High- and intermediate-risk susceptibility variants in melanoma families from the Mediterranean area: A multicentre cohort from the MelaNostrum Consortium.

BACKGROUND: Most of large epidemiological studies on melanoma susceptibility have been conducted on fair skinned individuals (US, Australia and Northern Europe), while Southern European populations, characterized by high UV exposure and dark-skinned individuals, are underrepresented. OBJECTIVES: We report a comprehensive pooled analysis of established high- and intermediate-penetrance genetic variants and clinical characteristics of Mediterranean melanoma families from the MelaNostrum Consortium. METHODS: Pooled epidemiological, clinical and genetic (CDKN2A, CDK4, ACD, BAP1, POT1, TERT, and TERF2IP and MC1R genes) retrospective data of melanoma families, collected within the MelaNostrum Consortium in Greece, Italy and Spain, were analysed. Univariate methods and multivariate logistic regression models were used to evaluate the association of variants with characteristics of families and of affected and unaffected family members. Subgroup analysis was performed for each country. RESULTS: We included 839 families (1365 affected members and 2123 unaffected individuals). Pathogenic/likely pathogenic CDKN2A variants were identified in 13.8% of families. The strongest predictors of melanoma were ≥2 multiple primary melanoma cases (OR 8.1; 95% CI 3.3-19.7), >3 affected members (OR 2.6; 95% CI 1.3-5.2) and occurrence of pancreatic cancer (OR 4.8; 95% CI 2.4-9.4) in the family (AUC 0.76, 95% CI 0.71-0.82). We observed low frequency variants in POT1 (3.8%), TERF2IP (2.5%), ACD (0.8%) and BAP1 (0.3%). MC1R common variants (≥2 variants and ≥2 RHC variants) were associated with melanoma risk (OR 1.4; 95% CI 1.0-2.0 and OR 4.3; 95% CI 1.2-14.6, respectively). CONCLUSIONS: Variants in known high-penetrance genes explain nearly 20% of melanoma familial aggregation in Mediterranean areas. CDKN2A melanoma predictors were identified with potential clinical relevance for cancer risk assessment.

Comparisons of beliefs in mental health stigma in communities and those who police them.

The police response towards people with mental illness (PwMI) is coming under increasingly intense scrutiny. Numerous jurisdictions have experienced incidents where the police have used force against persons who were exhibiting symptoms of severe mental illness. PwMI are subject to long-held stereotypes and stigma, and recent research indicates these negative attitudes remain, even with training and awareness campaigns. Available literature provides research on citizen and police perceptions of PwMI separately, but no recent studies have compared perceptions of police officers to those held by the members of the communities they patrol. The current study involves a comparison of residents in five southern New Jersey counties and police officers working in these same counties. Both sets of participants responded to a series of statements about perceptions of PwMI. Police were more likely to report supporting stigmatizing views of PwMI than were community members. Negative community response and rejection of police tactics may be rooted partly in differing expectations of treatment towards PwMI in crisis.

Officer Trust Towards Community Members and Critical Incidents: a Comparison of Factors.

Current scholarship suggests attention should be focused on differences in specific job-related conditions to understand help-seeking behavior among police officers. This project examines how officers' feelings of department satisfaction and on-the-job emotions may be associated with trust in members of the community they police. Specifically, officers were asked to report trust levels both in a general sense and in the context of a potential officer-involved shooting (OIS) incident. Print and electronic surveys were completed by 169 police officers across 9 agencies located in 5 New Jersey counties between September 2019 and March 2020. Survey questions covered frequency of on-the-job emotions, satisfaction with department administration, and knowledge of local culture. Bivariate comparisons show officers' levels of both general and post-OIS community trust significantly differ based on reported frequency of emotion, assessment of job satisfaction and department administration, and wider cultural context. Furthermore, multivariate analyses indicate significant factors associated with trust levels include frequency of both positive (fulfillment) and negative (frustration) emotions, satisfaction with training, and attitudes towards the importance of understanding local culture. Findings suggest the complexity of police-community relationships should be more fully explored in relation to supporting aspects of job-related mental wellness in police officers.

Occurrence and accumulation of pharmaceutical products in water and biota of urban lowland rivers.

We evaluated the distribution of eleven groups of pharmaceutically active compounds (PhACs) in surface waters and biota of different trophic levels, in five sites of two lowland urban rivers in Argentine. Twenty-nine out of 39 PhACs and two metabolites were detected in at least one water sample (2-9622 ng/L), eleven detected in biofilms (1-179 ng/g d.w.) and eight in the macrophyte Lemna gibba (4-112 ng/g d.w). The two more polluted sites had a similar distribution of the main groups of compounds. In surface waters, the largest concentrations were for the analgesic acetaminophen (9622 ng/L), the antibiotic sulfamethoxazole (326 ng/L), the antihypertensive valsartan (963 ng/L), the ß-blocking agent atenolol (427 ng/L), the diuretic hydrochlorothiazide (445 ng/L) and the psychiatric drug carbamazepine (99 ng/L). The antibiotic ciprofloxacin exhibited the highest concentration in the biofilm (179 ng/g d.w.) and in the macrophyte L. gibba (112 ng/g d.w.) Several compounds were detected in the water but not in the biota (e.g., codeine and bezafibrate), and others (e.g., azithromycin and citalopram) were found in the biota but not in the surface water. Significant bioaccumulation factors (>1000 L/kg d.w.) were obtained for venlafaxine and ciprofloxacin in biofilm. Our results show that PhACs may accumulate in several biological compartments. Within an environmental compartment, similar PhACs profile and concentrations were found in different sites receiving urban pollution. Among different compartments, biofilms may be the most suitable biota matrix to monitor the immediate reception of PhACs in the biota. Our results indicate that the presence of PhACs in urban rivers and their accumulation in the biota could be incorporated as symptoms of the urban stream syndrome.

Seizure outcome after epilepsy surgery in tuberous sclerosis complex: Results and analysis of predictors from a multicenter study.

Epilepsy surgery is recommended in selected patients with Tuberous Sclerosis Complex (TSC). However, reports on predictive factors of seizure outcome are variable. Here we report on seizure and cognitive outcome of 35 TSC patients who received surgery for refractory epilepsy in 7 Italian centers over a period of 22 years (1997-2019). The rate of seizure-free individuals at last follow-up (mean 7.5 years, range 1-21 years) was 51%. Patients with longer follow-up (≥10 years) had a lower rate of Engel I outcome (11.1%) than those who received surgery in the last 10 years (65.4%, p = 0.003). Factors associated with Engel II, III, IV outcome in our cohort included: high number of cortical tubers (≥5); presence of subependymal nodules (SENs); seizure onset before age 1 year; and multifocal interictal epileptic discharges (IEDs) on electroencephalogram (EEG). A subset of patients evaluated with Vineland Adaptive Behaviour Scales (VABS) showed developmental gains, in line with their developmental trajectories, but no improvement in standard scores after surgery was noted. Our study demonstrates that the rates of successful seizure outcome of epilepsy surgery in TSC have improved in the last 10 years. More than half of the patients achieved seizure freedom, and a high proportion of affected individuals experienced a reduction in seizure burden and in antiseizure medications. A comprehensive assessment after surgery should be performed in TSC patients to evaluate the overall neurodevelopmental outcome, as measures that are based only on seizure control do not adequately identify the benefits of surgery on global functioning in these patients.

Reliability and accuracy of the brachial plexus neurodynamic test.

STUDY DESIGN: Observational study. INTRODUCTION: The brachial plexus neurodynamic test (BPNT), based on previous neurodynamic tests, is considered a clinically meaningful tool to objectively assess brachial plexus extensibility. This novel test's psychometric properties have yet to be determined. PURPOSE OF THE STUDY: The primary study aim was to assess the inter- and intrarater reliability and accuracy of the BPNT, which biases the median nerve and brachial plexus, among clinicians of various professional experience levels and geographic US regions. The secondary study aim was to determine if professional experience or geographic region affects the accuracy levels of this test. METHODS: In phase 1, inter-rater reliability and accuracy was determined. About 307 participants attending neural mobilization conferences and courses were instructed in the BPNT and asked to score 7 different videos of 14 possible test levels. In phase 2, intrarater reliability was determined via scoring the same test videos twice. RESULTS: High inter-rater intraclass correlation coefficient (range, 0.98-0.99) and accuracy (range, 0.88-0.94) levels were determined for all clinical experience levels and geographic regions. Intrarater intraclass correlation coefficient values were high (range, 0.96-1.0) among all participants. One-way analysis of variance indicated no significant differences on test accuracy based on professional clinical experience (F = 0.104; P = .958) and geographic region (F = 0.416; P = .416) among all 307 participants. DISCUSSION: Excellent inter- and intrarater reliability and accuracy levels may allow clinicians to correctly identify BPNT positions regardless of their professional experience or geographic location. CONCLUSION: The BPNT can reliably and accurately quantify outcomes in neural mobility scoring.

Cardiac Gab1 deletion leads to dilated cardiomyopathy associated with mitochondrial damage and cardiomyocyte apoptosis.

A vital step in the development of heart failure is the transition from compensatory cardiac hypertrophy to decompensated dilated cardiomyopathy (DCM) during cardiac remodeling under mechanical or pathological stress. However, the molecular mechanisms underlying the development of DCM and heart failure remain incompletely understood. In the present study, we investigate whether Gab1, a scaffolding adaptor protein, protects against hemodynamic stress-induced DCM and heat failure. We first observed that the protein levels of Gab1 were markedly reduced in hearts from human patients with DCM and from mice with experimental viral myocarditis in which DCM developed. Next, we generated cardiac-specific Gab1 knockout mice (Gab1-cKO) and found that Gab-cKO mice developed DCM in hemodynamic stress-dependent and age-dependent manners. Under transverse aorta constriction (TAC), Gab1-cKO mice rapidly developed decompensated DCM and heart failure, whereas Gab1 wild-type littermates exhibited adaptive left ventricular hypertrophy without changes in cardiac function. Mechanistically, we showed that Gab1-cKO mouse hearts displayed severe mitochondrial damages and increased cardiomyocyte apoptosis. Loss of cardiac Gab1 in mice impaired Gab1 downstream MAPK signaling pathways in the heart under TAC. Gene profiles further revealed that ablation of Gab1 in heart disrupts the balance of anti- and pro-apoptotic genes in cardiomyocytes. These results demonstrate that cardiomyocyte Gab1 is a critical regulator of the compensatory cardiac response to aging and hemodynamic stress. These findings may provide new mechanistic insights and potential therapeutic target for DCM and heart failure.

Extending the transposable payload limit of Sleeping Beauty (SB) using the Herpes Simplex Virus (HSV)/SB amplicon-vector platform.

The ability of a viral vector to safely deliver and stably integrate large transgene units (transgenons), which not only include one or several therapeutic genes, but also requisite native transcriptional regulatory elements, would be of significant benefit for diseases presently refractory to available technologies. The herpes simplex virus type-1 (HSV-1) amplicon vector has the largest known payload capacity of approximately 130 kb, but its episomal maintenance within the transduced cell nucleus and induction of host cell silencing mechanisms limits the duration of the delivered therapeutic gene(s). Our laboratory developed an integration-competent version of the HSV-1 amplicon by adaptation of the Sleeping Beauty (SB) transposon system, which significantly extends transgene expression in vivo. The maximum size limit of the amplicon-vectored transposable element remains unknown, but previously published plasmid-centric studies have established that DNA segments longer than 6-kb are inefficiently transposed. Here, we compared the transposition efficiency of SB transposase in the context of both the HSV amplicon vector as well as the HSV amplicon plasmid harboring 7 and 12-kb transposable reporter transgene units. Our results indicate that the transposition efficiency of the 12-kb transposable unit via SB transposase was significantly reduced as compared with the 7-kb transposable unit when the plasmid version of the HSV amplicon was used. However, the packaged HSV amplicon vector form provided a more amenable platform from which the 12-kb transposable unit was mobilized at efficiency similar to that of the 7-kb transposable unit via the SB transposase. Overall, our results indicate that SB is competent in stably integrating transgenon units of at least 12 kb in size within the human genome upon delivery of the platform via HSV amplicons.

Regulating intensity using perceived exertion: effect of exercise duration.

To examine whether the validity of perception-based intensity regulation would be affected by exercise duration, 20 subjects were recruited to complete a maximal exercise test (GXT) and four submaximal trials of varying duration and intensity using a cyle ergometer. During GXT, ratings of perceived exertion (RPE), oxygen uptake VO2, heart rate (HR), and power output (PO) equivalent to 50 and 75% VO2peak were determined. During each trial, subjects were to produce and maintain a workload using RPE estimated at 50 or 75% VO2peak for 20 or 40 min, and VO2, HR, and PO were measured throughout the exercise. No differences in average VO(2) were found between the estimation and production trial of either duration. However, average HR and PO were lower (P < 0.05) during the production trial of both durations. It appears that exercise duration has a minimal impact upon the accuracy of using RPE to regulate a target metabolic demand.

Cardiovascular fitness in obese versus nonobese 8-11-year-old boys and girls.

The purpose of this study was to compare cardiovascular fitness between obese and nonobese children. Based on body mass index, 118 were classified as obese (boys [OB] = 62, girls [OG] = 56), while 421 were nonobese (boys [NOB] = 196, girls [NOG] = 225). Cardiovascular fitness was determined by a 1-mile [1.6 km] run/walk (MRW) and estimated peak oxygen uptake (VO2peak) and analyzed using two-way analyses of variance (Gender x Obese/Nonobese). MRW times were significantly faster (p < .05) for the NOB (10 min 34 s) compared to the OB (13 min 8 s) and the NOG (13 min 15 s.) compared to the OG (14 min 44 s.). Predicted VO2peak values (mL x kg(-1) x min(-1)) were significantly higher (p < .05) for the NOB (48.29) compared to the OB (41.56) and the NOG (45.99) compared to the OG (42.13). MRW was compared between obese and nonobese participants on the President's Challenge (2005), the National Children and Youth Fitness Study, and FITNESSGRAM HFZ standards. The nonobese boys and girls scored higher on all three, exhibiting better cardiovascular fitness as compared to obese counterparts.

Early-onset hereditary neuropathy with liability to pressure palsy.

The clinical onset of hereditary neuropathy with liability to pressure palsy (HNPP) in childhood is rarely reported. On the basis of a 5-year-old affected patient, we reviewed the cases reported in the literature to evaluate the clinical and genetic characteristics of patients with an early onset (<10 years) of HNPP.

Spinal cord and vertebral stroke: a paediatric case.

Spinal cord ischaemia is a rare entity and very few cases of simultaneous spinal cord and vertebral body infarction have been reported: all of them in adult age. We observed a 15-year-old girl with abrupt onset of myelopathy and pain at the vertebral column studied by means of serial magnetic resonance imaging (MRI), and in whom bone infarction was a confirmatory sign of the vascular origin of the spinal lesion. This is to the best of our knowledge the first paediatric case described in the literature.

Coeficientes de partición de hidrocarburos aromáticos policíclicos con sustancias húmicas: un método simple para su determinación / Binding coefficients of polycyclic aromatic hydrocarbons to humic substances: a simple method for their determination

Las sustancias húmicas son componentes importantes de las aguas naturales, son polímeros ácidos, predominantemente aromáticos, que no resultan nocivos a los seres vivos. Sin embargo, su rol en el medio ambiente es importante porque afectan a la biodisponibilidad y toxicidad de muchos compuestos en el ambiente acuático. Por otra parte, entre los contaminantes de los sistemas acuáticos, se hallan los hidrocarburos aromáticos policíclicos (HAPs), algunos de los cuales son cancerígenos. Esta serie de compuestos en general está presente en el ambiente como mezclas complejas, presentando un rango muy variado de propiedades químicas, físicas y toxicológicas. En el presente trabajo, se estudió la interacción de sustancias húmicas con fenantreno y antraceno, separados o en mezcla, determinándose los coeficientes de partición (Koc) de las sustancias entre el carbono orgánico disuelto y la fase líquida por una metodología sencilla que utiliza extracción en fase sólida y determinación por espectrofotometría UV-visible. Los valores de Koc obtenidos son comparables con los referidos para estos compuestos por aplicación de otras técnicas. El método descrito es una herramienta que puede ser útil para analizar la interacción de los contaminantes orgánicos hidrofóbicos con las sustancias húmicas

Humic substances are major components of natural water. They are acidic polymers, mostly aromatic and usually harmless. However, they play an important role because they affect bioavailability and toxicity of many compounds in aquatic environments. Polycyclic aromatic hydrocarbons (some of them carcinogenic) are considered to be some of the most common pollutants of aquatic systems. They are usually found in the environment as complex mixtures exhibiting a wide range of physical, chemical and toxicological properties. In the present work, the interaction between humic substances and phenantrene and anthracene, individually or in mixtures, was studied. Partition coefficients of the substances between dissolved organic carbon and liquid phase were estimated by a simple methodology involving solid phase extraction and UVVIS spectrophotometry. Koc values obtained by this means are comparable with those obtained using other methods. The method described is a valuable tool for analyzing interactions of hydrophobic pollutants with humic substances

Metabolic and perceptual responses during Spinning cycle exercise.

PURPOSE: The present investigation was undertaken to compare metabolic and perceptual responses between exercise performed at constant intensity (CON) and with a Spinning protocol of variable intensity (VAR). METHOD: Fifteen subjects, including seven males and eight females (23 +/- 5 yr, 72 +/- 17 kg, and 171 +/- 10 cm), underwent two experimental trials. During each trial, subjects performed a 30-min cycle exercise protocol that was followed by a 30-min recovery period. Exercise was performed at 67 +/- 3% (means +/- SD) of HR(max) in CON. In VAR, the similar intensity (68 +/- 4% HR(max)) was also achieved, although the protocol entailed alternating phases of both higher and lower intensity arranged similarly to what is designed for a typical Spinning workout. Oxygen uptake (VO2) and HR were measured at rest and throughout both exercise and recovery, whereas RPE were recorded during exercise only. Plasma lactate concentrations [La] were determined at rest, the end of exercise, and the end of recovery. RESULTS: No differences in average VO2, HR, and RPE were found during exercise between CON and VAR. However, average VO2 and HR were higher (P < 0.05) in VAR than CON (0.33 +/- 0.03 vs 0.26 +/- 0.02 L x min(-1) and 91 +/- 3 vs 80 +/- 2 beats x min(-1), respectively). [La] was higher (P < 0.05) at the end of exercise in VAR than CON (7.2 +/- 0.8 vs 2.7 +/- 0.3 mmol x L(-1)), but became similar at the end of recovery. CONCLUSION: An exercise regimen in which intensity varies exerts no added effect on metabolic and perceptual responses during exercise as long as the average intensity is kept the same. However, VAR resulted in a greater [latin capital V with dot above]O2 after exercise, and this augmented postexercise oxygen consumption may be mediated in part by elevated plasma [La].

Interleukin-6 infusion blunts proinflammatory cytokine production without causing systematic toxicity in a swine model of uncontrolled hemorrhagic shock.

BACKGROUND: Serum elevations of interleukin-6 (IL-6) correlate with multiple organ dysfunction syndrome and mortality in critically injured trauma patients. Data from rodent models of controlled hemorrhage suggest that recombinant IL-6 (rIL-6) infusion protects tissue at risk for ischemia-reperfusion injury. Exogenous rIL-6 administered during shock appears to abrogate inflammation, providing a protective rather than a deleterious influence. In an examination of this paradox, the current study aimed to determine whether rIL-6 decreases inflammation in a clinically relevant large animal model of uncontrolled hemorrhagic shock, (UHS), and to investigate the mechanism of protection. METHODS: Swine were randomized to four groups (8 animals in each): (1) sacrifice, (2) sham (splenectomy followed by hemodilution and cooling to 33 degrees C), (3) rIL-6 infusion (sham plus UHS using grade 5 liver injury with packing and resuscitation plus blinded infusion of rIL-6 [10 mcg/kg]), and (4) placebo (UHS plus blinded vehicle). After 4 hours, blood was sampled, estimated blood loss determined, animals sacrificed, and lung harvested for RNA isolation. Quantitative reverse transcriptase-polymerase chain reaction was used to assess granulocyte colony-stimulating factor (G-CSF), IL-6, and tumor necrosis factor-alpha (TNFalpha) messenger ribonucleic acid (mRNA) levels. Serum levels of IL-6 and TNFalpha were measured by enzyme-linked immunoassay (ELISA). RESULTS: As compared with placebo, IL-6 infusion in UHS did not increase estimated blood loss or white blood cell counts, nor decrease hematocrit or platelet levels. As compared with the sham condition, lung G-CSF mRNA production in UHS plus placebo increased eightfold (*p < 0.05). In contrast, rIL-6 infusion plus UHS blunted G-CSF mRNA levels, which were not significantly higher than sham levels (p = 0.1). Infusion of rIL-6 did not significantly affect endogenous production of either lung IL-6 or mRNA. As determined by ELISA, rIL-6 infusion did not increase final serum levels of IL-6 or TNFalpha over those of sham and placebo conditions. CONCLUSIONS: Exogenous rIL-6 blunts lung mRNA levels of the proinflammatory cytokine G-CSF. The administration of rIL-6 does not increase the local expression of IL-6 nor TNFalpha mRNA in the lung. Additionally, rIL-6 infusion does not appear to cause systemic toxicity.

Predicting anaerobic capabilities in 11-13-year-old boys.

Anaerobic exercise is involved in many recreational and competitive sport activities. This study first established regression equations to predict maximal anaerobic power and then cross-validated these prediction equations. Using stepwise multiple regression analysis prediction equations for relative (watts per kilogram of body mass) and absolute (watts) mean and peak anaerobic power using the 30-second Wingate Test as the power measure were determined for 40 boys (age, 11-13 years). Percentage of body fat, free-fat weight, midthigh circumference, and 30-m dash were the independent predictive variables with the generated regression equations subsequently cross-validated using 20 different boys (age, 11-13 years). Significant correlations (Pearson r) were found for the cross-validation subjects between the measured power outputs and predicted power outputs for relative mean power (r = 0.48, p < 0.05), absolute mean power (r = 0.77, p < 0.01), and absolute peak power (r = 0.76, p < 0.01). Using paired t-tests, no significant mean differences (p > 0.05) were found for the same subjects between actual and predicted power outputs for relative mean power, absolute mean power, and absolute peak power. Prediction of maximal anaerobic power from selected anthropometric measurements and 30-m dash appears tenable in 11-13-year-old boys and can be accomplished in a simple cost- and time-effective manner.

Determinants of competency judgments by experienced laparoscopic surgeons.

BACKGROUND: The definitive criteria for assessing competence remain elusive. In our study, we aimed to identify the determinants of competence assessment used by individual laparoscopic surgeons. METHODS: In a blinded fashion, five laparoscopic surgeons rated 27 subjects on three laparoscopic simulations in four skill categories: clinical judgment, dexterity, serial/simultaneous complexity, and spatial orientation. The raters then assessed overall subject competence for each procedure. Point-biserial correlational analyses and cluster analyses were performed to ascertain the relationships among the various scales. RESULTS: All of the correlations between the skills' ratings and competence judgments were statistically significant ( p <.05). No skill rating was consistently more highly correlated with the competence rating. There were no distinct patterns of correlations for each rater or each procedure. One factor emerged from each cluster analysis of the skills measures. CONCLUSIONS: The results suggest that the four skills scored in the study are highly correlated with each other and are important in determining competence. The cluster analyses revealed that the surgeon raters shared a common perception of competence.