Nevin Manimala

JAMA Netw Open. 2022 Jun 1;5(6):e2219678. doi: 10.1001/jamanetworkopen.2022.19678.

ABSTRACT

IMPORTANCE: Many older adults with depression do not experience remission with antidepressant treatment, and markers of cellular senescence in late-life depression (LLD) are associated with greater severity of depression, greater executive dysfunction, and higher medical illness burden. Since these clinical characteristics are associated with remission in LLD, molecular and cellular senescence abnormalities could be a possible biological mechanism underlying poor treatment response in this population.

OBJECTIVE: To examine whether the senescence-associated secretory phenotype (SASP) index was associated with the likelihood of remission from a depressive episode in older adults.

DESIGN, SETTING, AND PARTICIPANTS: A nonrandomized, open-label clinical trial was conducted between August 2009 and August 2014 in Pittsburgh, Pennsylvania; St Louis, Missouri; and Toronto, Ontario, Canada, with older adults in a current major depressive episode according to the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Revision) diagnostic criteria. Data from biomarker analyses were reported according to the clinical trial archived plasma samples run in March 2021. Data were analyzed from June to November 2021.

EXPOSURE: Venlafaxine extended release (dose ranging from 37.5 mg to 300 mg daily) for up to 12 weeks.

MAIN OUTCOMES AND MEASURES: The association between a composite biomarker-based index (SASP index) and treatment remission in older adults with major depression was measured using clinical data and blood samples.

RESULTS: There were 416 participants with a mean (SD) age of 60.02 (7.13) years; 64% (265 participants) were self-reported female, and the mean (SD) Montgomery-Asberg Depression Rating Scale score was 26.6 (5.7). Higher SASP index scores were independently associated with higher rates of nonremission, with an increase of 1 unit in the SASP index score increasing the odds of nonremission by 19% (adjusted odds ratio, 1.19; 95% CI, 1.05-1.35; P = .006). In contrast, no individual SASP factors were associated with remission in LLD.

CONCLUSIONS AND RELEVANCE: Using clinical data and blood samples from a nonrandomized clinical trial, the results of this study suggest that molecular and cellular senescence, as measured with the SASP index, is associated with worse treatment outcomes in LLD. Combining this index score reflecting interrelated biological processes with other molecular, clinical, and neuroimaging markers may be useful in evaluating antidepressant treatment outcomes. These findings inform a path forward for geroscience-guided interventions targeting senescence to improve remission rates in LLD.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00892047.

PMID:35771573 | DOI:10.1001/jamanetworkopen.2022.19678

JAMA Netw Open. 2022 Jun 1;5(6):e2219814. doi: 10.1001/jamanetworkopen.2022.19814.

ABSTRACT

IMPORTANCE: The ability of computed tomography (CT) to distinguish between benign congenital lung malformations and malignant cystic pleuropulmonary blastomas (PPBs) is unclear.

OBJECTIVE: To assess whether chest CT can detect malignant tumors among postnatally detected lung lesions in children.

DESIGN, SETTING, AND PARTICIPANTS: This retrospective multicenter case-control study used a consortium database of 521 pathologically confirmed primary lung lesions from January 1, 2009, through December 31, 2015, to assess diagnostic accuracy. Preoperative CT scans of children with cystic PPB (cases) were selected and age-matched with CT scans from patients with postnatally detected congenital lung malformations (controls). Statistical analysis was performed from January 18 to September 6, 2020. Preoperative CT scans were interpreted independently by 9 experienced pediatric radiologists in a blinded fashion and analyzed from January 24, 2019, to September 6, 2020.

MAIN OUTCOMES AND MEASURES: Accuracy, sensitivity, and specificity of CT in correctly identifying children with malignant tumors.

RESULTS: Among 477 CT scans identified (282 boys [59%]; median age at CT, 3.6 months [IQR, 1.2-7.2 months]; median age at resection, 6.9 months [IQR, 4.2-12.8 months]), 40 cases were extensively reviewed; 9 cases (23%) had pathologically confirmed cystic PPB. The median age at CT was 7.3 months (IQR, 2.9-22.4 months), and median age at resection was 8.7 months (IQR, 5.0-24.4 months). The sensitivity of CT for detecting PPB was 58%, and the specificity was 83%. High suspicion for malignancy correlated with PPB pathology (odds ratio, 13.5; 95% CI, 2.7-67.3; P = .002). There was poor interrater reliability (κ = 0.36 [range, 0.06-0.64]; P < .001) and no significant difference in specific imaging characteristics between PPB and benign cystic lesions. The overall accuracy rate for distinguishing benign vs malignant lesions was 81%.

CONCLUSIONS AND RELEVANCE: This study suggests that chest CT, the current criterion standard imaging modality to assess the lung parenchyma, may not accurately and reliably distinguish PPB from benign congenital lung malformations in children. In any cystic lung lesion without a prenatal diagnosis, operative management to confirm pathologic diagnosis is warranted.

PMID:35771571 | DOI:10.1001/jamanetworkopen.2022.19814

Am J Respir Crit Care Med. 2022 Jun 30. doi: 10.1164/rccm.202109-2166OC. Online ahead of print.

ABSTRACT

RATIONALE: A common MUC5B gene polymorphism, rs35705950-T, is associated with idiopathic pulmonary fibrosis (IPF), but its role in SARS-CoV-2 infection and disease severity is unclear.

OBJECTIVES: To assess whether rs35705950-T confers differential risk for clinical outcomes associated with COVID-19 infection among participants in the Million Veteran Program (MVP).

METHODS: The MUC5B rs35705950-T allele was directly genotyped among MVP participants; clinical events and comorbidities were extracted from the electronic health records. Associations between the incidence or severity of COVID-19 and rs35705950-T were analyzed within each ancestry group in the MVP followed by trans-ancestry meta-analysis. Replication and joint meta-analysis were conducted using summary statistics from the COVID-19 Host Genetics Initiative (HGI). Sensitivity analyses with adjustment for additional covariates (BMI, Charlson comorbidity index, smoking, asbestosis, rheumatoid arthritis with interstitial lung disease and IPF) and associations with post-COVID-19 pneumonia were performed in MVP subjects.

MEASUREMENTS AND MAIN RESULTS: The rs35705950-T allele was associated with fewer COVID-19 hospitalizations (Ncases=4,325/, Ncontrols=507,640; OR=0.89 [0.82-0.97], p=6.86 x 10-03) in trans-ancestry meta-analysis within MVP and joint meta-analyses with the HGI (Ncases=13,320, Ncontrols=1,508,841; OR=0.90 [0.86-0.95], p =8.99 x 10-05). The rs35705950-T allele was not associated reduced COVID-19 positivity in trans-ancestry meta-analysis within MVP (Ncases=19,168/Ncontrols=492,854; OR=0.98 [0.95-1.01], p=0.06) but was nominally significant (p<0.05) in the joint meta-analysis with HGI (Ncases=44,820/Ncontrols=1,775,827; OR=0.97 [0.95-1]; p=0.03). We did not observe associations with severe outcomes or mortality. Among MVP individuals of European ancestry, rs35705950-T was associated with fewer post-COVID-19 pneumonia events (OR=0.82 [0.72-0.93], p=0.001).

CONCLUSIONS: The MUC5B variant rs35705950-T may confer protection in COVID-19 hospitalizations. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

PMID:35771531 | DOI:10.1164/rccm.202109-2166OC

J Consult Clin Psychol. 2022 Jun;90(6):503-512. doi: 10.1037/ccp0000739.

ABSTRACT

OBJECTIVE: Prolonged exposure (PE) therapy is a first-line posttraumatic stress disorder (PTSD) treatment, but the manualized 90-min session format constitutes a barrier to adopting PE in most settings because they use 60-min sessions for scheduling and billing. We examined whether 60-min PE sessions were as effective and efficient as 90-min PE sessions.

METHOD: In total, 160 active-duty military personnel with PTSD were randomized to 8-15 sessions of 60- or 90-min PE sessions and assessed pre- and posttreatment, and 3- and 6-month posttreatment, using the Clinician Administered PTSD Scale for Diagnostic and Statistical Manual for Mental Disorders, 5th edition [DSM-5] (CAPS-5). Participants were also assessed weekly during treatment using the PTSD Checklist for DSM-5 (PCL-5). A 60-min PE was hypothesized to be noninferior to 90-min PE based on preliminary studies.

RESULTS: Using intent-to-treat analyses, the 95% CI for the difference between 60- and 90-min PE was less than the noninferiority margin (4.69 for the CAPS-5 and 7.38 for the PCL-5) at all three endpoints, suggesting that the efficacy of 60-min PE was noninferior to that of 90-min PE. Similarly, the rate of improvement per session for 60-min PE was noninferior to the rate for 90-min sessions for the PCL-5. Sensitivity analyses and Bayes factors were consistent with these results.

CONCLUSIONS: 60-min sessions of PE are noninferior to 90-min sessions with regard to both efficacy and efficiency. Thus, PE can be effectively delivered in shorter sessions, making it easier for behavioral health providers to implement within the military health system and in other mental health systems that use 60-min session appointments. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

PMID:35771512 | DOI:10.1037/ccp0000739

J Fam Psychol. 2022 Jun 30. doi: 10.1037/fam0001006. Online ahead of print.

ABSTRACT

Parenting is known to impact children’s executive function (EF) skills. However, nearly all the evidence comes from analyses of mother-child interaction. Using the National Longitudinal Study of Child Development and Care Database in Taiwan, the relations between both mother-child and father-child interaction and 3-year-olds’ EF were investigated in 2,164 families. The results showed that mothers interacted with their children differently from fathers in terms of time distribution. Mothers were more equally involved in all aspects of parental involvement, whereas fathers spent more time in play. In addition, both mother-child and father-child play contributed to children’s EF; however, the mediating effect of child motor skills was more prominent for father-child play. This study not only suggests a potential distinct and complementary role of fathers in young children’s EF development but also indicates a unique mediating effect of motor skills in the path from parent-child play to child EF. Implications for parent education are discussed. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

PMID:35771502 | DOI:10.1037/fam0001006

Med Sci Monit Basic Res. 2022 Jun 15;28:e936675. doi: 10.12659/MSMBR.936675.

ABSTRACT

BACKGROUND A hermetic seal at the apical terminus is required for healthy periradicular tissue. Root canal obturation sealers that are used in endodontics are based on zinc oxide eugenol, calcium hydroxide, resins, glass ionomers, silicone, or bioceramics, but no optimal sealer material has been identified to date. Therefore, the aim of this in vitro study was to evaluate apical leakage after crown-down preparation and root canal obturation with Endomethasone N, glass ionomer cement, and EndoRez sealers. MATERIAL AND METHODS For this in vitro study, we tested 92 extracted human teeth, which were divided into 3 groups after a preparation technique and obturation with Endomethasone N sealer, glass ionomer cement, and EndoRez sealer in combination with Thermafil obturator. Apical leakage was evaluated and compared among the tested groups using a dye leakage method through a stereomicroscope. The values were measured from the apex to the coronal extent of dye penetration. For statistical analysis, the t test was used for comparison of the arithmetic averages of tested groups. RESULTS After preparation with rotary files, tested groups obturated with Thermafil obturator in combination with Endomethasone sealer showed higher average dye penetration than tested groups obturated with EndoRez and glass ionomer sealer. CONCLUSIONS Although all experimental groups showed dye leakage, the glass ionomer sealer in combination with Thermafil showed the least leakage, compared with EndoRez and Endomethason N.

PMID:35771493 | DOI:10.12659/MSMBR.936675

Pharmacoeconomics. 2022 Jun 30. doi: 10.1007/s40273-022-01162-6. Online ahead of print.

ABSTRACT

OBJECTIVES: As obesity-associated events impact long-term survival, health economic (HE) modelling is commonly applied, but modelling approaches are diverse. This research aimed to compare the events simulation and the HE outcomes produced by different obesity modelling approaches.

METHODS: An external validation, using the Swedish obesity subjects (SOS) study, of three main structural event modelling approaches was performed: (1) continuous body mass index (BMI) approach; (2) risk equation approach; and (3) categorical BMI-related approach. Outcomes evaluated were mortality, cardiovascular events, and type 2 diabetes (T2D) for both the surgery and the control arms. Concordance between modelling results and the SOS study were investigated by different state-of-the-art measurements, and categorized by the grade of deviation observed (grades 1-4 expressing mild, moderate, severe, and very severe deviations). Furthermore, the costs per quality-adjusted life-year (QALY) gained of surgery versus controls were compared.

RESULTS: Overall and by study arm, the risk equation approach presented the lowest average grade of deviation (overall grade 2.50; control arm 2.25; surgery arm 2.75), followed by the continuous BMI approach (overall 3.25; control 3.50; surgery 3.00) and by the categorial BMI approach (overall 3.63; control 3.50; surgery 3.75). Considering different confidence interval limits, the costs per QALY gained were fairly comparable between all structural approaches (ranging from £2,055 to £6,206 simulating a lifetime horizon).

CONCLUSION: None of the structural approaches provided perfect external event validation, although the risk equation approach showed the lowest overall deviations. The economic outcomes resulting from the three approaches were fairly comparable.

PMID:35771486 | DOI:10.1007/s40273-022-01162-6

Head Neck Pathol. 2022 Jun 30. doi: 10.1007/s12105-022-01466-1. Online ahead of print.

ABSTRACT

BACKGROUND: Lymph node metastasis (LNM) is a well-known prognostic factor in Oral Squamous Cell Carcinoma(OSCC). A biological marker that predicts the Lymph Node Metastasis (LNM) in OSCC cases is the need of the hour. A Disintegrin And Metalloproteinases (ADAMs), a family of proteins that exhibit a metalloproteinase domain play a pivotal role in the pathogenesis of tumor growth and metastasis. This study aims to evaluate whether ADAM 10 can be used as a predictor of lymph node metastasis in OSCC using immunohistochemistry.

METHOD: A total of 90 samples that were categorized into 3 groups were included in the present study. Group I consisted of 30 samples of the normal oral mucosa, and Group II consisted of 30 samples of OSCC without lymph node metastasis. Group III consisted of 30 samples of OSCC with lymph node metastasis. Esophageal Squamous Cell Carcinoma was used as external positive control. Immunohistochemical expression of ADAM10 in their corresponding stained sections was assessed and staining intensity was calculated.

RESULTS: ADAM10 immunoreactivity was considered positive when located in cytoplasm or membrane or both. This method is similar to that used by Bamane et al. for OSCC cases. The mean value of the Staining Index score “AxB” was highest in Group III (7.90), followed by Group II (3.13) and least in Group I (0.27). These values were statistically significant.

CONCLUSION: Considering the findings of a higher percentage of ADAM10 positive cells, higher staining intensity, and higher staining index, the overexpression of ADAM10 can be used as an independent marker for OSCC patients to predict the lymph node metastasis.

PMID:35771404 | DOI:10.1007/s12105-022-01466-1

Patient. 2022 Jun 30. doi: 10.1007/s40271-022-00584-w. Online ahead of print.

ABSTRACT

INTRODUCTION: When determining if changes on patient-reported outcome (PRO) scores in clinical trials convey a meaningful treatment benefit, statistical significance tests alone may not communicate the patient perspective. Appraising within-patient changes on PRO scores against established thresholds can determine if improvements or deteriorations experienced by individuals are meaningful. To evaluate the appropriateness of thresholds for interpreting meaningful improvements and deterioration within individuals on the European Organisation for Research and Treatment of Cancer (EORTC) 30-item core instrument (QLQ-C30) and 13-item lung cancer module (QLQ-LC13), a series of psychometric methods were applied to data from a phase III randomized controlled clinical trial in non-small cell lung cancer.

METHODS: Anchor-based methods of empirical cumulative distribution functions and classification statistics were employed using change scores from Baseline to Week 7 using changes on the QLQ-C30 Global Health Status item as an anchor. Distribution-based methods of one-half standard deviation and standard error of measurement identified the minimum amount of change each domain score can reliably measure.

RESULTS: While the correlations between the domain scores and the anchor item were modest in size (i.e., r ≥ 0.30 for only 5 of 24 domains), consideration of multiple methods along with the magnitude of possible step changes on the score allowed for patterns to emerge. The triangulation process planned a priori resulted in different methods being the source for different domain scores. Absolute values of the proposed thresholds ranged from 11.11 to 33.33, and all resulted in the same classifications for all EORTC domains, except QLQ-C30 Fatigue, as would the 10-point threshold that is traditionally used.

CONCLUSION: This study confirms the appropriateness of the 10-point EORTC score threshold generally used by the field for interpreting within-patient changes, but the thresholds proposed from this study enhance interpretability by corresponding to only observable locations along the domain score scale.

PMID:35771392 | DOI:10.1007/s40271-022-00584-w

BioDrugs. 2022 Jun 30. doi: 10.1007/s40259-022-00542-w. Online ahead of print.

ABSTRACT

BACKGROUND: Previous observational studies utilizing administrative claims data have largely been unable to consider clinical factors that may be related to patterns of drug use among patients with rheumatoid arthritis (RA).

OBJECTIVE: To understand predictors of treatment changes following initiation of a tumor necrosis factor inhibitor (TNFi) using nation-wide electronic health record (EHR) data in the USA.

METHODS: The Optum Immunology Condition EHR data (01/01/2011-09/30/2019) was used to identify a population of adult patients with RA initiating a TNFi as the first line biologic disease-modifying anti-rheumatic drug (DMARD). The primary outcome was any treatment change during the 1-year post-index period defined as cycling to a different TNFi or switching to non-TNFi biologic or targeted synthetic DMARDs. Secondary outcomes were the individual components of TNFi cycling and switching, examined separately. To identify predictors of DMARD treatment changes, we used a least absolute shrinkage and selection operator (LASSO) regression model. Model c-statistics and odds ratios (ORs, 95% confidence intervals (CIs)) of predictors were reported.

RESULTS: We identified 24,871 patients with RA who initiated a TNFi. The mean age was 55.5 (± 13.7) years and 77.2% were female. Among the TNFi initiators, 22.2% experienced TNFi cycling or switching during the 1-year follow-up time. Predictors that are associated with higher likelihood of TNFi cycling or switching included female gender (OR: 1.26, 95% CI: 1.16-1.36) and glucocorticoid use (OR: 1.30, 95% CI: 1.21-1.40). In contrast, inflammatory bowel disease (OR: 0.62, 95% CI: 0.48-0.78), psoriasis (OR: 0.82, 95% CI: 0.70-0.95), recent use of methotrexate (OR: 0.89, 95% CI: 0.81-0.97), and vitamin D intake (OR: 0.92, 95% CI: 0.85-0.99) were negatively associated with TNFi cycling or switch.

CONCLUSIONS: Gender, glucocorticoid use, inflammatory bowel disease, psoriasis, and vitamin D intake were identified as significant predictors of TNFi cycling or switching for TNFi initiators in the RA population. Predicting treatment change remains challenging even with large detailed EHR data. This study aimed to identify key determinants of treatment changes among patients with rheumatoid arthritis (RA) initiating a tumor necrosis factor inhibitor (TNFi) as their first-line biologic disease-modifying antirheumatic drug (DMARD) in routine care settings using a US nation-wide longitudinal electronic health record (EHR). Among 24,871 patients with RA who initiated a TNFi, 22.2% experienced TNFi cycling or switching during the 1-year follow-up time. Female patients and those who used glucocorticoids were more likely to experience TNFi cycling or switching, whereas inflammatory bowel disease, psoriasis, recent methotrexate use, and vitamin D intake were negatively associated with the outcome. However, predicting treatment change remains challenging even with larger detailed EHR data potentially due to unmeasured factors such as prescriber’s preference or patient’s belief in the medication.

PMID:35771381 | DOI:10.1007/s40259-022-00542-w