The effect of level of injury on diabetes incidence and mortality after spinal cord injury - a longitudinal cohort study.

STUDY DESIGN: Retrospective longitudinal cohort study of veterans with SCI. OBJECTIVES: Spinal cord injury (SCI) is associated with an increased risk of developing diabetes mellitus (DM), likely due to body composition alterations and autonomic nervous system dysfunction. These factors are more pronounced in persons with tetraplegia (TP) versus paraplegia (PP). However, the effect of level of injury (LOI) on DM incidence is largely unknown. Therefore, the objective is to examine the effect of LOI on DM incidence in persons with SCI. SETTING: South Texas Veterans Health Care System. METHODS: We obtained electronic record data on age, sex, race/ethnicity, LOI and HbA1c concentration from January 1st 2001 through December 31st 2021. Cox proportional hazard regression analyses were used to assess the association between LOI, DM and all-cause mortality. RESULTS: Among 728 non-diabetic veterans with SCI (350 TP/ 378 PP, 52 ± 15 years, 690 male/38 female) 243 developed DM, of which 116 with TP and 127 with PP. Despite chronological variations between TP and PP, DM risk over the entire follow-up did not differ between the groups (hazard ratio (HR): 1.06, 95% CI: 0.82-1.38). Mortality was higher in TP versus PP (HR: 1.40, 95% CI: 1.09-1.78). However, developing DM did not increase the risk of death, regardless of LOI (HR: 1.07, 95% CI: 0.83-1.37). CONCLUSION: Despite chronological variations between both groups, the level of injury had minimal effect on long-term DM development in this cohort of veterans with SCI. Sponsorship NIH (DK105379; MS), RR&D SPiRE (I21RX003724-01A1; MT and SH).

Ambulatory blood pressure monitoring in children: A retrospective single-center study.

Objectives: (1) Compare 24-hour ambulatory blood pressure monitoring (ABPM) diagnoses in a pediatric population with the new 2022 guidelines to the original diagnoses with the 2014 guidelines. (2) Determine whether findings of hypertension from ABPM could be predicted from prior patient data. (3) Determine whether ABPM readings could predict left ventricular mass index (LVMI) in patients who obtained an echocardiogram (ECHO). Study design: Single-center retrospective study on patients referred to Pediatric Nephrology Clinic for evaluation of elevated blood pressure who underwent ABPM from 2015 to 2018. Predictions of hypertension were obtained using a logistic regression model, and predictions of LVMI were performed using regression models including (a) the wake systolic and diastolic BP indices, or (b) additionally including the standard deviation (SD) of wake SBP and DBP. Results: With the change in 2022 to new ABPM guidelines from the AHA, comparing the old and new guidelines led to 70% of previous pre-hypertensive diagnoses now meeting criteria for diagnosis of hypertension, and a rise from 21% of the ABPMs meeting criteria for hypertension to 51% now meeting criteria. In a logistic regression model, prior patient data were not predictive of a diagnosis of hypertension from ABPM (Nagelkerke's R 2 = 0.04). Among the individual variables studied, none were statistically significant. For prediction of LVMI, the SD of wake SBP and DBP were significantly associated with increased LVMI, but the wake SBP and DBP indices were not. Conclusions: In our patient population, the new ABPM guidelines led to a significant increase in diagnoses of hypertension. Prior patient data was not sufficient to predict a diagnosis of hypertension by ABPM, supporting the need for evaluation by ABPM as the gold standard. Our analysis of the relationship between ABPM readings and LVMI supports the hypothesis that BP variability contributes to increased LVMI. These data are consistent with growing evidence in the adult literature that BP variability detected by ABPM is associated with left-ventricular hypertrophy.

Meta-analysis on the Effectiveness of ECG Screening for Conditions Related to Sudden Cardiac Death in Young Athletes.

Controversy exists over the use of electrocardiograms (ECGs) in sports pre-participation screening. We performed a meta-analysis comparing the effectiveness of history and physical examination (H&P) with ECG at detecting both cardiac disease and sudden cardiac death-associated conditions (SCD-AC). Pre-participation studies published from 2015 to 2020 with athletes 10 to 35 years old were included. This yielded 28 011 athletes screened and 124 cardiac diagnoses, 103 of which were SCD-AC. A meta-analysis of log odds ratios (ORs) was conducted using a random-effects model. The ORs for the association between H&P and detecting both cardiac disease and SCD-AC were not statistically significant (OR = 3.4, P = .076; OR = 2.9, P = .078). The ORs for the association between ECG and detecting both cardiac disease and SCD-AC were statistically significant (60, P < .001; 148, P < .0001). In conclusion, the odds of detecting both cardiac disease and conditions related to SCD with ECG are greater than with H&P during sports pre-participation screening.

Capsaicin 8% Patch for Spinal Cord Injury Focal Neuropathic Pain, a Randomized Controlled Trial.

BACKGROUND: Neuropathic pain (NP) after spinal cord injury (SCI) exacerbates disability, decreases quality of life (QOL), and is often refractory to available therapies. Patients report willingness to trade potential recovery of strength, bowel, bladder, or sexual function for pain relief. One proposed mechanism causing NP is up-regulation of transient receptor potential vanilloid 1 (TRPV 1) proteins in uninjured C fibers and dorsal root ganglia causing neuronal excitability. Recent studies have found up-regulation of TRPV 1 proteins after SCI. OBJECTIVE: We hypothesize the application of capsaicin 8% patch (C8P), FDA approved for NP in diabetic peripheral neuropathy and post-herpetic neuralgia, will improve pain, function and QOL in persons with SCI. METHODS: Randomized single-blind crossover design in which 11 persons with SCI and NP refractory to two oral pain medications received C8P or a control low dose Capsaicin 0.025% patch (CON) over two 12-week periods. Pain (VAS, MPI-SCI), quality of life (WHO-QOL), and functional status (SCIM) were measured at 2-4-week intervals. RESULTS: There was a main treatment effect of C8P over CON on VAS and MPI-SCI outcomes with pain reduction of 35% and 29% at weeks 2 and 4, respectively. C8P also demonstrated a main treatment effect over CON on the SCIM mobility subscale. WHO-QOL scores did not improve with C8P. CONCLUSIONS: C8P improves pain and mobility for patients with SCI and refractory NP. Larger studies should be performed to evaluate impact of repeat applications and QOL outcomes.

Faster Serotonin Clearance in CA3 Region of Hippocampus and Antidepressant-like Effect of Decynium-22 in Juvenile Mice Are Putatively Linked to Increased Plasma Membrane Monoamine Transporter Function: Implications for Efficacy of Antidepressants in Juveniles.

Selective serotonin reuptake inhibitors (SSRIs) are less efficacious in treating depression in children than in adults. SSRIs block serotonin uptake via the high-affinity, low-capacity serotonin transporter. However, the low-affinity, high-capacity organic cation transporter 3 (OCT3) and plasma membrane monoamine transporter (PMAT) are emerging as important players in serotonin uptake. We hypothesized that OCT3 and/or PMAT are functionally upregulated in juveniles, thereby buffering SSRIs' ability to enhance serotonergic neurotransmission. Unlike in adult mice, we found the OCT/PMAT blocker, decynium-22, to have standalone antidepressant-like effects in juveniles. Using in vivo high-speed chronoamperometry, we found that juveniles clear serotonin from the CA3 region of the hippocampus ~2-fold faster than adult mice. Cell density did not differ between ages, suggesting that faster serotonin clearance in juveniles is unrelated to faster diffusion through the extracellular matrix. Western blot and immunohistochemistry showed that juvenile mice have modestly greater expression of PMAT than adults, whereas OCT3 expression in the CA3 region of the hippocampus was similar between ages. Together, these data suggest that faster serotonin clearance and antidepressant-like effects of decynium-22 in juvenile mice may be due to functionally upregulated PMAT. Faster serotonin clearance via PMAT in juveniles may contribute to reduced therapeutic efficacy of SSRIs in children relative to adults.

The discriminative stimulus effects of baclofen and gamma hydroxybutyrate in C57BL/6J mice.

Baclofen and γ-hydroxybutyrate (GHB) exert γ-aminobutyric acid (GABA)B receptor agonism and have therapeutic utility but possess different pharmacological activities. We examined whether separate groups of mice could be trained to discriminate either baclofen or GHB, and the contribution of GABAB receptors to discriminative stimulus effects. Male C57BL/6J mice were trained to discriminate either baclofen (3.2 mg/kg, intraperitoneal) or GHB (178 mg/kg, intraperitoneal) from saline under a fixed-ratio 10 schedule. The GABAB antagonist 3-aminopropyl(diethoxymethyl)phosphinic acid (CGP 35348) was used to pharmacologically assess GABAB receptor involvement. The selectivity of the resulting discriminations was assessed with the opioid agonist morphine and the benzodiazepine midazolam. In baclofen-trained mice, both baclofen and GHB were readily discriminated. Baclofen produced a maximum of 86% baclofen-appropriate responding. CGP 35348 (320 mg/kg, i.p.) produced a 4.7-fold rightward shift in the dose-effect function. GHB produced a maximum of 85.8% baclofen-appropriate responding. In GHB-trained mice, both GHB and baclofen were readily discriminated. In GHB-trained mice, GHB produced a maximum of 85.3% drug-appropriate responding; CGP 35348 (320 mg/kg, i.p.) produced a 1.8-fold rightward shift in the GHB discrimination dose-effect function. Baclofen produced up to 70.0% GHB-appropriate responding. CGP 35348 (320 mg/kg, i.p.) significantly antagonized baclofen discrimination and baclofen produced up to 37% GHB-appropriate responding up to doses that disrupted operant responding. Morphine did not produce substitution for either baclofen or GHB. Midazolam produced partial substitution for both. GHB and baclofen discrimination assays in mice provide a useful approach for examining different receptor types mediating the effects of these two drugs.

Thyroid nodules of indeterminate cytology in Hispanic/Latinx patients.

BACKGROUND: Behavior of differentiated thyroid cancer (DTC) varies among ethnic groups. Recommended management of thyroid nodules with indeterminate cytology (TN-IC) is based on molecular analysis from predominantly non-Hispanic white patients. We hypothesized that TN-IC in Hispanic/Latinx patients would have different features, management, and outcomes and that molecular testing might perform differently in Hispanic/Latinx patients. METHODS: Retrospective chart review was performed on 127 TN-IC analyzed with Afirma. Patient characteristics were compared using linear model ANOVA and Fisher's exact test. RESULTS: Out of 127 TN-IC, 71 (56%) were Hispanic/Latinx. Hispanic/Latinx had a greater prevalence of diabetes, but Afirma results (benign or suspicious) were similar between ethnic groups. Fourteen patients had malignant pathology. Their management and outcomes were similar across groups. The negative predictive value for our cohort (97.9%) was similar to published data. CONCLUSIONS: Data from our predominantly-Hispanic/Latinx cohort suggest that Afirma performs similarly in Hispanic/Latinx and non-Hispanic white patients with TN-IC.

Impact of tetraplegia vs. paraplegia on venoarteriolar, myogenic and maximal cutaneous vasodilation responses of the microvasculature: Implications for cardiovascular disease.

Objective: Cardiovascular disease (CVD) is a leading cause of mortality in persons with SCI. While macrovascular remodeling and function after SCI is well documented, changes in the microvascular structure and function are comparably understudied, but importantly predict CVD risk. Specifically, the integrity of venoarteriolar (VAR), myogenic (MYO) and maximal vasodilation responses are largely unknown after SCI, especially in persons with tetraplegia (TP) at highest risk of CVD. This is the first to examine the differences in VAR (cuff inflation), MYO (limb dependency) and maximal vasodilation responses of the microvasculature between able bodied (AB) versus those with TP and paraplegia (PP).Design: Observational.Setting: Laboratory.Participants: Eight AB, 6 TP, and 8 PP persons.Interventions: One forearm and calf were treated topically with lidocaine 2.5%/prilocaine 2.5% while contralateral limb served as a control. Laser doppler flowmeters were applied over treated and control sites during limb dependency, cuff inflation and local skin heating (Tloc) up to 42°C.Outcome measures: Skin vascular resistance (SkVR) change with cuff inflation and limb dependency and maximal cutaneous vascular conductance (CVC) during local heating.Results: Change in SkVR was not significantly different between groups or extremity (upper vs. lower) during cuff inflation or limb dependency. However, CVC at Tloc 42°C was significantly different in the lower extremity (LE) of TP and PP (P = 0.007, 0.35) compared to AB.Conclusion: Increases in SkVR during cuff inflation (VAR) and limb dependency (VAR and MYO) are unaltered after SCI, however maximal vasodilation in the LE post-SCI is higher than AB persons.

Role of Organic Cation Transporter 3 and Plasma Membrane Monoamine Transporter in the Rewarding Properties and Locomotor Sensitizing Effects of Amphetamine in Male andFemale Mice.

A lack of effective treatment and sex-based disparities in psychostimulant addiction and overdose warrant further investigation into mechanisms underlying the abuse-related effects of amphetamine-like stimulants. Uptake-2 transporters such as organic cation transporter 3 (OCT3) and plasma membrane monoamine transporter (PMAT), lesser studied potential targets for the actions of stimulant drugs, are known to play a role in monoaminergic neurotransmission. Our goal was to examine the roles of OCT3 and PMAT in mediating amphetamine (1 mg/kg)-induced conditioned place preference (CPP) and sensitization to its locomotor stimulant effects, in males and females, using pharmacological, decynium-22 (D22; 0.1 mg/kg, a blocker of OCT3 and PMAT) and genetic (constitutive OCT3 and PMAT knockout (-/-) mice) approaches. Our results show that OCT3 is necessary for the development of CPP to amphetamine in males, whereas in females, PMAT is necessary for the ability of D22 to prevent the development of CPP to amphetamine. Both OCT3 and PMAT appear to be important for development of sensitization to the locomotor stimulant effect of amphetamine in females, and PMAT in males. Taken together, these findings support an important, sex-dependent role of OCT3 and PMAT in the rewarding and locomotor stimulant effects of amphetamine.

The treatment of neurogenic lower urinary tract dysfunction in persons with spinal cord injury: An open label, pilot study of anticholinergic agent vs. mirabegron to evaluate cognitive impact and efficacy.

STUDY DESIGN: Pre-post intervention. OBJECTIVES: 1. To test whether replacement of oral anticholinergic (AC) agents with mirabegron for neurogenic lower urinary tract dysfunction (NLUTD) yields improved cognitive function in older persons with spinal cord injury (SCI). 2. To test whether mirabegron is safe and as efficacious as AC. SETTING: USA. METHODS: Pilot study: Twenty older (>60 y/o) persons with SCI taking chronic (>6 months) AC medication for NLUTD were enrolled. All participants were first studied on AC at baseline then switched to mirabegron for 6 months. Primary outcomes were cognitive tests of (1) executive function (TEXAS, SDMT); (2) attention (SCWT); and (3) memory (SLUMS and WMS-IV Story A/B). Secondary outcomes assessed efficacy and safety including Neurogenic Bladder Symptom Score (NBSS), bladder diary, neurogenic bowel dysfunction (NBD) survey, heart rate (HR), electrocardiogram (EKG), and mean arterial pressure (MAP). RESULTS: When switching from AC to mirabegron for NLUTD, older persons with SCI exhibited statistically significant improvements in immediate Story A recall (p = 0.01), delayed story A and B recall (p = 0.01, 0.004), and in TEXAS (p = 0.04). Three subscores within NBSS significantly improved (p = 0.001) and the frequency of incontinence decreased (p = 0.03) on mirabegron. NBD, HR, MAP, and EKGs were unchanged. CONCLUSIONS: Older persons with SCI on AC for NLUTD demonstrated improved short-term and delayed memory (WMS-IV Story A/B) as well as executive function (TEXAS) when switched to mirabegron. Efficacy of mirabegron for NLUTD symptoms was superior to AC with no adverse effects on bowel or cardiovascular function. SPONSORSHIP: Claude D. Pepper Older Americans Independence Center.

Phosphatidylethanol in whole blood of rhesus monkeys correlates with ethanol consumption.

BACKGROUND: Phosphatidylethanol (PEth) homologs are ethanol metabolites used to identify and monitor alcohol drinking in humans. In this study, we measured levels of the 2 most abundant homologs, PEth 16:0/18:1 and PEth 16:0/18:2, in whole blood samples from rhesus macaque monkeys that drank ethanol daily ad libitum to assess the relationship between PEth levels and recent ethanol exposure in this animal model. METHODS: Blood samples were obtained from The Monkey Alcohol Tissue Research Resource. The monkeys were first induced to consume 4% (w/v) ethanol in water from a panel attached to their home cage. Then, monkeys were allowed to drink ethanol and water ad libitum 22 h daily for 12 months and the daily amount of ethanol each monkey consumed was measured. Whole, uncoagulated blood was collected from each animal at the end of the entire experimental procedure. PEth 16:0/18:1 and PEth 16:0/18:2 levels were analyzed by HPLC with tandem mass spectrometry, and the ethanol consumed during the preceding 14 days was measured. Combined PEth was the sum of the concentrations of both homologs. RESULTS: Our results show that (1) PEth accumulates in the blood of rhesus monkeys after ethanol consumption; (2) PEth homolog levels were correlated with the daily average ethanol intake during the 14-day period immediately preceding blood collection; (3) the application of established human PEth 16:0/18:1 cutoff concentrations indicative of light social or no ethanol consumption (<20 ng/ml), moderate ethanol consumption (≥ 20 and < 200 ng/ml) and heavy ethanol consumption (≥ 200 ng/ml) predicted significantly different ethanol intake in these animals. PEth homologs were not detected in ethanol-naïve controls. CONCLUSIONS: This study confirms that PEth is a sensitive biomarker for ethanol consumption in rhesus macaque monkeys. This nonhuman primate model may prove useful in evaluating sources of variability previously shown to exist between ethanol consumption and PEth homolog levels among humans.

Correlation of neurological level and sweating level of injury in persons with spinal cord injury.

Objective: Thermoregulatory dysfunction after spinal cord injury (SCI) impairs quality of life and predisposes persons to life-threatening sequela of heat-related illness (HRI) in conditions of high ambient temperature. SCI clinicians currently have no objective way to predict which persons are at greatest risk of HRI. Evaporative cooling via sweating is the body's most efficient mechanism of heat dissipation. The relationship between the neurological level of injury (NLOI) and the degree of sudomotor dysfunction is not well defined. This study examines the relationship between the NLOI and sweating level of injury (SwLOI). This information can assist SCI clinicians in identifying individuals with SCI who have most impaired sudomotor function and thus highest risk of HRI.Design: Observational.Setting: Human physiology laboratory.Participants: 10 persons with tetraplegia (TP), 14 with paraplegia (PP) and 10 able-bodied (AB).Intervention: Passive heat stress (1°C rise in core temperature) with sweat responses (SR) quantified with the starch iodine test.Outcome measures: The most caudal dermatomal level in which sweating was visualized was recorded as the SwLOI, which was compared to the NLOI. Minimum, maximum and median differences between NLOI and SwLOI were calculated.Results: Persons with tetraplegia demonstrated no SR. Persons with paraplegia demonstrated SR at a median of 1 level below NLOI. Able-bodied controls demonstrated sweating on all skin surface areas.Conclusions: Persons with motor complete tetraplegia lack evaporative cooling capacity through SR during passive heat stress predisposing them to HRI. Meanwhile, persons with paraplegia sweat on average 1 dermatomal level below their NLOI.

Serotonin Transporter and Plasma Membrane Monoamine Transporter Are Necessary for the Antidepressant-Like Effects of Ketamine in Mice.

Major depressive disorder is typically treated with selective serotonin reuptake inhibitors (SSRIs), however, SSRIs take approximately six weeks to produce therapeutic effects, if any. Not surprisingly, there has been great interest in findings that low doses of ketamine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, produce rapid and long-lasting antidepressant effects. Preclinical studies show that the antidepressant-like effects of ketamine are dependent upon availability of serotonin, and that ketamine increases extracellular serotonin, yet the mechanism by which this occurs is unknown. Here we examined the role of the high-affinity, low-capacity serotonin transporter (SERT), and the plasma membrane monoamine transporter (PMAT), a low-affinity, high-capacity transporter for serotonin, as mechanisms contributing to ketamine's ability to increase extracellular serotonin and produce antidepressant-like effects. Using high-speed chronoamperometry to measure real-time clearance of serotonin from CA3 region of hippocampus in vivo, we found ketamine robustly inhibited serotonin clearance in wild-type mice, an effect that was lost in mice constitutively lacking SERT or PMAT. As expected, in wild-type mice, ketamine produced antidepressant-like effects in the forced swim test. Mapping onto our neurochemical findings, the antidepressant-like effects of ketamine were lost in mice lacking SERT or PMAT. Future research is needed to understand how constitutive loss of either SERT or PMAT, and compensation that occurs in other systems, is sufficient to void ketamine of its ability to inhibit serotonin clearance and produce antidepressant-like effects. Taken together with existing literature, a critical role for serotonin, and its inhibition of uptake via SERT and PMAT, cannot be ruled out as important contributing factors to ketamine's antidepressant mechanism of action. Combined with what is already known about ketamine's action at NMDA receptors, these studies help lead the way to the development of drugs that lack ketamine's abuse potential but have superior efficacy in treating depression.

Effect of concurrent organic cation transporter blockade on norepinephrine clearance inhibiting- and antidepressant-like actions of desipramine and venlafaxine.

Depression is a major health problem for which most patients are not effectively treated. This underscores a need to identify new targets for the development of antidepressants with improved efficacy. Studies have shown that blockade of low-affinity/high-capacity transporters, such as organic cation transporters (OCTs) and the plasma membrane monoamine transporter (PMAT), with decynium-22 can produce antidepressant-like effects and inhibit serotonin clearance in brain when the serotonin transporter is pharmacologically or genetically compromised. In vitro studies show that OCTs/PMAT are also capable of norepinephrine transport, raising the possibility that decynium-22 might enhance the antidepressant-like effects of norepinephrine transporter inhibitors. Using in vivo electrochemistry, we show that local administration of decynium-22 into dentate gyrus of hippocampus enhanced the ability of the norepinephrine transporter blocker, desipramine, but not the dual norepinephrine/serotonin transporter blocker venlafaxine, to inhibit norepinephrine clearance. In parallel, systemic administration of decynium-22 (0.32 mg/kg) enhanced the antidepressant-like effects of desipramine (32 mg/kg), but not those of venlafaxine, in the tail suspension test, underscoring the heterogeneous response of mice to antidepressants, including those that share similar mechanisms of action. Systemic administration of normetanephrine, a potent blocker of OCT3, failed to potentiate the antidepressant-like effects of desipramine, suggesting that the actions of decynium-22 to augment the antidepressant-like effects of desipramine are likely mediated by another OCT isoform and/or PMAT. Taken together with existing literature, concurrent blockade of OCTs and/or PMAT merits further investigation as an adjunctive therapeutic for desipramine-like antidepressant drugs.

Correlation of Medical College Admission Test Scores and Self-assessment Materials with the United States Medical Licensing Examination Step 1 Performance.

Purpose Candidates' performance on the United States Medical Licensing Examination (USMLE) Step 1 examination had been correlated with the Medical College Admission Test (MCAT). However, in 2015, a new MCAT format was released and its correlation with Step 1 remains to be fully analyzed. Preparation for Step 1 typically involves purchasing and perusing practice tests from the National Board of Medical Examiners (NBME) and UWorld; however, their predictive value to performance on Step 1 remains to be ascertained, especially with the release of five new NBME practice tests. Additionally, there is a need for accurately predicting Step 1 scores to self-evaluate study progress and reduce student anxiety. Rationale Program directors rank USMLE Step 1 scores as the number one criterion in selecting interviewees for residency. Step 1 scores are more important than Step 2 scores, Dean's letter, or other letters of recommendation in determining the overall ranking of a candidate after interviews. Hypotheses The authors hypothesized that the new MCAT scores correlated positively with Step 1 scores and that the new NBME practice tests were more predictive of performance on Step 1 as compared to old NBME tests.  Methods Linear regression analysis followed by either analysis of variance (ANOVA) or Student's t-tests were used to analyze 399 responses. Data obtained was used to update an existing Step 1 score predictor, which was then validated. Results A positive correlation between the MCAT (average score: 510.1 ± 6.3) and Step 1 scores (average score: 246.1 ± 14.2) was observed. While new NBME practice tests were more predictive of Step 1 scores than old NBME tests, UWorld test scores were the most predictive. Students who practiced with the new NBME practice tests scored significantly higher than students who did not use them. However, students using any of the UWorld practice tests did significantly better than students who practiced using only NBME practice tests but not UWorld practice tests. Ironically, NBME16,the second-most correlativetest to Step 1 performance, is no longer available for purchase. Overall, taking six or more practice tests significantly enhanced Step 1 scores; the optimal number of tests was found to be between six and nine. The predicted score by an updated Step 1 score predictor was within 3.8 points or 1.6% of the actual Step 1 score. Conclusions We believe this study will aid in the selection and purchase of appropriate self-assessment tests as preparatory material for the USMLE Step 1 examination. It will also introduce them to an existing Step 1 score predictor that will help determine their readiness for Step 1.

Factors that prevent, prompt, and delay disclosures in female victims of child sexual abuse.

BACKGROUND: Several studies conducted in clinical and non-clinical settings have described why and when children disclose sexual abuse. Yet, there is incomplete understanding of how adolescents and young children may differ in factors that delay, prompt and deter disclosure that could inform strategies for clinical practice and prevention. OBJECTIVE: The aim of this study was to identify factors that prevent, prompt, and delay disclosure among pediatric patients presenting for acute and non-acute medical evaluations of sexual abuse or assault, and to examine any differences in disclosure tendencies among female adolescents and pre-adolescents. PARTICIPANTS AND SETTING: A chart review of a consecutive sample of pediatric patients presenting to the emergency department or outpatient clinic identified 601 patients who were diagnosed with sexual abuse and were willing to answer examiner questions about their disclosure. METHODS: Data collection included attainment of patient narratives which were utilized to gather information about abuse disclosures. Recursive abstraction was applied to categorize patient statements for further analysis, while Pearson chi square and logistic regression were utilized for quantitative data. RESULTS: Young age (<11 years) at abuse onset was the strongest predictor of, and fear of consequences to self was the most common reason for, disclosure delay in both adolescent and pre-adolescent females. Severity of abuse, adult perpetrator, and self-blame predicted delays only in pre-adolescent females. CONCLUSIONS: Social and moral development during middle childhood likely has a strong influence on disclosure tendency. Strategies to promote disclosure should consider reducing fear of consequences associated with the adult-child paradigm.

Efficacy of water spray for evaporative cooling in athletes with spinal cord injury.

Study design: Interventional crossover study. Objective: Spinal cord injury (SCI) disrupts afferent input to the hypothalamus and impairs efferent vaso- and sudomotor output, especially in lesions above the sympathetic chain (T1-L2). In consequence, persons with SCI under heat stress experience impairment in the ability to dissipate heat proportional to the lesion level. Thermoregulatory dysfunction places an individual at high risk of hyperthermia, which can be life threatening, especially for athletes with SCI during exercise. Current evidence on therapeutic cooling techniques in athletes with SCI is limited, but basic physiologic and research data suggest water spray (WS) might be efficacious, particularly in athletes with tetraplegia (TP), who are most impaired in thermoregulation. The aim of this study was to evaluate the effect of WS on core temperature (Tc) during exercise in athletes with SCI. Setting: Texas, USA. Methods: Eleven individuals with SCI: seven with TP, four with paraplegia (PP); and sixteen able-bodied (AB) controls underwent a wheelchair intermittent sprint exercise for 90 min under two conditions: (1) WS application every 15 min and (2) control (C), without WS. Tc was measured every 15 min and was analyzed for the effect of group (TP, PP, and AB) and time. Change in Tc (ΔTc) was also compared between groups. Results: ΔTc was significantly higher in TP vs. PP (p < 0.0001) and TP vs. AB (p < 0.0001) groups under C treatment. WS significantly attenuated ΔTc in TP (p = 0.001), but did not change ΔTc in PP or AB. Conclusion: WS effectively attenuated Tc elevation during exercise in athletes with TP. Sponsorship: Texas chapter of the Paralyzed Veterans of America.

Prolactin receptor expression in mouse dorsal root ganglia neuronal subtypes is sex-dependent.

Sensory neurones exhibit sex-dependent responsiveness to prolactin (PRL). This could contribute to sexual dimorphism in pathological pain conditions. The present study aimed to determine the mechanisms underlying sex-dependent PRL sensitivity in sensory neurones. A quantitative reverse transcriptase-polymerase chain reaction shows that prolactin receptor (Prlr) long and short isoform mRNAs are expressed at comparable levels in female and male mouse dorsal root ganglia (DRG). In Prlrcre/+ ;Rosa26LSL-tDTomato/+ reporter mice, percentages of Prlr+ sensory neurones in female and male DRG are also similar. Characterisation of Prlr+ DRG neurones using immunohistochemistry and electrophysiology revealed that Prlr+ DRG neurones are mainly peptidergic nociceptors in females and males. However, sensory neurone type-dependent expression of Prlr is sex dimorphic. Thus, Prlr+ populations fell into three small- and two medium-large-sized sensory neuronal groups. Prlr+ DRG neurones are predominantly medium-large sized in males and are proportionally more comprised of small-sized sensory neurones in females. Specifically, Prlr+ /IB4+ /CGRP+ neurones are four- to five-fold higher in numbers in female DRG. By contrast, Prlr+ /IB4- /CGRP+ /5HT3a+ /NPYR2- are predominant in male DRG. Prlr+ /IB4- /CGRP- , Prlr+ /IB4- /CGRP+ and Prlr+ /IB4- /CGRP+ /NPYR2+ neurones are evenly encountered in female and male DRG. These differences were confirmed using an independently generated single-cell sequencing dataset. Overall, we propose a novel mechanism by which sensory neurone type-dependent expression of Prlr could explain the unique sex dimorphism in responsiveness of nociceptors to PRL.

Comparative analysis of novel decynium-22 analogs to inhibit transport by the low-affinity, high-capacity monoamine transporters, organic cation transporters 2 and 3, and plasma membrane monoamine transporter.

Growing evidence supports involvement of low-affinity/high-capacity organic cation transporters (OCTs) and plasma membrane monoamine transporter (PMAT) in regulating clearance of monoamines. Currently decynium-22 (D22) is the best pharmacological tool to study these transporters, however it does not readily discriminate among them, underscoring a need to develop compounds with greater selectivity for each of these transporters. We developed seven D22 analogs, and previously reported that some have lower affinity for α1-adrenoceptors than D22 and showed antidepressant-like activity in mice. Here, we extend these findings to determine the affinity of these analogs for OCT2, OCT3 and PMAT, as well as serotonin, norepinephrine and dopamine transporters (SERT, NET and DAT) using a combination of uptake competition with [3H]methyl-4-phenylpyridinium acetate in overexpressed HEK cells and [3H]citalopram, [3H]nisoxetine and [3H]WIN 35428 displacement binding in mouse hippocampal and striatal preparations. Like D22, all analogs showed greater binding affinities for OCT3 than OCT2 and PMAT. However, unlike D22, some analogs also showed modest affinity for SERT and DAT. Dual OCT3/SERT and/or OCT3/DAT actions of certain analogs may help explain their ability to produce antidepressant-like effects in mice and help account for our previous findings that D22 lacks antidepressant-like effects unless SERT function is either genetically or pharmacologically compromised. Though these analogs are not superior than D22 in discriminating among OCTs/PMAT, our findings point to development of compounds with combined ability to inhibit both low-affinity/high-capacity transporters, such as OCT3, and high-affinity/low-capacity transporters, such as SERT, as therapeutics with potentially improved efficacy for treatment of psychiatric disorders.

Pharmacokinetics of Phosphatidylethanol 16:0/20:4 in Human Blood After Alcohol Intake.

BACKGROUND: The purpose of this study was to characterize the pharmacokinetics of the phosphatidylethanol (PEth) 16:0/20:4 homolog in uncoagulated human blood samples taken from 18 participants in a clinical laboratory setting after consumption of 2 standard doses of ethanol (EtOH). METHODS: Male and female participants received either 0.4 or 0.8 g/kg oral doses of EtOH during a 15-minute period. Blood samples were collected before and throughout 6 hours immediately after alcohol administration and then again at days 2, 4, 7, 11, and 14 of the follow-up period. PEth 16:0/20:4 levels were quantified by high-performance liquid chromatography with tandem mass spectrometry detection. RESULTS: (i) The increase in PEth 16:0/20:4 from baseline to maximum concentration was less than that of PEth 16:0/18:1 or PEth 16:0/18:2 homologs during the 6-hour period after EtOH administration; (ii) the mean half-life of PEth 16:0/20:4 was 2.1 ± 3 (SD) days, which was shorter than the mean half-life of either PEth 16:0/18:1 or PEth 16:0/18:2, 7.6 ± 3 (SD) or 6.8 ± 4 (SD) days, respectively. CONCLUSIONS: The pharmacokinetics of PEth 16:0/20:4 in whole blood samples is detectable after alcohol consumption and differs in amount synthesized and rate of elimination versus PEth 16:0/18:1 and 16:0/18:2. Measuring the concentrations of these 3 homologs has the potential to provide more information about the amount and time frame of alcohol consumption than any one alone.