Nevin Manimala

Int J Epidemiol. 2022 Apr 23:dyac073. doi: 10.1093/ije/dyac073. Online ahead of print.

ABSTRACT

BACKGROUND: Estimates of effect heterogeneity (i.e. the extent to which the causal effect of one exposure varies across strata of a second exposure) can be biased if the exposure-outcome relationship is subject to uncontrolled confounding whose severity differs across strata of the second exposure.

METHODS: We propose methods, analogous to the E-value for total effects, that help to assess the sensitivity of effect heterogeneity estimates to possible uncontrolled confounding. These E-value analogues characterize the severity of uncontrolled confounding strengths that would be required, hypothetically, to ‘explain away’ an estimate of multiplicative or additive effect heterogeneity in the sense that appropriately controlling for those confounder(s) would have shifted the effect heterogeneity estimate to the null, or alternatively would have shifted its confidence interval to include the null. One can also consider shifting the estimate or confidence interval to an arbitrary non-null value. All of these E-values can be obtained using the R package EValue.

RESULTS: We illustrate applying the proposed E-value analogues to studies on: (i) effect heterogeneity by sex of the effect of educational attainment on dementia incidence and (ii) effect heterogeneity by age on the effect of obesity on all-cause mortality.

CONCLUSION: Reporting these proposed E-values could help characterize the robustness of effect heterogeneity estimates to potential uncontrolled confounding.

PMID:35460421 | DOI:10.1093/ije/dyac073

Hum Reprod. 2022 Apr 23:deac076. doi: 10.1093/humrep/deac076. Online ahead of print.

ABSTRACT

STUDY QUESTION: Are patients’ characteristics, such as anti-Müllerian hormone (AMH) and BMI, reliable factors to predict ovarian response in couples with unexplained subfertility undergoing IUI with ovarian hyperstimulation (IUI-OH)?

SUMMARY ANSWER: We observed no solid relationship between serum AMH and ovarian response.

WHAT IS KNOWN ALREADY: Ovarian stimulation during IUI treatment could lead to a higher chance of pregnancy, but also a higher incidence of multiple pregnancies, unless strict cancellation criteria are being used. Several factors could influence the result of the stimulation, such as age, BMI and hormonal status of the female. In IVF treatment, AMH has shown to be a useful predictor of ovarian stimulation to optimize the outcome; however, in a milder stimulation protocol, such as IUI, this has not been investigated.

STUDY DESIGN, SIZE, DURATION: We performed a prospective cohort study and evaluated the first IUI stimulation cycle of 492 patients. The study was conducted between 2012 and 2017. Follow-up ended if patients were not pregnant after the first cycle. If pregnancy did occur, follow-up lasted until delivery.

PARTICIPANTS/MATERIALS, SETTING, METHODS: PRORAILS is a large multicentre nationwide cohort study executed in the Netherlands. Eligible women aged 18-43 years who were diagnosed with unexplained subfertility or mild male subfertility according to the Dutch guideline, with a regular indication for IUI-OH, were asked to participate. Ovarian response was assessed using a transvaginal ultrasound 5-7 days after initiation of the stimulation and was repeated according to the size of the leading follicles. Ovarian response was defined as optimal or suboptimal based on the total number of dominant follicles >15 mm. A successful stimulation was defined as the presence of two to three follicles >15 mm on the day of hCG administration. Serum AMH (µg/l) was measured by ELISA, and samples were taken on day 2, 3 or 4 of the menstrual cycle. Poisson regression was used to estimate the risk of a suboptimal ovarian response.

MAIN RESULTS AND THE ROLE OF CHANCE: Of the 492 participants, the mean age was 33 years and the mean subfertility duration was 2.5 years. The median serum AMH was 2.1 (µg/l). The majority of patients had a suboptimal response: 326 women (66%), of whom 224 (45%) had a hypo response (defined as <two follicles sized > 15 mm) and 102 (21%) had a hyper response (defined as more than three follicles sized >15 mm). The lowest AMH category showed a trend towards a smaller risk of a suboptimal response (relative risk ratio 0.76 (95% CI 0.54, 1.06)), but this effect did not reach statistical significance. In the prediction models, BMI and serum basal FSH were significant predictors of a hypo response, while for hyper response the factors age, BMI and serum FSH were significant. A higher BMI showed a higher risk for hypo response, as did a higher FSH whereas a lower BMI and lower FSH showed a higher risk for hyper response. The addition of AMH to the models did not improve the predictive abilities.

LIMITATIONS, REASONS FOR CAUTION: Although the study was prospective, the main analyses were cross-sectional with characteristics measured at one time-point. The study was not powered to provide insight into predictors of pregnancy and live births and, therefore, the result for pregnancy should be interpreted with caution.

WIDER IMPLICATIONS OF THE FINDINGS: This was the first large multicentre study that investigated the characteristics of ovarian response categories using standardized methods and centrally analysed laboratory measures. PRORAILS is a nationwide study with 15 hospitals and, therefore, these results are generalizable to other hospitals in the Netherlands. This study provides high-quality outcomes advancing the subfertility research field. Future studies would benefit from a randomized design investigating the effectiveness of an individualized approach versus a fixed dose. Also, the relation between a good ovarian stimulation and pregnancy rate could be further investigated.

STUDY FUNDING/COMPETING INTEREST(S): The PRORAILS study is sponsored by Merck B.V., Schiphol-Rijk, the Netherlands, an affiliation of Merck KGaA, Darmstadt, Germany (EMR700623_612). Merck KGaA, Darmstadt, Germany, reviewed the manuscript prior to submission. The opinions remain those of the authors. Merck KGaA, Darmstadt, Germany, had no influence on the use of medication in this study. The recombinant FSH was mostly provided by Merck B.V. or MSD. F.B. is a member of the external advisory board for Merck B.V., Schiphol-Rijk, the Netherlands, and has received a research grant from Merck B.V., Schiphol-Rijk. H.v.B. is an employee from IQVIA, which is a commercial data-analysing company, and received payment for her part in the article.

TRIAL REGISTRATION NUMBER: NCT01662180.

PMID:35460412 | DOI:10.1093/humrep/deac076

Age Ageing. 2022 Apr 1;51(4):afac092. doi: 10.1093/ageing/afac092.

ABSTRACT

OBJECTIVE: To assess the effectiveness of a pharmacist-led intervention using validated tools to reduce medicine-induced deterioration and adverse reactions.

DESIGN AND SETTING: Multicenter, open-label parallel randomised controlled trial involving 39 Australian aged-care facilities.

PARTICIPANTS: Residents on ≥4 medicines or ≥1 anticholinergic or sedative medicine.

INTERVENTION: Pharmacist-led intervention using validated tools to detect signs and symptoms of medicine-induced deterioration which occurred every 8 weeks over 12 months.

COMPARATOR: Usual care (Residential Medication Management Review) provided by accredited pharmacists.

OUTCOMES: Primary outcome was change in Frailty Index at 12 months. Secondary outcomes included changes in cognition, 24-hour movement behaviour by accelerometry, grip strength, weight, adverse events and quality of life.

RESULTS: 248 persons (median age 87 years) completed the study; 120 in the interventionand, 128 in control arms. In total 575 pharmacist, sessions were undertaken in the intervention arm. There was no statistically significant difference for change in frailty between groups (mean difference: 0.009, 95% CI: -0.028, 0.009, P = 0.320). A significant difference for cognition was observed, with a mean difference of 1.36 point change at 12 months (95% CI: 0.01, 2.72, P = 0.048). Changes in 24-hour movement behaviour, grip strength, adverse events and quality of life were not significantly different between groups. Point estimates favoured the intervention arm at 12 months for frailty, 24-hour movement behaviour and grip strength.

CONCLUSIONS: The use of validated tools by pharmacists to detect signs of medicine-induced deterioration is a model of practice that requires further research, with promising results from this trial, particularly with regards to improved cognition.

PMID:35460410 | DOI:10.1093/ageing/afac092

Eur J Epidemiol. 2022 Apr 23. doi: 10.1007/s10654-022-00858-5. Online ahead of print.

ABSTRACT

Chocolate is a rich dietary source of various bioactive flavonoid compounds. Despite being one of the most popular foods worldwide, the association between chocolate consumption and long-term mortality remains unclear. The objective of this study is to determine the associations between chocolate consumption and long-term overall and cause-specific mortality, to evaluate dose-response and potential mediators, and to conduct an updated meta-analysis based on prospective cohort studies. We performed a prospective analysis in the Alpha-Tocopherol, Beta-Carotene cancer prevention (ATBC) Study with a total of 27,111 men who were recruited between 1985 and 1988 and followed through 2015. Exposure data of daily chocolate consumption was obtained from validated baseline food frequency questionnaire. Hazard ratios (HRs) and 30-year absolute risk differences (ARDs) including 95% confidence intervals (CI) for overall and cause-specific mortality were estimated using multivariable-adjusted Cox proportional hazards regression models. An updated meta-analysis of cohort studies was also conducted. During 482,807 person-years of follow-up, a total of 22,064 men died. The multivariable analyses showed a statistically significant inverse association between chocolate consumption and risk of overall mortality, with HRs of 0.91, 0.89, 0.89, and 0.88 for the increasing categories 2-5 as compared with those in the lowest category (P_trend < 0.0001, and P for nonlinearity < 0.0001). We observed significantly lower mortality from cardiovascular disease (CVD), heart disease and cancer, representing 13%, 16% and 12% risk reductions for the highest compared to lowest chocolate category, respectively (all P_trend ≤ 0.002; all P for nonlinearity < 0.0001). The inverse associations of chocolate consumption with risk of overall, CVD and heart disease mortality were generally consistent across cohort subgroups (e.g., body mass index and serum cholesterol). Mediation analysis showed that 4.3% of the inverse association of chocolate and overall mortality was mediated through reducing blood pressure. Within the updated meta-analysis of cohort studies (21 risk estimates, 908,390 participants and 65,407 events), greater consumption of chocolate (per 5 g/day) was associated with a lower risk of CVD incidence and mortality (pooled relative risk = 0.98, P value < 0.001; P for nonlinearity < 0.001). The predefined subgroup analyses generally revealed consistent inverse chocolate-CVD risk associations. In this prospective study, calorie-balanced greater consumption of chocolate was inversely associated with lower overall, CVD, heart disease and cancer mortality. The systematic review and meta-analysis provide support for the inverse chocolate-CVD association. Our findings may provide evidence to partially allay concerns regarding adverse health outcomes from low-to-moderate chocolate consumption.

PMID:35460393 | DOI:10.1007/s10654-022-00858-5

Primates. 2022 Apr 23. doi: 10.1007/s10329-022-00989-z. Online ahead of print.

ABSTRACT

Bornean orangutan is a critically endangered non-human primate; however, the threat of extinction is not merely from poaching and habitat loss. Orangutan survival is also threatened by the genetic loss and genetic bottleneck due to the low effective population, prompting the dire need for an immediate genetic preservation program through systematic biobanking and assisted reproductive technology (ART). This study aims to provide integral data to the semen characteristics, extension, and cryopreservation of the Bornean orangutan and the potential relationship to male traits. Five captive orangutans from Sepilok Orangutan Rehabilitation Centre (SORC) with a mean body weight of 52.81 ± 7.00 kg were used for this study. Semen collection was performed using electroejaculation (EE) under complete general anesthesia. Semen was subjected to macroscopic and microscopic evaluation while testicular measurement was obtained using digital calipers. The semen characteristics of the orangutans are volume (778 ± 250.21 µl), pH (7.80 ± 0.25), concentration (32.38 ± 17.40 × 10⁶ sperm/ml), total motility (61.00 ± 12.88%), adjusted motility index (48.76 ± 11.32%), live spermatozoa (77.75 ± 6.94%) and normal spermatozoa (11.48 ± 11.34%). Analysis of variance statistical analysis test was used to compare the significant difference between means, at (p < 0.05). Spermatozoa concentration was the only significant different parameter between individuals. Testes biometry parameters are statistically significant between the flanged and unflanged individuals. Live spermatozoa are different in adult and sub-adult individual while teratospermia was found to be consistently high in all individuals. Chilled and post-thaw quality after cryopreservation suggests promising survivability of spermatozoa. Semen collection with EE yields a consistent and acceptable quality of spermatozoa for cryopreservation, biobanking purposes, and potential application of ART.

PMID:35460385 | DOI:10.1007/s10329-022-00989-z

ACR Open Rheumatol. 2022 Apr 23. doi: 10.1002/acr2.11434. Online ahead of print.

ABSTRACT

OBJECTIVE: Although a high-resolution computed tomography (HRCT) scan of the chest is the gold standard test for the detection of interstitial lung disease (ILD), there is no consensus among rheumatologists regarding the use of HRCT to screen for ILD in their patients with systemic sclerosis (SSc). The aims of this study were to describe the HRCT ordering practices at SSc centers in the United States and to determine which patient characteristics are associated with HRCT performance.

METHODS: We performed a prospective cohort study of patients with SSc enrolled in the US-based Collaborative National Quality and Efficacy Registry (CONQUER). We performed univariate logistic regression followed by multivariable logistic regression to determine which patient characteristics were associated with HRCT performance.

RESULTS: Of the 356 patients with SSc enrolled in CONQUER, 286 (80.3%) underwent HRCT at some point during their disease course. On multivariable analyses, missing total lung capacity percent predicted (odds ratio [OR] 3.26, 95% confidence interval [CI]: 1.53-7.41, P = 0.007) was positively associated with ever having undergone HRCT, whereas a positive anti-centromere antibody (OR 0.27, 95% CI: 0.12-0.61, P = 0.008) and missing forced vital capacity percent predicted (OR 0.29, 95% CI: 0.10-0.80, P = 0.005) were negatively associated with ever having undergone HRCT. There was a trend toward a positive association between crackles on pulmonary exam and ever having undergone HRCT (OR 2.28, 95% CI: 0.97-6.05, P = 0.058), although this relationship did not reach statistical significance.

CONCLUSION: The majority of patients with SSc enrolled in CONQUER underwent HRCT. A positive anti-centromere antibody was the key clinical variable inversely associated with performance of HRCT.

PMID:35460213 | DOI:10.1002/acr2.11434

Dermatol Ther. 2022 Apr 22:e15534. doi: 10.1111/dth.15534. Online ahead of print.

ABSTRACT

Melasma is a benign, acquired disorder of hyperpigmentation commonly affecting the face. Though easily diagnosable, a tangible treatment for melasma still remains elusive. To compare the therapeutic efficacy and safety of tranexamic acid (TXA) and platelet rich plasma (PRP) microinjections in treating patients with melasma. In total, 40 patients with melasma (10 males, 30 females; age range: 21-54 years) were enrolled, and randomly assigned to one of the two groups consisting of 20 patients each. Group A (3 males, 17 females) received intradermal microinjections of TXA (4 mg/mL) and group B (5 males, 15 females) received intradermal microinjections of PRP, once every 4 weeks for a total of 5 treatment sessions. Clinical images were taken at each visit and improvement in melasma was evaluated using both melasma area severity index (MASI) and modified melasma area severity index (mMASI) scoring systems. Percentage reduction of both MASI and mMASI scores were also assessed at each visit, and the grade of melasma improvement was accordingly outlined for each patient. The study was completed by 18 patients in group A (TXA) and 15 patients in group B (PRP). In group A, both MASI and mMASI scores reduced significantly from 16.6 ± 9.227 at baseline to 10.028 ± 8.07 at end point; and 8.885 ± 5.418 at baseline to 4.639 ± 3.863 at end point respectively (p value <0.01). Similarly in group B significant reduction in both scores were observed at the end of treatment. MASI declined from 20.42 ± 7.979 to 12.253 ± 7.37; and mMASI plummeted to 5.613 ± 3.98 from 10.673 ± 4.642 (p value <0.01). In group A, the difference in mean reduction of MASI and mMASI from baseline to end point was 6.572 ± 4.528 and 4.211 ± 2.647 respectively. In group B, the difference in mean reduction of both scores at the end of treatment reflected values of 8.167 ± 4.975(MASI) and 5.06 ± 2.977 (mMASI). No significant adverse effects were encountered in both treatment arms during the entire duration of study. Both TXA and PRP microinjections are effective and safe therapeutic options for melasma, and provide rapid and substantial improvement even when used as a standalone therapy. Although PRP mesotherapy was found to be slightly better than intradermal TXA in our study, the results were not significant statistically. This article is protected by copyright. All rights reserved.

PMID:35460158 | DOI:10.1111/dth.15534

J Obstet Gynaecol Res. 2022 Apr 23. doi: 10.1111/jog.15262. Online ahead of print.

ABSTRACT

AIMS: To introduce and compare the modified laparoscopic Vecchietti and Davydov techniques for vaginoplasty in patients with Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome. Moreover, the long-term treatment of vaginal agenesis was followed-up.

METHODS: This comparative retrospective cohort study enrolled a total of 53 women with MRKH syndrome. The patients underwent surgical creation of a neovagina including 32 patients who underwent the modified laparoscopic Vecchietti technique, and 21 patients who underwent the modified laparoscopic Davydov technique from January 2009 to February 2019. The perioperative parameters, complications, anatomical, and functional outcomes of the two groups were compared. Patients’ sexual functions were evaluated over a long-term follow-up using the female sexual function index (FSFI) and the revised female sexual distress scale (FSDS-R).

RESULTS: The medians (25th-75th) of the surgery duration for modified Vecchietti procedures was 50.0 (40.0-59.0) minutes, comparing to 135.0 (117.5-162.5) min for Davydov procedures (p < 0.001). The intraoperative blood loss was 20 (7.5-20.0) mL versus 50.0 (50.0-100.0) mL using the modified Vecchietti and Davydov approaches (p < 0.001), respectively. In the 39 follow-up cases, the lengths of the neovagina of the patients for Vecchietti group versus Davydov group were 7.9 ± 1.0 cm versus 8.6 ± 1.2 cm at 6 months after the vaginoplasty and 8.3 ± 0.7 cm versus 8.5 ± 0.9 cm after 2 years. There was no statistical difference in the FSFI and FSDS-R scores between the two groups.

CONCLUSIONS: Both the modified Davydov and Vecchietti laparoscopic procedures successfully achieved optimal anatomic and functional outcomes in treatments of vaginal agenesis. The modified Vecchietti technique is relatively simpler than the modified Davydov technique.

PMID:35460152 | DOI:10.1111/jog.15262

J Appl Clin Med Phys. 2022 Apr 23:e13609. doi: 10.1002/acm2.13609. Online ahead of print.

ABSTRACT

OBJECTIVE: To quantify the clinical performance of a machine learning (ML) algorithm for organ-at-risk (OAR) dose prediction for lung stereotactic body radiation therapy (SBRT) and estimate the treatment planning benefit from having upfront access to these dose predictions.

METHODS: ML models were trained using multi-center data consisting of 209 patients previously treated with lung SBRT. Two prescription levels were investigated, 50 Gy in five fractions and 54 Gy in three fractions. Models were generated using a gradient-boosted regression tree algorithm using grid searching with fivefold cross-validation. Twenty patients not included in the training set were used to test OAR dose prediction performance, ten for each prescription. We also performed blinded re-planning based on OAR dose predictions but without access to clinically delivered plans. Differences between predicted and delivered doses were assessed by root-mean square deviation (RMSD), and statistical differences between predicted, delivered, and re-planned doses were evaluated with one-way analysis of variance (ANOVA) tests.

RESULTS: ANOVA tests showed no significant differences between predicted, delivered, and replanned OAR doses (all p ≥ 0.36). The RMSD was 2.9, 3.9, 4.3, and 1.7Gy for max dose to the spinal cord, great vessels, heart, and trachea, respectively, for 50 Gy in five fractions. Average improvements of 1.0, 1.4, and 2.0 Gy were seen for spinal cord, esophagus, and trachea max doses in blinded replans compared to clinically delivered plans with 54 Gy in three fractions, and 1.8, 0.7, and 1.5 Gy, respectively, for the esophagus, heart and bronchus max doses with 50 Gy in five fractions. Target coverage was similar with an average PTV V100% of 94.7% for delivered plans compared to 97.3% for blinded re-plans for 50 Gy in five fractions, and respectively 98.4% versus 99.2% for 54 Gy in three fractions.

CONCLUSION: This study validated ML-based OAR dose prediction for lung SBRT, showing potential for improved OAR dose sparing and more consistent plan quality using dose predictions for patient-specific planning guidance.

PMID:35460150 | DOI:10.1002/acm2.13609

J Sleep Res. 2022 Apr 22. doi: 10.1111/jsr.13604. Online ahead of print.

ABSTRACT

Insomnia disorder comprises symptoms during night and day that strongly affect quality of life and wellbeing. Prolonged sleep latency, difficulties to maintain sleep and early morning wakening characterize sleep complaints, whereas fatigue, reduced attention, impaired cognitive functioning, irritability, anxiety and low mood are key daytime impairments. Insomnia disorder is well acknowledged in all relevant diagnostic systems: Diagnostic and Statistical Manual of the American Psychiatric Association, 5th revision, International Classification of Sleep Disorders, 3rd version, and International Classification of Diseases, 11th revision. Insomnia disorder as a chronic condition is frequent (up to 10% of the adult population, with a preponderance of females), and signifies an important and independent risk factor for physical and, especially, mental health. Insomnia disorder diagnosis primarily rests on self-report. Objective measures like actigraphy or polysomnography are not (yet) part of the routine diagnostic canon, but play an important role in research. Disease concepts of insomnia range from cognitive-behavioural models to (epi-) genetics and psychoneurobiological approaches. The latter is derived from knowledge about basic sleep-wake regulation and encompass theories like rapid eye movement sleep instability/restless rapid eye movement sleep. Cognitive-behavioural models of insomnia led to the conceptualization of cognitive-behavioural therapy for insomnia, which is now considered as first-line treatment for insomnia worldwide. Future research strategies will include the combination of experimental paradigms with neuroimaging and may benefit from more attention to dysfunctional overnight alleviation of distress in insomnia. With respect to therapy, cognitive-behavioural therapy for insomnia merits widespread implementation, and digital cognitive-behavioural therapy may assist delivery along treatment guidelines. However, given the still considerable proportion of patients responding insufficiently to cognitive-behavioural therapy for insomnia, fundamental studies are highly necessary to better understand the brain and behavioural mechanisms underlying insomnia. Mediators and moderators of treatment response/non-response and the associated development of tailored and novel interventions also require investigation. Recent studies suggest that treatment of insomnia may prove to add significantly as a preventive strategy to combat the global burden of mental disorders.

PMID:35460140 | DOI:10.1111/jsr.13604