Nevin Manimala

BMC Cancer. 2022 Sep 29;22(1):1022. doi: 10.1186/s12885-022-10046-z.

ABSTRACT

OBJECTIVE: This study aims to systematically validate the performance of surrogate endpoints in phase II and III clinical trials for NSCLC patients under various trial settings.

METHODS: A literature search retrieved all registered phase II and III trials of NSCLC patients in which OS, with at least one of ORR and PFS, were reported. Associations between surrogate and true endpoints were assessed on two levels. On the arm level, three pairs of correlations, i.e., ORR vs. median OS, ORR vs. median PFS, and median PFS vs. median OS, were analysed using Spearman’s rho. On the trial level, similarly, three pairs of correlations, i.e., ΔORR vs. HR of OS, ΔORR vs. HR of PFS, and HR of PFS vs. HR of OS, were analysed using Spearman’s rho and weighted linear regression model respectively. Finally, sensitivity analyses were performed to explore surrogacy under various trial settings.

RESULTS: At arm level, three pairs of correlations are all high (Spearman’s rho = 0.700, 0.831, 0.755, respectively). At trial level, there is a low correlation between ΔORR and HR of OS, a high correlation between ΔORR and HR of PFS and a moderate correlation between HR of PFS and HR of OS (Spearman’s rho = 0.462, 0.764, 0.584, respectively). In the sensitivity analysis, we find correlations between surrogate and true endpoints vary by different trial settings. It is noteworthy that the strength of surrogacy of these intermediate endpoints in targeted therapy is greater than that in immunotherapy.

CONCLUSION: According to the arm-level and trial level-analysis, we suggest that in phase II and III trials of targeted therapy and immunotherapy for NSCLC patients: 1) ORR lacks validity for the surrogacy of OS, excluding in first-line therapy, and 2) ORR may be an appropriate surrogate endpoint for PFS, and 3) PFS may be considered a modest surrogacy for OS, with better performance in first-line therapy trials. Moreover, to provide more convincing evidence of surrogacy of the surrogate endpoints, patient-level analyses are in desperate need.

PMID:36171546 | DOI:10.1186/s12885-022-10046-z

BMC Cardiovasc Disord. 2022 Sep 28;22(1):427. doi: 10.1186/s12872-022-02867-4.

ABSTRACT

BACKGROUND: The large-scale changes in cardiac rehabilitation (CR) programme delivery in response to COVID-19 has led to diminished provision. The influence of these service changes on the depression symptoms of patients in CR programmes is unknown. Our study investigated the extent of depressive symptoms prior to and during the COVID-19 periods in patients with a previous history of depression at the start of CR.

METHODS: Use of Registry routine practice data, National Audit of Cardiac Rehabilitation (NACR), from COVID-19 period Feb 2020 and Jan 2021, as well as pre COVID-19 period Feb 2019 and Jan 2020, was extracted. Depressive symptoms were defined according to Hospital Anxiety and Depression Score ≥ 8. Chi-square tests and independent samples t-tests were used to investigate baseline characteristics. Additionally, a binary logistic regression to examine the factors associated with high levels of depressive symptoms.

RESULTS: In total 3661 patients with a history of depression were included in the analysis. Patients attending CR during COVID-19 were found to be 11% more likely to have high levels of acute depressive symptoms compared to patients attending CR prior to COVID-19. Physical inactivity, increased anxiety, a higher total number of comorbidities, increased weight, and living in the most deprived areas were statistically significant factors associated with high levels of acute depressive symptoms at the start of CR following multivariate adjustments.

CONCLUSION: Our research suggests that following a cardiac event patients with prior history of depression have high levels of acute depressive symptoms at CR baseline assessment. This finding exists in both the pre Covid-19 and Covid-19 periods in patients with a history of depression.

PMID:36171545 | DOI:10.1186/s12872-022-02867-4

BMC Cardiovasc Disord. 2022 Sep 28;22(1):426. doi: 10.1186/s12872-022-02864-7.

ABSTRACT

BACKGROUND: Heart failure (HF) is considered one of the main causes of morbidity and death among chronic diseases worldwide. Patients have increasingly reported chronic pain in long-standing heart failure as a disturbing symptom. Its unknown etiology and mechanism, in addition to its insidious progressive nature, made both the doctor and the patient not notice it until it affects the quality of life (QoL) and general health status. The primary objective of this study is to find the prevalence of pain in chronic heart failure patients and its impact on their QoL. The secondary objective is to determine the predictors of QoL in HF patients.

METHODS: A multicenter cross-sectional design was used. The European Quality of Life scale five dimensions scale and the Brief Pain Inventory were adopted to evaluate QoL and pain, respectively. The Statistical Package for the Social Sciences version 25 was applied to present the data. The Mann-Whitney U, Kruskal-Wallis, and Cronbach alpha tests were used.

RESULTS: The final study had a total of 142 individuals. The prevalence of pain among HF patients was 84.5%. Knee pain was the main complaint among patients. Our patients’ median pain severity score was 18 [5.00-25.00], while the median pain interference score was 39 [24.75-53.00]. They had a median EQ-5D score of 0.34 [0.0-0.6] and an EQ-VAS score of 50 [30-70]. Pain severity (p = 0.004 and p < 0.001, respectively) and pain interference (p < 0.001 and p = 0.001, respectively) were found to significantly associated with both QoL scores; the visual analogue scale (EQ-VAS) and EQ-5D-5L. In multivariate analysis, monthly income was the only variable significantly correlated with EQ-VAS and EQ-5D-5L, along with pain variables.

CONCLUSIONS: Pain is a common symptom among patients with HF and is significantly associated with their QoL. Low income is also highly associated with poor QoL. Definitive guidelines should be achieved to increase awareness and understanding of the importance of pain management, reaching a higher QoL level, less pain, and good adherence to HF medications.

PMID:36171539 | DOI:10.1186/s12872-022-02864-7

Eur Arch Paediatr Dent. 2022 Sep 28. doi: 10.1007/s40368-022-00757-z. Online ahead of print.

ABSTRACT

PURPOSE: To evaluate and compare the wear of selected resin-based fissure sealants with different compositions properties under erosive, abrasive, and erosive/abrasive conditions.

METHODS: Forty-five samples of the following resin-based fissure sealants were prepared: Fissurit (fluoride free), Fissurit F (with fluoride), Fissurit FX (55 wt.% filler content), Grandio Seal (70 wt.% nano-filler content) and bovine enamel. Fifteen samples from each material were randomly allocated into three groups according to the wear condition they would be subjected to as follows: erosive condition (citric acid, 1 min, pH 2.3), abrasive condition (120 brushing strokes at 2 N, toothpaste slurry RDA value = 69), and erosive/abrasive condition (combination of both). The wear challenges were repeated six times each day for 10 days. The material wear was measured using a stylus profilometer. Kruskal-Wallis and Conover’s test was applied to compare the resulting material wear between the groups.

RESULTS: Under erosive conditions, Grandio Seal and Fissurit FX showed statistically significantly the least material wear. Under abrasive and erosive/abrasive conditions, Grandio Seal showed statistically significantly the least material wear. Fissurit F showed statistically significantly the highest material wear under abrasive and erosive/abrasive conditions, after dental enamel (p < 0.05).

CONCLUSION: Higher filler content in sealants leads to better wear resistance. Incorporating fluoride into sealants seems to reduce their wear resistance at similar filler contents.

PMID:36171525 | DOI:10.1007/s40368-022-00757-z

J Community Genet. 2022 Sep 28. doi: 10.1007/s12687-022-00607-x. Online ahead of print.

ABSTRACT

Sickle cell disease is a genetic disorder characterised by the tendency of haemoglobin to polymerise and deform red blood cells to a sickle or crescent shape; this consequently results in vaso-occlusive condition. A better knowledge and awareness about sickle cell disease amongst the population can help reduce its prevalence. This study aimed at assessing awareness and knowledge of unmarried adults in Nigeria’s capital. A cross sectional survey was undertaken amongst unmarried individuals residing in the Federal Capital Territory. Questionnaires were administered to participants using convenience sampling strategy. Data were analysed using Statistical Package for Social Sciences version 25. Descriptive and inferential statistical analyses were carried out. A total of 1423 questionnaires were completed and returned, response rate was 83.71%, male participants were in the majority as indicated by 52% of the sample, and the dominant age group was 21 to 30 years (47.90%). Almost all the study participants (92.50%), have heard about sickle cell disease. Knowledge about sickle cell disease was average, as mean score for all the participants was 9.01 ± 3.18, with a range of 0 to 17. Some misconceptions were observed, for instance some participants believed that bacterial or viral infections could cause sickle cell disease. Male participants had a higher knowledge score compared to females (p < 0.001), and older participants were more knowledgeable about sickle cell disease (p < 0.001). This study identified that knowledge gaps exist about sickle cell disease. Emergent findings can underpin government, policymakers’ and stakeholders’ contextual strategies to prevent sickle cell through public health enlightenment and other relevant means.

PMID:36171517 | DOI:10.1007/s12687-022-00607-x

Sleep Breath. 2022 Sep 29. doi: 10.1007/s11325-022-02715-x. Online ahead of print.

ABSTRACT

OBJECTIVE: Some studies have pointed to gabapentinoids as promising medications in postoperative pain control. The objective of the present study was to evaluate the efficacy of pregabalin in reducing postoperative pain in tonsillectomy and lateral pharyngoplasties.

STUDY DESIGN: Double-blind randomized controlled trial.

SETTING: Tertiary care center.

METHODS: A double-blind randomized controlled trial was conducted with patients undergoing tonsillectomies and lateral pharyngoplasties between Aug 29, 2017, and Oct 31, 2020. Data of interest such as opioid consumption, pain scores, and adverse outcomes such as dizziness, nausea, headache, and sedation within 7 days following surgeries were analyzed.

RESULTS: No statistically significant difference was observed in pain scores and opioid consumption between the groups studied in the pilot project. The use of pregabalin was associated with lower incidence of dizziness compared to controls.

CONCLUSION: Gabapentinoids, especially pregabalin, are drugs whose potential for controlling pain after pharyngeal surgery, such as tonsillectomy and sleep apnea surgery, still needs to be more fully evaluated. After the conclusion of the present study, we hope to answer this question about the role of pregabalin in oropharyngeal surgeries.

PMID:36171512 | DOI:10.1007/s11325-022-02715-x

Surg Endosc. 2022 Sep 28. doi: 10.1007/s00464-022-09666-0. Online ahead of print.

ABSTRACT

BACKGROUND: The assessment of laparoscopic cholecystectomy (LC) skills using operating times has not been well reported. We examined the total and partial operating times for LC procedures performed by surgical trainees to determine the required number of surgeries until the surgical time stabilizes.

METHODS: We reviewed the video records of 514 consecutive LCs using the three-port method, performed by 16 surgical trainees. The total and partial surgical times were calculated and correlated to the surgeons’ experience.

RESULTS: The median total surgical time for a trainee’s first LC was 112 (range 71-226) minutes. It reduced rapidly after the first 20 LCs and plateaued to its minimum after approximately 60 cases. A statistically significant time decrease was observed between the first 10 (median, range 112, 46-252 min) and the next 50-59 cases (64, 34-198 min), but not between the 50-59 and the subsequent 100-109 cases (71, 33-127 min). The total times taken by trainees who had performed > 50 operations were not significantly different from those taken by instructors during the study period. Surgery for 125 patients with acute cholecystitis took a significantly longer time (median 99 vs. 74 min with non-acute cholecystitis); however, the abovementioned time reduction findings showed similar results regardless of the patient’s acute inflammation status. The partial operating times around the cervical/cystic duct and gallbladder bed reduced uniformly between the first 10 and the following 50-59 cases. Although time variations in total and cervical/cystic duct operating times were not correlated to the surgical experience, time fluctuation of gallbladder bed procedures reduced after 60 cases.

CONCLUSION: The time required to perform an LC was inversely correlated with the experience of surgical trainees and halved after the first 60 cases. The surgical experience required for LC time stabilization is approximately 60 cases.

PMID:36171452 | DOI:10.1007/s00464-022-09666-0

Sci Rep. 2022 Sep 28;12(1):16203. doi: 10.1038/s41598-022-20500-4.

ABSTRACT

BRCA1 (Breast Cancer 1, early onset) is linked to breast and ovarian cancer predisposition. Still, the risks conferred by a significant portion of BRCA1 variants identified in the population remains unknown. Most of these variants of uncertain significance are missense alterations. However, the functional implications of small in-frame deletions and/or insertions (indels) are also difficult to predict. Our group has previously evaluated the functional impact of 347 missense variants using an extensively validated transcriptional activity assay. Here we show a systematic assessment of 30 naturally occurring in-frame indels located at the C-terminal region of BRCA1. We identified positions sensitive and tolerant to alterations, expanding the knowledge of structural determinants of BRCA1 function. We further designed and assessed the impact of four single codon deletions in the tBRCT linker region and six nonsense variants at the C-terminus end of BRCA1. Amino acid substitutions, deletions or insertions in the disordered region do not significantly impact activity and are not likely to constitute pathogenic alleles. On the other hand, a sizeable fraction of in-frame indels at the BRCT domain significantly impact function. We then use a Bayesian integrative statistical model to derive the probability of pathogenicity for each variant. Our data highlights the importance of assessing the impact of small in-frame indels in BRCA1 to improve risk assessment and clinical decisions for carriers.

PMID:36171434 | DOI:10.1038/s41598-022-20500-4

Pharmacogenomics J. 2022 Sep 28. doi: 10.1038/s41397-022-00289-1. Online ahead of print.

ABSTRACT

Available drugs have been used as an urgent attempt through clinical trials to minimize severe cases of hospitalizations with Coronavirus disease (COVID-19), however, there are limited data on common pharmacogenomics affecting concomitant medications response in patients with comorbidities. To identify the genomic determinants that influence COVID-19 susceptibility, we use a computational, statistical, and network biology approach to analyze relationships of ineffective concomitant medication with an adverse effect on patients. We statistically construct a pharmacogenetic/biomarker network with significant drug-gene interactions originating from gene-disease associations. Investigation of the predicted pharmacogenes encompassing the gene-disease-gene pharmacogenomics (PGx) network suggests that these genes could play a significant role in COVID-19 clinical manifestation due to their association with autoimmune, metabolic, neurological, cardiovascular, and degenerative disorders, some of which have been reported to be crucial comorbidities in a COVID-19 patient.

PMID:36171417 | DOI:10.1038/s41397-022-00289-1

Eur J Nucl Med Mol Imaging. 2022 Sep 29. doi: 10.1007/s00259-022-05984-6. Online ahead of print.

ABSTRACT

PURPOSE: We aimed to evaluate whether [⁶⁸ Ga]Ga-FAPI-04 PET/CT could characterize the early stages of cardiac fibrosis in pressure overload heart failure.

METHODS: Sprague-Dawley rats underwent abdominal aortic constriction (AAC) (n = 12) and sham surgery (n = 10). All rats were scanned with [⁶⁸ Ga]Ga-FAPI-04 PET/CT at 2, 4, and 8 weeks after surgery. The expression of fibroblast activation protein (FAP) in the myocardium was detected by immunohistochemistry. [⁶⁸ Ga]Ga-FAPI-04 PET signal and FAP expression were compared between two groups.

RESULTS: Compared with the sham group, the AAC group presented with decreased ejection fraction (EF) and fractional shortening (FS) and increased left ventricular internal dimensions in diastole (LVIDd) and systole (LVIDs) at 4 and 8 weeks (all p < 0.01). The AAC group showed higher [⁶⁸ Ga]Ga-FAPI-04 accumulation in the heart than the sham group at 2, 4, and 8 weeks, and FAPI increased significantly from 2 to 8 weeks (all p < 0.001). Immunohistochemistry confirmed the higher density of the FAP⁺ area in the AAC group. The intensity of the [⁶⁸ Ga]Ga-FAPI-04 correlated with the density of the FAP⁺ area (p < 0.001). The expression of the [⁶⁸ Ga]Ga-FAPI-04 at 4 weeks correlated with the deterioration of cardiac function at 8 weeks (EF: R = – 0.87; FS: R = – 0.72; LVIDd: R = 0.77; LVIDs: R = 0.79; all p < 0.001). The AAC group also showed an increased [⁶⁸ Ga]Ga-FAPI-04 signal in the liver, peaking at 4 weeks and then declining. Cardiac and liver PET signals correlated at 4 weeks in the AAC group (R = 0.69, p = 0.0010), suggesting an early fibrotic link between organs. A combination of the [⁶⁸ Ga]Ga-FAPI-04 intensity in the heart and liver at 4 weeks better predicted the deterioration of cardiac function at 8 weeks.

CONCLUSIONS: The activated fibroblasts in the heart and liver after pressure overload can be monitored by [⁶⁸ Ga]Ga-FAPI-04 PET/CT, which reveals an early fibrotic link in cardio-liver interactions and could better predict nonischemic heart failure prognosis.

PMID:36171409 | DOI:10.1007/s00259-022-05984-6