Nevin Manimala

Biometrics. 2022 May 8. doi: 10.1111/biom.13690. Online ahead of print.

ABSTRACT

Identifying a biomarker or treatment-dose threshold that marks a specified level of risk is an important problem, especially in clinical trials. In view of this goal, we consider a covariate-adjusted threshold-based interventional estimand, which happens to equal the binary treatment-specific mean estimand from the causal inference literature obtained by dichotomizing the continuous biomarker or treatment as above or below a threshold. The unadjusted version of this estimand was considered in Donovan et al. (2019). Expanding upon Stitelmen et al. (2010), we show that this estimand, under conditions, identifies the expected outcome of a stochastic intervention that sets the treatment dose of all participants above the threshold. We propose a novel nonparametric efficient estimator for the covariate-adjusted threshold-response function for the case of informative outcome missingness, which utilizes machine learning and Targeted Minimum-Loss Estimation (TMLE). We prove the estimator is efficient and characterize its asymptotic distribution and robustness properties. Construction of simultaneous 95% confidence bands for the threshold-specific estimand across a set of thresholds is discussed. In the supplementary information, we discuss how to adjust our estimator when the biomarker is missing-at-random, as occurs in clinical trials with biased sampling designs, using inverse-probability-weighting. Efficiency and bias-reduction of the proposed estimator are assessed in simulations. The methods are employed to estimate neutralizing antibody thresholds for virologically confirmed dengue risk in the CYD14 and CYD15 dengue vaccine trials. This article is protected by copyright. All rights reserved.

PMID:35526218 | DOI:10.1111/biom.13690

JMIR Form Res. 2022 May 8. doi: 10.2196/37302. Online ahead of print.

ABSTRACT

BACKGROUND: Digital applications are commonly used to support mental health and well-being. However, successfully retaining and engaging users to complete digital interventions is challenging, and comorbidities such as chronic pain further reduce user engagement. Digital conversational agents may improve user engagement by applying engagement principles that have been implemented within in-person care settings.

OBJECTIVE: To evaluate user retention and engagement with an artificial intelligence (AI)-led digital mental health application (app) that is customized for individuals managing mental health symptoms and coexisting chronic pain (Wysa for Chronic Pain).

METHODS: In this ancillary survival analysis of a clinical trial, participants included 51 adults who presented to a tertiary care center for chronic musculoskeletal pain, who endorsed coexisting symptoms of depression and/or anxiety (PROMIS Depression and/or Anxiety score ≥ 55), and initiated onboarding to an 8-week subscription of Wysa for Chronic Pain. The study outcomes were user retention, defined as revisiting the app each week and the last day of engagement, and user engagement, defined by the number of sessions the user completed.

RESULTS: Users engaged in a cumulative mean of 33.3 sessions during the eight-week study period. The survival analysis depicted a median user retention period (i.e., time to complete disengagement) of 51 days, with the usage of a morning check-in feature statistically significant in its relationship with a longer retention period (p = .001).

CONCLUSIONS: Our findings suggest that the user retention and engagement with a CBT-based conversational agent which is built for users with chronic pain is higher than standard industry metrics. These results have clear implications for addressing issues of suboptimal engagement of digital health interventions and improving access to care for chronic pain. Future work should use these findings to inform the design of evidence-based interventions for individuals with chronic pain and to enhance user retention and engagement of digital health interventions more broadly.

CLINICALTRIAL: NCT04640090, Clinicaltrials.gov.

PMID:35526201 | DOI:10.2196/37302

Int J Epidemiol. 2022 May 8:dyac078. doi: 10.1093/ije/dyac078. Online ahead of print.

ABSTRACT

Nearly all diseases are caused by different combinations of exposures. Yet, most epidemiological studies focus on estimating the effect of a single exposure on a health outcome. We present the Causes of Outcome Learning approach (CoOL), which seeks to discover combinations of exposures that lead to an increased risk of a specific outcome in parts of the population. The approach allows for exposures acting alone and in synergy with others. The road map of CoOL involves (i) a pre-computational phase used to define a causal model; (ii) a computational phase with three steps, namely (a) fitting a non-negative model on an additive scale, (b) decomposing risk contributions and (c) clustering individuals based on the risk contributions into subgroups; and (iii) a post-computational phase on hypothesis development, validation and triangulation using new data before eventually updating the causal model. The computational phase uses a tailored neural network for the non-negative model on an additive scale and layer-wise relevance propagation for the risk decomposition through this model. We demonstrate the approach on simulated and real-life data using the R package ‘CoOL’. The presentation focuses on binary exposures and outcomes but can also be extended to other measurement types. This approach encourages and enables researchers to identify combinations of exposures as potential causes of the health outcome of interest. Expanding our ability to discover complex causes could eventually result in more effective, targeted and informed interventions prioritized for their public health impact.

PMID:35526156 | DOI:10.1093/ije/dyac078

Hum Reprod Update. 2022 May 8:dmac016. doi: 10.1093/humupd/dmac016. Online ahead of print.

ABSTRACT

BACKGROUND: The beneficial effects of hormonal therapy in stimulating spermatogenesis in patients with non-obstructive azoospermia (NOA) and either normal gonadotrophins or hypergonadotropic hypogonadism prior to surgical sperm retrieval (SSR) is controversial. Although the European Association of Urology guidelines state that hormone stimulation is not recommended in routine clinical practice, a significant number of patients undergo empiric therapy prior to SSR. The success rate for SSR from microdissection testicular sperm extraction is only 40-60%, thus hormonal therapy could prove to be an effective adjunctive therapy to increase SSR rates.

OBJECTIVE AND RATIONALE: The primary aim of this systematic review and meta-analysis was to compare the SSR rates in men with NOA (excluding those with hypogonadotropic hypogonadism) receiving hormone therapy compared to placebo or no treatment. The secondary objective was to compare the effects of hormonal therapy in normogonadotropic and hypergonadotropic NOA men.

SEARCH METHODS: A literature search was performed using the Medline, Embase, Web of Science and Clinicaltrials.gov databases from 01 January 1946 to 17 September 2020. We included all studies where hormone status was confirmed. We excluded non-English language and animal studies. Heterogeneity was calculated using I2 statistics and risk of bias was assessed using Cochrane tools. We performed a meta-analysis on all the eligible controlled trials to determine whether hormone stimulation (irrespective of class) improved SSR rates and also whether this was affected by baseline hormone status (hypergonadotropic versus normogonadotropic NOA men). Sensitivity analyses were performed when indicated.

OUTCOMES: A total of 3846 studies were screened and 22 studies were included with 1706 participants. A higher SSR rate in subjects pre-treated with hormonal therapy was observed (odds ratio (OR) 1.96, 95% CI: 1.08-3.56, P = 0.03) and this trend persisted when excluding a study containing only men with Klinefelter syndrome (OR 1.90, 95% CI: 1.03-3.51, P = 0.04). However, the subgroup analysis of baseline hormone status demonstrated a significant improvement only in normogonadotropic men (OR 2.13, 95% CI: 1.10-4.14, P = 0.02) and not in hypergonadotropic patients (OR 1.73, 95% CI: 0.44-6.77, P = 0.43). The literature was at moderate or severe risk of bias.

WIDER IMPLICATIONS: This meta-analysis demonstrates that hormone therapy is not associated with improved SSR rates in hypergonadotropic hypogonadism. While hormone therapy improved SSR rates in eugonadal men with NOA, the quality of evidence was low with a moderate to high risk of bias. Therefore, hormone therapy should not be routinely used in men with NOA prior to SSR and large scale, prospective randomized controlled trials are needed to validate the meta-analysis findings.

PMID:35526153 | DOI:10.1093/humupd/dmac016

JPEN J Parenter Enteral Nutr. 2022 May 8. doi: 10.1002/jpen.2393. Online ahead of print.

ABSTRACT

BACKGROUND: Indirect calorimetry (IC) is the gold standard for measuring resting energy expenditure. Energy expenditure (EE) estimated by ventilator-derived carbon dioxide consumption (EEVCO₂ ) has also been proposed. In the absence of indirect calorimetry predictive weight-based equations have been recommended to estimate daily energy requirements. This study aims to compare simple predictive weight-based equations with those estimated by EEVCO2 and indirect calorimetry in mechanically ventilated patients of Covid-19.

METHODS: Retrospective study of a cohort of adult critically ill COVID-19 patients requiring mechanical ventilation and artificial nutrition to compare energy estimations by three methods through the calculation of bias and precision agreement, reliability and accuracy rates.

RESULTS: In 58 mechanically ventilated patients, a total of 117 paired measurements were obtained. The mean estimated energy derived from weight-based calculations was 2576±469 kcals/24hours, as compared to 1507±499 kcal/24hours when estimation of EE by indirect calorimetry, resulting in a significant bias of 1069 kcal/day (95% CI (-2158 – 18.7 kcal); p < 0.001). Similarly estimated mean EEVCO2 was 1388±467 kcals/24hours, when compared with estimation of EE from indirect calorimetry, a significant bias of only 118 kcal/day (95% CI (-187 – 422 kcal); p < 0.001) compared by the Bland-Altman plot was noted.

CONCLUSION: The energy estimated with EEVCO2 correlated better with IC values, than energy derived from weight-based calculations. Our data suggests that the use of simple predictive equations may potentially lead to overfeeding in mechanically ventilated Covid-19 patients.

CLINICAL RELEVANCY STATEMENT: Both overfeeding and underfeeding of intensive care unit (ICU) patients are associated with worse outcomes. Ideally, the individual caloric target is based on the frequent assessment of energy expenditure (EE). Indirect calorimetry is considered the gold standard but is not always available. EE estimated by ventilator-derived carbon dioxide consumption (EEVCO2) derived from ventilator and stand-alone monitors has also been proposed as an alternative. Guidelines recommend predictive weight-based dosing when indirect calorimetry (IC) is not feasible to estimate daily energy requirements. This study was able to prove that guideline-recommended weight-based calculations overestimated the energy requirements and we were able to arrive at an energy estimation that can be closer to the EE with IC and EEVCO2 among COVID-19 patients. This study would help in standardizing the more commonly used weight-based calculations for energy estimation. This article is protected by copyright. All rights reserved.

PMID:35526145 | DOI:10.1002/jpen.2393

Mol Ther. 2022 May 6:S1525-0016(22)00299-4. doi: 10.1016/j.ymthe.2022.05.002. Online ahead of print.

ABSTRACT

A promising treatment for β-hemoglobinopathies is the de-repression of γ-globin expression leading to increased fetal hemoglobin (HbF) by targeting BCL11A. Here, we aim to improve a lentivirus vector (LV) containing a single BCL11A shmiR (SS) to further increase γ-globin induction. We engineered a novel LV to express two shmiRs simultaneously targeting BCL11A and the γ-globin repressor, ZNF410. Erythroid cells derived from human HSCs transduced with the double shmiR (DS) showed up to 70% reduction of both BCL11A and ZNF410 proteins. There was a consistent and significant additional 10% increase in HbF compared to targeting BCL11A alone in erythroid cells. Erythrocytes differentiated from SCD HSCs transduced with the DS demonstrated significantly reduced in vitro sickling phenotype compared to the SS. Erythrocytes differentiated from transduced HSCs from β-thalassemia major patients demonstrated improved globin chain balance by increased γ-globin with reduced microcytosis. Reconstitution of DS-transduced cells from Berkeley SCD mice was associated with a statistically larger reduction in peripheral blood hemolysis markers compared with the SS vector. Overall, these results indicate that the DS LV targeting BCL11A and ZNF410 can enhance HbF induction for treating β-hemoglobinopathies and could be used as a model to simultaneously and efficiently target multiple gene products.

PMID:35526095 | DOI:10.1016/j.ymthe.2022.05.002

J Clin Nurs. 2022 May 7. doi: 10.1111/jocn.16343. Online ahead of print.

ABSTRACT

AIM AND OBJECTIVES: To describe nurses with substance use disorder (SUD) in authority disciplinary actions.

BACKGROUND: Nurses with SUD risk patient safety. Research evidence on the identification of nurses’ SUD and related management procedures is currently sparse.

DESIGN: Retrospective document analysis of decisions related to SUD in nurses’ disciplinary actions.

METHOD: Decisions on nurses (N = 171) made by the Finnish National Supervisory Authority for Welfare and Health in Finland during 2007-2016 were used as data. An electronic extraction sheet was developed for data collection including variables (N = 34), of which 18 were analysed in this study with descriptive statistical methods and chi-squared statistics. The study reported in accordance with the STROBE checklist for cross-sectional studies.

RESULTS: The mean age of the nurses was 43 years (SD 8.7). The most mentioned reasons for notifications leading to disciplinary actions were substance abuse with working while intoxicated and drug theft. The most mentioned intoxicants used were medicines and alcohol. On average, the first disciplinary decision was given at 6.4 months (SD 3.9) and the final decision was given at 17.9 months (SD 13.1). The most common decision was restriction of the right to practice.

CONCLUSION: The results supported findings from previous decades and different continents, showing similar trends are prevalent globally and continue today. In future studies, countries’ registers of nurses with SUD could be used to clarify the profile of nurses and develop appropriate procedures. Qualitative studies could be conducted to investigate to shed light on concealment of the phenomenon.

RELEVANCE TO CLINICAL PRACTICE: There is a need for early identification, intervention and referral to treatment as well as effective protocols for reducing nurses’ risks of disciplinary actions related to SUD. It is important to be aware of the signs and symptoms of SUD and training for this is needed.

PMID:35526092 | DOI:10.1111/jocn.16343

Chemphyschem. 2022 May 7. doi: 10.1002/cphc.202200205. Online ahead of print.

ABSTRACT

In this study, a series of tetrafluoroborates with non- π -conjugated [BF 4 ] tetrahedra are investigated systematically by utilizing the first-principles calculations. Theoretical studies demonstrate that tetrafluoroborates with alkali and/or alkaline-earth metals are more favorable for deep-ultraviolet transmission and are comparable to the classical deep-ultraviolet (deep-UV) material, MgF 2 . Furthermore, bandgap decrease with the increasing of ionic radii in alkali and/or alkaline-earth metals. Introducing highly polarizable cations with d 10 -configuration or cations with lone pair electrons into the structure will decrease the bandgaps. The birefringence and second harmonic generation effects are not large enough in tetrafluoroborates because polarizability anisotropy and hyperpolarizability in non- π -conjugated [BF 4 ] tetrahedra are much smaller than those in π -conjugated groups. However, the second harmonic generation effect for [BF 4 ] tetrahedra has a higher contribution in comparison with that due to birefringence. To effectively synthesize the borate fluorides or fluorooxoborates in the deep-UV region, raw materials with B-F bonds are preferred.

PMID:35524646 | DOI:10.1002/cphc.202200205

J Health Popul Nutr. 2022 May 7;41(1):17. doi: 10.1186/s41043-022-00296-9.

ABSTRACT

BACKGROUND: Balanced nutrition is crucial for adolescent’s proper physical and mental development. Dietary habits change significantly with a child’s development. Along with increasing age and the shift towards adolescence, unhealthy diet-related habits become more common. The objective of the survey study was to determine the differences in nutritional habits between children and adolescents according to their age and body mass index (BMI).

METHODS: “Let’s get the kids moving” campaign (pol. “Uruchamiamy dzieciaki”) was launched in 2016. Within the campaign, the survey study was conducted in 2913 participants between 6 and 17 years old from primary and junior high schools in Wroclaw (Poland). The survey was anonymous, and its supplement was voluntary. Participants were divided into age groups. The study group of 2913 consisted of 29.8% of 6-9-year-olds, 32.7% of 10-12-year-olds, and 37.5% of 13-17-year-olds. Body mass index (BMI) was calculated and further interpreted as a BMI z-scores depending on children’s age and gender.

RESULTS: A total of 19.3% of participants consumed 3 meals a day or less. Children from the oldest age group (13-17) consumed statistically significantly fewer meals per day than younger children (p < 0.001). Children from the oldest age group (13-17) consumed breakfast statistically less often than children of age group 10-12 years (75.0% vs. 83.6%; p < 0.001) and children of age group 6-9 years (75.0% vs. 84.0%; p < 0.001). Severely thin children consumed breakfast significantly more often than overweight (85.8% vs. 76.3%; p = 0.004) and children with obesity (85.8% vs. 75.9%; p = 0.021). Children with obesity consumed vegetables significantly less often than severely thin (p < 0.008), thin (p < 0.001), and children with normal body weight (p < 0.007). The oldest children (13-17 years) consumed Coca-Cola and SSB (p < 0.001) and fruit-flavored beverages (p < 0.05) significantly more often than children from other age groups. Boys consumed carbonated beverages with added sugar significantly more often than girls (p < 0.01).

CONCLUSIONS: Unhealthy diet-related behaviors in children and adolescents may promote overweight and obesity and should be targeted in health promotion programs. Special attention should be paid to 13-17-year-olds, as adolescents from this group made more unhealthy choices than younger children.

PMID:35526064 | DOI:10.1186/s41043-022-00296-9

Alzheimers Res Ther. 2022 May 7;14(1):63. doi: 10.1186/s13195-022-00997-7.

ABSTRACT

BACKGROUND: The combined effects of increased life expectancy and the considerable number of persons reaching old age will magnify the dementia epidemic in the USA. Demonstration that subclinical atherosclerosis precedes and is associated with cognitive impairment suggests a modifiable risk factor for age-associated cognitive impairment and dementia. The purpose of this study is to determine whether subclinical atherosclerosis as measured by carotid artery intima-media thickness (CIMT) is associated with changes in cognitive function over time in older adults.

METHODS: This study combined longitudinal data from three clinical trials conducted between 2000 and 2013: the B-Vitamin Atherosclerosis Intervention Trial (BVAIT), the Women’s Isoflavone Soy Health (WISH) trial, and the Early versus Late Intervention Trial with Estradiol (ELITE). Participants were recruited from the general population in the Greater Los Angeles area and were free of cardiovascular disease and diabetes; no cognitive or psychiatric exclusion criteria were specified. The same standardized protocol for ultrasound image acquisition and measurement of CIMT was used in all trials. CIMT measurements performed at baseline and 2.5 years were used in these analyses. Cognitive function was assessed at baseline and 2.5 years using a battery of 14 standardized cognitive tests. All clinical trials were conducted at the University of Southern California Atherosclerosis Research Unit, Los Angeles, and had at least 2.5 years of cognitive follow-up.

RESULTS: A total of 308 men and 1187 women, mean age of 61 years, were included in the combined longitudinal dataset for the primary analysis. No associations were found between CIMT and cognitive function at baseline or at 2.5 years. There was a weak inverse association between CIMT measured at baseline and change in global cognition assessed over 2.5 years (β (SE) = – 0.056 (0.028) units per 0.1 mm CIMT, 95% CI – 0.110, – 0.001, p = 0.046). No associations between CIMT at baseline and changes in executive function, verbal memory, or visual memory were found.

CONCLUSIONS: In this sample of healthy older adults, our findings suggest an association between subclinical atherosclerosis and change in global cognitive function over 2.5 years. Stronger associations were observed longitudinally over 2.5 years than cross-sectionally. When analysis was stratified by age group (<65 and ≥65 years old), the inverse association remained statistically significant for participants in the older age group. Subclinical atherosclerosis of the carotid artery may be a modifiable correlate of cognitive decline in middle and older age.

TRIAL REGISTRATION: BVAIT, NCT00114400 . WISH, NCT00118846 . ELITE, NCT00114517 .

PMID:35526057 | DOI:10.1186/s13195-022-00997-7