Open-label, phase II, multicenter study of lasofoxifene plus abemaciclib for treating women with metastatic ER+/HER2- breast cancer and an ESR1 mutation after disease progression on prior therapies: ELAINE 2.

BACKGROUND: Acquired ESR1 mutations in estrogen receptor-positive (ER+) metastatic breast cancer (mBC) drive treatment resistance and tumor progression; new treatment strategies are needed. Lasofoxifene, a next-generation, oral, endocrine therapy and tissue-specific ER antagonist, provided preclinical antitumor activity, alone or combined with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) in ESR1-mutated mBC. PATIENTS AND METHODS: In the open-label, phase II, ELAINE 2 trial (NCT04432454), women with ESR1-mutated, ER+/human epidermal growth factor receptor 2-negative (HER2-) mBC who progressed on prior therapies (including CDK4/6i) received lasofoxifene 5 mg/day and abemaciclib 150 mg b.i.d until disease progression/toxicity. The primary endpoint was safety/tolerability. Secondary endpoints included progression-free survival (PFS), clinical benefit rate (CBR), and objective response rate (ORR). RESULTS: Twenty-nine women (median age 60 years) participated; all but one were previously treated with a CDK4/6i (median duration 2 years). The lasofoxifene-abemaciclib combination was well tolerated with primarily grade 1/2 treatment-emergent adverse events (TEAEs), most commonly diarrhea, nausea, fatigue, and vomiting. One patient (with no prior CDK4/6i) discontinued treatment due to grade 2 diarrhea. No deaths occurred during the study. Median PFS was 56.0 weeks [95% confidence interval (CI) 31.9 weeks-not estimable; ∼13 months]; PFS rates at 6, 12, and 18 months were 76.1%, 56.1%, and 38.8%, respectively. CBR at 24 weeks was 65.5% (95% CI 47.3% to 80.1%). In 18 patients with measurable lesions, ORR was 55.6% (95% CI 33.7% to 75.4%). ESR1-mutant circulating tumor DNA (ctDNA) allele fraction decreased from baseline to week 4 in 21/26 (80.8%) patients. CONCLUSIONS: Lasofoxifene plus abemaciclib had an acceptable safety profile, was well tolerated, and exhibited meaningful antitumor activity in women with ESR1-mutated, ER+/HER2- mBC after disease progression on prior CDK4/6i. Observed decreases in ESR1-mutant ctDNA with lasofoxifene concordant with clinical response suggest target engagement. If the ELAINE 2 findings are confirmed in the initiated, phase III, ELAINE 3 trial, these data could be practice-changing and help address a critical unmet need.

Hypothalamic-Extended Amygdala Circuit Regulates Temporal Discounting.

Choice behavior is characterized by temporal discounting, i.e., preference for immediate rewards given a choice between immediate and delayed rewards. Agouti-related peptide (AgRP)-expressing neurons located in the arcuate nucleus of the hypothalamus (ARC) regulate food intake and energy homeostasis, yet whether AgRP neurons influence choice behavior and temporal discounting is unknown. Here, we demonstrate that motivational state potently modulates temporal discounting. Hungry mice (both male and female) strongly preferred immediate food rewards, yet sated mice were largely indifferent to reward delay. More importantly, selective optogenetic activation of AgRP-expressing neurons or their axon terminals within the posterior bed nucleus of stria terminalis (BNST) produced temporal discounting in sated mice. Furthermore, activation of neuropeptide Y (NPY) type 1 receptors (Y1Rs) within the BNST is sufficient to produce temporal discounting. These results demonstrate a profound influence of hypothalamic signaling on temporal discounting for food rewards and reveal a novel circuit that determine choice behavior.SIGNIFICANCE STATEMENT Temporal discounting is a universal phenomenon found in many species, yet the underlying neurocircuit mechanisms are still poorly understood. Our results revealed a novel neural pathway from agouti-related peptide (AgRP) neurons in the hypothalamus to the bed nucleus of stria terminalis (BNST) that regulates temporal discounting in decision-making.

Low volumetric bone density is a risk factor for early complications after spine fusion surgery.

This study aims to investigate lumbar spine (LS) volumetric bone density (vBMD) as a risk factor for complications (pseudoarthrosis, instrumentation failure, adjacent fractures), re-operation, and time to complication after fusion. INTRODUCTION: Lumbar spine (LS) fusion surgery is increasingly performed worldwide. Complications after fusion result in significant morbidity and healthcare costs. Multiple factors, including osteoporosis, have been suggested to contribute to risk of complications and re-operation. However, most studies have used DXA, which is subject to artifact in patients with spine pathology, and none have investigated the relationship between BMD and timing of post-operative complications. This study aims to investigate LS volumetric bone density (vBMD) as a risk factor for complications (pseudoarthrosis, instrumentation failure, adjacent fractures), re-operation, and time to complication after fusion. METHODS: We evaluated a cohort of 359 patients who had initial LS fusion surgery at our institution, had pre-operative LS CTs and post-operative imaging available for review. Demographic factors, smoking status, vBMD, and details of surgical procedure were related to likelihood and timing of post-operative complications. RESULTS: Mean age was 60 ± 14 years, vBMD 122 ± 37 g/cm3. Median follow-up was 11 months. Skeletal complications occurred in 47 patients (13%); 34 patients (10%) required re-operation. Low vBMD (directly measured and estimated using HU) and smoking were associated with increased risk of skeletal complications. Each increase in baseline vBMD of 10 g/cm3 decreased the complication hazard and increased the complication-free duration in time-to-event analysis (hazard ratio 0.91, 95% CI 0.83-0.98, p < 0.02). CONCLUSIONS: Low vBMD was a significant risk factor for early post-operative complications in patients undergoing LS fusion. Prospective studies are needed to confirm these findings and to elucidate the optimal timing for follow-up and strategies for prevention of post-operative complications in this population.

Systematic review of cognitive deficits in adult mitochondrial disease.

The profile and trajectory of cognitive impairment in mitochondrial disease are poorly defined. This systematic review sought to evaluate the current literature on cognition in mitochondrial disease, and to determine future research directions. A systematic review was conducted, employing PubMed, Medline, Psycinfo, Embase and Web of Science, and 360-degree citation methods. English language papers on adult patients were included. The literature search yielded 2421 articles, of which 167 met inclusion criteria. Case reports and reviews of medical reports of patients yielded broad diagnoses of dementia, cognitive impairment and cognitive decline. In contrast, systematic investigations of cognitive functioning using detailed cognitive batteries identified focal cognitive rather than global deficits. Results were variable, but included visuospatial functioning, memory, attention, processing speed and executive functions. Conclusions from studies have been hampered by small sample sizes, variation in genotype and the breadth and depth of assessments undertaken. Comprehensive cognitive research with concurrent functional neuroimaging and physical correlates of mitochondrial disease in larger samples of well-characterized patients may discern the aetiology and progression of cognitive deficits. These data provide insights into the pattern and trajectory of cognitive impairments, which are invaluable for clinical monitoring, health planning and clinical trial readiness.

Hippocampal dysfunction in the pathophysiology of schizophrenia: a selective review and hypothesis for early detection and intervention.

Scientists have long sought to characterize the pathophysiologic basis of schizophrenia and develop biomarkers that could identify the illness. Extensive postmortem and in vivo neuroimaging research has described the early involvement of the hippocampus in the pathophysiology of schizophrenia. In this context, we have developed a hypothesis that describes the evolution of schizophrenia-from the premorbid through the prodromal stages to syndromal psychosis-and posits dysregulation of glutamate neurotransmission beginning in the CA1 region of the hippocampus as inducing attenuated psychotic symptoms and initiating the transition to syndromal psychosis. As the illness progresses, this pathological process expands to other regions of the hippocampal circuit and projection fields in other anatomic areas including the frontal cortex, and induces an atrophic process in which hippocampal neuropil is reduced and interneurons are lost. This paper will describe the studies of our group and other investigators supporting this pathophysiological hypothesis, as well as its implications for early detection and therapeutic intervention.

Recurrent ACTG2 gene variation in African degenerative visceral leiomyopathy.

INTRODUCTION: Visceral myopathies remain difficult and frustrating clinical entities, a distinctive form of acquired degenerative visceral myopathy, African degenerative leiomyopathy, a myogenic functional intestinal obstruction without aganglionosis which affects smooth muscle of the intestine, in young indigenous African children. The Actin G2 gene is the main gene encoding smooth muscle actin found in enteric tissues. Recent research has identified Actin G2 alpha gene variation as an important causative biomarker in visceral myopathies and megacystis microcolon. This study of the Actin G2 gene (ACTG2) in an African population explores a possible molecular basis abnormal muscle function in a visceral myopathy. PATIENTS AND METHODS: Following ethical permission and informed consent, DNA was extracted from whole blood samples in five patients with histologically proven African degenerative leiomyopathy. PCR amplification of ACTG2 alpha gene products by semi-automated bi-directional sequencing analysis. Results were analysed using FinchTV Sequence Alignment Software and predicting bioinformatic investigation by PolyPhen 2 software. RESULTS: Five new patients with the ADL phenotypes were prospectively investigated for variation in the Actin G2 gamma gene (ACTG2). ACTG2 gene variation occurred in exon 5 (c.463 A>G K119R), in three (60%). In addition, intronic variation t > c-IVS3 was identified in three with the K119 mutation plus further g > c -IVS12 and t > c + IVS16(2), suggesting a possible haplotype. Bioinformatic modelling showed that these ACTG2 gene variations are highly non-conservative altering protein expression. CONCLUSIONS: Recurrent Actin G2 smooth muscle gene variation in African degenerative visceral leiomyopathy is associated with abnormal muscle actin development.

Life Goals Over Time Among Homeless Adults in Permanent Supportive Housing.

Permanent supportive housing (PSH) is a widely-accepted solution to the challenge of chronic homelessness. While housing support and retention, physical health, and healthcare continue to be important for formerly homeless persons in PSH, "higher-order" and humanistic needs such as thriving have received less attention and as a result are less well understood in this population. One important indicator of thriving is the ability to establish and articulate life goals. This study utilizes longitudinal data from 421 formerly homeless adults prior to their move into PSH, and at 3-, 6- and 12-months after move-in (369 respondents completed all four interviews), to examine what life goals are articulated by this population and how those goals change over time. Prior to housing, most respondents articulated housing attainment as their primary life goal, whereas at follow-up interviews health goals, housing relocation, and financial goals became more prevalent. Aspirational goals (e.g., independence, self-improvement, artistic pursuits) were also common, but demonstrated a decrease over time in housing. Relationship goals remained common and consistent over time. Findings indicate that housing is a necessary, but perhaps not sufficient, step for improving thriving among formerly homeless adults. Implications for practice and future research are discussed.

Epidemiological, clinical and genetic aspects of adult onset isolated focal dystonia in Ireland.

BACKGROUND: Adult onset idiopathic isolated focal dystonia presents with a number of phenotypes. Reported prevalence rates vary considerably; well-characterized cohorts are important to our understanding of this disorder. AIM: To perform a nationwide epidemiological study of adult onset idiopathic isolated focal dystonia in the Republic of Ireland. METHODS: Patients with adult onset idiopathic isolated focal dystonia were recruited from multiple sources. Diagnosis was based on assessment by a neurologist with an expertise in movement disorders. When consent was obtained, a number of clinical features including family history were assessed. RESULTS: On the prevalence date there were 592 individuals in Ireland with adult onset idiopathic isolated focal dystonia, a point prevalence of 17.8 per 100 000 (95% confidence interval 16.4-19.2). Phenotype numbers were cervical dystonia 410 (69.2%), blepharospasm 102 (17.2%), focal hand dystonia 39 (6.6%), spasmodic dysphonia 18 (3.0%), musician's dystonia 17 (2.9%) and oromandibular dystonia six (1.0%). Sixty-two (16.5%) of 375 consenting index cases had a relative with clinically confirmed adult onset idiopathic isolated focal dystonia (18 multiplex and 24 duplex families). Marked variations in the proportions of patients with tremor, segmental spread, sensory tricks, pain and psychiatric symptoms by phenotype were documented. CONCLUSIONS: The prevalence of adult onset idiopathic isolated focal dystonia in Ireland is higher than that recorded in many similar service-based epidemiological studies but is still likely to be an underestimate. The low proportion of individuals with blepharospasm may reflect reduced environmental exposure to sunlight in Ireland. This study will serve as a resource for international comparative studies of environmental and genetic factors in the pathogenesis of the disorder.

Randomised Controlled Trial: Potential Benefit of a Footplate Neuromuscular Electrical Stimulation Device in Patients with Chronic Venous Disease.

OBJECTIVES: Chronic venous disease (CVD) is common, affecting a quarter of the population. Current conservative methods of treatment aim to prevent progression of disease by reducing ambulatory venous pressure. Neuromuscular electrical stimulation (NMES) refers to the use of electrical impulses to elicit muscle contraction. This pilot randomised controlled trial investigates the effect of a footplate NMES device (REVITIVE) on venous flow parameters, limb oedema, and quality of life outcome measures in patients with CVD. METHODS: Twenty-two patients with Clinical Etiological Anatomical and Pathophysiological (CEAP) clinical class C2-C4 venous disease were randomised to receive a sham or test device. The recommended duration of use was for 30 minutes daily for 6 weeks. Venous flow parameters (duplex ultrasound), limb volume (optoelectric volumeter), and quality of life outcome measures were measured at baseline and after 6 weeks. RESULTS: The mean age of participants was 62 years, body mass index 28.6, with a 15:7 female preponderance. There was a significant difference in the percentage change in femoral vein flow parameters (from baseline) between the test and sham group while using the device (Week 0 time-averaged mean velocity 102.4% vs. -9.1%, p < .0001; volume flow 107.9% vs. -3.7%, p < .0001; peak velocity 377.7% vs. -6.7%, p < .0001). Limb volume was observed to increase significantly in the sham group (2.0% at Week 0 and 1.2% at Week 6; p < .01). This was prevented in the test group (+0.8% at Week 0 and 1.0% at Week 6; p = .06). There was a significant difference in the Aberdeen Varicose Vein Questionnaire between the two groups over the 6 weeks. CONCLUSIONS: This trial demonstrated a significant difference in venous flow parameters and prevention of orthostatic limb oedema with NMES. There was a positive effect on quality of life. Larger studies are required to determine the clinical significance of this in patients with venous disease.

Characterizing the risk of respiratory syncytial virus in infants with older siblings: a population-based birth cohort study.

From a population-based birth cohort of 245 249 children born in Western Australia during 1996-2005, we used linkage of laboratory and birth record datasets to obtain data including all respiratory syncytial virus (RSV) detections during infancy from a subcohort of 87 981 singleton children born in the Perth metropolitan area from 2000 to 2004. Using log binomial regression, we found that the risk of infant RSV detection increases with the number of older siblings, with those having ⩾3 older siblings experiencing almost three times the risk (relative risk 2·83, 95% confidence interval 2·46-3·26) of firstborn children. We estimate that 45% of the RSV detections in our subcohort were attributable to infection from an older sibling. The sibling effect was significantly higher for those infants who were younger during the season of peak risk (winter) than those who were older. Although older siblings were present in our cohort, they had very few RSV detections which could be temporally linked to an infant's infection. We conclude that RSV infection in older children leads to less severe symptoms but is nevertheless an important source of infant infection. Our results lend support to a vaccination strategy which includes family members in order to provide maximum protection for newborn babies.

Using record linkage to examine testing patterns for respiratory viruses among children born in Western Australia.

Changes in respiratory pathogen testing can affect disease burden estimates. Using linked data, we describe changes in respiratory virus testing among children born in Western Australia in 1996-2012. We extracted data on respiratory specimens from these children from birth to age 9 years. We estimated testing rates by age, year, Aboriginal status and geographical location. Predictors of testing among children hospitalised at least once before their 10th birthday were identified using logistic regression. We compared detection methods for respiratory viruses from nasal/nasopharyngeal (NP) specimens by age and year. Of 83 199 virology testing records in 2000-2012, 80% were nasal/NP specimens. Infants aged <1 month had the highest testing rates. Testing rates in all children increased over the study period with considerable yearly fluctuations. Among hospitalised children, premature children <32 weeks gestation had over three times the odds of being tested (95% CI 3·47-4·13) than those born at term. Testing using molecular methods increased from 5% to 87% over the study period. Proportion of positive samples increased from 36·3% to 44·4% (P < 0·01); this change was greatest in children aged 2-9 years. These findings will assist in interpreting results from future epidemiology studies assessing the pathogen-specific burden of disease.

Epidemiology of seasonal influenza infection in pregnant women and its impact on birth outcomes.

Seasonal influenza can cause significant morbidity in pregnant women. Much of the existing epidemiological evidence on influenza during pregnancy has focused on the 2009 A/H1N1 pandemic. To measure the epidemiological characteristics of seasonal influenza infection among pregnant women and the impact on infant health, a cohort of 86 779 pregnancies during the influenza season (2012-2014) was established using probabilistic linkage of notifiable infectious disease, hospital admission, and birth information. A total of 192 laboratory-confirmed influenza infections were identified (2·2 per 1000 pregnancies), 14·6% of which were admitted to hospital. There was no difference in the proportion of infections admitted to hospital by trimester or subtype of infection. Influenza B infections were more likely to occur in second trimester compared with influenza A/H3N2 and influenza A/H1N1 infections (41·3%, 23·6%, and 33·3%, respectively), and on average, infants born to women with influenza B during pregnancy had 4·0% (95% CI 0·3-7·6%) lower birth weight relative to optimal compared with infants born to uninfected women (P = 0·03). Results from this linked population-based study suggest that there are differences in maternal infection by virus type and subtype and support the provision of seasonal influenza vaccine to pregnant women.

A Review of the Evidence to Support Neuromuscular Electrical Stimulation in the Prevention and Management of Venous Disease.

INTRODUCTION: The prevention and management of venous disease is a therapeutic challenge. Movement of blood through the venous system is augmented by the action of muscles on the deep veins, and can be achieved through the application of electrical current. The efficacy of currently available clinical devices for this purpose is unknown, and is investigated here. METHODS: A literature search of the EMBASE and Medline databases was performed, and studies were included if they were full text articles, written in english, pertaining to venous disease and neuromuscular electrical stimulation (NMES). RESULTS: NMES devices increase venous haemodynamic parameters such as peak velocity and volume flow. Studies report them to be non-inferior to intermittent pneumatic compression. They are effective in the prevention of venous thromboembolism, though inferior to low molecular weight heparin. NMES can reduce symptoms of chronic venous disease. DISCUSSION: NMES is an important tool in the prevention and management of venous disease, and avoids the significant risks associated with heparin administration. Data explored here is heterogenous in device, protocol, and reported end-points, therefore should be interpreted with care. Long term effects of treatment with NMES have not been explored.

Factors impacting on patient perception of procedural success and satisfaction following treatment for varicose veins.

BACKGROUND: Patient-reported outcome measures (PROMs) have been collected from patients undergoing varicose vein treatments in the National Health Service since 2009. The aim of this retrospective cohort study was to examine PROMs for varicose vein interventions, characterizing factors that might predict patient-reported perception of procedural success and satisfaction. METHODS: Centrally compiled PROMs data for varicose vein procedures carried out from 2009 to 2011 were obtained from the Hospital Episode Statistics data warehouse for England. As data were not distributed normally, non-parametric statistical tests were employed. RESULTS: Data for 35 039 patient episodes (62·8 per cent women) were available for analysis. Some 23·4 per cent of patients reported a degree of anxiety or depression before treatment; a formal diagnosis of depression was present in 7·8 per cent. Quality of life, measured by generic EQ-5D-3L™ index and the Aberdeen Varicose Vein Questionnaire (AVVQ) improved after intervention by 11·7 per cent (0·77 to 0·86) and 40·1 per cent (18·95 to 11·36) respectively. No significant improvement was found in EQ-5D™ visual analogue scale scores. There was a significant improvement in self-perceived anxiety or depression after the intervention (P < 0·001, McNemar-Bowker test). Both preoperative and postoperative depression or anxiety had a statistically significant relationship with self-reported success and satisfaction (both P < 0·001, χ(2) test). CONCLUSION: This analysis of PROMs is evidence that treatment of varicose veins improves quality of life, and anxiety or depression. Preoperative and postoperative anxiety or depression scores impact on patient-perceived success and satisfaction rates.

Age-related sperm DNA methylation changes are transmitted to offspring and associated with abnormal behavior and dysregulated gene expression.

Advanced paternal age (APA) has been shown to be a significant risk factor in the offspring for neurodevelopmental psychiatric disorders, such as schizophrenia and autism spectrum disorders. During aging, de novo mutations accumulate in the male germline and are frequently transmitted to the offspring with deleterious effects. In addition, DNA methylation during spermatogenesis is an active process, which is susceptible to errors that can be propagated to subsequent generations. Here we test the hypothesis that the integrity of germline DNA methylation is compromised during the aging process. A genome-wide DNA methylation screen comparing sperm from young and old mice revealed a significant loss of methylation in the older mice in regions associated with transcriptional regulation. The offspring of older fathers had reduced exploratory and startle behaviors and exhibited similar brain DNA methylation abnormalities as observed in the paternal sperm. Offspring from old fathers also had transcriptional dysregulation of developmental genes implicated in autism and schizophrenia. Our findings demonstrate that DNA methylation abnormalities arising in the sperm of old fathers are a plausible mechanism to explain some of the risks that APA poses to resulting offspring.

Risk assessment of wandering behavior in mild dementia.

OBJECTIVE: This prospective longitudinal study aims to determine the risk factors of wandering-related adverse consequences in community-dwelling persons with mild dementia. These adverse consequences include negative outcomes of wandering (falls, fractures, and injuries) and eloping behavior. METHODS: We recruited 143 dyads of persons with mild dementia and their caregivers from a veteran's hospital and memory clinic in Florida. Wandering-related adverse consequences were measured using the Revised Algase Wandering Scale - Community Version. Variables such as personality (Big Five Inventory), behavioral response to stress, gait, and balance (Tinetti Gait and Balance), wayfinding ability (Wayfinding Effectiveness Scale), and neurocognitive abilities (attention, cognition, memory, language/verbal skills, and executive functioning) were also measured. Bivariate and logistic regression analyses were performed to assess the predictors of these wandering-related adverse consequences. RESULTS: A total of 49% of the study participants had falls, fractures, and injuries due to wandering behavior, and 43.7% demonstrated eloping behaviors. Persistent walking (OR = 2.6) and poor gait (OR = 0.9) were significant predictors of negative outcomes of wandering, while persistent walking (OR = 13.2) and passivity (OR = 2.55) predicted eloping behavior. However, there were no correlations between wandering-related adverse consequences and participants' characteristics (age, gender, race, ethnicity, and education), health status (Charlson comorbidity index), or neurocognitive abilities. CONCLUSION: Our results highlight the importance of identifying at-risk individuals so that effective interventions can be developed to reduce or prevent the adverse consequences of wandering.

Ovarian suppression using luteinizing hormone-releasing hormone agonists during chemotherapy to preserve ovarian function and fertility of breast cancer patients: a meta-analysis of randomized studies.

BACKGROUND: The role of temporary ovarian suppression with luteinizing hormone-releasing hormone agonists (LHRHa) in the prevention of chemotherapy-induced premature ovarian failure (POF) is still controversial. Our meta-analysis of randomized, controlled trials (RCTs) investigates whether the use of LHRHa during chemotherapy in premenopausal breast cancer patients reduces treatment-related POF rate, increases pregnancy rate, and impacts disease-free survival (DFS). METHODS: A literature search using PubMed, Embase, and the Cochrane Library, and the proceedings of major conferences, was conducted up to 30 April 2015. Odds ratios (ORs) and 95% confidence intervals (CIs) for POF (i.e. POF by study definition, and POF defined as amenorrhea 1 year after chemotherapy completion) and for patients with pregnancy, as well hazard ratios (HRs) and 95% CI for DFS, were calculated for each trial. Pooled analysis was carried out using the fixed- and random-effects models. RESULTS: A total of 12 RCTs were eligible including 1231 breast cancer patients. The use of LHRHa was associated with a significant reduced risk of POF (OR 0.36, 95% CI 0.23-0.57; P < 0.001), yet with significant heterogeneity (I(2) = 47.1%, Pheterogeneity = 0.026). In eight studies reporting amenorrhea rates 1 year after chemotherapy completion, the addition of LHRHa reduced the risk of POF (OR 0.55, 95% CI 0.41-0.73, P < 0.001) without heterogeneity (I(2) = 0.0%, Pheterogeneity = 0.936). In five studies reporting pregnancies, more patients treated with LHRHa achieved pregnancy (33 versus 19 women; OR 1.83, 95% CI 1.02-3.28, P = 0.041; I(2) = 0.0%, Pheterogeneity = 0.629). In three studies reporting DFS, no difference was observed (HR 1.00, 95% CI 0.49-2.04, P = 0.939; I(2) = 68.0%, Pheterogeneity = 0.044). CONCLUSION: Temporary ovarian suppression with LHRHa in young breast cancer patients is associated with a reduced risk of chemotherapy-induced POF and seems to increase the pregnancy rate, without an apparent negative consequence on prognosis.

Assessing the non-motor symptoms of Parkinson's disease: MDS-UPDRS and NMS Scale.

BACKGROUND AND PURPOSE: Although Parkinson's disease (PD) is characterized by typical motor manifestations, non-motor symptoms (NMS) are an outstanding part of the disease. At present, several specific instruments for assessment of NMS are available. The objective of our study was to determine the performance of the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS): Part I - Non-Motor Aspects of Experiences of Daily Living (nM-EDL) compared with the Non-Motor Symptoms Scale (NMSS). METHODS: To this purpose, 434 consecutive patients with PD were included in an international, observational, cross-sectional study. The association between scores of both scales was determined by the Spearman rank correlation coefficient. Equations for transformation of total score of a scale to the other were constructed from weighted regression models and both, transformed and observed score, contrasted by means of the Lin's Concordance Correlation Coefficient (LCCC) and Bland-Altman plot. RESULTS: As a whole, the prevalence of the NMS according to each scale was quite similar, and most of the correlations between their corresponding components were high (r(S) > 0.60). The total score correlation of the MDS-UPDRS Part I with the NMSS was high (r(S) = 0.81). Concerning the transformed scores, estimated scores only partially approach the observed ones (sharing about 60-64% of the variance) because residual variance increased with increasing magnitudes of the scores, i.e. the most severe patients (Bland-Altman plot; LCCC < 0.60 for severe patients). CONCLUSIONS: (i) MDS-UPDRS Part I (nM-EDL) and NMSS showed a strong convergent validity; (ii) however, transformed scores using the equations from weighted regression models showed that for patients with the most severe NMS they are not concordant.

A systematic review of the effectiveness of individual, community and societal-level interventions at reducing socio-economic inequalities in obesity among adults.

BACKGROUND: Socioeconomic inequalities in obesity are well established in high-income countries. There is a lack of evidence of the types of intervention that are effective in reducing these inequalities among adults. OBJECTIVES: To systematically review studies of the effectiveness of individual, community and societal interventions in reducing socio-economic inequalities in obesity among adults. METHODS: Nine electronic databases were searched from start date to October 2012 along with website and grey literature searches. The review examined the best available international evidence (both experimental and observational) of interventions at an individual, community and societal level that might reduce inequalities in obesity among adults (aged 18 years or over) in any setting and country. Studies were included if they reported a body fatness-related outcome and if they included a measure of socio-economic status. Data extraction and quality appraisal were conducted using established mechanisms and narrative synthesis was conducted. RESULTS: The 'best available' international evidence was provided by 20 studies. At the individual level, there was evidence of the effectiveness of primary care delivered tailored weight loss programmes among deprived groups. Community based behavioural weight loss interventions and community diet clubs (including workplace ones) also had some evidence of effectiveness-at least in the short term. Societal level evaluations were few, low quality and inconclusive. Further, there was little evidence of long term effectiveness, and few studies of men or outside the USA. However, there was no evidence to suggest that interventions increase inequalities. CONCLUSIONS: The best available international evidence suggests that some individual and community-based interventions may be effective in reducing socio-economic inequalities in obesity among adults in the short term. Further research is required particularly of more complex, multi-faceted and societal-level interventions.

Germline genetic variants in ABCB1, ABCC1 and ALDH1A1, and risk of hematological and gastrointestinal toxicities in a SWOG Phase III trial S0221 for breast cancer.

Hematological and gastrointestinal toxicities are common among patients treated with cyclophosphamide and doxorubicin for breast cancer. To examine whether single-nucleotide polymorphisms (SNPs) in key pharmacokinetic genes were associated with risk of hematological or gastrointestinal toxicity, we analyzed 78 SNPs in ABCB1, ABCC1 and ALDH1A1 in 882 breast cancer patients enrolled in the SWOG trial S0221 and treated with cyclophosphamide and doxorubicin. A two-SNP haplotype in ALDH1A1 was associated with an increased risk of grade 3 and 4 hematological toxicity (odds ratio=1.44, 95% confidence interval=1.16-1.78), which remained significant after correction for multiple comparisons. In addition, four SNPs in ABCC1 were associated with gastrointestinal toxicity. Our findings provide evidence that SNPs in pharmacokinetic genes may have an impact on the development of chemotherapy-related toxicities. This is a necessary first step toward building a clinical tool that will help assess risk of adverse outcomes before undergoing chemotherapy.