The hidden fragility in the heart of the athletes: A review of genetic biomarkers

Sudden cardiac death (SCD) is a devastating event which can also affect people in apparent good health, such as young athletes. It is known that intense and continuous exercise along with a genetic background that predisposes a person to the risk of fatal arrhythmias is a trigger for SCD. Therefore, knowledge of the athlete’s genetic conditions underlying the onset of SCD must be extended, in order to develop new effective prevention and/or therapeutic strategies. Arrhythmic features occur across a broad spectrum of cardiac diseases, sometimes presenting with overlapping phenotypes. The genetic basis of arrhythmogenic disorders has been greatly highlighted in the last 30 years, and has shown marked heterogeneity. The advent of next-generation sequencing has constantly updated our understanding of the genetic basis of arrhythmogenic diseases and is laying the foundation for precision medicine. With the exception of a few clinical cases involving a single athlete showing a highly suspected phenotype for the presence of a heart disease, there are few studies to date that analysed the applicability of genetic testing on cohorts of athletes. This evidence shows that genetic testing can contribute to the diagnosis of up to 13% of athletes; however, the presence of clinical markers is essential. This review aims to provide a reference collection on current knowledge of the genetic basis of sudden cardiac death in athletes and to review updated evidence on the effectiveness of genetic testing in early identification of athletes at risk for SCD

IKZF1 alterations are not associated with outcome in 498 adults with B-precursor ALL enrolled in the UKALL14 trial

IKZF1 deletions (ΔIKZF1) are commonly detected in B-precursor acute lymphoblastic leukemia (ALL; B-ALL) and are widely assumed to have a significant impact on outcome. We compared the ability of multiplex ligand-dependent probe amplification (MLPA) and polymerase chain reaction (PCR) to detect ΔIKZF1 and to determine the impact on event-free survival of patients with precursor B-ALL aged 23 to 65 years recruited to the completed trial UKALL14 (ISRCTN 66541317). From 655 recruits with BCR-ABL1+ and BCR-ABL1− B-ALL, all available diagnostic DNA samples (76% of the recruited population) were screened by multiplex end point PCR covering 4 deletions: dominant-negative (DN) Δ4-7 or the loss of function Δ2-7, Δ4-8, and Δ2-8 (n = 498), MLPA (n = 436), or by both (n = 420). Although patients with BCR-ABL1− ΔIKZF1 were more likely to have minimal residual disease at the end of induction, we did not find any impact of ΔIKZF1 (including subgroup analysis for DN or loss-of-function lesions) or the IKZF1plus genotype on event-free, overall survival, or relapse risk by univariable or multivariable analyses. Consistent with the technical approach, MLPA not only detected a wider range of deletions than PCR but also failed to detect some PCR-detected lesions. The main difference between our study and others reporting an association between ΔIKZF1 and outcome is the older age of participants in our population. The impact of ΔIKZF1 in ALL may be less marked in an older population of patients. Our study underscores the need for analyses in large, harmonized data sets. This trial was registered at www.clinicaltrials.gov as #NCT01085617

The role of diet and exercise and of glucosamine sulfate in the prevention of knee osteoarthritis: Further results from the PRevention of knee Osteoarthritis in Overweight Females (PROOF) study

Background and objectives: The PRevention of knee Osteoarthritis in Overweight Females (PROOF) study (ISRCTN 42823086) described a trend for a decrease in the incidence of knee osteoarthritis (OA) by a tailored diet and exercise program (DEP) or by oral glucosamine sulfate in women at risk for the disease, using a composite clinical and/or radiological outcome. The aim of this updated post-hoc analysis was to re-assess the results according to more precise techniques and take advantage of the 2×2 factorial design. Methods: A total of 407 overweight (BMI ≥ 27 kg/m2) women of 50-60 years of age with no diagnosis of knee OA were randomized to: (1) no DEP + placebo (Control, N = 102), (2) DEP + placebo (DEP, N = 101), (3) glucosamine sulfate + no DEP (GS, N = 102), and (4) DEP + glucosamine sulfate (DEP + GS, N =102) and followed for 2.5 years, with standardized postero-anterior, semiflexed (MTP) view knee radiographs at baseline and end of the study. DEP consisted of a tailored low fat and/or low caloric diet and easy to implement physical activities. Glucosamine was given as oral crystalline glucosamine sulfate 1500 mg once daily, double-blinded vs. placebo. Incident knee OA was defined as radiographic progression of ≥1 mm minimum joint space narrowing (mJSN) in the medial tibiofemoral compartment, as previously assessed by the visual (manual) technique and by a new semi-automated method. Logistic regression analysis was used to calculate the odds ratio for the effect of the interventions. Results: After 2.5 years, 11.8% of control subjects developed knee OA. This incidence was decreased with glucosamine sulfate, either alone or in combination with the DEP, but not by the DEP alone. Since there was no statistical interaction between treatments, the 2×2 factorial design allowed analysis of patients receiving glucosamine sulfate (= 204) vs. those not receiving it (= 203), similarly for those on the DEP (= 203) or not (= 204). Glucosamine sulfate significantly decreased the risk of developing knee OA: odds ratio (OR) = 0.41 (95% CI: 0.20-0.85, P = 0.02) by the manual JSN assessment method and OR = 0.42 (95% CI: 0.20-0.92, P = 0.03) by the semi-automated technique. Conversely, there was no decrease in risk with the DEP. Conclusions: Glucosamine sulfate decreased the risk of developing radiographic knee OA over 2.5 years in overweight, middle-aged women at risk, as determined by medial mJSN progression. Conversely a tailored diet and exercise program exerted no preventive effect, possibly because of the lower than expected effect on weight loss

Effects of aircraft noise on annoyance, sleep disorders, and blood pressure among adult residents near the Orio al Serio International Airport (BGY), Italy

Introduzione: Il rumore aeroportuale pu\uf2 causare effetti extra-uditivi quali annoyance, disturbi del sonno, ipertensione, patologie cardiovascolari e alterazioni delle abilit\ue0 cognitive nei bambini. Obiettivi: Condurre un\u2019indagine trasversale tra gli adulti residenti in prossimit\ue0 dell\u2019Aeroporto Internazionale di Orio al Serio (BGY), per studiare l\u2019associazione tra rumore aeroportuale, annoyance, disturbi del sonno, pressione arteriosa e ipertensione. Metodi: Soggetti di et\ue0 45-70 anni sono stati suddivisi, sulla base della residenza, in tre zone acustiche di rumore aeroportuale: <60 (Riferimento), 60-65 (Zona A) e 65-75 dBA (Zona B). Un campione di soggetti \ue8 stato invitato a sottoporsi a intervista e misurazioni della pressione arteriosa. Per analizzare variabili quantitative e categoriche, sono stati utilizzati modelli di regressione lineare multipla e di Poisson robusta, rispettivamente. Risultati: Tra giugno e settembre 2013 sono stati reclutati 400 soggetti (166 nella Zona di Riferimento, 164 nella Zona A e 70 nella Zona B). Rispetto al riferimento, sono stati rilevati elevati punteggi di annoyance (diurni e notturni) nelle Zone A (+2,7) e B (+4,0) (p<0,001) e circa il doppio di soggetti fortemente infastiditi in entrambe le zone (p<0,001). Anche i disturbi del sonno riferiti nel mese precedente erano pi\uf9 frequenti nelle Zone A e B. I disturbi del sonno considerati complessivamente corrispondevano a 19,9% nella Zona di Riferimento, 29,9% nella Zona A e 35,7% nella Zona B (p<0,001). Conclusioni: \uc8 stata evidenziata una forte associazione tra rumore aeroportuale, annoyance e disturbi del sonno. Non \ue8 stata riscontrata alcuna relazione con i livelli di pressione arteriosa e la prevalenza di ipertensione.Background: Aircraft noise may cause several non-auditory health effects, including annoyance, sleep disorders, hypertension, cardiovascular diseases, and impaired cognitive skills in children. Objectives: To perform a cross-sectional study among adult residents near the Orio al Serio International Airport (BGY), Italy to investigate the association between aircraft noise, annoyance, sleep disorders, blood pressure levels, and prevalence of hypertension. Methods: Residential addresses of subjects aged 45-70 years were geocoded and classified in three groups according to noise levels: <60 (Reference), 60-65 (Zone A), and 65-75 dBA (Zone B). A sample of subjects was invited to undergo a personal interview and blood pressure measurements. Multiple linear and robust Poisson regression models were used to analyze quantitative and categorical variables, respectively. Results: Between June and September 2013, we enrolled 400 subjects (166 in the Reference Zone, 164 in Zone A, and 70 in Zone B). Compared to the Reference Zone, we found elevated adjusted annoyance scores (day and night) in Zone A (+2.7) and Zone B (+4.0) (p<0.001) and about doubled proportions of severely annoyed subjects (p<0.001). Reported sleep disorders in the previous month were also more frequent in Zones A and B. Sleep disorders in general were 19.9% in the Reference Zone, 29.9% in Zone A, and 35.7% in Zone B (p<0.001). Conclusions: We found a strong association between aircraft noise levels, annoyance, and sleep disorders among adult residents near the Orio al Serio International Airport. We found no relationship with blood pressure levels and prevalence of hypertension

Selective intrauterine growth restriction in monochorionic twins : changing patterns in umbilical artery Doppler flow and outcomes

Objectives: To describe changes in umbilical artery (UA) Doppler flow in monochorionic diamniotic (MCDA) twins affected by selective intrauterine growth restriction (sIUGR), to correlate Doppler findings with pregnancy course and perinatal outcome, and to report postnatal follow-up. Methods: This was a retrospective study of 140 MCDA twins with sIUGR. UA end-diastolic flow, defined as Doppler waveform pattern Type I (persistently positive), Type II (persistently absent or persistently reversed) or Type III (intermittently absent or intermittently reversed), was recorded at first examination and monitored weekly until double or single intrauterine fetal death (IUFD), bipolar cord coagulation or delivery. All neonates had an early neonatal brain scan, magnetic resonance imaging, when indicated, and neurological assessment during infancy. Rates (per 100 person-weeks) and hazard ratios (HR) of IUFD in the IUGR twin in each pregnancy were calculated considering UA Doppler pattern as a time-dependent variable. Results: At first examination, there were 65 cases with UA Doppler waveform pattern Type I, 62 with Type II and 13 with Type III. Of the 65 Type-I cases, 48 (74%) remained stable, while 17 (26%) changed to either Type II absent (14%), Type II reversed (9%) or Type III (3%). Of 62 Type-II cases (47 with absent and 15 with reversed flow), 33 (53%) remained stable (18 with absent and all 15 with reversed flow). The 29 Type-II absent cases which changed became Type II reversed (24/47, 51%) or Type III (5/47, 11%). All 13 Type-III cases remained stable. Compared with Type I, the risk of IUFD (adjusted for estimated fetal weight discordance and amniotic fluid deepest vertical pocket) was highest when the pregnancy was or became Type II reversed (HR, 9.5; 95% CI, 2.7\u201332.7) or Type II absent (HR, 4.3; 95% CI, 1.3\u201314.3). Mild neurological impairment was more prevalent in the IUGR twin than in the large cotwin (7% vs 1%, P = 0.02). Conclusions: Risk stratification based on UA Doppler is useful for planning ultrasound surveillance. However, patterns can change over time, with important consequences for management and outcome

Analysis of Sentinel Node Biopsy and Clinicopathologic Features as Prognostic Factors in Patients With Atypical Melanocytic Tumors.

BACKGROUND: Atypical melanocytic tumors (AMTs) include a wide spectrum of melanocytic neoplasms that represent a challenge for clinicians due to the lack of a definitive diagnosis and the related uncertainty about their management. This study analyzed clinicopathologic features and sentinel node status as potential prognostic factors in patients with AMTs. PATIENTS AND METHODS: Clinicopathologic and follow-up data of 238 children, adolescents, and adults with histologically proved AMTs consecutively treated at 12 European centers from 2000 through 2010 were retrieved from prospectively maintained databases. The binary association between all investigated covariates was studied by evaluating the Spearman correlation coefficients, and the association between progression-free survival and all investigated covariates was evaluated using univariable Cox models. The overall survival and progression-free survival curves were established using the Kaplan-Meier method. RESULTS: Median follow-up was 126 months (interquartile range, 104-157 months). All patients received an initial diagnostic biopsy followed by wide (1 cm) excision. Sentinel node biopsy was performed in 139 patients (58.4%), 37 (26.6%) of whom had sentinel node positivity. There were 4 local recurrences, 43 regional relapses, and 8 distant metastases as first events. Six patients (2.5%) died of disease progression. Five patients who were sentinel node-negative and 3 patients who were sentinel node-positive developed distant metastases. Ten-year overall and progression-free survival rates were 97% (95% CI, 94.9%-99.2%) and 82.2% (95% CI, 77.3%-87.3%), respectively. Age, mitotic rate/mm2, mitoses at the base of the lesion, lymphovascular invasion, and 9p21 loss were factors affecting prognosis in the whole series and the sentinel node biopsy subgroup. CONCLUSIONS: Age >20 years, mitotic rate >4/mm2, mitoses at the base of the lesion, lymphovascular invasion, and 9p21 loss proved to be worse prognostic factors in patients with ATMs. Sentinel node status was not a clear prognostic predictor

Genetic and genomic analysis of acute lymphoblastic leukaemia in older adults reveals a distinct profile of abnormalities: analysis of 210 patients from the UKALL14 and UKALL60+ clinical trials

Despite being predominantly a childhood disease, the incidence of ALL has a second peak in adults aged 60 years and over. These older adults fare extremely poorly with existing treatment strategies and very few studies have undertaken a comprehensive genetic and genomic characterisation to improve prognosis in this age group. We performed cytogenetic, single nucleotide polymorphism (SNP) array and next generation sequencing (NGS) analyses on samples from 210 patients aged ≥60 years from the UKALL14 and UKALL60+ clinical trials. BCR-ABL1 positive disease was present in 26% (55/210) of patients, followed by low hypodiploidy/near triploidy in 13% (28/210). Cytogenetically cryptic rearrangements in CRLF2, ZNF384 and MEF2D were detected in 5%, 1% and 1% of patients respectively. Copy number abnormalities were common and deletions in ALL driver genes were seen in 77% of cases. IKZF1 deletion was present in 51% (40/78) of samples tested and the IKZF1plus profile identified in over a third (28/77) of BCP-ALL cases. The genetic good risk abnormalities high hyperdiploidy (n=2), ETV6-RUNX1 (no cases) and ERG deletion (no cases) were exceptionally rare in this cohort. RAS pathway mutations were seen in 17% (4/23) of screened samples. KDM6A abnormalities, including biallelic deletions, were discovered in 5% (4/78) of SNP array and 9% (2/23) of NGS samples, and represent a novel, potentially therapeutically actionable lesions using EZH2 inhibitors. Outcome remained poor with five-year event-free (EFS) and overall survival (OS) rates of 17% and 24% respectively across the cohort indicating a need for novel therapeutic strategies

The personal and national costs of mental health conditions: impacts on income, taxes, government support payments due to lost labour force participation

<p>Abstract</p> <p>Background</p> <p>Mental health conditions have the ability to interrupt an individual's ability to participate in the labour force, and this can have considerable follow on impacts to both the individual and the state.</p> <p>Method</p> <p>Cross-sectional analysis of the base population of Health&WealthMOD, a microsimulation model built on data from the Australian Bureau of Statistics' <it>Survey of Disability, Ageing and Carers </it>and STINMOD, an income and savings microsimulation model was used to quantify the personal cost of lost income and the cost to the state from lost income taxation, increased benefits payments and lost GDP as a result of early retirement due to mental health conditions in Australians aged 45-64 in 2009.</p> <p>Results</p> <p>Individuals aged 45 to 64 years who have retired early due to depression personally have 73% lower income then their full time employed counterparts and those retired early due to other mental health conditions have 78% lower incomes. The national aggregate cost to government due to early retirement from these conditions equated to $278 million (£152.9 million) in lost income taxation revenue,$407 million (£223.9 million) in additional transfer payments and around $1.7 billion in GDP in 2009 alone.</p> <p>Conclusions</p> <p>The costs of mental health conditions to the individuals and the state are considerable. While individuals has to bear the economic costs of lost income in addition to the burden of the conditions itself, the impact on the state is loss of productivity from reduced workforce participation, lost income taxation revenue, and increased government support payments - in addition to direct health care costs.</p