Modelling the Distribution of Cognitive Outcomes for Early-Stage Neurocognitive Disorders: A Model Comparison Approach.

Background: Cognitive assessments for patients with neurocognitive disorders are mostly measured by the Montreal Cognitive Assessment (MoCA) and Visual Cognitive Assessment Test (VCAT) as screening tools. These cognitive scores are usually left-skewed and the results of the association analysis might not be robust. This study aims to study the distribution of the cognitive outcomes and to discuss potential solutions. Materials and Methods: In this retrospective cohort study of individuals with subjective cognitive decline or mild cognitive impairment, the inverse-transformed cognitive outcomes are modelled using different statistical distributions. The robustness of the proposed models are checked under different scenarios: with intercept-only, models with covariates, and with and without bootstrapping. Results: The main results were based on the VCAT score and validated via the MoCA score. The findings suggested that the inverse transformation method improved the modelling the cognitive scores compared to the conventional methods using the original cognitive scores. The association of the baseline characteristics (age, gender, and years of education) and the cognitive outcomes were reported as estimates and 95% confidence intervals. Bootstrap methods improved the estimate precision and the bootstrapped standard errors of the estimates were more robust. Cognitive outcomes were widely analysed using linear regression models with the default normal distribution as a conventional method. We compared the results of our suggested models with the normal distribution under various scenarios. Goodness-of-fit measurements were compared between the proposed models and conventional methods. Conclusions: The findings support the use of the inverse transformation method to model the cognitive outcomes instead of the original cognitive scores for early-stage neurocognitive disorders where the cognitive outcomes are left-skewed.

Evaluation of Continuous Infusion Vancomycin in a Pediatric Hematology/Oncology Population.

BACKGROUND: Continuous infusion vancomycin (CIV) may benefit children who are unable to achieve therapeutic concentrations with intermittent vancomycin dosing and may facilitate outpatient administration by alleviating the burden of frequent dosing intervals. Previous studies have used variable dosing regimens and steady-state concentration goals. The purpose of this study was to evaluate the total daily dose (TDD) of CIV required to achieve therapeutic steady-state concentrations of 15-25 µg/mL in pediatric hematology/oncology patients. METHODS: A single-center retrospective study was performed for patients treated with CIV from January 2017 to June 2019. The primary outcome was the TDD required to achieve therapeutic steady-state concentrations on CIV. Secondary outcomes included time to reach therapeutic steady-state concentrations, CIV indications and adverse events associated with CIV. RESULTS: Data were collected for 71 courses of CIV in 60 patients. Median patient age was 4 years (range: 0.4-20 years). The median TDD required to achieve initial therapeutic concentrations was 50.3 mg/kg/d (interquartile range: 38.8-59.2) and was further divided into age-based cohorts. TDD in mg/kg was significantly lower in the older cohort ( P < 0.001), but there was no statistically significant difference between age-based cohorts with TDD in mg/m 2 ( P = 0.97). Median time to achieve first therapeutic concentration was 19.3 hours (range: 8.6-72.3 hours). The most common indication for CIV was ease of outpatient administration (69.0%). Acute kidney injury incidence was minimal (4.2%). CONCLUSIONS: CIV is associated with rapid attainment of target concentrations in pediatric hematology/oncology patients and is safe and well tolerated.

SARS-CoV-2 infection in high-risk children following tixagevimab-cilgavimab (Evusheld) pre-exposure prophylaxis: a single-center observational study.

From 8 December 2021 to 26 January 2023, tixagevimab-cilgavimab (T-C) was authorized for pre-exposure prophylaxis of COVID-19. During this period, we used a multidisciplinary team to communicate, screen, approach, and administer T-C to eligible patients. Twenty-seven patients were eligible. Of these, 24 (88.9%) received at least one dose of T-C and three patients received two doses. Majority of patients were White, non-Hispanic, and women. Only two patients had COVID-19 prior to receiving T-C. Seventeen (70.8%) had received two or more doses of SARS-CoV-2 vaccine. No serious adverse events were noted. Seven patients developed SARS-CoV-2 infection within 180 days of receiving T-C (median 102 days; range 28-135), and only one patient developed severe COVID-19 requiring intensive mechanical ventilation in the intensive care unit.

Mixed-surface polyamidoamine polymer variants retain nucleic acid-scavenger ability with reduced toxicity.

Nucleic acid-binding polymers can have anti-inflammatory properties and beneficial effects in animal models of infection, trauma, cancer, and autoimmunity. PAMAM G3, a polyamidoamine dendrimer, is fully cationic bearing 32 protonable surface amines. However, while PAMAM G3 treatment leads to improved outcomes for mice infected with influenza, at risk of cancer metastasis, or genetically prone to lupus, its administration can lead to serosal inflammation and elevation of biomarkers of liver and kidney damage. Variants with reduced density of cationic charge through the interspersal of hydroxyl groups were evaluated as potentially better-tolerated alternatives. Notably, the variant PAMAM G3 50:50, similar in size as PAMAM G3 but with half the charge, was not toxic in cell culture, less associated with weight loss or serosal inflammation after parenteral administration, and remained effective in reducing glomerulonephritis in lupus-prone mice. Identification of such modified scavengers should facilitate their development as safe and effective anti-inflammatory agents.

A Guide to Observable Differences in Stated Preference Evidence.

BACKGROUND AND OBJECTIVE: In health preference research, studies commonly hypothesize differences in parameters (i.e., differential or joint effects on attribute importance) and/or in choice predictions (marginal effects) by observable factors. Discrete choice experiments may be designed and conducted to test and estimate these observable differences. This guide covers how to explore and corroborate various observable differences in health preference evidence. METHODS: The analytical process has three steps: analyze the exploratory data, analyze the confirmatory data, and interpret and disseminate the evidence. In this guide, we demonstrate the process using dual samples (where exploratory and confirmatory samples were collected from different sources) on 2020 US COVID-19 vaccination preferences; however, investigators may apply the same approach using split samples (i.e., single source). RESULTS: The confirmatory analysis failed to reject ten of the 17 null hypotheses generated by the exploratory analysis (p < 0.05). Apart from demographic, socioeconomic, and geographic differences, political independents and persons who have never been vaccinated against influenza are among those least likely to be vaccinated (0.838 and 0.872, respectively). CONCLUSIONS: For all researchers in health preference research, it is essential to know how to identify and corroborate observable differences. Once mastered, this skill may lead to more complex analyses of latent differences (e.g., latent classes, random parameters). This guide concludes with six questions that researchers may ask themselves when conducting such analyses or reviewing published findings of observable differences.

A randomized double-blind placebo-controlled trial of the effectiveness of melatonin on neurocognition and sleep in survivors of childhood cancer.

BACKGROUND: Adult survivors of childhood cancer are at risk of developing sleep and neurocognitive problems, yet few efficacious interventions exist targeting these prevalent late effects. Melatonin has known sleep-promoting effects; however, it has not been well studied among childhood cancer survivors. METHOD: Survivors (n = 580; mean age = 33.5 years; 26 years post-diagnosis) from the St. Jude Lifetime Cohort were randomized (1:1) to a six-month double-blind placebo-controlled trial of 3 mg time-release melatonin within three strata (stratum 1: neurocognitive impairment only; stratum 2: neurocognitive and sleep impairment; stratum 3: sleep impairment only). Neurocognitive performance was assessed at baseline and post-intervention using standardized measures. Sleep was assessed via self-report and actigraphy. Independent sample t tests compared mean change scores from baseline to six months. Post-hoc analyses compared the prevalence of clinically significant treatment responders among melatonin and placebo conditions within and across strata. RESULTS: Intent-to-treat analyses revealed no statistically significant differences in neurocognitive performance or sleep from baseline to post-intervention. However, among survivors with neurocognitive impairment only, a larger proportion randomized to melatonin versus placebo demonstrated a treatment response for visuomotor speed (63% vs 41%, P = 0.02) and nonverbal reasoning (46% vs 28%, P = 0.04). Among survivors with sleep impairment only, a larger proportion treated with melatonin demonstrated a treatment response for shifting attention (44% vs 28%, P = 0.05), short-term memory (39% vs 19%, P = 0.01), and actigraphy-assessed sleep duration (47% vs 29%, P = 0.05). CONCLUSION: Melatonin was not associated with improved neurocognitive performance or sleep in our intent-to-treat analyses; however, a subset of survivors demonstrated a clinically significant treatment response.

A case of not just Pott's disease.

Spinal tuberculosis (TB) is a rare cause of vertebral osteomyelitis in the developed world. Co-infections with other microorganisms are seldom reported in the literature. Here we report a case of Mycobacterium tuberculosis and Streptococcus anginosus causing acute on chronic vertebral osteomyelitis with an epidural abscess.

Addressing the burden of student loan debt: A case-based review of influencing considerations.

PURPOSE: The following review is offered as an aid for encouraging deeper understanding by pharmacy graduates of approaches to debt management. SUMMARY: The phenomenon of growing debt for pharmacists and other professionals has been well described. Significant debt is widespread with both pharmacy students and graduates; a recent study described the debt-to-income ratio for pharmacists to have risen by 141% between 2010 and 2016. This increasing debt burden causes significant pressure for these individuals-whether while in training, early in their career, or, increasingly, even in midcareer. Dealing with debt has become a major consideration in the profession. Given that financial education is addressed only minimally, if at all, in pharmacy curricula, pharmacists find it challenging to understand and fully consider the myriad factors influencing the accumulation and repayment of debt in the context of their financial goals. Personal financial, repayment, behavioral, and emotional/psychological factors must be considered to choose an optimal strategy to address debt. This article describes various repayment plans, particularly focusing on those offered with direct loans, and it reviews in some detail 5 comprehensive repayment strategies (using these plans). Three case studies derived from real-life pharmacist-planner interactions illustrate the many factors that must be considered as a pharmacist chooses the optimal approach to debt repayment in their unique life situation. CONCLUSION: Education of students and pharmacists regarding the various factors related to handling student debt may facilitate decision-making that is both financially and personally beneficial.

Does the U.S. Navy's reliance on objective standards prevent discrimination in promotions and retentions?

To prevent discrimination, the U.S. Navy enlisted-personnel promotion process relies primarily on objective measures. However, it also uses the subjective opinion of a sailor's superior. The Navy's promotion and retention process involves two successive decisions: The Navy decides whether to promote an individual, and conditional on that decision, the sailor decides whether to stay. Using estimates of these correlated decision-making processes, we find that during 1997-2008, Blacks and Hispanics were less likely to be promoted than Whites, especially during wartime. The Navy's decision-making affects Blacks' differential promotion rates by twice as much as differences in the groups' characteristics. However, Nonwhite retention probabilities, even when not promoted, are higher than for Whites, in part because they have fewer opportunities in the civilian market. Females have lower promotion rates than males and slightly lower retention rates during wartime.

Kidney Function after Treatment for Childhood Cancer: A Report from the St. Jude Lifetime Cohort Study.

BACKGROUND: Survivors of childhood cancer may be at increased risk for treatment-related kidney dysfunction. Although associations with acute kidney toxicity are well described, evidence informing late kidney sequelae is less robust. METHODS: To define the prevalence of and risk factors for impaired kidney function among adult survivors of childhood cancer who had been diagnosed ≥10 years earlier, we evaluated kidney function (eGFR and proteinuria). We abstracted information from medical records about exposure to chemotherapeutic agents, surgery, and radiation treatment and evaluated the latter as the percentage of the total kidney volume treated with ≥5 Gy (V5), ≥10 Gy (V10), ≥15 Gy (V15), and ≥20 Gy (V20). We also used multivariable logistic regression models to assess demographic and clinical factors associated with impaired kidney function and Elastic Net to perform model selection for outcomes of kidney function. RESULTS: Of the 2753 survivors, 51.3% were men, and 82.5% were non-Hispanic White. Median age at diagnosis was 7.3 years (interquartile range [IQR], 3.3-13.2), and mean age was 31.4 years (IQR, 25.8-37.8) at evaluation. Time from diagnosis was 23.2 years (IQR, 17.6-29.7). Approximately 2.1% had stages 3-5 CKD. Older age at evaluation; grade ≥2 hypertension; increasing cumulative dose of ifosfamide, cisplatin, or carboplatin; treatment ever with a calcineurin inhibitor; and volume of kidney irradiated to ≥5 or ≥10 Gy increased the odds for stages 3-5 CKD. Nephrectomy was significantly associated with stages 3-5 CKD in models for V15 or V20. CONCLUSIONS: We found that 2.1% of our cohort of childhood cancer survivors had stages 3-5 CKD. These data may inform screening guidelines and new protocol development.

Experience using intravenous posaconazole in paediatric and young adult oncology patients.

BACKGROUND: Posaconazole exhibits broad-spectrum antifungal activity. An IV formulation became available in 2014. Few studies describing the use of this formulation exist in patients under the age of 18 years. This study describes our experience using IV posaconazole in paediatric and young adult cancer patients. METHODS: This single-centre retrospective chart review evaluated patients who received IV posaconazole and had at least one posaconazole plasma concentration obtained after five or more days with a consistent dosage. Relationships between doses required to achieve a plasma concentration of ≥1 µg/mL and patient age, weight and body surface area (BSA) were evaluated. The clinical record was reviewed to identify descriptions of any adverse events. RESULTS: Twenty-five patients were analysed, with a median age of 10.5 years (range 1.9-22.9 years; 92% were <18 years). All patients were able to achieve a posaconazole plasma concentration ≥1 µg/mL during their treatment course. The daily mg/kg/day dose required to achieve the target concentration decreased significantly with increasing age of the patient (P = 0.018). Assessment of dosage based on BSA suggested a requirement of 225 mg/m2/day across all age groups <18 years. Adverse events documented in the clinical record were consistent with those described with the oral formulations. No CNS toxicities were observed with use of IV posaconazole. CONCLUSIONS: Concentrations ≥1 µg/mL are achievable and a BSA-based dosing approach may allow a consistent empirical dose for patients <18 years of age. Therapeutic drug monitoring is recommended to ensure patients achieve therapeutic concentrations.

Medical Student Spirituality and Substance Use.

OBJECTIVES: Although medical students report relatively high levels of substance use, little is known about the risk and protective factors associated with substance use in this population. This study sought to examine the link between spirituality and substance use among medical students. METHODS: As part of a larger study, medical students from all 9 medical schools in the state of Florida were invited to complete an anonymous survey pertaining to distress and well-being. Responses to items assessing self-reported spirituality and substance use were examined and descriptive statistics were analyzed. RESULTS: Data from 868 medical students (57% female) were included. Of these, 22.6% described themselves as "non-spiritual," 31.0% described themselves as "spiritual," 18.5% engaged in informal spiritual practices, and 27.9% reported formal spiritual/religious practices. Students who reported stronger spirituality also reported lower rates of substance use. Though 31% of respondents across all levels of spirituality reported that their alcohol consumption increased since starting medical school, rates of binge drinking after exams were inversely related to level of spirituality. CONCLUSIONS: Self-reported spirituality appears to be associated with decreased risk of substance use in medical school. Future studies should examine this relation in greater depth.

Randomized trial to assess safety/feasibility of memantine administration during residential treatment for alcohol use disorder: a pilot study.

The N-methyl-D-aspartate receptor (NMDAr) system is critically involved in the pathogenesis and neurobehavioral sequelae of alcohol use disorder (AUD), and constitutes a potential pharmacotherapeutic target. Memantine (Namenda) is an FDA-approved NMDAr antagonist with suggested utility in AUD, however its safety and tolerability during long-term administration among recently-detoxified patients remains uncharacterized. This pilot study assessed safety, feasibility, and several secondary measures of interest, during a 4-week period of residential AUD treatment. Participants (N = 18) met diagnostic criteria for AUD. A double-blind, placebo-controlled, escalating-dose design was utilized. Assessments of medication side-effects were conducted weekly. At intake, week 2, and study completion, participants completed a battery assessing affective symptomatology, craving, and neurocognitive function. Medication groups reported equivalent side effects and severity. Medication compliance was high, and did not differ by group. No memantine effects were observed in secondary outcome measures. Memantine maintains a profile of high tolerability and low side-effects during post-detoxification AUD treatment. These data suggest a more aggressive dosing/escalation schedule may be used safely in future trials designed to ascertain improvements in neurocognitive function, affect, and/or craving as primary measures.

Change in Pain Status and Subsequent Opioid and Marijuana Use Among Long-Term Adult Survivors of Childhood Cancer.

We evaluated pain status change and associations with subsequent opioid/marijuana use among 1208 adult survivors of childhood cancer. Pain status and opioid/marijuana were self-reported at baseline and follow-up evaluation (mean interval = 4.2 years). Over time, 18.7% of survivors endorsed persistent/increasing significant pain; 4.8% and 9.0% reported having used opioids and marijuana at follow-up. Persistent/increased (vs none/decreased) pain, persistent/increased (vs none/decreased) anxiety, and lack of health insurance increased odds of subsequent opioid use by 7.69-fold (95% confidence interval [CI] = 3.71 to 15.95), 2.55-fold (95% CI = 1.04 to 6.24), and 2.50-fold (95% CI = 1.07 to 5.82), respectively. Persistent/increased (vs none/decreased) depression increased odds of subsequent marijuana use by 2.64-fold (95% CI = 1.10 to 6.33).

Serum Alanine Aminotransferase Elevations in Survivors of Childhood Cancer: A Report From the St. Jude Lifetime Cohort Study.

The purpose of this study was to define the prevalence of and risk factors for elevated serum alanine aminotransferase (ALT) level among adult childhood cancer survivors (CCS). The study cohort comprised 2,751 CCS from the St. Jude Lifetime Cohort Study (>10 years postdiagnosis, age ≥18 years). Serum ALT level was graded using the Common Terminology Criteria for Adverse Events v. 4.03. Modified Poisson regression models were used to estimate relative risks and 95% confidence intervals for the association between demographic and clinical factors and grades 1-4 ALT on the selected models. A total of 1,339 (48.7%) CCS were female; 2,271 (82.6%) were non-Hispanic white. Median age at evaluation was 31.4 years (interquartile range [IQR] = 25.8-37.8); median elapsed time from diagnosis to evaluation was 23.2 years (IQR = 17.6-29.7). A total of 1,137 (41.3%) CSS had ALT > upper limit of normal (Common Terminology Criteria for Adverse Events v. 4.03 grade 1-1,058 (38.5%); grade 2-56 (2.0%); grade 3-23 (0.8%); grade 4-none). Multivariable models demonstrated non-Hispanic white race/ethnicity, age at evaluation in years, being overweight or obese, presence of the metabolic syndrome, current treatment with atorvastatin or rosuvastatin or simvastatin, hepatitis C virus infection, prior treatment with busulfan or thioguanine, history of hepatic surgery, and the percentage of liver treated with ≥10 Gray, ≥15 Gray, or ≥20 Gray were associated with elevated ALT. Conclusion: Grade 3 or 4 hepatic injury is infrequent in CCS. Mild hepatic injury in this group may be amenable to lifestyle modifications.

Pentamidine for Prophylaxis against Pneumocystis jirovecii Pneumonia in Pediatric Oncology Patients Receiving Immunosuppressive Chemotherapy.

Pneumocystis jirovecii pneumonia is a life-threatening opportunistic infection in children receiving immunosuppressive chemotherapy. Without prophylaxis, up to 25% of pediatric oncology patients receiving chemotherapy will develop Pneumocystis jirovecii pneumonia. Trimethoprim-sulfamethoxazole is the preferred agent for prophylaxis against Pneumocystis jirovecii pneumonia. Pentamidine may be an acceptable alternative for pediatric patients unable to tolerate trimethoprim-sulfamethoxazole. A retrospective review was conducted of pediatric oncology patients who received ≥1 dose of pentamidine for Pneumocystis jirovecii pneumonia prophylaxis between January 2007 and August 2014. Electronic medical records were reviewed to determine the incidence of breakthrough Pneumocystis jirovecii pneumonia or discontinuation of pentamidine associated with adverse events. A total of 754 patients received pentamidine prophylaxis during the period. There were no cases of probable or proven Pneumocystis pneumonia, and 4 cases (0.5%) of possible Pneumocystis pneumonia. The incidence of possible breakthrough Pneumocystis pneumonia was not significantly different between subgroups based on age (<12 months [1.7%] versus ≥12 months [0.4%], P = 0.3), route of administration (aerosolized [0%] versus intravenous [1.0%], P = 0.2), or hematopoietic stem cell transplant status (transplant [0.4%] versus no transplant [0.8%], P = 0.6). Pentamidine was discontinued due to an adverse drug event in 23 children (3.1%), more frequently for aerosolized than for intravenous administration (7.6% versus 2.2%, respectively, P = 0.004). Intravenous or inhaled pentamidine may be a safe and effective second-line alternative for prophylaxis against Pneumocystis jirovecii pneumonia in children with cancer receiving immunosuppressive chemotherapy or hematopoietic stem cell transplantation.

Misreporting and econometric modelling of zeros in survey data on social bads: An application to cannabis consumption.

When modelling "social bads," such as illegal drug consumption, researchers are often faced with a dependent variable characterised by a large number of zero observations. Building on the recent literature on hurdle and double-hurdle models, we propose a double-inflated modelling framework, where the zero observations are allowed to come from the following: nonparticipants; participant misreporters (who have larger loss functions associated with a truthful response); and infrequent consumers. Due to our empirical application, the model is derived for the case of an ordered discrete-dependent variable. However, it is similarly possible to augment other such zero-inflated models (e.g., zero-inflated count models, and double-hurdle models for continuous variables). The model is then applied to a consumer choice problem of cannabis consumption. We estimate that 17% of the reported zeros in the cannabis survey are from individuals who misreport their participation, 11% from infrequent users, and only 72% from true nonparticipants.