Category: Statistics

PLoS Comput Biol. 2021 Dec 23;17(12):e1009295. doi: 10.1371/journal.pcbi.1009295. Online ahead of print.

ABSTRACT

Pre-exposure prophylaxis (PrEP) is an important pillar to prevent HIV transmission. Because of experimental and clinical shortcomings, mathematical models that integrate pharmacological, viral- and host factors are frequently used to quantify clinical efficacy of PrEP. Stochastic simulations of these models provides sample statistics from which the clinical efficacy is approximated. However, many stochastic simulations are needed to reduce the associated sampling error. To remedy the shortcomings of stochastic simulation, we developed a numerical method that allows predicting the efficacy of arbitrary prophylactic regimen directly from a viral dynamics model, without sampling. We apply the method to various hypothetical dolutegravir (DTG) prophylaxis scenarios. The approach is verified against state-of-the-art stochastic simulation. While the method is more accurate than stochastic simulation, it is superior in terms of computational performance. For example, a continuous 6-month prophylactic profile is computed within a few seconds on a laptop computer. The method’s computational performance, therefore, substantially expands the horizon of feasible analysis in the context of PrEP, and possibly other applications.

PMID:34941864 | DOI:10.1371/journal.pcbi.1009295

Vet Sci. 2021 Dec 13;8(12):328. doi: 10.3390/vetsci8120328.

ABSTRACT

Feline infectious peritonitis (FIP) is a fatal disease caused by feline coronavirus or its variant, referred to as the FIP virus. Recently, favorable treatment outcomes of the anti-viral drug Mutian^® Xraphconn (Mutian X) were noted in cats with FIP. Thus, the therapeutic efficacy of Mutian X in cats with FIP must be explored, although the predictors of therapeutic success remain unknown. In the present study, we administered Mutian X to 141 pet cats with effusive FIP following initial veterinarian examinations. Of these, 116 cats survived but the remaining 25 died during treatment. Pre-treatment signalment, viral gene expression, and representative laboratory parameters for routine FIP diagnosis (i.e., hematocrit, albumin-to-globulin ratio, total bilirubin, serum amyloid-A, and α1-acid glycoprotein) were statistically compared between the survivor and non-survivor groups. The majority of these parameters, including hematocrit, albumin-to-globulin ratio, serum amyloid-A, α1-acid glycoprotein, and viral gene expression, were comparable between the two groups. Interestingly, however, total bilirubin levels in the survivor group were significantly lower than those in the non-survivor group (p < 0.0001). Furthermore, in almost all surviving cats with effusive FIP (96.6%, 28/29), the pre-treatment total bilirubin levels were below 0.5 mg/dL; however, the survival rate decreased drastically (14.3%, 1/7) when the pre-treatment total bilirubin levels exceeded 4.0 mg/dL. Thus, circulating total bilirubin levels may act as a prognostic risk factor for severe FIP and may serve as the predictor of the therapeutic efficacy of Mutian X against this fatal disease.

PMID:34941855 | DOI:10.3390/vetsci8120328

J Cardiovasc Med (Hagerstown). 2021 Dec 16. doi: 10.2459/JCM.0000000000001267. Online ahead of print.

ABSTRACT

BACKGROUND: Data of the EMPA-REG OUTCOME study have demonstrated a beneficial effect of the sodium-glucose cotransporter 2 inhibitor empagliflozin on cardiovascular outcome in patients with type 2 diabetes. The reduction in cardiovascular mortality and hospitalization due to heart failure might be in part explained by the direct effects of empagliflozin on cardiac diastolic function. The EmDia trial investigates the short-term effects of empagliflozin compared to placebo on the left ventricular E/E’ ratio as a surrogate of left ventricular diastolic function.

METHODS AND RESULTS: EmDia is a single-center, randomized, double-blind, two-arm, placebo-controlled, parallel group study of phase IV. Individuals with diabetes mellitus type 2 (T2DM) are randomized 1:1 to receive empagliflozin 10 mg per day or a placebo for 12 weeks. The main inclusion criteria are diagnosed as T2DM with stable glucose-lowering and/or dietary treatment, elevated HbA1c level (6.5-10.0% if receiving glucose-lowering therapy, or 6.5-9.0% if drug-naive), and diastolic cardiac dysfunction with left ventricular E/E’>=8. The primary end point is the difference of the change in the E/E’ ratio by treatment groups after 12 weeks. Secondary end points include assessment of the effect of empagliflozin on left ventricular systolic function, measures of vascular structure and function, as well as humoral cardiovascular biomarkers (i.e. brain natriuretic peptide, troponin, C-reactive protein). In addition, the multidimensional biodatabase enables explorative analyses of molecular biomarkers to gain insights into possible mechanisms of the effects of empagliflozin on human health in a systems medicine-oriented, multiomics approach.

CONCLUSION: By evaluating the short-term effect of empagliflozin with a comprehensive biobanking program, the EmDia Study offers an opportunity to primarily assess the effects on diastolic function but also to examine effects on clinical and molecular cardiovascular traits.

TRIAL REGISTRATION: ClinicalTrials.gov; NCT02932436. Registration date, 2016/10/13.

PMID:34939776 | DOI:10.2459/JCM.0000000000001267

Andrology. 2021 Dec 22. doi: 10.1111/andr.13148. Online ahead of print.

ABSTRACT

BACKGROUND: In the literature, there is not sufficient data on factors affecting the development of complications in patients with penile fracture after early surgical intervention.

OBJECTIVES: To investigate the predictors of long-term complications in patients who underwent immediate surgical repair for penile fracture.

MATERIALS/METHODS: This clinical study included a total of 31 cases of penile fracture in which surgical treatment was performed within the first 24 hours and penile fracture was confirmed during the operation. The patients with and without late complications were compared in terms of parameters such as age, tear size of the tunica albuginea of the penis, bilateral involvement of the corpora cavernosa involvement, urethral injuries, and duration from penile fracture to surgery.

RESULTS: The median age of the patients was 42 (interquartile range [IQR]: 34-51) years. The median time from penile fracture to surgery was 13 (8-18) hours. The median tear size was 16 (11-21) mm. Late complications were seen in 13 (41.9%) patients in the postoperative period. Erectile dysfunction (ED) developed in five (16.1%) patients in the postoperative period. There was no statistically significant relationship between age, tear size, time from penile fracture to surgery, and bilateral corporeal involvement in terms of ED development. Painful erections, penile deviations, urethral strictures, tunical scars, and re-fracture were the other late complications. There was a significant relationship between the development of any complication and time from penile fracture to surgery (p = 0.028) and tear size (p = 0.031). In the receiver operating characteristic analysis of complication development, the cut-off value for the time from penile fracture to surgery was 13.5 hours.

DISCUSSION AND CONCLUSION: We found that the longer time interval between penile fracture and surgery worsened the patient outcomes. In addition, tear size was determined to be a predictor for long-term complications. In our opinion, early treatment of penile fracture can prevent severe complications in these cases. This article is protected by copyright. All rights reserved.

PMID:34939748 | DOI:10.1111/andr.13148

Cell J. 2021 Nov;23(6):626-632. doi: 10.22074/cellj.2021.7308. Epub 2021 Nov 23.

ABSTRACT

OBJECTIVE: Epstein-Barr virus (EBV) and Human Herpes virus 6 (HHV-6) are believed to involve in multiple sclerosis (MS) pathogenesis. Natural killer (NK) and CD8⁺ T cells have essential roles in handling viral infections and their phenotypic and functional properties may be influenced following exposure to viral infections. Here, we investigated the association of NK and CD8⁺ T cells subpopulations frequency with EBV and HHV-6 viral load in MS patients.

MATERIALS AND METHODS: In this case-control study, EBV and HHV-6 viral load were evaluated in plasma of newly diagnosed relapsing-remitting MS (RRMS) patients at relapse phase (n=23), who were not on disease-modifying therapy (DMT), and sex- and age-matched healthy controls (n=19) using real-time polymerase chain reaction (PCR). The frequency of NK and CD8⁺ T cells subsets were assessed by CD27, CD28, CD45RO, CD56, and CD57 markers using flow cytometry.

RESULTS: Despite the increased level of EBV viral load in RRMS patients compared to the control group, there was no statistically significant difference in EBV and HHV-6 copy numbers between the studied groups. In addition, a significant decrease was observed in the percentages of CD56^bright CD57^– and CD56^dim CD57⁺ CD8^low CD45RO- NK cells in RRMS patients in comparison to healthy controls. Analysis of CD8⁺ T cell subsets showed a substantially high proportion of CD27⁺ CD28⁺ CD45RO⁺ CD57^– CD8^hi T cells in patients at relapse phase compared to controls. The frequency of NK and T cells subtypes was not associated with EBV and HHV6 plasma viral loads.

CONCLUSION: These findings further highlight the variation of NK and CD8⁺ T cells subsets frequency in clinically active RRMS patients. Since the composition of cells was not associated with EBV and HHV-6 viral load, perhaps other viral infections may be involved in altered NK and CD8⁺ T cells subpopulation. Larger cohort studies are needed to confirm these results.

PMID:34939755 | DOI:10.22074/cellj.2021.7308

J Intellect Disabil Res. 2021 Dec 23. doi: 10.1111/jir.12907. Online ahead of print.

ABSTRACT

BACKGROUND: There is no widely used instrument to detect frailty in people with intellectual disabilities (IDs). We aimed to develop and validate a shorter and more practical version of a published frailty index for people with IDs.

METHOD: This study was part of the longitudinal ‘Healthy Ageing and Intellectual Disability’ study. We included 982 people with IDs aged 50 years and over. The previously developed and validated ID-Frailty Index consisting of 51 deficits was used as the basis for the shortened version, the ID-FI Short Form. Content of the ID-FI Short Form was based on statistics and clinical and practical feasibility. We evaluated the precision and validity of the ID-FI Short Form using the internal consistency, the correlation between the ID-FI Short Form and the original ID-Frailty Index, the agreement in dividing participants in the categories non-frail, pre-frail and frail, and the association with survival.

RESULTS: Seventeen deficits from the original ID-Frailty Index were selected for inclusion in the ID-FI Short Form. All deficits of the ID-FI Short Form are clinically and practically feasible to assess for caregivers and therapists supporting people with ID. We showed acceptable internal consistency with Cronbach’s alpha of 0.75. The Pearson correlation between the ID-Frailty Index and the ID-FI Short Form was excellent (r = 0.94, P < 0.001). We observed a good agreement between the full and short forms in dividing the participants in the frailty categories, with a kappa statistic of 0.63. The ID-FI Short Form was associated with survival; with every 1/100 increase on the ID-FI Short Form, the mortality probability increased by 7% (hazard ratio 1.07, P < 0.001).

CONCLUSION: The first validation of the ID-FI Short Form shows it to be a promising, practical tool to assess the frailty status of people with ID.

PMID:34939710 | DOI:10.1111/jir.12907

Acta Ophthalmol. 2021 Dec 23. doi: 10.1111/aos.15085. Online ahead of print.

ABSTRACT

PURPOSE: To study the safety and efficacy of indirect ophthalmoscopy with (Sp) or without (speculum free, SpF) the use of lid speculum and scleral indentation for retinopathy of prematurity (ROP) screening.

METHODS: In this crossover randomized controlled trial, preterm infants received either the Sp on their first and the SpF technique on their second examination a week later or vice versa. Video recordings of the infants’ reactions were assessed by two observers, using Premature Infant Pain Profile-Revised score and the crying score of the Bernese Pain Scale for Neonates. Fundoscopy adequacy, its duration and adverse events within the first 24 hr postscreening were also recorded.

RESULTS: Thirty-seven infants with median (interquartile range) gestational age of 28.7 (28.0, 30.2) weeks and mean (standard deviation, SD) birth weight 1225 (377) grams were enrolled. The mydriasis-induced stress was similar between the Sp and SpF exam (mean difference [MD]: 0.78, 95% confidence interval [CI]: -0.83, 2.38; p = 0.33). The stress induced by fundoscopy (MD: 4.98, 95% CI: 3.58, 6.37; p < 0.001) and examination overall (MD: 2.32, 95% CI: 0.96, 3.67; p = 0.001) were higher in the Sp than in the SpF exam, and so was the crying score during fundoscopy (MD: 1.31, 95% CI: 1.06, 1.56; p < 0.001). Adverse events in the two groups were similar (p = 0.13). Fundoscopy was adequate in identifying the absence of treatment-requiring ROP in all cases, and lasted longer in the Sp than in the SpF exam (p < 0.001).

CONCLUSION: Our study suggests that the use of speculum and indentation should be reserved for the few cases where fundus visualization is insufficient for excluding the presence of severe ROP.

PMID:34939742 | DOI:10.1111/aos.15085

J Magn Reson Imaging. 2021 Dec 23. doi: 10.1002/jmri.28021. Online ahead of print.

ABSTRACT

BACKGROUND: Because of long diagnostic intervals, soft-tissue sarcoma (STS) patients can undergo several MRIs before treatments. However, only the latest pre-treatment MRI is used in clinical practice and the natural changes in MRI presentations of STS occurring before any medical procedure remain unknown.

PURPOSE: To qualitatively and quantitatively depict the natural history of MRI presentations of STS prior to medical intervention, to investigate their prognostic value, and to compare methods to calculate the changes in radiomics features (named delta-radiomics features).

STUDY TYPE: Retrospective.

SUBJECTS: Sixty-eight patients with locally advanced histologically proven STS and two pre-treatment contrast-enhanced (CE) MRIs (median age: 64 years, median delay between MRIs: 77 days).

FIELD STRENGTH/SEQUENCE: Two-dimensional (2D) turbo spin echo (TSE) T1-weighted-imaging (WI) and T2-WI; 2D TSE or 3D gradient echo CE-T1-WI at 1.5 T. Radiomics analysis was performed on 2D TSE CE-T1-WI.

ASSESSMENT: Three radiologists independently reported morphological features, evaluating changes in STS dimensions, intra-tumoral necrotic and hemorrhagic signals and heterogeneity, and changes in the tumor peritumoral enhancement, edema, and tail sign. After homogenizing the MRIs to account for differences in acquisition parameters, STS were 3D-segmented on both CE-T1-WI MRIs and radiomic features (RFs) were extracted. Changes in RFs between the two MRIs were calculated according to five methods: absolute, absolute/time between MRIs, relative, relative/time between MRIs, and log ratio. Histopathological samples were reviewed to count mitosis and Ki67 immunostaining. Survival data regarding local relapse, metastatic relapse, and disease-related deaths were collected.

STATISTICAL TESTS: Reproducibility analysis (using intra-class correlation coefficient and [weighted] kappa), hierarchical clusterings based on changes in RFs, survival analyses (using Cox regressions), and association with histopathology (using Student’s t-test, Wilcoxon, or Chi-squared test). A P-value of <0.05 was considered to be statistically significant.

RESULTS: There were 15 and 26 local and metastatic progressions, respectively. Average tumor size increase between scans was +39.8%. Metastatic relapse-free survival (MFS) was associated with: increases in size, tumor heterogeneity on T1-WI, T2-WI, and CE-T1-WI, necrotic signal, peritumoral enhancement, and tail sign. Local relapse-free survival (LFS) was associated with: increase in tumor heterogeneity on T1-WI, necrotic signal, hemorrhagic signal and peritumoral edema, and clusters based on the logarithmic changes in RFs (Log-RF). Increase in heterogeneity on CE-T1-WI and Log-RF clusters were independent predictors for MFS and LFS, respectively, in stepwise multivariate Cox regression (hazard ratio [HR] = 2.78 and HR = +∞ respectively). Associations were found between changes in necrotic signal, heterogeneity on CE-T1-WI and peritumoral enhancement, and histological markers of proliferation.

DATA CONCLUSION: Changes in MRI presentation of STS before any treatment are frequent, associated with histopathology, and could help in patients’ prognostication, in addition to baseline MRI feature.

LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 3.

PMID:34939705 | DOI:10.1002/jmri.28021

Indoor Air. 2021 Dec 23. doi: 10.1111/ina.12978. Online ahead of print.

ABSTRACT

A three-dimensional (3D) printing pen is a popular writing instrument that uses a heated nozzle, and is similar to a 3D-printer. Processing thermoplastic filaments with a 3D-pen can emit ultrafine particles (UFPs). 3D-pen education sessions were held with “∏”-shaped partitions for the prevention of coronavirus disease (COVID-19). This study aimed to characterize UFP emissions from two types of 3D-pens and evaluate the influence of “∏”-shaped partitions on UFP exposure. Measurements of UFP emission rates and the size distribution of particles emitted from 3D-pens were conducted in a chamber (2.5 m³ ). The partition’s influence on UFP exposure was evaluated with and without a “∏”-shaped partition on a desk. A scanning mobility particle sizer (SMPS) and an optical particle spectrometer (OPS) were used to measure the particle number concentration (PNC) and size distribution. For both 3D-pen A and B, the average emission rates were statistically significantly highest for acrylonitrile butadiene styrene (ABS) filament (8.4 × 10⁶ [3.4] particles/min and 1.1 × 10⁶ [1.8] particles/min), followed by polylactic acid (PLA) (2.8 × 10⁵ [1.5] particles/min and 4.8 × 10⁴ [1.8] particles/min) and polycaprolactone (PCL) filaments (1.4 × 10⁴ [2.8] particles/min and 2.0 × 10⁴ [2.8] particles/min). For all filaments, particles in the Aitken mode (30-100 nm) accounted for the highest proportion. In 3D-pen A, PNCs were higher with the partition than without it for ABS (1.2 × 10⁶ [1.15] particles/cm³ vs. 1.4 × 10⁵ [1.29] particles/cm³ ) and PLA (6.2 × 10⁵ [1.38] particles/cm³ vs. 8.9 × 10⁴ [1.12] particles/cm³ ), whereas for 3D-pen B, they were higher with the partition for ABS (9.6 × 10⁵ [1.13] particles/cm³ vs. 4.9 × 10⁵ [1.22] particles/cm³ ) only. With the partition installed, PNCs decreased to the background level after the operation ended, whereas it took 2-6 min without the partition. However, the mass concentrations of PLA and PCL with 3D-pen A were not statistically significantly different with respect to the partition status. The use of 3D-pens with a partition can lead to high UFP exposure. Therefore, guidelines are required for the safe use of 3D-pens and partitions.

PMID:34939703 | DOI:10.1111/ina.12978

J Child Psychol Psychiatry. 2021 Dec 23. doi: 10.1111/jcpp.13564. Online ahead of print.

ABSTRACT

BACKGROUND: Measures based on pupillometry, such as the pupillary light reflex (PLR) and baseline pupil size, reflect physiological responses linked to specific neural circuits that have been implicated as atypical in some psychiatric and neurodevelopmental conditions.

METHODS: We investigated the contribution of genetic and environmental factors to the baseline pupil size and the PLR in 510 infant twins assessed at 5 months of age (281 monozygotic and 229 dizygotic pairs), and its associations with common genetic variants associated with neurodevelopmental (autism spectrum disorder and attention deficit hyperactivity disorder) and mental health (bipolar disorder, major depressive disorder and schizophrenia) conditions using genome-wide polygenic scores (GPSs).

RESULTS: Univariate twin modelling showed high heritability at 5 months for both pupil size (h² = .64) and constriction in response to light (h² = .62), and bivariate twin modeling indicated substantial independence between the genetic factors influencing each (r_G = .38). A statistically significant positive association between infant tonic pupil size and the GPS for schizophrenia was found (β = .15, p = .024), while there was no significant association with the GPS for autism or any other GPSs.

CONCLUSIONS: This study shows that some pupil measures are highly heritable in early infancy, although substantially independent in their genetic etiologies, and associated with common genetic variants linked to schizophrenia. It illustrates how genetically informed studies of infants may help us understand early physiological responses associated with psychiatric disorders which emerge much later in life.

PMID:34939671 | DOI:10.1111/jcpp.13564