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BACKGROUNDDonepezil exerts pro-cognitive effects by non-selectively enhancing acetylcholine (ACh) across multiple brain systems. The brain systems that mediate pro-cognitive effects of attentional control and cognitive flexibility are the prefrontal cortex and the anterior striatum which have different pharmacokinetic sensitivities to ACh modulation. We speculated that these area-specific ACh profiles lead to distinct optimal dose-ranges for donepezil to enhance the cognitive domains of attention and flexible learning.METHODSTo test for dose-specific effects of donepezil on different cognitive domains we devised a multi-task paradigm for nonhuman primates (NHPs) that assessed attention and cognitive flexibility. NHPs received either vehicle or variable doses of donepezil prior to task performance. We measured donepezil intracerebral and how strong it prevented the breakdown of ACh within prefrontal cortex and anterior striatum using solid-phase-microextraction neurochemistry.RESULTSThe highest administered donepezil dose improved attention and made subjects more robust against distractor interference, but it did not improve flexible learning. In contrast, only a lower dose range of donepezil improved flexible learning and reduced perseveration, but without distractor-dependent attentional improvement. Neurochemical measurements confirmed a dose-dependent increase of extracellular donepezil and decreases in choline within the prefrontal cortex and the striatum.CONCLUSIONSThe donepezil dose for maximally improving attention functions differed from the dose range that enhanced cognitive flexibility despite the availability of the drug in the major brain systems supporting these cognitive functions. Thus, the non-selective acetylcholine esterase inhibitor donepezil inherently trades improvement in the attention domain for improvement in the cognitive flexibility domain at a given dose range.

Context The single-legged squat (SLS) is appropriate for targeting activation, strengthening, and neuromuscular retraining of the gluteus maximus, gluteus medius, and quadriceps. However, the effects of different nonstance-limb positions on muscle activity have not been fully evaluated. Objective To compare the muscle activity of selected stance-limb hip muscles during the SLS using 3 nonstance-limb positions: in front (SLS-Front), in the middle (SLS-Middle), and in back (SLS-Back). Design Controlled laboratory study. Setting Biomechanics laboratory. Patients or Other Participants A total of 17 healthy adults (8 men, 9 women; age = 22.6 ± 3.6 years, height = 173.3 ± 10.7 cm, mass = 71.2 ± 11.0 kg) participated. Main Outcome Measure(s) Surface electromyographic data of the gluteus maximus, gluteus medius, lateral hamstrings, medial hamstrings, rectus femoris, and tensor fascia lata (TFL) as well as kinetic data of the hip and knee were collected while participants performed the 3 SLS tasks. Mean muscle-activation levels during the descent and ascent phases for the selected hip muscles and hip and knee kinetics in all 3 planes were compared for the 3 tasks. Each variable of interest was analyzed using a separate linear regression model with a generalized estimating equations correction. Results Muscle-activation levels of the gluteus maximus, gluteus medius, medial hamstrings, rectus femoris, and TFL for the stance limb during descent (P ≤ .04) and the medial hamstrings and TFL during ascent (P ≤ .002) were different among the SLS tasks. The greatest number of differences occurred between SLS-Front and SLS-Back. During descent, gluteal muscle activity was greater in SLS-Front (P ≤ .03) and SLS-Middle (P = .03) than in SLS-Back. For both phases, TFL activity was greater during SLS-Front than during both SLS-Middle and SLS-Back (P ≤ .006). Kinetic differences at the hip and knee between SLS tasks were also observed (P values ≤ .02). Conclusions The 3 SLS tasks had different muscle-activation and kinetic profiles. Clinicians and researchers can vary nonstance-limb position during the SLS to manipulate muscle-activation levels and tailor the exercise to assist with goals at different stages of rehabilitation.

OBJECTIVE This study aimed to compare lipid and blood pressure (BP) control before and after implementing a certified pharmacy technician (CPhT) protocol that optimized electronic health record (EHR) capabilities and shifted work from clinical pharmacy specialists (CPSs) to CPhT. SETTING Kaiser Permanente Colorado's pharmacist-managed cardiac risk reduction service (which manages dyslipidemia, hypertension, and diabetes for all patients with atherosclerotic cardiovascular disease). PRACTICE DESCRIPTION In 2019, a protocol that optimized EHR capabilities and allowed work to be offloaded from CPS to CPhT was implemented. Filtered views within the EHR were created that bucketed patients with specific lipid results criteria. The CPhT protocol provided guidance to CPhT on determining whether patients were at low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein (non-HDL) goals, on appropriate statin intensity, adherent to medications, and whether the most recent BP was controlled. The CPhT notified CPS of uncontrolled patients who would assess and manage these patients, as necessary. The CPhT notified controlled patients of their results. PRACTICE INNOVATION Data on the outcomes of incorporating pharmacy technicians to support CPS clinical activities in ambulatory clinical pharmacy are limited. EVALUATION METHODS This retrospective study compared a "Pharmacist-Driven" (index date: January 1, 2016) with a "Tech-Enhanced" (index date: January 1, 2019) group. The primary outcome was the proportion of patients at all goals defined as LDL-C < 70 mg/dL, non-HDL

Checkpoint inhibitor-based immunotherapy is increasingly used in the treatment of gynecologic cancers, and most often targets the PD-1/PD-L1 axis. Pathologists should be familiar with the biomarkers required to determine candidacy for these treatments based on existing FDA approvals, including mismatch repair protein immunohistochemistry, microsatellite instability testing, tumor mutation burden testing, and PD-L1 immunohistochemistry. This review summarizes the rationale behind these treatments and their associated biomarkers and delivers guidance on how to utilize and readout these tests. It also introduces additional biomarkers which may provide information regarding immunotherapeutic vulnerability in the future such as neoantigen load; POLE mutation status; and immunohistochemical expression of immunosuppressive checkpoints like LAG-3, TIM-3, TIGIT, and VISTA; immune-activating checkpoints such as CD27, CD40, CD134, and CD137; enzymes such as IDO-1 and adenosine-related compounds; and MHC class I.

Cardiogenic shock (CS) represents a spectrum of hemodynamic deficits in which the cardiac output is insufficient to provide adequate tissue perfusion. The Impella (Abiomed Inc, Danvers, MA) device, a contemporary percutaneous ventricular support, is most often indicated for classic, deteriorating, and extremis Society for Coronary Angiography and Intervention stages of CS, which describe CS that is not responsive to optimal medical management and conventional treatment measures. Impella devices are an evolving field of mechanical support that is used with increasing frequency. Critical care transport medicine crews are required to transport patient support by the Impella device with increasing frequency. It is important that critical care transport medicine crews are familiar with the Impella device and are able to troubleshoot complications that may arise in the transport environment. This article reviews many aspects of the Impella device critical to the transport of this complex patient population.

Biologics are indicated for the treatment of a wide range of conditions and have transformed care in several therapeutic areas; however, they are expensive for both health care systems and patients. The use of biosimilars, which are approved by the US Food and Drug Administration as being “highly similar” to the originator biologic, has the potential to change the health care landscape in the biologic space through considerable cost savings for both payors and patients. With the introduction of biosimilars, organizations are increasingly evaluating how to switch patients from originator biologics to biosimilars. While published studies have evaluated the outcomes of patients switched from originator biologics to biosimilars, there are few publications describing the process health care systems have used to adopt and switch patients to biosimilars. Since 2016, Kaiser Permanente Colorado (KPCO) has undertaken several biosimilar switches starting with the first biosimilar introduced to the market, filgrastim, and has been able to successfully switch 91.8% of patients receiving infliximab, 99.8% receiving rituximab, and 100% receiving filgrastim, trastuzumab, and bevacizumab originator biologics to their respective biosimilars. In an effort to support other health care systems and provide a framework for implementing biosimilar switches, the purpose of this paper is to describe the biosimilar switch model and share learnings from the KPCO experience.

Objectives To explore pharmacy colleges’ experiences and challenges worldwide with the transition to online teaching during the coronavirus disease 2019 (COVID-19) pandemic. Methods From the six World Health Organization regions, 28 countries with the highest number of COVID-19 cases were identified, and 111 pharmacy colleges were randomly selected from these countries. Two online surveys were sent to faculty members and senior administrators. They assessed changes in teaching and learning, experiential training, assessment, readiness for and challenges with distance e-learning and work-related stress. Key findings Data were collected from 46 colleges. The majority (80.4%) of colleges transitioned to distance e-learning. On-site experiential training was discontinued in 55.5% of colleges and 25.0% redesigned on-site training into remote learning experiences. Assessments were modified in 75.9% of colleges. Assuring the integrity of assessments and delivering practical classes were the most prominent faculty challenges. The majority of faculty (75.0%) and administrators (61.9%) reported moderate work-related stress. Nevertheless, most academics felt that they received adequate support from their institutions and had positive perceptions of the transition to distance e-learning during the pandemic. Conclusions The COVID-19 pandemic required drastic changes for most programs’ teaching methods. Our results showed that educational institutions were somewhat able to support faculty and the needs of educational programs were largely met. However, academic rigour and provision of experiential training can be improved. Faculty emotional support and training needs were not fully addressed in these difficult times. These results shed light on how the global pharmacy academy has addressed the COVID-19 pandemic and help rethink crisis response models.

Phenylketonuria (PKU) is the most common inborn error of metabolism of the liver, and results from mutations of both alleles of the phenylalanine hydroxylase gene (PAH). As such, it is a suitable target for gene therapy via gene delivery with a recombinant adeno-associated virus (AAV) vector. Here we use the synthetic AAV vector Anc80 via systemic administration to deliver a functional copy of a codon-optimized human PAH gene, with or without an intron spacer, to the Pahenu2 mouse model of PKU. Dose-dependent transduction of the liver and expression of PAH mRNA were present with both vectors, resulting in significant and durable reduction of circulating phenylalanine, reaching near control levels in males. Coat color of treated Pahenu2 mice reflected an increase in pigmentation from brown to the black color of control animals, further indicating functional restoration of phenylalanine metabolism and its byproduct melanin. There were no adverse effects associated with administration of AAV up to 5 × 1012 VG/kg, the highest dose tested. Only minor and/or transient variations in some liver enzymes were observed in some of the AAV-dosed animals which were not associated with pathology findings in the liver. Finally, there was no impact on cell turnover or apoptosis as evaluated by Ki-67 and TUNEL staining, further supporting the safety of this approach. This study demonstrates the therapeutic potential of AAV Anc80 to safely and durably cure PKU in a mouse model, supporting development for clinical consideration.

Pelvic drop is caused by decreased hip abductor muscle activity and is associated with lower-extremity injury. Hip abductor strengthening exercises are well established; however, no standard method exists to increase hip abductor activity during functional activities. The purpose of this research was to study the effects of walking with a unilateral weight. A total of 26 healthy adults walked on an instrumented treadmill with and without handheld weight (15%–20% body weight). Muscle activity, kinematic, and kinetic data were collected using surface electromyography, motion capture, and force plates, respectively. Average hip and trunk muscle activity, hip, pelvic, and trunk angles, and peak internal hip moments during stance were compared for each side (contralateral/ipsilateral to the weight) between conditions (unweighted/weighted) using a generalized linear model with generalized estimating equation correction. Interactions between condition and side were observed for muscle activity, frontal plane pelvic and trunk angles, and frontal plane hip moments (P ≤ .003). Compared with the unweighted condition, the weighted condition had higher hip abductor activity contralateral to the weight (P P ≥ .790). Similar changes were found for kinematic and kinetic variables. Walking with a unilateral weight may be a therapeutic option to increase functional hip abductor activity.

Surgical options for advanced Kienböck’s disease include proximal row carpectomy or lunate reconstruction with a medial femoral trochlea osteochondral flap. This study compares morphology of the proximal capitate and the medial femoral trochlear surfaces to the proximal lunate using three-dimensional geometric morphometric analysis. Virtual articular surfaces were extracted from MRI studies of ten healthy volunteers. Distances between corresponding points on the proximal lunate and proximal capitate or medial femoral trochlear surfaces were measured. In seven subjects, mean inter-surface distance for the medial femoral trochlea–proximal lunate pair was significantly lower than the proximal capitate–proximal lunate pairing. In three subjects, mean proximal capitate–proximal lunate distance was significantly lower. We conclude that the medial femoral trochlear flap was anatomically closer to the shape of the proximal lunate in the majority of the examined subjects. However, we found that in three out of ten cases, the proximal capitate was a better match.

Background: Postoperative atrial fibrillation (POAF) commonly occurs after coronary artery bypass graft (CABG) surgery. Patients with POAF are at higher risk of stroke and mortality. The use of oral anticoagulation (OAC) in POAF remains inconsistent, and the care gap is unknown. Objective: We sought to evaluate rate of adherence and factors associated with OAC use in POAF patients after isolated CABG. Methods: In this study, all patients who had an isolated CABG between April 1, 2019 and March 30, 2020, at Health Sciences North, Sudbury retrospectively were evaluated. We identified all patients who developed POAF and captured the use of OAC. Multivariable logistic regression models were used to identify predictors of OAC prescription. Results: In total, 339 CABG patients between April 1, 2019 and March 30, 2020, were identified; 86 patients developed POAF. No patients had major perioperative bleeding. All POAF patients had an indication for OAC therapies based on CHADS 65 score. However, only 17 (19.8%) patients with POAF had OAC prescription at the time of hospital discharge. Baseline characteristics were similar between those with or without OAC. In multivariable analysis, the use of dual antiplatelet therapy was associated with a decreased use of OAC therapy in POAF (OR 0.037 (95% CI 0.005, 0.29), P = .002). Moreover, in comparison to surgeon A, surgeon B was associated with a decreased use of OAC therapy, whereas surgeon C was associated with an increased use of OAC therapy in POAF (OR 0.15 (95% CI 0.03, 0.83), P = .03 and OR 6.49 (95% CI 1.21, 34.82), P = .03, respectively). None of the CHADS 65 elements, including age, hypertension, stroke, diabetes mellitus or congestive heart failure, correlated with the use of OAC. Key findings: Eighty percent of patients who developed POAF after isolated CABG failed to receive stroke prevention therapies. The use of dual antiplatelet therapy and individual surgeons’ preference were associated with the use of OAC therapy among POAF. Conclusions: This data set suggests that approximately only 1 in 5 patients with POAF after isolated CABG got prescribed OAC.

Treating and monitoring type 2 diabetes mellitus (T2DM) in NHP can be challenging. Multiple insulin and hypoglycemic therapies and management tools exist, but few studies demonstrate their benefits in a NHP clinical setting. The insulins glargine and degludec are long-acting insulins; their duration of action in humans exceeds 24 and 42 h, respectively. In the first of this study's 2 components, we evaluated whether insulin degludec could be dosed daily at equivalent units to glargine to achieve comparable blood glucose (BG) reduction in diabetic rhesus macaques (Macaca mulatta) with continuous glucose monitoring (CGM) devices. The second component assessed the accuracy of CGM devices in rhesus macaques by comparing time-stamped CGM interstitial glucose values, glucometer BG readings, and BG levels measured by using an automated clinical chemistry analyzer from samples that were collected at the beginning and end of each CGM device placement. The CGM devices collected a total of 21,637 glucose data points from 6 diabetic rhesus macaques that received glargine followed by degludec every 24 h for 1 wk each. Ultimately, glucose values averaged 29 mg/dL higher with degludec than with glargine. Glucose values were comparable between the CGM device, glucometer, and chemistry analyzer, thus validating that CGM devices as reliable for measuring BG levels in rhesus macaques. Although glargine was superior to degludec when given at the same dose (units/day), both are safe and effective treatment options. Glucose values from CGM, glucometers, and chemistry analyzers provided results that were analogous to BG values in rhesus macaques. Our report further highlights critical clinical aspects of using glargine as compared with degludec in NHP and the benefits of using CGM devices in macaques.

The posterior cruciate ligament (PCL) is the largest intra-articular ligament in the knee and is the primary stabilizer to posterior tibial translation. Historically, the PCL’s functional dynamics and appropriate management after injury have been controversial. However, recent biomechanical and anatomic studies have elucidated a better understanding of PCL function, which has led to development of more anatomic reconstruction techniques. The larger anterolateral bundle and the smaller posteromedial bundle of the PCL exhibit a codominant relationship and have a wide femoral attachment footprint. For these reasons, the native kinematics of the knee is better restored with a double-bundle PCL reconstruction (DB-PCLR) technique than with a single-bundle PCL reconstruction (SB-PCLR). Likewise, clinical studies have demonstrated excellent outcomes for DB-PCLR compared to SB-PCLR, with decreased posterior knee laxity on stress radiography and improved International Knee Documentation Committee scores. This review will provide a detailed overview of the clinically relevant anatomy, biomechanics, injury evaluation, and treatment options, with an emphasis on arthroscopic DB-PCLR.

Background The Blastomyces antigen concentration in urine (BACU) test is used to diagnose blastomycosis and monitor treatment in dogs. It is unknown if a higher BACU is associated with shorter survival. Objectives To determine if the magnitude of BACU before treatment is associated with survival in dogs with blastomycosis. Animals Fifty‐two dogs with blastomycosis. Methods Retrospective case review. BACU, radiographic lung severity (RLS) score (0‐4 scale), and survival time up to 1 year after diagnosis were obtained through medical record review of dogs with Blastomyces dermatitidis. Results The overall survival was: discharge, 87%; 1 week, 85%; 2 months, 74%; and 6 months, 69%. BACU correlated with RLS score (r s = 0.33, P = .02). BACU and RLS scores were lower in survivors to 2 months than nonsurvivors (average BACU difference of 2.5 ng/mL, 95% confidence interval [CI]: 0.2‐4.8 ng/mL, P = .04; median RLS difference of 2; range, 0‐4, P = .02). Dogs with BACU 5 ng/mL (P = .03) and dogs with severe (3‐4) RLS scores (P = .04). All dogs with a BACU

BACKGROUND: Homologous recombination deficiency (HRD) score is related to chemotherapy response in some cancers, but its role in endometrial cancer in not known. We determined frequency and clinical significance of alterations in the HR pathway in endometrial cancer. METHODS: 253 endometrioid endometrial adenocarcinoma (EEA) samples from two independent cohorts (discovery and replication) were tested for HRD score using the Myriad HRD assay, microsatellite instability (MSI) and tumor mutation burden (TMB) using a next generation sequencing assay. HRD scores were also generated on endometrial cancer cell lines and in vivo response to olaparib was assessed. RESULTS: ROC curves were employed to determine optimal cutoffs of HRD in relation to survival impact in endometrial cancer and a cutoff of HRD ≥ 4 was suggested for DFS using discovery cohort. Patients from two independent cohorts with HRD score ≥ 4 trended toward worse survival as compared to those with HRD score

Major histocompatibility complex (MHC) class I is a membrane-bound protein complex expressed on nucleated human cells. MHC class I presents intracellular protein fragments to cytotoxic T cells and triggers an activation cascade upon neoantigen detection by these cells. MHC class I loss by tumor cells decreases tumor neoantigen presentation to the immune system and therefore represents a possible mechanism of immunotherapeutic resistance even among cancers that otherwise appear to be good candidates for checkpoint inhibition, such as mismatch repair (MMR)-deficient and PD-L1-positive malignancies. We herein assess MHC class I expression in a range of endometrial carcinomas, including MMR-deficient and PD-L1-positive cancers. Immunohistochemical staining for combined MHC class I A-, B-, and C-heavy chains was performed on 76 cases of endometrial carcinoma and was classified as present, subclonally lost, or diffusely lost. Tumoral PD-L1 expression, PD-L1 combined positive score, and CD3-positive T lymphocytes were also quantified. Forty-two percent of tumors showed loss of MHC class I expression, either in a subclonal (26%) or diffuse (16%) pattern. This included 46% of MMR-deficient and 25% of PD-L1-positive cancers. These findings suggest that tumoral MHC class I status may be an important factor to consider when selecting endometrial cancer patients for checkpoint inhibition.

MLH1/PMS2 loss due to epigenetic hypermethylation of the MLH1 promoter is the most common cause of mismatch repair deficiency in endometrial carcinoma, and typically provides reassurance against an associated germline mutation. To further characterize the genetic features of MLH1/PMS2-deficient endometrial cancers, the departmental database was searched for cases with dual MLH1/PMS2 loss and retained MSH2/6 expression which underwent MLH1 hypermethylation testing. Genetic testing results were obtained when available. One hundred seventeen endometrial cancers met inclusion criteria: 100 (85%) were MLH1-hypermethylated, 3 (3%) were low-level/borderline, 7 (6%) were nonmethylated, and 7 (6%) were insufficient for testing. Sixteen cases (12 MLH1-hypermethylated, 3 nonmethylated, and 1 insufficient for testing) underwent germline testing, 6 of which (37.5%) demonstrated germline variants of unknown significance (VUS) (MSH6, PMS2, POLD1, BRIP1, RAD51D, CHEK2) but no known deleterious mutations. Notably, however, the patients harboring the MSH6 and PMS2 germline VUS had clinical features concerning for Lynch syndrome. One nonmethylated, germline-normal case underwent somatic tumor testing, and demonstrated a somatic MLH1 mutation. In summary, MLH1-hypermethylation accounts for the vast majority of MLH1/PMS2-deficient cancers in a universally screened population, although MLH1 somatic and germline mutations can occur. Occasionally, patients with MLH1-hypermethlated tumors also bear germline VUS in other mismatch repair genes as well as genes implicated in other hereditary cancer syndromes, but their clinical relevance is unclear. Family and personal cancer histories must always be evaluated to determine the need for germline testing in women with loss of MLH1/PMS2, even in the setting of hypermethylation.

PURPOSE: Fertility is a quality of life outcome adversely affected by cancer therapy. Many childhood cancer patients, however, are not offered options to preserve their fertility. Providers acknowledge difficulty discussing impaired fertility to patients due to lack of knowledge of available options. Our objective was to review the impact of a pediatric multidisciplinary fertility preservation program on providers’ fertility preservation counseling and discussion of options. METHODS: A retrospective medical chart review was conducted for pediatric cancer patients prior to and following program establishment. Fertility preservation discussions, consults, and incidence were noted. Following filtering and stratification, 198 and 237 patients were seen prior to and following program establishment, respectively. RESULTS: Following program establishment, provider–patient discussions of impaired fertility (p = 0.007), fertility preservation consults (p = 0.01), and incidence of fertility preservation procedures (p < 0.001) increased among patients. Furthermore, the number of patients who received fertility preservation consults after receiving gonadotoxic treatment decreased (p < 0.001). This trend was particularly noted in pre-pubertal and female patients, for whom fertility preservation options are limited without an established program. CONCLUSION: The establishment of a formal program greatly improved access to fertility preservation consults and procedures in children with cancer.

Objective The aim of this study was to evaluate whether the effects of transcranial direct current stimulation (tDCS) on cognitive performance are influenced by the state-dependency of targeted cortical regions. Methods In a mixed within- and between-participants design, we targeted either the right parietal or left dorsolateral prefrontal cortex and measured effects on visual search versus inhibitory control (respectively). Critically, during active and sham stimulation, participants were exposed to an unrelated or task-congruent prime. Results Analyses examined whether priming induced state-dependent changes in behavior on a subsequent visual search or inhibitory control task. Results demonstrated consistent support for the null hypothesis, with neither tDCS nor priming influencing behavioral outcomes. Conclusions This outcome does not provide direct support for state-dependency or activity-selectivity models of tDCS effects on cognitive outcomes. We discuss the possibility that behavioral patterns supporting these mechanistic models may only be found when the priming and outcome tasks share critical neurocognitive features. Overall, we found no evidence that offline (pretask) tDCS targeting the right parietal or left dorsolateral prefrontal induces reliable changes in visual search or inhibitory control behavior, and this pattern is not modulated by state-dependency induced by priming task-related activity.

Aromatherapy is defined as the use of essential oils, through inhalation or direct application to the skin, to achieve physical, psychological, and spiritual well-being. It has become an increasingly popular trend in modern-day holistic approaches to health care. Essential oils are thought to be natural and pure products, some of the most common being lavender, tea tree, peppermint, and ylang-ylang. In recent years, however, the composition of these oils has been found to be more complex than previously thought. Increased use has led to increasing reports of allergic contact dermatitis (ACD), a delayed-type hypersensitivity reaction to allergens in sensitized individuals. Inquiring about essential oil use is important when conducting clinical evaluations of suspected ACD. Herein, the authors seek to highlight the possibility that natural products may not be necessarily as safe as once thought and in particular seek to highlight ACD caused by essential oils.

Supplemental material, sj-docx-1-cjk-10.1177_20543581221081258 for Development and Feasibility of a Multidisciplinary Approach to AKI Survivorship in Care Transitions: Research Letter by Erin F. Barreto, Heather P. May, Diana J. Schreier, Laurie A. Meade, Brenda K. Anderson, Megan E. Rensing, Kari L. Ruud, Andrea G. Kattah, Andrew D. Rule, Rozalina G. McCoy, Dawn M. Finnie, Joseph R. Herges and Kianoush B. Kashani in Canadian Journal of Kidney Health and Disease

The effectiveness of cell-based therapies to treat liver failure is often limited by the diseased liver environment. Here, we provide preclinical proof of concept for hepatocyte transplantation into lymph nodes as a cure for liver failure in a large-animal model with hereditary tyrosinemia type 1 (HT1), a metabolic liver disease caused by deficiency of fumarylacetoacetate hydrolase (FAH) enzyme. Autologous porcine hepatocytes were transduced ex vivo with a lentiviral vector carrying the pig Fah gene and transplanted into mesenteric lymph nodes. Hepatocytes showed early (6 h) and durable (8 months) engraftment in lymph nodes, with reproduction of vascular and hepatic microarchitecture. Subsequently, hepatocytes migrated to and repopulated the native diseased liver. The corrected cells generated sufficient liver mass to clinically ameliorate the acute liver failure and HT1 disease as early as 97 days post-transplantation. Integration site analysis defined the corrected hepatocytes in the liver as a subpopulation of hepatocytes from lymph nodes, indicating that the lymph nodes served as a source for healthy hepatocytes to repopulate a diseased liver. Therefore, ectopic transplantation of healthy hepatocytes cures this pig model of liver failure and presents a promising approach for the development of cures for liver disease in patients., Graphical Abstract, Lillegard and colleagues demonstrate that ectopic hepatocyte transplantation into lymph nodes cures liver failure in a large-animal model of metabolic disease, hereditary tyrosinemia type-1 (HT1). Autologous hepatocytes were transduced ex vivo with a lentiviral vector carrying the Fah gene, missing in HT1. Transplanted hepatocytes generated sufficient liver mass to cure the disease.

The lower urinary tract (LUT) and micturition reflexes are sexually dimorphic across mammals. Sex as a biological variable is also of critical importance for the development and translation of new medical treatments and therapeutics interventions affecting pelvic organs, including the LUT. However, studies of LUT function with comparisons between the sexes have remained sparse, especially for larger mammals. Detrusor function was investigated by filling cystometry and pressure flow studies in 16 male and 22 female rhesus macaques. By filling cystometry, male subjects exhibited a significantly larger bladder capacity and compliance compared to females. Pressure flow studies showed a significantly higher bladder pressure at voiding onset, peak pressure, and elevation in detrusor-activated bladder pressure from the end of bladder filling to peak pressure in the male subjects. The activation of reflex micturition, with associated detrusor contractions, resulted in voiding in a significantly larger proportion of female compared to male subjects. A higher urethral outlet resistance is suggested in the male subjects. We conclude that sexual dimorphism of detrusor function is prominent in rhesus macaques, shares many features with the human, and merits consideration in translational and pre-clinical research studies of micturition and LUT function in non-human primates.

Impairment of fertility and sexual/reproductive health are common after oncologic therapy, and are known to have negative impacts on romantic relationships and psychosocial well-being among childhood cancer survivors. The Pediatric Initiative Network (PIN) is an international, multidisciplinary group of providers within the Oncofertility Consortium dedicated to preserving and protecting the fertility of children and adolescents at risk for infertility due to medical conditions or treatments. The PIN and its Best Practices and Research committees meet virtually throughout the year, with one annual in-person meeting. The purpose of this “proceedings” is to highlight key discussion points from the annual PIN meeting which took place on November 11, 2019, to 1) provide a context for pediatric groups across the country on what oncofertility programs are currently doing and why, and 2) inform stakeholders of past, present and future initiatives that may be of value to them and the patient populations they serve.

Introduction There is a growing population of childhood cancer survivors at risk for adverse outcomes, including sexual dysfunction. Aim To estimate the prevalence of and risk factors for sexual dysfunction among adult female survivors of childhood cancer and evaluate associations between dysfunction and psychological symptoms/quality of life (QOL). Methods Female survivors (N = 936, mean 7.8 ± 5.6 years at diagnosis; 31 ± 7.8 years at evaluation) and noncancer controls (N = 122) participating in the St. Jude Lifetime Cohort Study completed clinical evaluations, Sexual Functioning Questionnaires (SFQ), and Medical Outcomes Survey Short Forms 36 (SF-36). Linear models compared SFQ scores between sexually active survivors (N = 712) and controls; survivors with scores Outcomes Sexual dysfunction was defined by scores Results Sexual dysfunction was prevalent among 19.9% (95% CI 17.1, 23.1) of survivors. Those diagnosed with germ cell tumors (OR = 8.82, 95% CI 3.17, 24.50), renal tumors (OR = 4.49, 95% CI 1.89, 10.67), or leukemia (OR = 3.09, 95% CI 1.50, 6.38) were at greater risk compared to controls. Age at follow-up (45–54 vs 18–24 years; OR = 5.72, 95% CI 1.87, 17.49), pelvic surgery (OR = 2.03, 95% CI 1.18, 3.50), and depression (OR = 1.96, 95% CI 1.10, 3.51) were associated with sexual dysfunction. Hypogonadism receiving hormone replacement (vs nonmenopausal/nonhypogonadal; OR = 3.31, 95% CI 1.53, 7.15) represented an additional risk factor in the physical problems (eg, vaginal pain and dryness) subscale. Survivors with sexual dysfunction, compared to those without sexual dysfunction, were more likely to score Clinical Implications Health care providers should be aware of the increased risk of sexual dysfunction in this growing population, inquire about symptomology, and refer for appropriate intervention. Strengths & Limitations Strengths of this study include the use of a validated tool for evaluating sexual function in a large population of clinically assessed female childhood cancer survivors. Limitations include potential for selection bias, and lack of clinically confirmed dysfunction. Conclusion Sexual dysfunction is prevalent among female childhood cancer survivors and few survivors receive intervention; further research is needed to determine if those with sexual dysfunction would benefit from targeted interventions.

Women with heart disease are at increased risk for maternal and fetal complications in pregnancy. Therefore, all women with heart disease should undergo evaluation and counseling, ideally before conception, or as early in pregnancy as possible. In this article we will review the role of risk assessment, the history of development of the cardiac risk prediction tools, and the role of current cardiac risk prediction tools.

Pediatric allergic contact dermatitis (Ped-ACD) is an increasingly recognized highly prevalent skin disease that has a significant impact on the quality of life of patients and their families. Accurate and appropriate patch testing is vital to diagnosing Ped-ACD. This requires knowledge of the most common allergens in the pediatric population, consideration of concurrent diseases that can complicate the clinical picture, and potential modification of techniques to lessen exposure to irritants and sensitizers while obtaining true positive results. This article reviews the most common pediatric allergens and discusses considerations when performing pediatric patch testing.

Activation of lipid-burning pathways in the fat-storing white adipose tissue (WAT) is a promising strategy to improve metabolic health and reduce obesity, insulin resistance, and type II diabetes. For unknown reasons, bilirubin levels are negatively associated with obesity and diabetes. Here, using mice and an array of approaches, including MRI to assess body composition, biochemical assays to measure bilirubin and fatty acids, MitoTracker-based mitochondrial analysis, immunofluorescence, and high-throughput coregulator analysis, we show that bilirubin functions as a molecular switch for the nuclear receptor transcription factor peroxisome proliferator–activated receptor α (PPARα). Bilirubin exerted its effects by recruiting and dissociating specific coregulators in WAT, driving the expression of PPARα target genes such as uncoupling protein 1 (Ucp1) and adrenoreceptor β 3 (Adrb3). We also found that bilirubin is a selective ligand for PPARα and does not affect the activities of the related proteins PPARγ and PPARδ. We further found that diet-induced obese mice with mild hyperbilirubinemia have reduced WAT size and an increased number of mitochondria, associated with a restructuring of PPARα-binding coregulators. We conclude that bilirubin strongly affects organismal body weight by reshaping the PPARα coregulator profile, remodeling WAT to improve metabolic function, and reducing fat accumulation.

LAG-3 is an immunosuppressive checkpoint molecule expressed on T cells. One of its ligands, GAL-3, can promote the progression of malignancy and has been identified on tumor cells. Both LAG-3 and GAL-3 are the targets of emerging immunotherapies, but have not been well-studied in endometrial carcinomas. LAG-3, CD3, and GAL-3 immunohistochemistry was performed on 75 endometrial cancers (25 nonmethylated mismatch repair-deficient, 25 MLH1-hypermethylated mismatch repair-deficient, and 25 mismatch repair-intact). LAG-3 and CD3 lymphocytes were averaged per high-power field. Tumoral GAL-3 expression was semiquantitatively scored. Tumor-infiltrating lymphocyte expression of LAG-3 and CD3 were positively correlated (Spearman ρ=0.521, P

OBJECTIVES: Multitarget stool DNA (MT-sDNA) testing has grown as a noninvasive screening modality for colorectal cancer (CRC), but real-world clinical data are limited in the post-FDA approval setting. The effect of previous colonoscopy on MT-sDNA performance is not known. We aimed to evaluate findings of colorectal neoplasia (CRN) at diagnostic colonoscopy in patients with positive MT-sDNA testing, stratified by patient exposure to previous colonoscopy. METHODS: We identified consecutive patients completing MT-sDNA testing over a 39-month period and reviewed the records of those with positive tests for neoplastic findings at diagnostic colonoscopy. MT-sDNA test positivity rate, adherence to diagnostic colonoscopy, and the positive predictive value (PPV) of MT-sDNA for any CRN and neoplastic subtypes were calculated. RESULTS: Of 16,469 MT-sDNA tests completed, testing returned positive in 2,326 (14.1%) patients. After exclusion of patients at increased risk for CRC, 1,801 patients remained, 1,558 (87%) of whom underwent diagnostic colonoscopy; 918 of 1,558 (59%) of these patients had undergone previous colonoscopy, whereas 640 (41%) had not. Any CRN was found in 1,046 of 1,558 patients (PPV = 67%). More neoplastic lesions were found in patients without previous colonoscopy (73%); however, the rates remained high among those who had undergone previous colonoscopy (63%, P < 0.0001). The large majority (79%) of patients had right-sided neoplasia. DISCUSSION: MT-sDNA has a high PPV for any CRN regardless of exposure to previous colonoscopy. Right-sided CRN was found at colonoscopy in most patients with positive MT-sDNA testing, representing a potential advantage over other currently available screening modalities for CRC.

Background Intrathecal baclofen (ITB) is a mainstay of treatment for patients with chronic spasticity. Up to 40% of all patients receiving ITB experience overdose or withdrawal symptoms, which in the most severe cases can lead to multisystem organ failure and death. There is currently no well-established treatment for ITB withdrawal. One previous case report details an intubated pediatric patient who underwent baclofen pump removal in which dexmedetomidine was used in combination with other medications to prevent baclofen withdrawal. Case Report We report a case of baclofen withdrawal where the decision was made to initiate a dexmedetomidine infusion, with subsequent improvement of the patient's hypertension and tachycardia. At no point during her stay did the patient require intubation for airway protection, and the patient was ultimately discharged to her previous nursing facility on hospital day 9 with no new neurologic deficits. Why Should an Emergency Physician Be Aware of This? Emergency physicians should be aware of dexmedetomidine as a promising option for the treatment of ITB withdrawal in the acute setting. Although little evidence is currently present, dexmedetomidine was used successfully in this case, and should be considered as a temporizing treatment for ITB withdrawal. Dexmedetomidine holds promise in the management of ITB withdrawal compared to other previously described treatments, including oral baclofen, cyproheptadine, and dantrolene. In addition, dexmedetomidine has a superior safety profile compared to propofol or large doses of benzodiazepines. Further research will be useful in supporting the use of dexmedetomidine for this purpose.

Rationale and Objectives The purpose of this study is to explore how representational paintings of radiology encounters with patients may impact medical students' understanding and impression of both radiologists and the radiology profession. Methods Participants included third year medical students at a single institution rotating through a one-week radiology elective. Three works of art were analyzed using the validated Visual Thinking Strategies technique. Data collected included a postsession questionnaire and transcriptions of audio-recorded sessions. Data analysis involved both qualitative and quantitative methodology. Results Fifty students participated; all participants completed the postsession questionnaire and 10 participated in the audio recorded sessions. Total 82% found the experience “very enjoyable” and 86% agreed that the paintings positively affected their understanding of how radiologists provide care to patients; 96% would recommend this session to others. Exploring representational paintings of radiology encounters seemed to influence perception and understanding of radiology with students reporting “light bulb moments;” create a dissonance between the student experience and the experience depicted in the paintings; and address gaps in content specific knowledge. Conclusion The findings of this study suggest that analyzing paintings depicting radiology encounters with patients can challenge negative stereotypes that medical students have of the radiology profession and radiologists. This arts-based learning module employing a learning strategy such as Visual Thinking Strategies, should be considered by the radiology profession as a strategy to positively inform and educate trainees about the specialty.

Children’s ability to identify perpetrators who are strangers is crucial. Both failures to identify actual perpetrators and false accusations have serious costs for children’s personal security and wellbeing or for innocent suspects. In the current study, we investigated the accuracy of children’s person identification after a very long delay (one year) and, for the first time, as a function of interviewer-provided socio-emotional support, children’s pre-existing social support reserves, state anxiety, and individual differences in children’s working memory capacity. One year after a play session, 7- to 8-year-old children were asked to identify a stranger from a target-present lineup that included four pictures, a “She’s not here” card, and an “I don’t know” option in the form of a question mark card. Overall, children made few correct identifications, but also few false identifications, preferring to give “I do not know” responses or incorrectly stating the person was not in the lineup. Contrary to predictions, there were no main effects of interviewer-provided social support nor of social support reserves, but as predicted, children with higher working memory capacity performed significantly more accurately than did children with lower working memory capacity, regardless of interview condition. Children’s state anxiety and their confidence in the identification were unrelated to their performance, although interviewer support did decrease state anxiety. Implications of these findings for children’s personal safety are discussed.

BACKGROUND Data on primary hypothyroidism and its long-term impact on the health, cognition, and quality of life (QOL) of childhood cancer survivors are limited. This study examined the prevalence of and risk factors for primary hypothyroidism and its associations with physical, neurocognitive, and psychosocial outcomes. METHODS This was a retrospective study with a cross-sectional health outcome analysis of an established cohort comprising 2965 survivors of childhood cancer (52.8% male; median current age, 30.9 years, median time since cancer diagnosis, 22.3 years). Multivariable logistic regression estimated odds ratios (ORs) and 95% confidence intervals (CIs) for associations between primary hypothyroidism and cancer-related risk factors, cardiovascular disease risk factors, frailty, neurocognitive and QOL outcomes, social attainment, and subsequent thyroid carcinoma. Associations between serum free thyroxine and thyrotropin levels at assessment and health outcomes were explored. RESULTS The prevalence of primary hypothyroidism was 14.7% (95% CI, 13.5%-16.0%). It was more likely in females (OR, 1.06; 95% CI, 1.03-1.08), was less likely in non-Whites (OR, 0.96; 95% CI, 0.93-0.99), was associated with thyroid radiotherapy (higher risk at higher doses), and was more common if cancer was diagnosed at an age ≥ 15.0 years versus an age

Posterior medial meniscus root tears (PMMRTs) make up a relatively notable proportion of all meniscus pathology and have been definitively linked to the progression of osteoarthritis (OA). While known risk factors for development of OA in the knee include abnormal tibial coronal alignment, obesity and female gender, PMMRTs have emerged in recent years as another significant driver of degenerative disease. These injuries lead to an increase in average contact pressure in the medial compartment, along with increases in peak contact pressure and a decrease in contact area relative to the intact state. Loss of the root attachment impairs the function of the entire meniscus and leads to meniscal extrusion, thus impairing the force-dissipating role of the meniscus. Anatomic meniscus root repairs with a transtibial pullout technique have been shown biomechanically to restore mean and peak contact pressures in the medial compartment. However, nonanatomic root repairs have been reported to be ineffective at restoring joint pressures back to normal. Meniscal extrusion is often a consequence of nonanatomic repair and is correlated with progression of OA. In this study, the authors will describe the biomechanical basis of the natural history of medial meniscal root tears and will support the biomechanical studies with a case series including patients that either underwent non-operative treatment (5 patients) or non-anatomic repair of their medial meniscal root tears (6 patients). Using measurements derived from axial MRI, the authors will detail the distance from native root attachment center of the non-anatomic tunnels and discuss the ongoing symptoms of those patients. Imaging and OA progression among patients who were treated nonoperatively before presentation to the authors will be discussed as well. The case series thus presented will illustrate the natural history of meniscal root tears, the consequences of non-anatomic repair, and the findings of symptomatic meniscal extrusion associated with a non-anatomic repair position of the meniscus.

Background: Individuals with hip osteoarthritis (OA) commonly walk with less hip extension compared to individuals without hip OA. This alteration is often attributed to walking speed, structural limitation, and/or hip pain. It is unclear if individuals who are at increased risk for future OA (i.e., individuals with pre-arthritic hip disease [PAHD]) also walk with decreased hip extension.Objectives: (1) Determine if individuals with PAHD exhibit less hip extension compared to individuals without hip pain during walking, and (2) investigate potential reasons for these motion alterations.Methods: Adolescent and adult individuals with PAHD and healthy controls without hip pain were recruited for the study. Kinematic data were collected while walking on a treadmill at three walking speeds: preferred, fast (25% faster than preferred), and prescribed (1.25 m/s). Peak hip extension, peak hip flexion, and hip excursion were calculated for each speed. Linear regression analyses were used to examine the effects of group, sex, side, and their interactions.Results: Individuals with PAHD had 2.9° less peak hip extension compared to individuals in the Control group (p = 0.014) when walking at their preferred speed. At the prescribed speed, the PAHD group walked with 2.7° less hip extension than the Control group (p = 0.022). Given the persistence of the finding despite walking at the same speed, differences in preferred speed are unlikely the reason for the reduced hip extension. At the fast speed, both groups increased their hip extension, hip flexion, and hip excursion by similar amounts. Hip extension was less in the PAHD group compared to the Control group (p = 0.008) with no significant group-by-task interaction (p = 0.206). Within the PAHD group, hip angles and excursions were similar between individuals reporting pain and individuals reporting no pain.Conclusions: The results of this study indicate that kinematic alterations common in individuals with hip OA exist early in the continuum of hip disease and are present in individuals with PAHD. The reduced hip extension during walking is not explained by speed, structural limitation, or current pain.

Despite the critical link between visual exploration and memory, little is known about how single-unit activity (SUA) in the human mesial temporal lobe (MTL) is modulated by saccadic eye movements (SEMs). Here we characterize SEM associated SUA modulations, unit-by-unit, and contrast them to image onset, and to occipital lobe SUA. We reveal evidence for a corollary discharge (CD)-like modulatory signal that accompanies SEMs, inhibiting/exciting a unique population of broad/narrow spiking units, respectively, before and during SEMs, and with directional selectivity. These findings comport well with the timing, directional nature, and inhibitory circuit implementation of a CD. Additionally, by linking SUA to event-related potentials (ERPs), which are directionally modulated following SEMs, we recontextualize the ERP associated with SEM as a proxy for both the strength of inhibition and saccade direction, providing a mechanistic underpinning for the more commonly recorded SEM-related ERP in the human brain.

Summary Teredinibacter turnerae is an intracellular bacterial symbiont in the gills of wood-eating shipworms, where it is proposed to use antibiotics to defend itself and its animal host. Several biosynthetic gene clusters are conserved in T. turnerae and their host shipworms around the world, implying that they encode defensive compounds. Here, we describe turnercyclamycins, lipopeptide antibiotics encoded in the genomes of all sequenced T. turnerae strains. Turnercyclamycins are bactericidal against challenging Gram-negative pathogens, including colistin-resistant Acinetobacter baumannii. Phenotypic screening identified the outer membrane as the likely target. Turnercyclamycins and colistin operate by similar cellular, although not necessarily molecular, mechanisms, but turnercyclamycins kill colistin-resistant A. baumannii, potentially filling an urgent clinical need. Thus, by exploring environments that select for the properties we require, we harvested the fruits of evolution to discover compounds with potential to target unmet health needs. Investigating the symbionts of shipworms is a powerful example of this principle.

Background The combination of milbemycin oxime (MO) and lotilaner (Credelio® Plus) is a novel systemic endectocide that provides month-long effectiveness in dogs after a single oral treatment. The safety of Credelio® Plus flavored chewable tablets was investigated in three target animal safety studies. Two studies (one in juveniles and one in adults) evaluated the long-term safety, and one study evaluated the acute safety of the product when administered orally at the upper end of the recommended dose range (0.75–1.53 mg/kg MO and 20–41 mg/kg lotilaner) and multiples of this dose. Methods The objectives of these studies were to determine the long-term and acute safety of MO and lotilaner flavored chewable tablets in healthy dogs. All three studies were randomized, blinded, parallel-group design studies in healthy Beagle dogs. In each of the two long-term studies, 32 dogs were randomized among four groups to untreated controls or to treated groups at target doses of 1X, 3X, or 5X. Treatment was administered on seven (adult dogs) or nine (juvenile dogs) occasions with dosing every 4 weeks. In the acute study, 48 dogs were randomized among four groups to untreated controls or to treated groups at 1X, 3X, or 6X. In all three studies, the control group was administered placebo tablets. All dogs were fed 30 to 45 min prior to treatment and the assessment of safety was based on health observations, complete physical/neurological examinations, and food consumption. For the long-term safety studies, safety assessments also included clinical pathology evaluations (hematology, clinical chemistry and urinalysis), body weight, pharmacokinetic blood collections, and macroscopic and microscopic examinations of collected tissues. Results MO and lotilaner did not induce any treatment-related adverse effects based on health observations, physical/neurological examinations, or food consumption in the long-term or acute studies. Additionally, in the long-term studies, MO and lotilaner did not induce any treatment-related effects on clinical pathology, body weight, and macroscopic and microscopic examinations. Conclusions These three studies demonstrate that Credelio® Plus has a wide safety margin when administered at monthly intervals to puppies and dogs at the high end of the commercial dose band. Graphical Abstract

Background: Childhood cancer survivors are at elevated risk for motor and/or sensory neuropathy. The study aims to evaluate the concordance between self-report peripheral neuropathy compared with clinically ascertained peripheral neuropathy, and to identify factors associated with misclassification of peripheral neuropathy among survivors. Methods: The concordance between self-report and clinically ascertained peripheral neuropathy was evaluated among 2,933 5+ years old childhood cancer survivors (mean age 33.3, SD = 8.9). The sensitivity, specificity, and accuracy of self-report peripheral motor neuropathy (PMN) and peripheral sensory neuropathy (PSN) were calculated with reference to clinically assessed peripheral neuropathy. Results: Female survivors were more likely than male survivors to have clinically ascertained PMN (8.4% vs. 5.6%, P = 0.004). For females, having either PSN or PMN the most sensitive, specific, and accurate self-reported symptom was endorsing ≥2 symptoms on the self-report questionnaire (43.2%, 90.3%, and 85.2%, respectively), with kappa of 0.304. For males, having either PSN or PMN the most sensitive, specific, and accurate self-reported symptom was endorsing ≥2 symptoms on the self-report questionnaire (38.8%, 90.5%, and 86.3%, respectively) with kappa of 0.242. Age at diagnosis, emotional distress, and reporting pain in legs in the past 4 weeks were associated with an increased risk for false-positive reporting of peripheral neuropathy. Race (White), age at assessment, and emotional distress were associated with increased risk for false-negative reporting of peripheral neuropathy. Conclusions: Agreement between self-report and clinically ascertained peripheral neuropathy was poor in survivors. Choosing self-report versus clinical ascertained peripheral neuropathy should be carefully considered. Impact: The current study identifies the need for a self-report questionnaire that accurately assesses symptoms of peripheral neuropathy among cancer survivors.

In the United States, tobacco use, alcohol consumption and substance use disorders are more prevalent among veterans when compared to nonveterans. This is also seen in Alabama, which led the researchers to review county level data to examine possible links between substance use, mental health and suicide by veteran status. This study sought to evaluate behavioural health outcomes and impacting factors for military veterans and nonveterans living in rural and urban areas of Alabama. In phase one, we developed Alabama-specific behavioural health outcomes at the state and county level for military veterans and nonveterans. In phase two, we examined county-level correlates of behavioural health outcomes among veterans and nonveterans. The data were retrieved from the 2015-2018 National Surveys on Drug Use and Health (NSDUH) and the United States Census Bureau. Regarding tobacco use rates at the county level, nonveteran rates ranged from 23.93% to 34.56% while veteran rates ranged from 24.47% to 38.56%. Nonveteran illicit drug use rates ranged from 9.40% to 13.15% while veteran illicit drug use rates ranged from 5.50% to 10.67%. Nonveteran heavy alcohol use rates ranged from 4.54% to 7.92% while veteran heavy alcohol use rates ranged from 4.59% to 8.41%. Lastly, nonveteran suicidal ideation rates ranged from 3.64% to 4.60% while veteran suicidal ideation rates ranged from 3.16% to 4.51%. Veterans have a significantly higher potential of having suicidal ideations. We showed that illicit drug use and suicidal ideation have increased in Alabama among veterans and nonveterans. Behavioural health programmes and policies aimed at eliminating disparities between veterans and nonveterans are needed in Alabama.

ObjectivesTo investigate the safety and outcomes of elective para-aortic (PA) nodal irradiation utilizing modern treatment techniques for patients with node positive cervical cancer.MethodsPatients with pelvic lymph node positive cervical cancer who received radiation were included. All patients received radiation therapy (RT) to either a traditional pelvic field or an extended field to electively cover the PA nodes. Factors associated with survival were identified using a Cox proportional hazards model, and toxicities between groups were compared with a chi-square test.Results96 patients were identified with a mean follow up of 40 months. The incidence of acute grade ≥ 2 toxicity was 31% in the elective PA nodal RT group and 15% in the pelvic field group (Chi-square p = 0.067. There was no significant difference in rates of grade ≥ 3 acute or late toxicities between the two groups (p>0.05). The KM estimated 5-year OS was not statistically different for those receiving elective PA nodal irradiation compared to a pelvic only field, 54% vs. 73% respectively (log-rank p = 0.11).ConclusionsElective PA nodal RT can safely be delivered utilizing modern planning techniques without a significant increase in severe (grade ≥ 3) acute or late toxicities, at the cost of a possible small increase in non-severe (grade 2) acute toxicities. In this series there was no survival benefit observed with the receipt of elective PA nodal RT, however, this benefit may have been obscured by the higher risk features of this population. While prospective randomized trials utilizing a risk adapted approach to elective PA nodal coverage are the only way to fully evaluate the benefit of elective PA nodal coverage, these trials are unlikely to be performed and instead we must rely on interpretation of results of risk adapted approaches like those used in ongoing clinical trials and retrospective data.

Exposure to and consumption of brackish water are associated with an elevated risk of infection, hypernatremia, and hypothermia. Minimal data exist to support the diagnosis and treatment of patients with long-term brackish water exposure. We present a case of a patient who spent 5 to 10 d semisubmerged in the Elizabeth River in coastal Virginia. A 55-y-old male presented via ambulance after 5 to 10 d of being "stuck in the mud." He was hypernatremic, with a sodium of 176 mEq·L-1, hypothermic to 34.5°C (94.1°F), and hypotensive at 88/50 mm Hg, with a sodium concentration of 176 mEq·L-1 and an osmolality of 412 mosm·kg-1. He developed pneumonia, with respiratory cultures growing Vibrio parahemolyticus, Klebsiella oxytoca, and Shewanella algae. He had pustules, which grew Aeromonas hydrophilia and Aeromonas caviae. A nasogastric tube was placed. Using suction, 500 mL of coarse sand and gravel was removed from his stomach. Antibiotics and intravenous fluids were given. The patient fully recovered after 3 wk and was discharged to rehabilitation. Exposure to brackish water can present a unique set of infectious and metabolic complications. Initial care should include treatment of metabolic derangements, such as hypovolemia, hypernatremia, and hypothermia, and treatment of infections with antibiotics based on knowledge of the most likely causative organisms.

Antecedent interventions are often used preventatively to address engagement, but few studies have evaluated their effectiveness with students at risk for disability. This study evaluated the effectiveness of two commonly recommended antecedent interventions that have limited empirical support for use with students at risk: social stories and visual supports. Both interventions were evaluated separately in the context of two single-case alternating treatments designs across five elementary students at risk for emotional and behavioral disorders. Social stories were not effective for improving students’ levels of engagement during targeted activities; visual supports resulted in increases in students’ engagement relative to baseline conditions. Future use of visual supports for students at risk should include evaluations of the feasibility of implementation by teaching staff.

Introduction: Mental distress frequently develops in sufferers of chronic diseases, including cancer. We examined the association between physical activity and mental distress among Veteran cancer survivors with heart disease or diabetes. Methods: Data for American military Veteran cancer survivors ( n = 16,643) were retrieved from the Centers for Disease Control and Prevention (CDC) Behavioral Risk Factor Surveillance System (BRFSS). Ordinary least squares (OLS) multiple linear regression was used to explore the effect of physical activity on self-reported mental distress among Veteran cancer survivors with coronary heart disease or diabetes. Geographic information system (GIS) software was used to examine the state-level distribution of mental distress among Veteran cancer survivors. Results: Geographic analysis showed that mental distress (in days) in the last month among Veteran cancer survivors was highest in Alabama (M = 3.99), while those in Wyoming reported the lowest number of days (M = 0.76). After controlling for relevant confounding factors, physical activity was associated with fewer days of mental distress days among Veteran cancer survivors with coronary heart disease. Discussion: Results of this study suggest that physical activity may be beneficial in reducing mental distress among Veteran cancer survivors with heart disease.