Tag: statistics

J Clin Hypertens (Greenwich). 2024 Mar 19. doi: 10.1111/jch.14793. Online ahead of print.

ABSTRACT

Previous work comparing safety and effectiveness outcomes for new initiators of angiotensin converting-enzyme inhibitors (ACEi) and thiazides demonstrated more favorable outcomes for thiazides, although cohort definitions allowed for addition of a second antihypertensive medication after a week of monotherapy. Here, we modify the monotherapy definition, imposing exit from cohorts upon addition of another antihypertensive medication. We determine hazard ratios (HR) for 55 safety and effectiveness outcomes over six databases and compare results to earlier findings. We find, for all primary outcomes, statistically significant differences in effectiveness between ACEi and thiazides were not replicated (HRs: 1.11, 1.06, 1.12 for acute myocardial infarction, hospitalization with heart failure and stroke, respectively). While statistical significance is similarly lost for several safety outcomes, the safety profile of thiazides remains more favorable. Our results indicate a less striking difference in effectiveness of thiazides compared to ACEi and reflect some sensitivity to the monotherapy cohort definition modification.

PMID:38501749 | DOI:10.1111/jch.14793

Foot Ankle Int. 2024 Mar 19:10711007241237532. doi: 10.1177/10711007241237532. Online ahead of print.

ABSTRACT

BACKGROUND: Acquired adult flatfoot deformity (AAFD) results in a loss of the medial longitudinal arch of the foot and dysfunction of the posteromedial soft tissues. Hintermann osteotomy (H-O) is often used to treat stage II AAFD. The procedure is challenging because of variations in the subtalar facets and limited intraoperative visibility. We aimed to assess the impact of augmented reality (AR) guidance on surgical accuracy and the facet violation rate.

METHODS: Sixty AR-guided and 60 conventional osteotomies were performed on foot bone models. For AR osteotomies, the ideal osteotomy plane was uploaded to a Microsoft HoloLens 1 headset and carried out in strict accordance with the superimposed holographic plane. The conventional osteotomies were performed relying solely on the anatomy of the calcaneal lateral column. The rate and severity of facet joint violation was measured, as well as accuracy of entry and exit points. The results were compared across AR-guided and conventional osteotomies, and between experienced and inexperienced surgeons.

RESULTS: Experienced surgeons showed significantly greater accuracy for the osteotomy entry point using AR, with the mean deviation of 1.6 ± 0.9 mm (95% CI 1.26, 1.93) compared to 2.3 ± 1.3 mm (95% CI 1.87, 2.79) in the conventional method (P = .035). The inexperienced had improved accuracy, although not statistically significant (P = .064), with the mean deviation of 2.0 ± 1.5 mm (95% CI 1.47, 2.55) using AR compared with 2.7 ± 1.6 mm (95% CI 2.18, 3.32) in the conventional method. AR helped the experienced surgeons avoid full violation of the posterior facet (P = .011). Inexperienced surgeons had a higher rate of middle and posterior facet injury with both methods (P = .005 and .021).

CONCLUSION: Application of AR guidance during H-O was associated with improved accuracy for experienced surgeons, demonstrated by a better accuracy of the osteotomy entry point. More crucially, AR guidance prevented full violation of the posterior facet in the experienced group. Further research is needed to address limitations and test this technology on cadaver feet. Ultimately, the use of AR in surgery has the potential to improve patient and surgeon safety while minimizing radiation exposure.

CLINICAL RELEVANCE: Subtalar facet injury during lateral column lengthening osteotomy represents a real problem in clinical orthopaedic practice. Because of limited intraoperative visibility and variable anatomy, it is hard to resolve this issue with conventional means. This study suggests the potential of augmented reality to improve the osteotomy accuracy.

PMID:38501722 | DOI:10.1177/10711007241237532

Pediatr Pulmonol. 2024 Mar 19. doi: 10.1002/ppul.26975. Online ahead of print.

ABSTRACT

BACKGROUND: Fetal exposure to tobacco smoking throughout pregnancy is associated with wheezing in infancy. We investigated the influence of in utero smoking exposure on lung ventilation homogeneity and the relationship between lung ventilation inhomogeneity at 7 weeks of age and wheezing in the first year of life.

METHODS: Maternal smoking was defined as self-reported smoking of tobacco or validated by exhaled (e)CO > 6 ppm. Lung function data from healthy infants (age 5-9 weeks) born to asthmatic mothers and parent-reported respiratory questionnaire data aged 12 months were collected in the Breathing for Life Trial (BLT) birth cohort. Tidal breathing analysis and SF₆ -based Multiple Breath Washout testing were performed in quiet sleep. Descriptive statistics and regression analysis were used to assess associations.

RESULTS: Data were collected on 423 participants. Infants born to women who self-reported smoking during pregnancy (n = 42) had higher lung clearance index (LCI) than those born to nonsmoking mothers (7.90 vs. 7.64; p = .030). Adjusted regression analyzes revealed interactions between self-reported smoking and LCI (RR: 1.98, 95% CI: 1.07-3.63, 0.028, for each unit increase in LCI) and between eCO > 6 ppm and LCI (RR: 2.25, 95% CI: 1.13-4.50, 0.022) for the risk of wheeze in the first year of life.

CONCLUSION: In utero tobacco smoke exposure induces lung ventilation inhomogeneities. Furthermore, an interaction between smoke exposure and lung ventilation inhomogeneities increases the risk of having a wheeze in the first year of life.

PMID:38501326 | DOI:10.1002/ppul.26975

Clin Transl Sci. 2024 Mar;17(3):e13772. doi: 10.1111/cts.13772.

ABSTRACT

Genetic variants affect drug responses, making pre-emptive genotyping crucial for averting serious adverse events (SAEs) and treatment failure. However, assessing the benefits of pre-emptive genotyping based on genetic distribution, drug exposure, and demographics is challenging. This study aimed to estimate the population-level benefits of pre-emptive genotyping in the Korean population using nationwide cohort data. We reviewed actionable gene-drug combinations recommended by both the Clinical Pharmacogenomics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group (DPWG) as of February 2022, identifying high-risk phenotypes. We collected reported risk reduction from genotyping and standardized it into population attributable risks. Healthcare reimbursement costs for SAEs and treatment failures were obtained from the Health Insurance Review and Assessment Service Statistics in 2021. The benefits of pre-emptive genotyping for a specific group were determined by multiplying drug exposure from nationwide cohort data by individual genotyping benefits. We identified 31 gene-drug-event pairs, with CYP2D6 and CYP2C19 demonstrating the greatest benefits for both male and female patients. Individuals aged 65-70 years had the highest individual benefit from pre-emptive genotyping, with $84.40 for men and $100.90 for women. Pre-emptive genotyping, particularly for CYP2D6 and CYP2C19, can provide substantial benefits.

PMID:38501281 | DOI:10.1111/cts.13772

Hypertension. 2024 Mar 19. doi: 10.1161/HYPERTENSIONAHA.123.22142. Online ahead of print.

ABSTRACT

BACKGROUND: Coarctation of the aorta (CoA) often leads to hypertension) posttreatment. Evidence is lacking for the current >20 mm Hg peak-to-peak blood pressure (BP) gradient (BPGpp) guideline, which can cause aortic thickening, stiffening, and dysfunction. This study sought to find the BPGpp severity and duration that avoid persistent dysfunction in a preclinical model and test if predictors translate to hypertension status in patients with CoA.

METHODS: Rabbits (n=75; 5-12/group) were exposed to mild, intermediate, or severe CoA (≤12, 13-19, ≥20 mm Hg BPGpp) for ≈1, 3, or 22 weeks using dissolvable and permanent sutures with thickening, stiffening, contraction, and endothelial function evaluated via multivariate regression. Relevance to patients with CoA (n=239; age, 0.01-46 years; median 3.7 months) was tested by retrospective review of predictors (preoperative BPGpp, surgical age, etc.) versus follow-up hypertension status.

RESULTS: CoA duration and severity were predictive of aortic remodeling and active dysfunction in rabbits, and hypertension in patients with CoA. Interaction between patient age and BPGpp at surgery contributed significantly to hypertension, similar to rabbits, suggesting preclinical findings translate to patients. Machine learning decision tree analysis uncovered that preoperative BPGpp and surgical age predict risk of hypertension along with residual postoperative BPGpp.

CONCLUSIONS: These findings suggest the current BPGpp threshold determined decades ago is likely too high to prevent adverse coarctation-induced aortic remodeling. The results and decision tree analysis provide a foundation for revising CoA treatment guidelines considering the interaction between CoA severity and duration to limit the risk of hypertension.

PMID:38501250 | DOI:10.1161/HYPERTENSIONAHA.123.22142

Hypertension. 2024 Mar 19. doi: 10.1161/HYPERTENSIONAHA.123.22418. Online ahead of print.

ABSTRACT

BACKGROUND: Whether individuals with gestational diabetes (GDM) had an increased risk of hypertension remains unclear. We conducted a systematic literature review and meta-analysis to examine the association between GDM and hypertension and performed a quantitative bias analysis to quantify the impact of uncontrolled confounding due to antenatal psychological stress.

METHODS: We searched databases (PUBMED, EMBASE, and Web of Science) through 2022/11. Eligible studies were cohort studies that reported the association of GDM with hypertension. We assessed the risk of bias using the Newcastle-Ottawa Scale for cohort studies. We pooled adjusted risk ratios with 95% CIs using a random effects model. We performed the quantitative bias analysis using the bias formula.

RESULTS: We included 15 cohort studies, with a total of 3 959 520 (GDM, 175 378; non-GDM, 3 784 142) individuals. During the follow-up of 2 to 20 years, 106 560 cases of hypertension were reported. We found that GDM was associated with a higher risk of hypertension (pooled risk ratio, 1.78 [95% CI, 1.47, 2.17]). The risk ratio was lower among cohorts assessing incident (1.58 [95% CI, 1.29, 1.95]) than prevalent hypertension (2.60 [95% CI, 2.40, 2.83]). However, other subgroup analyses showed no differences. The quantitative bias analysis revealed that if the uncontrolled confounder of antenatal psychological stress was additionally adjusted, the positive association between GDM and hypertension would attenuate slightly (≤18%) but remains positive.

CONCLUSIONS: Limitations of this study included residual confounding and discrepancies in GDM and hypertension ascertainments. Our findings indicate that GDM is positively associated with hypertension after the index pregnancy.

PMID:38501243 | DOI:10.1161/HYPERTENSIONAHA.123.22418

Environ Microbiol. 2024 Mar;26(3):e16615. doi: 10.1111/1462-2920.16615.

ABSTRACT

Microbial communities are commonly characterised through the metabarcoding of environmental DNA. This DNA originates from both viable (including dormant and active) and dead organisms, leading to recent efforts to distinguish between these states. In this study, we further these approaches by distinguishing not only between viable and dead cells but also between dormant and actively growing cells. This is achieved by sequencing both rRNA and rDNA, in conjunction with propidium monoazide cross-linked rDNA, to partition the active, dormant and relic fractions in environmental samples. We apply this method to characterise the diversity and assemblage structure of these fractions of microeukaryotes in intertidal sediments during a wet-dry-rewet incubation cycle. Our findings indicate that a significant proportion of microeukaryotic phylotypes detected in the total rDNA pools originate from dormant and relic microeukaryotes in the sediments, both in terms of richness (dormant, 13 ± 2%; relic, 47 ± 5%) and read abundance (dormant, 20 ± 7%; relic, 14 ± 5%). The richness and sequence proportion of dormant microeukaryotes notably increase during the transition from wet to dry conditions. Statistical analyses suggest that the dynamics of diversity and assemblage structure across different activity fractions are influenced by various environmental drivers. Our strategy offers a versatile approach that can be adapted to characterise other microbes in a wide range of environments.

PMID:38501240 | DOI:10.1111/1462-2920.16615

Cancer Med. 2024 Mar;13(5). doi: 10.1002/cam4.6776.

ABSTRACT

Mivavotinib (TAK-659/CB-659), a dual SYK/FLT3 inhibitor, reduced immunosuppressive immune cell populations and suppressed tumor growth in combination with anti-PD-1 therapy in cancer models. This dose-escalation/expansion study investigated the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of mivavotinib plus nivolumab in patients with advanced solid tumors. Patients received oral mivavotinib 60-100 mg once-daily plus intravenous nivolumab 3 mg/kg on days 1 and 15 in 28-day cycles until disease progression or unacceptable toxicity. The dose-escalation phase evaluated the recommended phase II dose (RP2D; primary endpoint). The expansion phase evaluated overall response rate (primary end point) at the RP2D in patients with triple-negative breast cancer (TNBC). During dose-escalation (n = 24), two dose-limiting toxicities (grade 4 lipase increased and grade 3 pyrexia) occurred in patients who received mivavotinib 80 mg and 100 mg, respectively. The determined RP2D was once-daily mivavotinib 80 mg plus nivolumab 3 mg/kg. The expansion phase was terminated at ~50% enrollment (n = 17) after failing to meet an ad hoc efficacy futility threshold. Among all 41 patients, common treatment-emergent adverse events (TEAEs) included dyspnea (48.8%), aspartate aminotransferase increased, and pyrexia (46.3% each). Common grade ≥3 TEAEs were hypophosphatemia and anemia (26.8% each). Mivavotinib plasma exposure was generally dose-proportional (60-100 mg). One patient had a partial response. Mivavotinib 80 mg plus nivolumab 3 mg/kg was well tolerated with no new safety signals beyond those of single-agent mivavotinib or nivolumab. Low response rates highlight the challenges of treating unresponsive tumor types, such as TNBC, with this combination and immunotherapies in general. TRIAL REGISTRATION ID: NCT02834247.

PMID:38501219 | DOI:10.1002/cam4.6776

JAMA. 2024 Mar 19. doi: 10.1001/jama.2024.2934. Online ahead of print.

ABSTRACT

IMPORTANCE: Supplemental oxygen is ubiquitously used in patients with COVID-19 and severe hypoxemia, but a lower dose may be beneficial.

OBJECTIVE: To assess the effects of targeting a Pao2 of 60 mm Hg vs 90 mm Hg in patients with COVID-19 and severe hypoxemia in the intensive care unit (ICU).

DESIGN, SETTING, AND PARTICIPANTS: Multicenter randomized clinical trial including 726 adults with COVID-19 receiving at least 10 L/min of oxygen or mechanical ventilation in 11 ICUs in Europe from August 2020 to March 2023. The trial was prematurely stopped prior to outcome assessment due to slow enrollment. End of 90-day follow-up was June 1, 2023.

INTERVENTIONS: Patients were randomized 1:1 to a Pao2 of 60 mm Hg (lower oxygenation group; n = 365) or 90 mm Hg (higher oxygenation group; n = 361) for up to 90 days in the ICU.

MAIN OUTCOMES AND MEASURES: The primary outcome was the number of days alive without life support (mechanical ventilation, circulatory support, or kidney replacement therapy) at 90 days. Secondary outcomes included mortality, proportion of patients with serious adverse events, and number of days alive and out of hospital, all at 90 days.

RESULTS: Of 726 randomized patients, primary outcome data were available for 697 (351 in the lower oxygenation group and 346 in the higher oxygenation group). Median age was 66 years, and 495 patients (68%) were male. At 90 days, the median number of days alive without life support was 80.0 days (IQR, 9.0-89.0 days) in the lower oxygenation group and 72.0 days (IQR, 2.0-88.0 days) in the higher oxygenation group (P = .009 by van Elteren test; supplemental bootstrapped adjusted mean difference, 5.8 days [95% CI, 0.2-11.5 days]; P = .04). Mortality at 90 days was 30.2% in the lower oxygenation group and 34.7% in the higher oxygenation group (risk ratio, 0.86 [98.6% CI, 0.66-1.13]; P = .18). There were no statistically significant differences in proportion of patients with serious adverse events or in number of days alive and out of hospital.

CONCLUSION AND RELEVANCE: In adult ICU patients with COVID-19 and severe hypoxemia, targeting a Pao2 of 60 mm Hg resulted in more days alive without life support in 90 days than targeting a Pao2 of 90 mm Hg.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04425031.

PMID:38501214 | DOI:10.1001/jama.2024.2934

JAMA. 2024 Mar 19. doi: 10.1001/jama.2024.3376. Online ahead of print.

NO ABSTRACT

PMID:38501213 | DOI:10.1001/jama.2024.3376