.0000000000002623. Online ahead of print.

ABSTRACT

BACKGROUND: Anal cancer is associated with high-risk human papillomavirus infection and oncoprotein expression. We have identified several protease inhibitors, used to treat HIV, that decrease oncogene expression.

OBJECTIVE: The aim of this project is to determine whether the protease inhibitor, Saquinavir, results in a treatment response in anal cancer spheroids.

DESIGN: K14E6/E7 transgenic mice (n=5), which express HPV16 oncoproteins E6 and E7 in their epithelium, were treated topically at the anus with carcinogen, 7,12 dimethylbenz[a]anthracene, to promote anal tumor growth. Tumors were excised and digested, and cells were plated. The tumor cells form 3D multicellular aggregates, known as spheroids.

SETTINGS: This study was performed in an American Association for Accreditation of Laboratory Animal Care approved facility.

INTERVENTIONS: Spheroids were placed in treatment groups: no treatment, vehicle (dimethyl sulfoxide), and 15 μM Saquinavir. Spheroids were imaged immediately prior to treatment and 24-hours post-treatment.

MAIN OUTCOME MEASURES: Spheroid diameters were measured using ImageJ and mean percent reduction was calculated for each spheroid to determine treatment effect on spheroid growth. Analysis of variance using pairwise comparisons were performed with Fisher’s protected least significant difference tests.

RESULTS: No treatment (n=119 spheroids) and vehicle (n=126 spheroids) groups demonstrated an increase in spheroid diameter over the treatment period. In contrast, spheroids treated with Saquinavir (n=151 spheroids), demonstrated a statistically significant percent reduction compared to no treatment (p value < 0.0001) and vehicle (p value = 0.002) groups.

LIMITATIONS: A limitation of this data is that some human error is likely present given that images were analyzed by three different scientists.

CONCLUSIONS: Saquinavir leads to a statistically significant percent reduction in mice anal tumor spheroid growth ex-vivo when compared to control groups. Protease inhibitor therapy may be an effective treatment or adjuvant therapy to the Nigro protocol to promote anal cancer tumor regression. See Video Abstract at http://links.lww.com/DCR/C82.

PMID:36599112 | DOI:10.1097/DCR.0000000000002623