Fat mass, weight and body shape changes at menopause - causes and consequences: a narrative review.

In addition to age-related weight gain, menopause adds additional challenges for women with the occurrence of significant metabolic alterations and central and visceral fat redistribution. The changes in body composition then influence risks of cardiovascular disease, metabolic disruption, cancer, fracture, lung disease, sexual dysfunction, mental health disorders and dementia. They may also heighten the severity of vasomotor symptoms. Treatment of these changes requires a flexible long-term strategy. This narrative review explores the pathogenesis of the metabolic changes at menopause and effective management options.

Society for Acute Medicine undergraduate syllabus for Acute Internal Medicine.

This syllabus is intended to act as a guide for students and their instructors in medical schools. It describes the range of clinical presentations that they should be able to recognize and the underlying conditions that they should know how to treat. It also includes knowledge of the practice of Acute Internal Medicine and systems of care. The appropriate level of knowledge is that which would be expected of a non-specialist Foundation level doctor.

Developing priorities for quality improvement in acute medicine using a modified Delphi method A consensus process hosted by the Society for Acute Medicine Quality Improvement Committee (SAM-QI).

INTRODUCTION: The SAM Quality Improvement Committee (SAM-QI), set up in 2016, has worked over the last year to determine the priority Acute Medicine QI topics. They have also discussed and put forward proposals to improve QI training for Acute Medicine professionals. METHODS: A modified Delphi process was completed over four rounds to determine priority QI topics. Online meetings were also used to develop proposals for QI training. RESULTS: Same Day Emergency Care (SDEC) was chosen as the priority topic for QI work within Acute Medicine. CONCLUSION: The SAM-QI group settled on SDEC being the priority topic for Acute Medicine QI development. Throughout the Delphi process SAM-QI has also developed proposals for QI training that will help Acute Medicine professionals deliver coordinated meaningful improvements in care.

Quality: What does it mean in Acute Medicine and how do we measure it?

Acute Medicine is a specialty that is not defined by a single organ system and sits at the interface between primary and secondary care. In order to document improvements in the quality of care delivered a system of metrics is required. A number of frameworks for measurements exist to quantify quality of care at the level of patients, teams and organisations, such as measures of population health, patient satisfaction and cost per patient. Measures can capture whether care is safe, effective, patient-centred, timely, efficient and equitable. Measurement in Acute Medicine is challenged by the often-transient nature of the contact between Acute Medicine clinicians and patients, the lack of diagnostic labels, a low degree of standardisation and difficulties in capturing the patient experience in the context. In a time of increasing ecological and financial constraints, reflecting about the most appropriate metrics to document the impact of Acute Medicine is required.

An exploration of mercaptopurine/methotrexate tolerance during maintenance therapy in children with acute lymphoblastic leukemia.

PURPOSE: Mercaptopurine (6MP) and methotrexate (MTX) cause myelosuppression and interruptions in therapy in children with lymphoblastic leukemia (ALL). Length of time off of therapy is related to poorer outcomes. To date the dose at which most children tolerate these agents without drops in blood counts has not been identified. This study attempts to determine the maximum tolerated dose of both 6MP/MTX. METHODS: A retrospective chart review of 77 ALL children, median age 4.5 years. Time to first interruption and dose, along with total number of interruptions were collected. Absolute neutrophil and platelet counts recorded at time of interruption. Subgroup analysis of age, sex, diagnosis and risk stratification were also completed. REB approval was gained. RESULTS: Of the 77 patients that were studied, 9 of them had no treatment interruptions. Descriptive statistics are reported using Strata software. The mean number of interruptions during maintenance was 3.2, the mean time to first interruption was 149.8 days. The mean dose percent of MTX and 6MP at first interruption was 94.4% and 106% respectively. Maintenance therapy was interrupted independent of age, sex, diagnosis or disease risk stratification. CONCLUSION: Few patients complete maintenance therapy without interruptions at the current dose escalation schedules outlined by the Children's Oncology Group protocols. The interruptions are due in part to intolerance of dose escalations of MTX and 6 MP above 100%. Future research should investigate doses of 6MP and MTX in maintenance therapy in relation to leukemia outcomes.

What the acute physician needs to know about Anti-NMDA receptor encephalitis: two case presentations.

These case reports look at two patients with anti-N-methyl-D-aspartate receptor (NMDAr) encephalitis presenting to the same acute medical unit within a month of each other. The following covers the characteristic signs, symptoms and timeline associated with this condition and discusses whether we should be sending CSF for anti-NMDAr antibody testing more readily.

Polygenic Risk Score Analysis of Alzheimer's Disease in Cases without APOE4 or APOE2 Alleles.

The We and others have previously shown that polygenic risk score analysis (PRS) has considerable predictive utility for identifying those at high risk of developing Alzheimer's disease (AD) with an area under the curve (AUC) of >0.8. However, by far the greatest determinant of this risk is the apolipoprotein E locus with the E4 allele alone giving an AUC of ~0.68 and the inclusion of the protective E2 allele increasing this to ~0.69 in a clinical cohort. An important question is to determine how good PRS is at predicting risk in those who do not carry the E4 allele (E3 homozygotes, E3E2 and E2E2) and in those who carry neither the E4 or E2 allele (i.e. E3 homozygotes). Previous studies have shown that PRS remains a significant predictor of AD risk in clinical cohorts after controlling for APOE ε4 carrier status. In this study we assess the accuracy of PRS prediction in a cohort of pathologically confirmed AD cases and controls. The exclusion of APOE4 carriers has surprisingly little effect on the PRS prediction accuracy (AUC ~0.83 [95% CI: 0.80-0.86]), and the accuracy remained higher than that in clinical cohorts with APOE included as a predictor. From a practical perspective this suggests that PRS analysis will have predictive utility even in E4 negative individuals and may be useful in clinical trial design.

Goal Attainment Scaling for haemophilia (GAS-Hem): testing the feasibility of a new patient-centric outcome measure in people with haemophilia.

INTRODUCTION: To address the need for a patient-reported outcome that can measure clinically and personally meaningful change in people with haemophilia (PwH) on prophylaxis, an approach based on Goal Attainment Scaling (GAS) was developed: the GAS-Hem. AIM: To establish real-world feasibility of GAS-Hem in PwH. METHODS: Patients aged 5-65 years were enroled from four North American centres for a 12-week study. The primary outcome was the proportion of participants who completed GAS-Hem interviews at baseline, 6 and 12 weeks. GAS-Hem scores were obtained by subject- and clinician-rated goal attainment at Weeks 6 and 12, and compared with quality of life (QoL) measures and annualized bleed rate (ABR) for construct validity. Goals were evaluated qualitatively for content validity. Responsiveness was calculated using standardized response means (SRM). RESULTS: Forty-two participants set 63 goals. Participants preferred to define (37/63) their own goals or further individualize (23/63) from the GAS-Hem menu. Thirty of the 37 self-defined goals were matched to goals on the GAS-Hem menu. The most common goal areas were: weight, exercise and nutrition (n = 17); leisure activities (n = 8); and joint problems (n = 7). Both participant- and clinician-rated GAS-Hem scores at 6 weeks (n = 40) and 12 weeks (n = 41) demonstrated satisfactory goal attainment (SRM [subject-rated] at 12 weeks for adult and paediatric groups was 1.25 and 1.16, respectively). Correlations of GAS-Hem scores with QoL measures and ABR were uniformly small. CONCLUSION: GAS-Hem was feasible and tapped constructs not captured by ABR or QoL measures.

Health-related quality of life questionnaires in individuals with haemophilia: a systematic review of their measurement properties.

BACKGROUND: The evaluation of health related quality of life (HRQOL) is essential for a full assessment of the influence of an illness on patients' lives. The aim of this paper is to critically appraise and compare the measurement properties of HRQOL questionnaires studied in haemophilia. METHODS: Bibliographic databases (Embase, Medline, Cinahl and PsycInfo) were searched for articles evaluating measurement properties of HRQOL questionnaires in haemophilia. Articles were excluded that did not report HRQOL measurement properties, or when <50% of the study population had haemophilia. The methodological quality of the selected studies was evaluated using the COSMIN checklist. The measurement properties of the HRQL questionnaires were rated as 'positive', 'indeterminate' or 'negative', accompanied by levels of evidence. RESULTS: The search resulted in 1597 unique hits, of which 22 studies were included. These articles evaluated three questionnaires for children (CHO-KLAT, Haemo-QoL and one unnamed measure) and five for adults (Hemofilia-QoL, Haemophilia Well-Being Index, HAEMO-QoL-A, Haem-A-QoL, and SF-36). The CHO-KLAT was the paediatric measure that showed the strongest measurement properties in high-quality studies. The Haemophilia Well-Being Index and HAEMO-QoL-A performed best among the adult measures. None of the studies reported measurement error and responsiveness. CONCLUSION: Our findings suggest that there is no need for new disease-specific HRQOL questionnaires for haemophilia, but rather that additional research is necessary to document the measurement properties of the currently available questionnaires, specifically focusing on the structural validity, measurement error and responsiveness of these questionnaires.

A Precision Medicine Initiative for Alzheimer's disease: the road ahead to biomarker-guided integrative disease modeling.

After intense scientific exploration and more than a decade of failed trials, Alzheimer's disease (AD) remains a fatal global epidemic. A traditional research and drug development paradigm continues to target heterogeneous late-stage clinically phenotyped patients with single 'magic bullet' drugs. Here, we propose that it is time for a paradigm shift towards the implementation of precision medicine (PM) for enhanced risk screening, detection, treatment, and prevention of AD. The overarching structure of how PM for AD can be achieved will be provided through the convergence of breakthrough technological advances, including big data science, systems biology, genomic sequencing, blood-based biomarkers, integrated disease modeling and P4 medicine. It is hypothesized that deconstructing AD into multiple genetic and biological subsets existing within this heterogeneous target population will provide an effective PM strategy for treating individual patients with the specific agent(s) that are likely to work best based on the specific individual biological make-up. The Alzheimer's Precision Medicine Initiative (APMI) is an international collaboration of leading interdisciplinary clinicians and scientists devoted towards the implementation of PM in Neurology, Psychiatry and Neuroscience. It is hypothesized that successful realization of PM in AD and other neurodegenerative diseases will result in breakthrough therapies, such as in oncology, with optimized safety profiles, better responder rates and treatment responses, particularly through biomarker-guided early preclinical disease-stage clinical trials.

Interleukin-10 family cytokines pathway: genetic variants and psoriasis.

BACKGROUND: Interleukin (IL)-10 family cytokines IL-10, IL-19, IL-20 and IL-24 have been implicated in autoimmune diseases and we have previously reported that genetic variants in the IL10 gene cluster were associated with psoriasis. OBJECTIVES: To analyse the relationship between genetic polymorphisms in the IL10 gene cluster and psoriasis. This study also explores whether there are gene-gene interactions among these genetic polymorphisms. METHODS: A total of 377 patients with psoriasis and 403 matched healthy controls were enrolled to carry out a case-control study for 48 single-nucleotide polymorphisms (SNPs) of the IL10 gene cluster. Genotyping for the SNPs was conducted on the Applied Biosystems 3730 DNA Analyzer using SNPlex® technology. Generalized multifactor dimensionality reduction (GMDR) analysis was applied to discover a likely gene-gene interaction model among the SNPs. RESULTS: The results showed that the allele distributions of IL10 gene cluster SNPs are significantly different between the case and control groups. Carriers of the IL10 T allele (rs1554286) and the IL20 T allele (rs1400986) conferred protection from psoriasis [odds ratio (OR) = 0·63, corrected P-value (Pc) = 0·007; OR = 0·62, Pc = 0·038, respectively]. GMDR analysis displayed a significant gene-gene interaction between IL10 (rs1554286) and IL20 (rs1518108) variants. The strongest protective effect was found with the block 1 haplotype ACATA in the IL10 gene (Pc = 0·004). CONCLUSIONS: This study presents a novel finding that the combination of the two SNPs, IL10 (rs1554286) and IL20 (rs1518108), is associated with a reduced risk of psoriasis. Our results indicate that genetic variants of the immunomodulatory IL10 and IL20 genes may offer a protective effect in Europeans from Russia. Independent studies are required to verify the results and find a possible functional explanation.

Rare variants analysis of cutaneous malignant melanoma genes in Parkinson's disease.

A shared genetic susceptibility between cutaneous malignant melanoma (CMM) and Parkinson's disease (PD) has been suggested. We investigated this by assessing the contribution of rare variants in genes involved in CMM to PD risk. We studied rare variation across 29 CMM risk genes using high-quality genotype data in 6875 PD cases and 6065 controls and sought to replicate findings using whole-exome sequencing data from a second independent cohort totaling 1255 PD cases and 473 controls. No statistically significant enrichment of rare variants across all genes, per gene, or for any individual variant was detected in either cohort. There were nonsignificant trends toward different carrier frequencies between PD cases and controls, under different inheritance models, in the following CMM risk genes: BAP1, DCC, ERBB4, KIT, MAPK2, MITF, PTEN, and TP53. The very rare TYR p.V275F variant, which is a pathogenic allele for recessive albinism, was more common in PD cases than controls in 3 independent cohorts. Tyrosinase, encoded by TYR, is the rate-limiting enzyme for the production of neuromelanin, and has a role in the production of dopamine. These results suggest a possible role for another gene in the dopamine-biosynthetic pathway in susceptibility to neurodegenerative Parkinsonism, but further studies in larger PD cohorts are needed to accurately determine the role of these genes/variants in disease pathogenesis.

Genome-wide analysis of over 106 000 individuals identifies 9 neuroticism-associated loci.

Neuroticism is a personality trait of fundamental importance for psychological well-being and public health. It is strongly associated with major depressive disorder (MDD) and several other psychiatric conditions. Although neuroticism is heritable, attempts to identify the alleles involved in previous studies have been limited by relatively small sample sizes. Here we report a combined meta-analysis of genome-wide association study (GWAS) of neuroticism that includes 91 370 participants from the UK Biobank cohort, 6659 participants from the Generation Scotland: Scottish Family Health Study (GS:SFHS) and 8687 participants from a QIMR (Queensland Institute of Medical Research) Berghofer Medical Research Institute (QIMR) cohort. All participants were assessed using the same neuroticism instrument, the Eysenck Personality Questionnaire-Revised (EPQ-R-S) Short Form's Neuroticism scale. We found a single-nucleotide polymorphism-based heritability estimate for neuroticism of ∼15% (s.e.=0.7%). Meta-analysis identified nine novel loci associated with neuroticism. The strongest evidence for association was at a locus on chromosome 8 (P=1.5 × 10(-15)) spanning 4 Mb and containing at least 36 genes. Other associated loci included interesting candidate genes on chromosome 1 (GRIK3 (glutamate receptor ionotropic kainate 3)), chromosome 4 (KLHL2 (Kelch-like protein 2)), chromosome 17 (CRHR1 (corticotropin-releasing hormone receptor 1) and MAPT (microtubule-associated protein Tau)) and on chromosome 18 (CELF4 (CUGBP elav-like family member 4)). We found no evidence for genetic differences in the common allelic architecture of neuroticism by sex. By comparing our findings with those of the Psychiatric Genetics Consortia, we identified a strong genetic correlation between neuroticism and MDD and a less strong but significant genetic correlation with schizophrenia, although not with bipolar disorder. Polygenic risk scores derived from the primary UK Biobank sample captured ∼1% of the variance in neuroticism in the GS:SFHS and QIMR samples, although most of the genome-wide significant alleles identified within a UK Biobank-only GWAS of neuroticism were not independently replicated within these cohorts. The identification of nine novel neuroticism-associated loci will drive forward future work on the neurobiology of neuroticism and related phenotypes.

Single nucleotide polymorphism in IL1B is associated with infection risk in paediatric acute myeloid leukaemia.

We evaluated single nucleotide polymorphisms (SNPs) associated with infection risk in children with newly diagnosed acute myeloid leukaemia (AML). We conducted a multicentre, prospective cohort study that included children aged ≤18 years with de novo AML. DNA was isolated from blood lymphocytes or buccal swabs, and candidate gene SNP analysis was conducted. Primary outcome was the occurrence of microbiologically documented sterile site infection during chemotherapy. Secondary outcomes were Gram-positive and -negative infections, viridans group streptococcal infection and proven/probable invasive fungal infection. Interpretation was guided by consistency in risk alleles and microbiologic agent with previous literature. Over the study period 254 children and adolescents with AML were enrolled. Overall, 190 (74.8%) had at least one sterile site microbiologically documented infection. Among the 172 with inferred European ancestry and DNA available, nine significant associations were observed; two were consistent with previous literature. Allele A at IL1B (rs16944) was associated with decreased microbiologically documented infection, and allele G at IL10 (rs1800896) was associated with increased risk of Gram-positive infection. We identified SNPs associated with infection risk in paediatric AML. Genotype may provide insight into mechanisms of infection risk that could be used for supportive-care novel treatments.

PRECISION MEDICINE - The Golden Gate for Detection, Treatment and Prevention of Alzheimer's Disease.

During this decade, breakthrough conceptual shifts have commenced to emerge in the field of Alzheimer's disease (AD) recognizing risk factors and the non-linear dynamic continuum of complex pathophysiologies amongst a wide dimensional spectrum of multi-factorial brain proteinopathies/neurodegenerative diseases. As is the case in most fields of medicine, substantial advancements in detecting, treating and preventing AD will likely evolve from the generation and implementation of a systematic precision medicine strategy. This approach will likely be based on the success found from more advanced research fields, such as oncology. Precision medicine will require integration and transfertilization across fragmented specialities of medicine and direct reintegration of Neuroscience, Neurology and Psychiatry into a continuum of medical sciences away from the silo approach. Precision medicine is biomarker-guided medicine on systems-levels that takes into account methodological advancements and discoveries of the comprehensive pathophysiological profiles of complex multi-factorial neurodegenerative diseases, such as late-onset sporadic AD. This will allow identifying and characterizing the disease processes at the asymptomatic preclinical stage, where pathophysiological and topographical abnormalities precede overt clinical symptoms by many years to decades. In this respect, the uncharted territory of the AD preclinical stage has become a major research challenge as the field postulates that early biomarker guided customized interventions may offer the best chance of therapeutic success. Clarification and practical operationalization is needed for comprehensive dissection and classification of interacting and converging disease mechanisms, description of genomic and epigenetic drivers, natural history trajectories through space and time, surrogate biomarkers and indicators of risk and progression, as well as considerations about the regulatory, ethical, political and societal consequences of early detection at asymptomatic stages. In this scenario, the integrated roles of genome sequencing, investigations of comprehensive fluid-based biomarkers and multimodal neuroimaging will be of key importance for the identification of distinct molecular mechanisms and signaling pathways in subsets of asymptomatic people at greatest risk for progression to clinical milestones due to those specific pathways. The precision medicine strategy facilitates a paradigm shift in Neuroscience and AD research and development away from the classical "one-size-fits-all" approach in drug discovery towards biomarker guided "molecularly" tailored therapy for truly effective treatment and prevention options. After the long and winding decade of failed therapy trials progress towards the holistic systems-based strategy of precision medicine may finally turn into the new age of scientific and medical success curbing the global AD epidemic.

Unmeasured costs of haemophilia: the economic burden on families with children with haemophilia.

INTRODUCTION AND OBJECTIVES: Although economic evaluations of haemophilia-related care have highlighted both the health care payer and societal perspectives, the costs to families with children with haemophilia have not been examined. This study determined the costs incurred by families of children with haemophilia, attending a haemophilia treatment centre (HTC), servicing a large geographical area in Eastern Canada. METHODS: Families recorded all direct and indirect costs associated with haemophilia-related care for a year. Costs incurred to receive care at the HTC and local health care centres were compared. The relationship between distance to the HTC and costs was modelled using linear regression. RESULTS: Participants included 31/45 children (68%) from 27 families attending the HTC. Median age was 12 years (range: 0.5-17 years); 24/31 (77%) had severe haemophilia. The median distance to the HTC and local health care facility was 230 km (range: 7-600 km) and 33.5 km (range: 2-400 km) respectively. Due to this difference in distance, 23/31 (74%) children do not attend the HTC for management of acute haemorrhage. The median annual total cost per family to attend the HTC is $775.93 (range: $200.00-$5741.00). The total cost to attend the HTC increases by $2.16 (95% CI 1.24-3.9) per kilometer from the HTC. The median total annual cost of haemophilia-related care per family is $1222.50 (range: $396.00-$8037.00). CONCLUSION: Families incur high costs related to haemophilia care. The distance to the HTC is a barrier to care. Improving access to HTCs is paramount in improving haemophilia-related outcomes.

A novel calcium scoring system accurately predicts likelihood and location of post-TAVI paravalvular leak.

AIM: Sclerosis distribution, topography and morphology in aortic stenosis may have an impact on the localisation of post-procedural paravalvular leakage (PVL) following transcatheter aortic valve implantation (TAVI). METHODS: Between 05/2005 and 03/2011 a total of 208 patients underwent either transapical (TA) or transvascular (TV) TAVI using the Edwards-SAPIEN(TM), or CoreValve(TM) system. Aortic cusp and annular sclerosis distribution and aortic valve sclerosis symmetry were evaluated by preoperative transesophageal echocardiography (TOE). Mild, moderate and severe PVL after TAVI (group 1, N.=117) were analysed and compared to those patients with no signs of postprocedural PVL (group 2, N.=91). Commercial available image processing and analysing software were used to evaluate all relevant calcific sections (aortic sclerosis score 0-66; symmetry score 0-5) and were matched with the localization of the PVLs. RESULTS: A total of 117 patients (83±6 years, mean logistic EuroSCORE 20.1±12.7%) were identified with a mild-moderate PVL (TV, N.=102; TA, N.=15). Mean aortic sclerosis score was 38.7±7.6 in group 1 compared to 33.7±8.3 in group 2 (P<0.001) showing highest calcification in the non-coronary part for both groups. The mean symmetry score was 1.9±1.0 group 1 compared to 1.7±1.0 in group 2 (P=0.12). Regression analysis showed a significant relation of preoperative cusp localisation to the corresponding paravalvular leakage (P<0.001). CONCLUSION: The present study shows that a aortic sclerosis score constructed by TOE enables prediction of postoperative PVL and moreover, the localisation of PVL after TAVI correlates with the corresponding preoperative amount of sclerosis for each cusp.

Invasive fungal infections in paediatric acute myeloid leukaemia.

Invasive fungal infections (IFIs) are a major cause of morbidity and mortality in paediatric acute myeloid leukaemia (AML). This study describes risk factors for IFI and IFI-related sepsis in this population. We conducted a population-based, retrospective cohort study of children with AML in Canada. IFIs during chemotherapy and prior to haematopoietic stem cell transplantation, relapse, persistent disease or death were identified. Risk factors for proven or probable IFI were examined. Among courses complicated by IFI, risk factors for sepsis were also evaluated. There were 341 children with AML included of which 41 (12.0%) experienced 46 different episodes of IFI. Candida species accounted for 23 (50.0%) of IFIs and Aspergillus spp. accounted for 14 (30.4%). Days of broad-spectrum antibiotics, days of corticosteroids and neutropenia at start of the course were independently associated with IFI. Only days of fever were independently associated with IFI-related sepsis. Invasive fungal infections occurred in 12.0% of paediatric AML patients. Risk factors for IFI and IFI-related sepsis were identified. This knowledge may help to consider targeted strategies.