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Background and Objectives: Chronic heart failure (CHF) caused by ischemic heart disease (IHD) is the leading cause of death worldwide and presents significant health challenges. Effective management of IHD requires prevention, early detection, and treatment to improve patient outcomes. This study aims to expand the diagnostic utility of various 24 h Holter ECG parameters, such as T-wave alternans (TWA), late ventricular potentials (LVPs), and heart rate variability (HRV) in patients with CHF caused by IHD. Additionally, we seek to explore the association between these parameters and other comorbid conditions affecting the prognosis of CHF patients. Materials and Methods: We conducted a prospective case–control study with 150 patients divided into two subgroups: 100 patients with CHF caused by IHD, and 50 patients in the control group. Data included medical history, physical examination, laboratory tests, echocardiography, and 24 h Holter monitoring. Results: Our comparative analysis demonstrated that both TWA and LVPs were significantly higher in patients with CHF compared to the control group (p < 0.01), indicating increased myocardial electrical vulnerability in CHF patients. Both time and frequency-domain HRV parameters were significantly lower in the CHF group. However, the ratio of NN50 to the total count of NN intervals (PNN50) showed a borderline significance (p = 0.06). While the low-frequency (LF) domain was significantly lower in CHF patients, the high-frequency (HF) domain did not differ significantly between groups. Acceleration and deceleration capacities were also significantly altered in CHF patients. Categorizing CHF patients by left ventricular ejection fraction (LVEF) revealed that the mean of the 5-min normal-to-normal intervals over the complete recording (SDNN Index) was significantly higher in patients with LVEF ≥ 50% compared to those with CHF with reduced EF and CHF with mildly reduced EF (p < 0.001), whereas the other HRV parameters showed no significant differences among the groups. Conclusions: Holter ECG parameters can become a reliable tool in the assessment of patients with CHF. The integration of multiple Holter ECG parameters, such as TWA, LVPs, and HRV, can significantly enhance the diagnostic assessment of CHF caused by IHD. This comprehensive approach allows for a more nuanced understanding of the patient’s condition and potential outcomes.

BackgroundIntelectin-1 (ITLN1) is an adipokine with multiple physiological functions, including a role in tumour formation and development. Previous research reported variable ITLN1 levels for cancer patients and healthy individuals. This study aimed to compare ITLN1 concentrations between controls and cancer patients and to determine the adipokine’s physiological level.MethodsFive databases were searched in January 2022 for studies that measured the level of ITLN1 in adults that were healthy or diagnosed with any type of cancer. After title, abstract and full-text screening, the methodological quality of the studies was assessed. The extracted data were meta-analysed using the R language and Bayesian statistical techniques.ResultsOverall, 15 studies compared circulating ITLN1 levels between healthy individuals (n=3424) and cancer patients (n=1538), but no differences were observed between these studies. ITLN1 was not different between groups in an analysis that evaluated high-quality studies only (n=5). The meta-analysis indicated considerably higher ITLN1 levels in gastrointestinal (i.e., colorectal, pancreatic, gastric) cancer compared to controls, while the other cancer types did not demonstrate differences between groups. The mean ITLN1 level of healthy individuals was 234 ± 21ng/ml (n=136), while the average value in high-quality studies (n=52) was 257 ± 31ng/ml.ConclusionDifferent types of cancer showed different circulating ITLN1 patterns. Circulating ITLN1 concentration was higher in gastrointestinal cancer compared to controls, with strong support from the meta-analytical model. Our analysis also determined the mean ITLN1 level in healthy individuals; this is a crucial starting point for understanding how this cytokine associates with diseases. Two-thirds of the studies were of low methodological quality and thus, future work in this field must focus on improved methods.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?RecordID=303406, identifier CRD42022303406.

Background and Objective: In the landscape of heart failure, non-cardiac comorbidities represent a formidable challenge, imparting adverse prognostic implications. Holter ECG monitoring assumes a supplementary role in delineating myocardial susceptibility and autonomic nervous system dynamics. This study aims to explore the potential correlation between Holter ECG parameters and comorbidities in individuals with ischemic cardiomyopathy experiencing heart failure (HF), with a particular focus on the primary utility of these parameters as prognostic indicators. Materials and Methods: In this prospective inquiry, a cohort of 60 individuals diagnosed with heart failure underwent stratification into subgroups based on the presence of comorbidities, including diabetes, chronic kidney disease, obesity, or hyperuricemia. Upon admission, a thorough evaluation of all participants encompassed echocardiography, laboratory panel analysis, and 24 h Holter monitoring. Results: Significant associations were uncovered between diabetes and unconventional physiological indicators, specifically the Triangular index (p = 0.035) and deceleration capacity (p = 0.002). Pertaining to creatinine clearance, notable correlations surfaced with RMSSD (p = 0.026), PNN50 (p = 0.013), and high-frequency power (p = 0.026). An examination of uric acid levels and distinctive Holter ECG patterns unveiled statistical significance, particularly regarding the deceleration capacity (p = 0.045). Nevertheless, in the evaluation of the Body Mass Index, no statistically significant findings emerged concerning Holter ECG parameters. Conclusions: The identified statistical correlations between non-cardiac comorbidities and patterns elucidated in Holter ECG recordings underscore the heightened diagnostic utility of this investigative modality in the comprehensive evaluation of individuals grappling with HF. Furthermore, we underscore the critical importance of the thorough analysis of Holter ECG recordings, particularly with regard to subtle and emerging parameters that may be overlooked or insufficiently acknowledged.

Abstract Sex and age associated differences in the tumor immune microenvironment of non-muscle invasive bladder (NMIBC) cancer and associated clinical outcomes are emerging indicators of treatment outcomes. The incidence of urothelial carcinoma of the bladder is four times higher in males than females; however, females tend to present with a more aggressive disease, a poorer response to immunotherapy and suffer worse clinical outcomes. Recent findings have demonstrated sex differences in the tumor immune microenvironment of non-muscle invasive and muscle invasive bladder cancer and associated clinical outcomes. However, a significant gap in knowledge remains with respect to the current pre-clinical modeling approaches to more precisely recapitulate these differences towards improved therapeutic design. Given the similarities in mucosal immune physiology between humans and mice, we evaluated the sex and age-related immune alterations in healthy murine bladders. Bulk-RNA sequencing and multiplex immunofluorescence-based spatial immune profiling of healthy murine bladders from male and female mice of age groups spanning young to old showed a highly altered immune landscape that exhibited sex and age associated differences, particularly in the context of B cell mediated responses. Spatial profiling of healthy bladders, using markers specific to macrophages, T cells, B cells, activated dendritic cells, high endothelial venules, myeloid cells and the PD-L1 immune checkpoint showed sex and age associated differences. Bladders from healthy older female mice also showed a higher presence of tertiary lymphoid structures (TLSs) compared to both young female and male equivalents. Spatial immune profiling of N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) carcinogen exposed male and female bladders from young and old mice revealed a similar frequency of TLS formation, sex differences in the bladder immune microenvironment and, age associated differences in latency of tumor induction. These findings support the incorporation of sex and age as factors in pre-clinical modeling of bladder cancer and will potentially advance the field of immunotherapeutic drug development to improve clinical outcomes.

Abstract Cancer cachexia is an unmet clinical need that affects more than 50% of patients with cancer. The systemic inflammatory response, which is mediated by a network of cytokines, has an established role in the genesis and maintenance of cancer as well as in cachexia; yet, the specific role of the cytokine milieu in cachexia requires elucidation. This systematic review aims to examine the relationship between cytokines and the cachexia syndrome in patients with incurable cancer. The databases MEDLINE, EMBASE, CINAHL, CENTRAL, PsycINFO, and Web of Science were searched for studies published between 01/01/2004 and 06/01/2020. Included studies measured cytokines and their relationship with cachexia and related symptoms/signs in adults with incurable cancer. After title screening (n = 5202), the abstracts (n = 1264) and the full‐text studies (n = 322) were reviewed independently by two authors. The quality assessment of the selected papers was conducted using the modified Downs and Black checklist. Overall, 1277 patients with incurable cancer and 155 healthy controls were analysed in the 17 eligible studies. The mean age of the patients was 64 ± 15 (mean ± standard deviation). Only 34% of included participants were female. The included studies were assessed as moderate‐quality to high‐quality evidence (mean quality score: 7.8; range: 5–10). A total of 31 cytokines were examined in this review, of which interleukin‐6 (IL‐6, 14 studies) and tumour necrosis factor‐α (TNF‐α, 12 studies) were the most common. The definitions of cachexia and the weight‐loss thresholds were highly variable across studies. Although the data could not be meta‐analysed due to the high degree of methodological heterogeneity, the findings were discussed in a systematic manner. IL‐6, TNF‐α, and IL‐8 were greater in cachectic patients compared with healthy individuals. Also, IL‐6 levels were higher in cachectic participants as opposed to non‐cachectic patients. Leptin, interferon‐γ, IL‐1β, IL‐10, adiponectin, and ghrelin did not demonstrate any significant difference between groups when individuals with cancer cachexia were compared against non‐cachectic patients or healthy participants. These findings suggest that a network of cytokines, commonly IL‐6, TNF‐α, and IL‐8, are associated with the development of cachexia. Yet, this relationship is not proven to be causative and future studies should opt for longitudinal designs with consistent methodological approaches, as well as adequate techniques for analysing and reporting the results.

Background: This work aims to study the levels of stress among students using e-learning platforms during the COVID-19 pandemic in higher education institutions. The major factors of higher-level stress among the student community focused on this study are: Changes in academic environment, family, social, personal, health and cognitive. Objective: the objective of this research the Partial Least Squares Structural Equation Modelling (PLS-SEM) procedure was used to explore the relationship and its impact on various levels of stress. Results: Data were collected by using a total of 1,000 email IDs of students that were made available by teachers from 12 Indian higher education institutions where they were enrolled and by using a random number method. With this procedure, a total of 800 email IDs were selected. The results drawn from this research are that students experienced more stress due to sudden changes in the academic environment, family, and personal factors. The stress levels of cognitive and social were found to be equally distributed among higher education students, but less than academic environment, family and personal. This research intends to fill the gap of short-term individual psychological changes that occur after the outbreak. Conclusion: Policy-makers can take note of the current study’s observations in continuing their fight against COVID-19 pandemic by improving the stability for student risk groups.

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Background: Non–muscle-invasive bladder cancer (NMIBC) is over three times as common in men as it is in women; however, female patients do not respond as well to immunotherapeutic treatments and experience worse clinical outcomes than their male counterparts. Based on the established sexual dimorphism in mucosal immune responses, we hypothesized that the tumor immune microenvironment of bladder cancer differs between the sexes, and this may contribute to discrepancies in clinical outcomes. Objective: To determine biological sex-associated differences in the expression of immune regulatory genes and spatial organization of immune cells in tumors from NMIBC patients. Design, setting, and participants: Immune regulatory gene expression levels in tumors from male (n = 357) and female (n = 103) patients were measured using whole transcriptome profiles of tumors from the UROMOL cohort. Multiplexe immunofluorescence was performed to evaluate the density and spatial distribution of immune cells and immune checkpoints in tumors from an independent cohort of patients with NMIBC (n = 259 males and n = 73 females). Outcome measurements and statistical analysis: Transcriptome sequencing data were analyzed using DESeq2 in R v4.0.1, followed by application of the Kruskal-Wallis test to determine gene expression differences between tumors from males and females. Immunofluorescence data analyses were conducted using R version 3.5.3. Survival analysis was performed using survminer packages. Results and limitations: High-grade tumors from female patients exhibited significantly increased expression of B-cell recruitment (CXCL13) and function (CD40)-associated genes and the immune checkpoint genes CTLA4, PDCD1, LAG3, and ICOS. Tumors from female patients showed significantly higher infiltration of PD-L1+ cells and CD163+ M2-like macrophages than tumors from male patients. Increased abundance of CD163+ macrophages and CD79a+ B cells were associated with decreased recurrence-free survival. Conclusions: These novel findings highlight the necessity of considering sexual dimorphism in the design of future immunotherapy trials in NMIBC. Patient summary: In this study, we measured the abundance of various immune cell types between tumors from male and female patients with non–muscle-invasive bladder cancer. We demonstrate that tumors from female patients have a significantly higher abundance of immunosuppressive macrophages that express CD163. Higher abundance of tumor-associated CD163-expressing macrophages and B cells is associated with shorter recurrence-free survival in both male and female patients.

Objective: To assess the outcome of empirical therapeutic interventions for synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome. Methods: The clinical features and treatment outcomes of a cohort of 21 patients diagnosed with SAPHO in Western Australia were reviewed retrospectively. Results: All 21 patients met published diagnostic criteria; 20 (95%) were Caucasian, and the median age was 47 years. The median follow-up was 6 years (range, 2 to 32 years). Three patients (14%) received no treatment; 18 (86%) required conventional synthetic disease-modifying antirheumatic drug (DMARDs). Thirteen (62%) had an initial good response to methotrexate; 8 relapsed and progressed to biologic DMARDs (bDMARDs) during a period of 14 years. Of the 13 recipients on a tumor necrosis factor inhibitor, 11 (85%) continued treatment for a median of 4 years (range, 1 to 14 years), whereas none of 3 recipients of interleukin 17/23 continued treatment (median, 4 months). Higher Physician Global Assessment scores (better outcomes) were observed in bDMARD recipients (mean, 7.06±2.24 [SD]) compared with non-bDMARD recipients (mean, 5.63±2.50; P=.1672) after a median of 3 years of therapy. Conclusion: This study describes the broad range of clinical manifestations in SAPHO, variable courses over time, and inconsistent outcomes with diverse empirical therapies. Moderately good long-term treatment outcomes were observed in most recipients of tumor necrosis factor inhibitor. Poorer outcomes were observed with bisphosphonates and interleukin 17/23 axis inhibitors; however, low numbers preclude robust comparison. Suboptimal treatment may be associated with poorer clinical outcomes and greater skeletal damage. Trial Registration: Australian and New Zealand Clinical Trials Registry: ACTRN12619000445178

BackgroundIntelectin (ITLN) is an adipokine with two homologs—ITLN1 and ITLN2—that has various physiological functions. Studies analyzing the relationship between ITLN and cancer are focused on ITLN1; the available literature on ITLN2 and cancer is limited. This review aims to evaluate the role of ITLN1 in cancer without imposing any inclusion criteria, to examine pro- and anticancer roles for ITLN1 and to discuss whether the relationship between ITLN and cancer is mediated by obesity.FindingsOverall, ITLN1 level was highly variable in cancer patients but different from healthy individuals. Compared with control groups, patients with gastrointestinal and prostate cancer showed increased concentrations of circulating ITLN1, while patients with gynecological, breast, bladder, and renal cancer had lower ITLN1 levels. Several studies also evaluated tissue and tumor expression of ITLN1. In gastrointestinal cancer, ITLN1 was increased in tumor tissue compared with adjacent healthy tissue and elevated in the visceral adipose tissue of patients compared with controls. Consequently, the high levels of circulating ITLN1 might be determined by the tumor and by the cancer-associated weight loss in gastrointestinal cancer. ITLN1 can activate the phosphoinositide-3-kinase-protein kinase B/Akt (PI3K/Akt) pathway. The improper regulation of this pathway may contribute to a series of cellular events that favor tumor development and progression. Obesity has been linked with an increased risk of developing some cancers. Indeed, low circulating ITLN1 levels may be a marker of the metabolic effects of obesity, rather than obesity per se, and might contribute to a deregulation of the PI3K/Akt pathway.ConclusionsITLN1 could be associated with cancer formation and progression. Since circulating ITLN1 levels are highly variable and differ between cancer types, the local tumor production of ITLN1 could be more relevant in determining malignant behavior. Future research should aim to identify the source of ITLN1 variability, to understand the differences in ITLN1 between distinct tumor types, and to further explore the signaling pathways through which this adipokine influences cancer biology.

Mucormycosis is a rare, emerging angioinvasive infection caused by ubiquitous filamentous fungi. In recent decades, an increase in cutaneous or post-traumatic mucormycosis has been reported. We describe two cases of post-traumatic wound infections with Mucor circinelloides, a mucor species only rarely reported as a cause of post-traumatic mucormycosis. Often considered lethal, management required a combination of medical and surgical therapies to achieve a favorable outcome in both cases.

Two new approaches for calculating box-counting fractal dimension (FD) estimates for gray-scale images are considered to overcome some of the limitations of the standard box-counting method, which requires setting a threshold in a pre-processing step. They include weighted gray-level box-counting (W-GBC) FD estimator and the probabilistic gray-level box-counting estimator in the image probability space (i. e., probability being proportional to pixel values) of an image (P-GBC-img). They are contrasted against the standard box-counting FD algorithm (BBC) and the probabilistic gray-level box-counting estimator in the intensity probability space (i. e., probability being proportional to the numerosity of a given range of pixel values) (P-GBC-int). A set of nine synthetic images and a set of 686 real gray-level images of tear film interferometry from normal and dry eye subjects were used for the evaluation of the considered estimators. Strong correlation (Pearson's ρ) was found between BBC and W-GBC (ρ = 0.998, p

Abstract Background Identifying optimal chemotherapy (CT) utilization rates can drive improvements in quality of care. We report a benchmarking approach to estimate the optimal rate of perioperative CT for muscle‐invasive bladder cancer (MIBC). Methods The Ontario Cancer Registry and linked treated records were used to identify neoadjuvant and adjuvant CT rates among patients with MIBC during 2004‐2013. Monte Carlo simulation was used to estimate the proportion of observed rate variation that could be due to chance alone. The criterion‐based benchmarking approach was used to explore whether social and health‐system factors were associated with CT rates. We also used the “pared‐mean” approach to identify a benchmark population of hospitals with the highest treatment rates. Hospital CT rates were adjusted for case mix and simulated using a multi‐level multivariable model and a parametric bootstrapping approach. Results The study population included 2581 patients; perioperative CT was delivered to 31% (798/2581). Multivariate analysis showed that treatment was strongly associated with patient socioeconomic status and hospital teaching status. The benchmark rate was 36%. Unadjusted CT rates were significantly different across hospitals (range 0%‐52%, P

Trata-se do capítulo 3 de Simultaneous structure in phonology, composto de seis capítulos: (1) Gesto, traços e autossegmentos, (2) Fonética na fonologia, (3) Definindo prosódia, (4) Modulações, (5) Sobre a dualidade da padronização e (6) Eventos fonológicos (segmentação, eventos simultâneos e paralelos).

Abstract Background Identifying optimal chemotherapy utilization rates can drive improvements in quality of care. We report a benchmarking approach to estimate the optimal rate of adjuvant chemotherapy (ACT) for stage III colon cancer. Methods The Ontario Cancer Registry and linked treated records were used to identify ACT utilization. Monte Carlo simulation was used to estimate the proportion of ACT rate variation that could be due to chance alone. The criterion‐based benchmarking approach was used to explore whether socioeconomic or system‐level factors were associated with ACT. We also used the “pared‐mean” approach to identify a benchmark population of hospitals with the highest ACT rates. Results The study population included 2801 patients; ACT was delivered to 66% (1861/2801). Monte Carlo simulation suggested that the observed component of variation (15.6%) in ACT rates was within the 95% CI (11.5%‐17.3%) of what could be expected due to chance alone; the nonrandom component of ACT rate variation across hospitals was only 1.5%. There was no difference in hospital ACT rate by teaching status (P = .107), cancer center status (P = .362), or having medical oncology on site (P = .840). Unadjusted ACT rates varied across hospitals (range 44%‐91%, P = .017). The unadjusted benchmark ACT rate was 81% (95%CI 76%‐86%); utilization rate in non‐benchmark hospitals was 65% (95%CI 63%‐66%). However, after adjusting for case mix, the difference in ACT utilization between benchmark and non‐benchmark populations was significantly smaller. Conclusions We did not find any system‐level factors associated with the utilization of ACT. Our results suggest that the observed variation in hospital ACT rate is not significantly different from variation due to chance alone. Using the “pared‐mean” approach may significantly overestimate optimal treatment rates if case mix is not considered.

Abstract Background Environmental exposure to phthalates and bisphenol A (BPA) may have endocrine disrupting effects that alter length of gestation. We assessed the association between the urinary concentrations of 11 phthalate metabolites and BPA with length of gestation in a cohort of women followed from before conception with daily 1st-morning urinary hormone measures that identified day of implantation. Methods Pre-implantation and post-implantation urinary phthalate metabolites and BPA concentrations were measured in pooled urine samples designed to limit single-measure variability due to the likely episodic nature of these exposures and the short half-life of these compounds. We estimated associations between these exposure biomarkers early in pregnancy with length of gestation from implantation to spontaneous birth. Cox proportional hazards models were used to estimate the hazard of birth among 125 naturally-conceived, singleton live births with censoring for medical interventions that artificially shortened pregnancy. Results Higher concentrations of mono (2-ethyl-5-hydroxyhexyl) phthalate (a metabolite of di (2-ethylhexyl) phthalate (DEHP)) during the pre-implantation window were associated with reduced probability of birth, i.e., longer gestations (hazard ratio (HR): 0.55, 95% CI: 0.35, 0.86; p = 0.01). The HR for the molar sum of the four DEHP metabolites measured showed a similar association (HR: 0.67, 95% CI: 0.43, 1.05). Higher concentrations of mono (3-carboxypropyl) phthalate (MCPP), a non-specific metabolite of several high molecular-weight phthalates, measured post-implantation were associated with increased risk of earlier birth, i.e. shorter length of gestation, HR: 1.59, CI: 1.02, 2.49. Conclusions Early gestational exposure to DEHP and possibly other high-molecular weight phthalates, (as reflected by urinary MCPP concentrations) may influence the length of pregnancy. Such effects could have consequences for neonatal and maternal health.

Abstract Background Molecular subtyping of urothelial cancer (UC) has significantly advanced the understanding of bladder tumor heterogeneity and development of prognostic and predictive biomarkers. Evolving evidence across cancers strongly suggests that tumor immunoediting has a profound impact on the behaviour of cancer cells and their adaptation to the co-evolving microenvironment and response to treatment. In alignment with these concepts, recent immune checkpoint blockade (ICB) therapies in UC have demonstrated the predictive potential of mutations in the DNA damage repair (DDR) genes. A comprehensive understanding of DDR gene inactivation associated expression of immune regulatory genes could thus aid in expansion of current immunotherapies and predictive biomarkers for the design of patient-tailored combination treatments. Methods We investigated pre-treatment tumor transcriptomic profiles of the five recently described molecular subtypes of muscle invasive urothelial cancer (MIUC; n = 408) from The Cancer Genome Atlas, to determine subtype specific immune cell abundance, expression of 67 immune regulatory genes, and association with DDR gene inactivation (via mutation, copy number alteration) profiles. Results Analysis using CIBERSORT immune cell abundance determination tool showed significant differences in immune cell profiles and abundance between MIUC subtypes. Expression patterns of a selected panel of 67 genes including both immune stimulatory and inhibitory genes, showed significant associations with subtypes, and DDR gene mutation status. Conclusion Findings from our study provide compelling evidence for co-expression of multiple immune checkpoint genes including, PD-1, PD-L1, IDO1, TIGIT, TIM-3, TGFB1, LAG3, and others, that potentially contribute to compensatory immune evasion in bladder tumors. Our findings also emphasize the urgent need for biomarker discovery approaches that combine molecular subtype, DDR gene mutation status, tumor immune landscape classification, and immune checkpoint gene expression to increase the number of patients responding to immunotherapies.

The key determinants of the range of clear focus in pre-presbyopes and their relative contributions to the difference between subjective range of focus and objective accommodation assessments have not been previously quantified. Fifty participants (aged 33.0 ± 6.4 years) underwent simultaneous monocular subjective (visual acuity measured with an electronic test-chart) and objective (dynamic accommodation measured with an Aston open-field aberrometer) defocus curve testing for lenses between +2.00 to −10.00 DS in +0.50 DS steps in a randomized order. Pupil diameter and ocular aberrations (converted to visual metrics normalized for pupil size) at each level of blur were measured. The difference between objective range over which the power of the crystalline lens changes and the subjective range of clear focus was quantified and the results modelled using pupil size, refractive error, tolerance to blur, and ocular aberrations. The subjective range of clear focus was principally accounted for by age (46.4%) and pupil size (19.3%). The objectively assessed accommodative range was also principally accounted for by age (27.6%) and pupil size (15.4%). Over one-quarter (26.0%) of the difference between objective accommodation and subjective range of clear focus was accounted for by age (14.0%) and spherical aberration at maximum accommodation (12.0%). There was no significant change in the objective accommodative response (F = 1.426, p = 0.229) or pupil size (F = 0.799, p = 0.554) of participants for levels of defocus above their amplitude of accommodation. Pre-presbyopes benefit from an increased subjective range of clear vision beyond their objective accommodation due in part to neural factors, resulting in a measured depth-of-focus of, on average, 1.0 D.

In a recent article, Mannion and Davies argue that there are a multitude of ways in which organizations (such as the National Health Service [NHS]) can deal with wrongdoing or ethical problems, including the formation of policies that encourage and protect would-be whistleblowers. However, it is important to distinguish internal reporting about wrongdoing from whistleblowing proper, because the two are morally quite different and should not be dealt with in the same way. This article argues that we should not understand the authors’ conclusions to apply to “whistleblowing” proper, because their recommended approach would be both unfeasible and undesirable for addressing whistleblowing defined in this way.

It is known that the mid vowel contrasts of Standard Italian distinguish few minimal pairs, may be lexically variable, and show some degree of phonological conditioning in certain varieties. As such, they are relevant to recent suggestions that phonemic contrast may be partial, gradient, or otherwise more cognitively complex than traditionally assumed. Production data and vowel height judgments from 17 speakers con rm that most have clear phonetic distinctions between higher and lower mid vowels. However, the lexical distribution of these vowels is variable, and (in some speakers) phonologically conditioned to some extent; and though phonological awareness for all speakers is broadly accurate, we also observe cases where production and speaker judgment fail to match, in part because individual speakers’ productions are variable. This suggests that the somewhat marginal status of the Italian mid vowel contrasts resides in the link between phonetic categories and individual lexical items, not in any indistinctness of the phonetic categories themselves.

IntroductionAdolescents and young adults are a vulnerable patient population for development of substance use disorder. However, the long-term impact of opioid prescribing in young adult patients with renal colic is not known. Our objective was to describe rates of opioid prescription and identify risk factors for persistent opioid use in patients age 25 years or younger with renal colic from kidney stones.MethodsUsing previously validated, linked administrative databases, we performed a population-based, retrospective cohort study of opioid-naive patients age 25 years or younger with renal colic between July 1, 2013 and September 30, 2017 in Ontario. All family practitioner, urgent care, and specialist visits in the province were captured. Our primary outcome was persistent opioid use, defined as filling a prescription for an opioid between 91 and 180 days after initial visit. Ontario uses a narcotic monitoring system, which captures all opioids dispensed in the province.ResultsOf the 6962 patients identified, 56% were prescribed an opioid at presentation and 34% of those were dispensed more than 200 oral morphine equivalents. There was persistent opioid use in 313 (8.1%) patients who filled an initial opioid prescription. In adjusted analysis, those prescribed an opioid initially had a significantly higher risk of persistent opioid use (odds ratio [OR] 1.85; 95% confidence interval [CI] 1.50-2.29) and opioid overdose (OR 3.45; 1.08-11.04). There was a dose-dependent increase in risk of persistent opioid use with escalating initial opioid dose. History of mental illness (OR 1.32; 1.02-1.71) and need for surgery (OR 1.71; 1.24-2.34) were also associated with persistent opioid use.ConclusionsAmong patients with kidney stones age 25 years or younger, filling an opioid prescription after presentation is associated with an increased risk of persistent opioid use 3-6 months later and a higher risk of serious long-term complications, such as opioid overdose.

For the past several years, there has been an increase in the number of job opportunities in the computing field. As a result, many schools and universities are facing a significant increase in the number of students seeking to major in one of several computing disciplines. This increase in the numbers and variety of majors in the computing field poses challenges for higher education institutions in the areas of advising, retention, scheduling, and enrollment management. This paper builds upon prior research documenting the association of personality type and affinity for a computing career, and proposes using personality testing early in a student's university experience by including it as one factor in the advising process. This study employs the Myers-Briggs Type Indicator (MBTI) as a tool to help students select an appropriate computing major better suited for their given personality. This initial exploratory study shows that there is a significant difference in personalities among computing majors, specifically in the area of introversion versus extroversion, and intuition versus sensing. Testing students early, before starting a specific major, allows institutions to provide better advising to students as they choose their major, with the goal of increasing retention, degree satisfaction and completion of the degree.

All curricula for any given academic discipline evolves over time. This is also true for the Information Systems (IS) model curriculum. Curriculum evolution is driven by several factors, such as changes in technologies, industry shifts to meet customer needs, and perceived student deficiencies. One outcome of such factors has been a change in the entry point into the IS major due to the perception that IS majors need a different method of entry from other computing majors [e.g., Computer Science (CS)]. The current entry point for many IS majors is a programming course, often taken by a variety of majors. This paper addresses the question: is there a difference in performance in this initial programming course for students of different majors? More precisely, does major differentiate performance in the first programming course, such as CS1? The data clearly show this is not the case when there is a level playing field. The paper demonstrates that non-computing majors perform as well as computing majors given equal preparation. It is a misconception that changes to the IS curriculum are necessary when based on the belief that IS majors, as compared to other computing majors, need a different entry point. The data presented in this paper suggest the underlying presuppositions for IS curricular changes are misguided--supporting the need for preparation prior to a first programming course.

BackgroundTenofovir disoproxil fumarate (TDF) decreases bone mineral density (BMD). We hypothesized that vitamin D3 (VITD3) would increase BMD in youth receiving TDF.MethodsThis was a randomized, double-blind, placebo-controlled trial of directly observed VITD3 vs placebo every 4 weeks for 48 weeks in youth aged 16-24 years with HIV, RNA load

ImportanceAdolescents represent a key population for implementing preexposure prophylaxis (PrEP) interventions worldwide, yet tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) for PrEP is only licensed for adults.ObjectiveTo examine the safety of and adherence to PrEP along with changes in sexual risk behavior among adolescent men who have sex with men (MSM).Design, setting, and participantsAdolescent Medicine Trials Network for HIV/AIDS Interventions 113 (Project PrEPare) was a PrEP demonstration project that evaluated the safety, tolerability, and acceptability of TDF/FTC and patterns of use, rates of adherence, and patterns of sexual risk behavior among healthy young MSM aged 15 to 17 years. Participants were recruited from adolescent medicine clinics and their community partners in 6 US cities, had negative test results for human immunodeficiency virus (HIV) but were at high risk for acquiring an infection, and were willing to participate in a behavioral intervention and accept TDF/FTC as PrEP.ExposuresAll participants completed an individualized evidence-based behavioral intervention and were provided with daily TDF/FTC as PrEP for 48 weeks.Main outcomes and measuresThe main objectives were to: (1) provide additional safety data regarding TDF/FTC use among young MSM who had negative test results for HIV; (2) examine the acceptability, patterns of use, rates of adherence, and measured levels of tenofovir diphosphate in dried blood spots; and (3) examine patterns of risk behavior when young MSM were provided with a behavioral intervention in conjunction with open-label TDF/FTC.ResultsAmong 2864 individuals screened (from August 2013 to September 2014), 260 were eligible and 78 were enrolled (mean [SD] age, 16.5 [0.73] years), of whom 2 (3%) were Asian/Pacific Islander, 23 (29%) were black/African American, 11 (14%) were white, 16 (21%) were white Hispanic, and 26 (33%) were other/mixed race/ethnicity. Over 48 weeks of PrEP use, 23 sexually transmitted infections were diagnosed in 12 participants. The HIV seroconversion rate was 6.4 (95% CI: 1.3-18.7) per 100 person-years. Tenofovir diphosphate levels consistent with a high degree of anti-HIV protection (>700 fmol/punch) were found in 42 (54%), 37 (47%), 38 (49%), 22 (28%), 13 (17%), and 17 (22%) participants at weeks 4, 8, 12, 24, 36, and 48, respectively.Conclusions and relevanceAdolescent Medicine Trials Network for HIV/AIDS Interventions 113 enrolled a diverse sample of adolescent MSM at risk for HIV who consented to study participation. Approximately half achieved protective drug levels during the monthly visits, but adherence decreased with quarterly visits. Youth may need additional contact with clinical staff members to maintain high adherence.Trial registrationclinicaltrials.gov Identifier: NCT01769456.