A phase I/II pharmacokinetics/pharmacodynamics study of irinotecan combined with S−1 for recurrent/metastatic breast cancer in patients with selected UGT1A1 genotypes (the JBCRG-M01 study)

Abstract

S-1 and irinotecan combination is attractive for breast cancer refractory to anthracyclines and taxanes. Patients with advanced human epidermal growth factor receptor 2 (HER2)-negative breast cancer previously treated with anthracyclines and taxanes were eligible. Patients with brain metastases and homozygous for UGT1A1 *6 or *28 or compound heterozygous (*6/*28) were excluded. A dose-escalation design was chosen for the phase I portion (level 1: irinotecan 80 mg/m² days 1–8 and S-1 80 mg/m² days 1–14 every 3 weeks; level 2: irinotecan 100 mg/m² and S-1 80 mg/m²). Study objectives included determination of the recommended dose for phase II, response rate, progression-free survival (PFS), and safety. Pharmacokinetics and CD34⁺ circulating endothelial cells (CECs) as pharmacodynamics were also analyzed. Thirty-seven patients were included. One patient at each level developed dose-limiting toxicities; therefore, level 2 was the recommended dose for phase II. Diarrhea was more common in patients possessing a *6 or *28 allele compared with wild-type homozygous patients (46% and 25%). Among 29 patients treated at level 2, PFS was longer for UGT1A1 wt/*6 and wt/*28 patients than for wt/wt patients (12 vs. 8 months, P = 0.06). PFS was significantly longer in patients with a larger-than-median SN-38 area under the curve (AUC) than in those with a smaller AUC (P = 0.039). There was an association between clinical benefit and reduction in baseline CD34⁺ CECs by S-1 (P = 0.047). The combination of irinotecan and S-1 is effective and warrants further investigation.

S-1 and irinotecan combination is an attractive option for advanced human epidermal growth factor receptor 2-negative breast cancer refractory to anthracyclines and taxanes. This study determined the recommended dose and safety/efficacy profile of this combination and demonstrated the association between clinical efficacy and pharmacogenomics/pharmacokinetics/pharmacodynamics profile.

http://ift.tt/2zTBBGD

Clinicopathological characteristics and survival outcomes in pleomorphic lobular breast carcinoma of the breast: a SEER population-based study

Abstract

The purpose of this study was to explore the clinicopathological features and survival outcome of pleomorphic lobular carcinoma (PLC) of breast, we identified 131 PLC patients and 460,109 invasive ductal carcinoma (IDC) patients in the Surveillance, Epidemiology, and End Result (SEER) database. PLCs presented with increased lymph node involvement, older age, higher AJCC stage and grade, and lower median survival months (PLC 84 ± 51.03 vs. IDC 105.2 ± 64.39 P < 0.01). Compared to IDC patients, PLC patients were more inclined to be treated with mastectomy. In univariate analysis, PLC patients showed a worse disease-specific survival (DSS) than that of IDC patients (hazard ratio = 0.691, 95% confidence interval 0.534–0.893, P < 0.01). In multivariate analysis, we took into account other prognostic factors and found that the histology types were no longer an independent prognostic factor (P = 0.120). DSS have no difference between matched IDC and PLC groups (P = 0.615). This result may be due to PLCs presenting higher tumor stage, higher tumor grade, and higher rate of LN metastasis than IDCs. Our conclusion is that PLC and IDC have many different characteristics, but there is not enough difference on the DSS.

PLC and IDC have many different characteristics, but there is not enough difference on the DSS.

http://ift.tt/2zzu1Aq

Functional Recovery of Cranial Nerves in Patients with Traumatic Orbital Apex Syndrome

Objective. Traumatic orbital apex syndrome (TOAS) is a rare disease characterized by the damage of cranial nerves (CNs) II, III, IV, and VI. The aim of our study was to analyze the functional recovery of CNs in TOAS and discuss the management of these patients. Methods. We retrospectively reviewed 28 patients with TOAS treated in the Department of Neurosurgery, Shanghai Changzheng Hospital from February 2006 to February 2016. Functional recovery of CNs was evaluated based on extraocular muscle movement and visual perception. Follow-up duration was at least 6 months. Results. There were 26 males and 2 females with a mean age of 35.3 years. The most common cause of TOAS was traffic accident. CN IV suffered the lightest injury among CNs III, IV, and VI. CN II achieved obvious improvement at 3-month follow-up, while other CNs enjoyed evident improvement at 6-month follow-up. There was no significant difference between conservative treatment and surgical decompression. Conclusion. CNs passing through orbital apex region might recover to different degrees several months after proper management. Clinical decision should be individualized and surgical decompression could be considered with evidence of fracture, hematoma, or deformation.

http://ift.tt/2i9PYfM

Risks for comorbidity in children with atopic disorders: an observational study in Dutch general practices

Objective

This study aimed to investigate both atopic and non-atopic comorbid symptoms and diseases in children with physician-diagnosed atopic disorders (atopic eczema, asthma and allergic rhinitis).

Methods

All children aged 0–18 years listed in a nationwide primary care database (the Netherlands Institute for Health Services Research-Primary Care Database) with routinely collected healthcare data in 2014 were selected. Children with atopic disorders were matched on age and gender with non-atopic controls within the same general practice. A total of 404 International Classification of Primary Care codes were examined. Logistic regression analyses were performed to examine the associations between the presence of atopic disorders and (non-)atopic symptoms and diseases by calculating ORs.

Results

Having one of the atopic disorders significantly increased the risk of having other atopic-related symptoms, even if the child was not registered as having the related atopic disorder. Regarding non-atopic comorbidity, children with atopic eczema (n=15 530) were at significantly increased risk for (infectious) skin diseases (OR: 1.2–3.4). Airway symptoms or (infectious) diseases (OR: 2.1–10.3) were observed significantly more frequently in children with asthma (n=7887). Children with allergic rhinitis (n=6835) had a significantly distinctive risk of ear-nose-throat-related symptoms and diseases (OR: 1.5–3.9). Neither age nor gender explained these increased risks.

Conclusion

General practitioners are not always fully aware of relevant atopic and non-atopic comorbidity. In children known to have at least one atopic disorder, specific attention is required to avoid possible insufficient treatment and unnecessary loss of quality of life.

http://ift.tt/2i9On9F

Factors contributing to medicine-related problems in adult patients with diabetes and/or cardiovascular diseases in Saudi Arabia: a qualitative study

Objectives

To investigate the factors contributing to medicine-related problems (MRPs) among patients with cardiovascular diseases (CVDs) and/or diabetes in Saudi Arabia.

Design

Qualitative semistructured interviews were conducted. Interviews were audio recorded then transcribed into Microsoft Word. The transcribed interviews were then imported into the qualitative analysis software NVivo where thematic analysis was applied. Thematic synthesis was achieved by coding and developing subthemes/themes from the findings of the interviews.

Setting

Five healthcare centres in Najran, Saudi Arabia.

Participants

25 adult patients with diabetes and/or CVDs.

Results

The study cohort included 16 men and 9 women with a median age of 61.8 years (40–85 years). Diabetes was the main condition encountered among 23 patients and CVDs were reported among 18 patients. Perceived factors leading to MRPs were of four types and related to: patient-, healthcare system-, clinical (condition-) and medicine-related factors. Patient-related factors were related to living situation, religious practices, diet/exercise and patients' behaviour towards the condition and medicines. Healthcare system-related factors comprised sources and availability of medicines, ease of access to healthcare system and patient satisfaction with healthcare providers. Clinical (condition-) related factors associated with both the knowledge and control over condition, and effects of the condition among medicines intake. Medicine-related factors included lack of knowledge about medicines and medicine use.

Conclusions

The results of this study uncovered many factors associated with MRPs among patients with CVDs and diabetes in Saudi Arabia, especially in reference to lifestyle and medicine use. Improving communication with healthcare professional alongside the introduction of national clinical guidance would mitigate the unwanted health complications related to medicine use.

http://ift.tt/2i9OvWH

Exploring perceptions and experiences of patients who have chronic pain as state prescription opioid policies change: a qualitative study in Indiana

Objectives

The misuse and abuse of prescription opioids (POs) is an epidemic in the USA today. Many states have implemented legislation to curb the use of POs resulting from inappropriate prescribing. Indiana legislated opioid prescribing rules that went into effect in December 2013. The rules changed how chronic pain is managed by healthcare providers. This qualitative study aims to evaluate the impact of Indiana's opioid prescription legislation on the patient experiences around pain management.

Setting

This is a qualitative study using interviews of patient and primary care providers to obtain triangulated data sources. The patients were recruited from an integrated pain clinic to which chronic pain patients were referred from federally qualified health clinics (FQHCs). The primacy care providers were recruited from the same FQHCs. The study used inductive, emergent thematic analysis.

Participants

Nine patient participants and five primary care providers were included in the study.

Results

Living with chronic pain is disruptive to patients' lives on multiple dimensions. The established pain management practices were disrupted by the change in prescription rules. Patient–provider relationships, which involve power dynamics and decision making, shifted significantly in parallel to the rule change.

Conclusions

As a result of the changes in pain management practice, some patients experienced significant challenges. Further studies into the magnitude of this change are necessary. In addition, exploring methods for regulating prescribing while assuring adequate access to pain management is crucial.

http://ift.tt/2Azlxq4

Identification of factors associated with resilience in medical students through a cross-sectional census

Objectives

Research on resilience has been gaining momentum, and it has already been shown that increased resilience creates positive changes at the individual and collective levels. Understanding of the factors associated with resilience may guide specific actions directed towards different populations. The objective of this study was to investigate these associated factors within a population of medical students.

Design

Cross-sectional census.

Setting

A public medical school in the state of Rio de Janeiro, Brazil.

Participants

Out of a total of 551 medical students, five students were excluded due to inactive registrations, and four transferred students were also excluded, resulting in a total of 542 remaining participants.

Measures

Adopting an anonymous questionnaire that included the Resilience Scale, in addition to questions related to sociodemographic, behavioural health-related and academic variables, the association between these variables and resilience was investigated.

Results

The high rate of answers to each item constitutes a indication of students' interest in participating, whereas the lowest percentile was 97.1%. The mean resilience score obtained was considered moderate. Factors such as gender, race, previous schools attended, financial independence, living situation, parents' education level, religion, quota-based admission, smoking, alcohol abuse and use of illegal drugs were not associated with resilience. In a multivariate analysis using ordinal logistic regression, associations were maintained only between the highest resilience score and the non-use of habit-forming prescription drugs (OR: 0.58; 95% CI 0.41 to 0.80), having a better perception of one's own health (OR: 0.57; 95% CI 0.41 to 0.81) and being older (OR: 1.37; 95% CI 1.12 to 1.67).

Conclusion

The census performed with the medical students showed, with the multivariate analysis, that besides age, the variables most closely tied with resilience were health and medicalisation, and the variables connected with income and religion showed no association.

http://ift.tt/2i9OCBB

Site-specific cancer mortality inequalities by employment and occupational groups: a cohort study among Belgian adults, 2001-2011

Objective

This study probes into site-specific cancer mortality inequalities by employment and occupational group among Belgians, adjusted for other indicators of socioeconomic (SE) position.

Design

This cohort study is based on record linkage between the Belgian censuses of 1991 and 2001 and register data on emigration and mortality for 01/10/2001 to 31/12/2011.

Setting

Belgium.

Participants

The study population contains all Belgians within the economically active age (25–65 years) at the census of 1991.

Outcome measures

Both absolute and relative measures were calculated. First, age-standardised mortality rates have been calculated, directly standardised to the Belgian population. Second, mortality rate ratios were calculated using Poisson's regression, adjusted for education, housing conditions, attained age, region and migrant background.

Results

This study highlights inequalities in site-specific cancer mortality, both related to being employed or not and to the occupational group of the employed population. Unemployed men and women show consistently higher overall and site-specific cancer mortality compared with the employed group. Also within the employed group, inequalities are observed by occupational group. Generally manual workers and service and sales workers have higher site-specific cancer mortality rates compared with white-collar workers and agricultural and fishery workers. These inequalities are manifest for almost all preventable cancer sites, especially those cancer sites related to alcohol and smoking such as cancers of the lung, oesophagus and head and neck. Overall, occupational inequalities were less pronounced among women compared with men.

Conclusions

Important SE inequalities in site-specific cancer mortality were observed by employment and occupational group. Ensuring financial security for the unemployed is a key issue in this regard. Future studies could also take a look at other working regimes, for instance temporary employment or part-time employment and their relation to health.

http://ift.tt/2iaZjUF

Effects of falls prevention interventions on falls outcomes for hospitalised adults: protocol for a systematic review with meta-analysis

Introduction

Falls are a major global public health problem and leading cause of accidental or unintentional injury and hospitalisation. Falls in hospital are associated with longer length of stay, readmissions and poor outcomes. Falls prevention is informed by knowledge of reversible falls risk factors and accurate risk identification. The extent to which hospital falls are prevented by evidence-based practice, patient self-management initiatives, environmental modifications and optimisation of falls prevention systems awaits confirmation. Published reviews have mainly evaluated community settings and residential care facilities. A better understanding of hospital falls and the most effective strategies to prevent them is vital to keeping people safe.

Objectives

To evaluate the effectiveness of falls prevention interventions on reducing falls in hospitalised adults (acute and subacute wards, rehabilitation, mental health, operating theatre and emergency departments). We also summarise components of effective falls prevention interventions.

Methods and analysis

This protocol has been registered. The systematic review will be informed by Cochrane guidelines and reported according to the Preferred Reporting Items for Systematic review and Meta-Analysis statement. Inclusion criteria: randomised controlled trials, quasi-randomised trials or controlled clinical trials that evaluate falls prevention interventions for use by hospitalised adults or employees. Electronic databases will be searched using key terms including falls, accidental falls, prevention, hospital, rehabilitation, emergency, mental health, acute and subacute. Pairs of independent reviewers will conduct all review steps. Included studies will be evaluated for risk of bias. Data for variables such as age, participant characteristics, settings and interventions will be extracted and analysed with descriptive statistics and meta-analysis where possible. The results will be presented textually, with flow charts, summary tables, statistical analysis (and meta-analysis where possible) and narrative summaries.

Ethics and dissemination

Ethical approval is not required. The systematic review will be published in a peer-reviewed journal and disseminated electronically, in print and at conferences. Updates will guide healthcare translation into practice.

Trail registration number

PROSPERO 2017: CRD 42017058887. Available from http://ift.tt/2yxllHe

http://ift.tt/2i9Op1h

Decisional needs assessment of patients with complex care needs in primary care: a participatory systematic mixed studies review protocol

Introduction

Patients with complex care needs (PCCNs) often suffer from combinations of multiple chronic conditions, mental health problems, drug interactions and social vulnerability, which can lead to healthcare services overuse, underuse or misuse. Typically, PCCNs face interactional issues and unmet decisional needs regarding possible options in a cascade of interrelated decisions involving different stakeholders (themselves, their families, their caregivers, their healthcare practitioners). Gaps in knowledge, values clarification and social support in situations where options need to be deliberated hamper effective decision support interventions. This review aims to (1) assess decisional needs of PCCNs from the perspective of stakeholders, (2) build a taxonomy of these decisional needs and (3) prioritise decisional needs with knowledge users (clinicians, patients and managers).

Methods and analysis

This review will be based on the interprofessional shared decision making (IP-SDM) model and the Ottawa Decision Support Framework. Applying a participatory research approach, we will identify potentially relevant studies through a comprehensive literature search; select relevant ones using eligibility criteria inspired from our previous scoping review on PCCNs; appraise quality using the Mixed Methods Appraisal Tool; conduct a three-step synthesis (sequential exploratory mixed methods design) to build taxonomy of key decisional needs; and integrate these results with those of a parallel PCCNs' qualitative decisional need assessment (semistructured interviews and focus group with stakeholders).

Ethics and dissemination

This systematic review, together with the qualitative study (approved by the Centre Intégré Universitaire de Santé et Service Sociaux du Saguenay-Lac-Saint-Jean ethical committee), will produce a working taxonomy of key decisional needs (ontological contribution), to inform the subsequent user-centred design of a support tool for addressing PCCNs' decisional needs (practical contribution). We will adapt the IP-SDM model, normally dealing with a single decision, for PCCNs who experience cascade of decisions involving different stakeholders (theoretical contribution). Knowledge users will facilitate dissemination of the results in the Canadian primary care network.

PROSPERO registration number

CRD42015020558.

http://ift.tt/2AA0qni

Associations of time of day with cardiovascular disease risk factors measured in older men: results from the British Regional Heart Study

Objective

We estimated associations of time of day with cardiovascular disease (CVD) risk factors measured in older men.

Methods

CVD risk factors (markers of inflammation and haemostasis, and cardiac markers) were measured on one occasion between 08:00 and 19:00 hours in 4252 men aged 60–79 years from the British Regional Heart Study. Linear models were used to estimate associations between time of day and risk factors. When an association was found, we examined whether the relationship between risk factors and cardiovascular mortality was affected by the adjustment for time of day using survival analyses.

Results

N-terminal pro-brain natriuretic peptide (NT-proBNP) levels increased by 3.3% per hour (95% CI 1.9% to 4.8%), interleukin-6 (IL-6) increased by 2.6% per hour (95% CI 1.8% to 3.4%), while tissue plasminogen activator (t-PA) decreased by 3.3% per hour (95% CI 3.7% to 2.9%); these associations were unaffected by adjustment for possible confounding factors. The percentages of variation in these risk factors attributable to time of day were less than 2%. In survival analyses, the association of IL-6, NT-proBNP and t-PA with cardiovascular mortality was not affected by the adjustment for time of day. C reactive protein, fibrinogen, D-dimer, von Willebrand factor and cardiac troponin T showed no associations with time of day.

Conclusions

In older men, markers of inflammation (IL-6), haemostasis (t-PA) and a cardiac marker (NT-proBNP) varied by time of day. The contribution of time of day to variations in these markers was small and did not appear to be relevant for the CVD risk prediction.

http://ift.tt/2i9Okuv

Testosterone in advance age: a New Zealand longitudinal cohort study: Life and Living in Advanced Age (Te Puawaitanga o Nga Tapuwae Kia Ora Tonu)

Objectives

Serum testosterone (T) levels in men decline with age. Low T levels are associated with sarcopenia and frailty in men aged >80 years. T levels have not previously been directly associated with disability in older men. We explored associations between T levels, frailty and disability in a cohort of octogenarian men.

Setting

Data from all men from Life and Living in Advanced Age Cohort Study in New Zealand, a longitudinal cohort study in community-dwelling older adults.

Participants

Community-dwelling (>80 years) adult men excluding those receiving T treatment or with prostatic carcinoma.

Outcomes measures

Associations between baseline total testosterone (TT) and calculated free testosterone (fT), frailty (Fried scale) and disability (Nottingham Extended Activities of Daily Living scale (NEADL)) (baseline and 24 months) were examined using multivariate regression and Wald's ² techniques. Subjects with the lowest quartile of baseline TT and fT values were compared with those in the upper three quartiles.

Results

Participants: 243 men, mean (SD) age 83.7 (2.0) years. Mean (SD) TT=17.6 (6.8) nmol/L and fT=225.3 (85.4) pmol/L. On multivariate analyses, lower TT levels were associated with frailty: β=0.41, p=0.017, coefficient of determination (R²)=0.10 and disability (NEADL) (β=–1.27, p=0.017, R²=0.11), low haemoglobin (β=–7.38, p=0.0016, R²=0.05), high fasting glucose (β=0.38, p=0.038, R²=0.04) and high C reactive protein (CRP) (β=3.57, p=0.01, R²=0.06). Low fT levels were associated with frailty (β=0.39, p=0.024, R²=0.09) but not baseline NEADL (β=–1.29, p=0.09, R²=0.09). Low fT was associated with low haemoglobin (β=–7.83, p=0.0008, R²=0.05) and high CRP (β=2.86, p=0.04, R²=0.05). Relationships between baseline TT and fT, and 24-month outcomes of disability and frailty were not significant.

Conclusions

In men over 80 years, we confirm an association between T levels and baseline frailty scores. The new finding of association between T levels and disability is potentially relevant to debates on T supplementation in older men, though, as associations were not present at 24 months, further work is needed.

http://ift.tt/2i93rV7

Effect of an intensive 3-week preoperative home rehabilitation programme in patients with chronic obstructive pulmonary disease eligible for lung cancer surgery: a multicentre randomised controlled trial

Introduction

Surgery is the standard curative treatment for lung cancer but is only possible in patients with local tumour and preserved exercise capacity. Improving fitness before surgery can reduce postoperative complications and mortality. However, preoperative rehabilitation remains difficult to implement for several reasons. We aim to investigate the effectiveness of an intensive 3-week home-based preoperative exercise training programme on hospital discharge ability, postoperative complications and physical performance in patients with chronic obstructive pulmonary disease (COPD) who are eligible for lung cancer surgery.

Methods and analysis

We designed a multicentre randomised controlled trial. The randomisation sequence will be generated and managed electronically by a research manager independent of assessments or interventions. We will recruit 90 patients with COPD and a diagnosis of lung cancer from four university hospitals. The rehabilitation group (R group) will receive a standardised preoperative home exercise programme for 3 weeks, combining both high-intensity training and usual physical therapy. The R group will perform 15 training sessions over 3 weeks on a cycloergometer. A physical therapist experienced in pulmonary rehabilitation will visit the patient at home and supervise one session a week. The R group will be compared with a control group receiving preoperative usual physical therapy only. The primary outcome will be hospital discharge ability assessed with a 10-item list. Secondary outcomes will be postoperative course (complication rate and mortality) as well as pulmonary function, exercise capacity and quality of life assessed 1 month before and the day before surgery.

Ethics and dissemination

This protocol has been approved by the French health authority for research (2016-A00622-49) and the research ethics committee/institutional review board (AU1267). Adverse events that occur during the protocol will be reported to the principal investigator. The results will be published in an international peer-reviewed journal.

Trial registration number

NCT03020251.

http://ift.tt/2AAEIzL

Study protocol for THINK: a multinational open-label phase I study to assess the safety and clinical activity of multiple administrations of NKR-2 in patients with different metastatic tumour types

Introduction

NKR-2 are autologous T cells genetically modified to express a chimeric antigen receptor (CAR) comprising a fusion of the natural killer group 2D (NKG2D) receptor with the CD3 signalling domain, which associates with the adaptor molecule DNAX-activating protein of 10 kDa (DAP10) to provide co-stimulatory signal upon ligand binding. NKG2D binds eight different ligands expressed on the cell surface of many tumour cells and which are normally absent on non-neoplastic cells. In preclinical studies, NKR-2 demonstrated long-term antitumour activity towards a breadth of tumour indications, with maximum efficacy observed after multiple NKR-2 administrations. Importantly, NKR-2 targeted tumour cells and tumour neovasculature and the local tumour immunosuppressive microenvironment and this mechanism of action of NKR-2 was established in the absence of preconditioning.

Methods and analysis

This open-label phase I study will assess the safety and clinical activity of NKR-2 treatment administered three times, with a 2-week interval between each administration in different tumour types. The study will contain two consecutive segments: a dose escalation phase followed by an expansion phase. The dose escalation study involves two arms, one in solid tumours (five specific indications) and one in haematological tumours (two specific indications) and will include three dose levels in each arm: 3x10⁸, 1x10⁹ and 3x10⁹ NKR-2 per injection. On the identification of the recommended dose in the first segment, based on dose-limiting toxicity occurrences, the study will expand to seven different cohorts examining the seven different tumour types separately. Clinical responses will be determined according to standard Response Evaluation Criteria In Solid Tumors (RECIST) criteria for solid tumours or international working group response criteria in haematological tumours.

Ethics approval and dissemination

Ethical approval has been obtained at all sites. Written informed consent will be taken from all participants. The results of this study will be disseminated through presentation at international scientific conferences and reported in peer-reviewed scientific journals.

Trial registration number

NCT03018405, EudraCT 2016-003312-12; Pre-result.

http://ift.tt/2AAbbGz

Characteristics and healthcare utilisation patterns of high-cost beneficiaries in the Netherlands: a cross-sectional claims database study

Objective

To determine medical needs, demographic characteristics and healthcare utilisation patterns of the top 1% and top 2%–5% high-cost beneficiaries in the Netherlands.

Design

Cross-sectional study using 1 year claims data. We broke down high-cost beneficiaries by demographics, the most cost-incurring condition per beneficiary and expensive treatment use.

Setting

Dutch curative health system, a health system with universal coverage.

Participants

4.5 million beneficiaries of one health insurer.

Measures

Annual total costs through hospital, intensive care unit use, expensive drugs, other pharmaceuticals, mental care and others; demographics; most cost-incurring and secondary conditions; inpatient stay; number of morbidities; costs per ICD10-chapter (International Statistical Classification of Diseases, 10th revision); and expensive treatment use (including dialysis, transplant surgery, expensive drugs, intensive care unit and diagnosis-related groups >30 000).

Results

The top 1% and top 2%–5% beneficiaries accounted for 23% and 26% of total expenditures, respectively. Among top 1% beneficiaries, hospital care represented 76% of spending, of which, respectively, 9.0% and 9.1% were spent on expensive drugs and ICU care. We found that 54% of top 1% beneficiaries were aged 65 years or younger and that average costs sharply decreased with higher age within the top 1% group. Expensive treatments contributed to high costs in one-third of top 1% beneficiaries and in less than 10% of top 2%–5% beneficiaries. The average number of conditions was 5.5 and 4.0 for top 1% and top 2%–5% beneficiaries, respectively. 53% of top 1% beneficiaries were treated for circulatory disorders but for only 22% of top 1% beneficiaries this was their most cost-incurring condition.

Conclusions

Expensive treatments, most cost-incurring condition and age proved to be informative variables for studying this heterogeneous population. Expensive treatments play a substantial role in high-costs beneficiaries. Interventions need to be aimed at beneficiaries of all ages; a sole focus on the elderly would leave many high-cost beneficiaries unaddressed. Tailored interventions are needed to meet the needs of high-cost beneficiaries and to avoid waste of scarce resources.

http://ift.tt/2AAfHVm

Association between visceral obesity and hepatitis C infection stratified by gender: a cross-sectional study in Taiwan

Objectives

The global prevalence of hepatitis C virus (HCV) is approximately 2%–3%, and the prevalence of the positive anti-HCV antibody has been increasing. Several studies have evaluated regional adipose tissue distribution and metabolism over the past decades. However, no study has focused on the gender difference in visceral obesity among patients with HCV infection.

Design

Retrospective cross-sectional study.

Setting

We reviewed the medical records of patients who visited a hospital in Southern Taiwan for health check-up from 2013 to 2015.

Participants

A total of 1267 medical records were collected. We compared patient characteristics, variables related to metabolic risk and body composition measured using bioelectrical impedance analysis between the groups. Regression models were built to adjust for possible confounding factors.

Results

The prevalence rate of the positive anti-HCV antibody was 8.8% in the study population, 8.5% in men and 9.2% in women. Men with HCV infection tended to be older and have lower total cholesterol levels and higher alanine aminotransferase (ALT) levels (p<0.001). Women with HCV infection tended to be older and have higher levels of fasting glucose and ALT (p<0.001). After adjusting for confounding factors, body fat percentage, fat-free mass/body weight (BW) and muscle mass/BW were found to be the independent determinants of visceral obesity in patients without HCV infection (p<0.001). However, the trend was not such obvious in patients with HCV infection, though still statistically significant (p<0.05). Furthermore, the trend was less significant in men with HCV infection.

Conclusions

The findings suggested that HCV modulates host lipid metabolism and distribution to some extent, and a gender difference was also noted.

http://ift.tt/2i8PPcs

Minimally invasive surgery versus open surgery in the treatment of lumbar spondylolisthesis: study protocol of a multicentre, randomised controlled trial (MISOS trial)

Introduction

Patients with symptomatic spondylolisthesis are frequently treated with nerve root decompression, in addition to pedicle screw fixation and interbody fusion. Minimally invasive approaches are gaining attention in recent years, although there is no clear evidence supporting the proclamation of minimally invasive spine surgery (MISS) being better than open surgery. We present the design of the MISOS (Minimal Invasive Surgery versus Open Surgery) trial on the effectiveness of MISS versus open surgery in patients with degenerative or spondylolytic spondylolisthesis.

Methods and analysis

All patients (age 18–75 years) with neurogenic claudication or radicular leg pain based on low-grade degenerative or spondylolytic spondylolisthesis with persistent complaints for at least 3 months are eligible. Patients will be randomised into mini-open decompression with bilateral interbody fusion with percutaneous pedicle screw fixation (MISS), or conventional surgery with decompression and instrumented fusion with pedicle screws and bilateral interbody fusion (open). The primary outcome measure is Visual Analogue Scale of self-reported low back pain. Secondary outcome measures include improvement of leg pain, Oswestry Disability Index, patients' perceived recovery, quality of life, resumption of work, complications, blood loss, length of hospital stay, incidence of reoperations and documentation of fusion. This study is designed as a multicentre, randomised controlled trial in which two surgical techniques are compared in a parallel group design. Based on a 20 mm difference of low back pain score at 6 weeks (power of 90%, assuming 8% loss to follow-up), a total of 184 patients will be needed. All analyses will be performed according to the intention-to-treat principle.

Ethics and dissemination

The study has been approved by the Medical Ethical Review Board Southwest Holland in August 2014 (registration number NL 49044.098.14) and subsequently approved by the board of all participating hospitals. Dissemination will include peer-reviewed publications and presentations at national and international conferences.

Trial registration number

NTR 4532, pre-results.

http://ift.tt/2Azs3wX

Examining the association between maternal atopy and birth outcomes using a retrospective cohort in the southeastern region of the USA

Objective

To assess birth outcomes in primiparous women with diagnosis of non-asthmatic atopy (NAA). Researchers hypothesised that women with NAA would have reduced the risk of adverse birth outcomes compared with women without NAA. NAA is defined as having allergic rhinitis and/or atopic dermatitis.

Setting

Women were mostly treated in primary care settings in South Carolina, USA.

Participants

This is a retrospective cohort study in which participants were identified using a Medicaid database. Participants were primiparous women aged 19 to 25. Births occurring between 2004 and 2014 were identified using the South Carolina's Vital Statistics (VS) records of live births. Incomplete records (ie, information on plural birth, gestational age at birth or birth weight missing), plural births or infants born before completing 24 weeks of gestation were excluded. This provided 65 650 complete maternal–infant dyads, representing 97.6% of the maternal records and 96.9% of the VS records. Women previously diagnosed with NAA were frequency matched 1:4 to non–atopic controls for a total of 9965 maternal–infant dyads used in the statistical analysis.

Primary outcome measures

Low birth weight, small for gestational age and preterm birth.

Results

Linear tests for trend were statistically significant (p<0.001), indicating that NAA was associated with improved birth weight and gestational age at birth. After controlling for potential confounders, mothers with NAA had equal risk for each outcome when compared with mothers with no diagnosis of NAA.

Conclusion

A diagnosis of NAA among women living in the southeastern region of the USA does not reduce the risk of adverse birth outcomes nor does it elevate the risk of same. Additional studies with more rigorous designs are warranted to confirm the findings in this study.

http://ift.tt/2AAoQ06

Easier said than done: a qualitative study conducted in the USA exploring Latino family child care home providers as role models for healthy eating and physical activity behaviours

Objective

Latinos are the largest and most rapidly growing minority population group in the USA and are disproportionally affected by obesity and related chronic diseases. Child care providers likely influence the eating and physical activity behaviours of children in their care, and therefore are important targets for interventions designed to prevent childhood obesity. Nonetheless, there is a paucity of research examining the behaviours of family child care home (FCCH) providers and whether they model healthy eating and physical activity behaviours. Therefore, this study explored Latino FCCH providers' beliefs and practices related to healthy eating, physical activity and sedentary behaviours, and how they view their ability to serve as role models for these behaviours for young children in their care.

Methods

This is a qualitative study consisting of six focus groups conducted in Spanish with a sample of 44 state-licensed Latino FCCH providers in the state of Massachusetts. Translated transcripts were analysed using thematic analyses to identify meaningful patterns.

Results

Analyses revealed that Latino FCCH providers have positive beliefs and attitudes about the importance of healthy eating and physical activity for children in their care, but personally struggle with these same behaviours and with maintaining a healthy weight status. The ability of Latino FCCH providers to model healthy eating and physical activity may be limited by their low self-efficacy in their ability to be physically active, eat a healthy diet and maintain a healthy weight.

Conclusions

Interventions designed to improve healthy eating and physical activity behaviours of children enrolled in FCCHs should address providers' own health behaviours as well as their modelling of these health behaviours. Future research can build on the findings of this qualitative study by quantifying Latino FCCH providers' eating and physical activity behaviours, and determining how these behaviours influence behaviours and health outcomes of children in their care.

http://ift.tt/2ABfLUH

Involvement of people with dementia in making decisions about their lives: a qualitative study that appraises shared decision-making concerning daycare

Objective

To explore how people with dementia, their informal caregivers and their professionals participate in decision making about daycare and to develop a typology of participation trajectories.

Design

A qualitative study with a prospective, multiperspective design, based on 244 semistructured interviews, conducted during three interview rounds over the course of a year. Analysis was by means of content analysis and typology construction.

Setting

Community settings and nursing homes in the Netherlands.

Participants

19 people with dementia, 36 of their informal caregivers and 38 of their professionals (including nurses, daycare employees and case managers).

Results

The participants' responses related to three critical points in the decision-making trajectory about daycare: (1) the initial positive or negative expectations of daycare; (2) negotiation about trying out daycare by promoting, resisting or attuning to others; and (3) trying daycare, which resulted in positive or negative reactions from people with dementia and led to a decision. The ways in which care networks proceeded through these three critical points resulted in a typology of participation trajectories, including (1) working together positively toward daycare, (2) bringing conflicting perspectives together toward trying daycare and (3) not reaching commitment to try daycare.

Conclusion

Shared decision making with people with dementia is possible and requires and adapted process of decision making. Our results show that initial preferences based on information alone may change when people with dementia experience daycare. It is important to have a try-out period so that people with dementia can experience daycare without having to decide whether to continue it. Whereas shared decision making in general aims at moving from initial preferences to informed preferences, professionals should focus more on moving from initial preferences to experienced preferences for people with dementia. Professionals can play a crucial role in facilitating the possibilities for a try-out period.

http://ift.tt/2AzrYJF

Psychological, behavioural and physiological effects of three long-acting reversible contraception (LARC) methods: protocol for an ancillary study of the ECHO randomised trial

Introduction

This is the protocol for an ancillary study to the multicentre Evidence for Contraceptive Options and HIV Outcomes (ECHO) Trial, a three-arm randomised trial comparing the effects of depot medroxyprogesterone acetate (DMPA), the levonorgestrel (LNG) implant and the copper intrauterine device (IUD) on HIV incidence (NCT02550067 pre-results). The ancillary study will compare other non-contraceptive effects of these three long-acting, reversible contraceptions about which there is little existing comparative evidence.

Methods and analysis

Women randomised to IUD, DMPA and LNG implant (1:1:1) at one of the ECHO trial sites will be asked to participate in the ancillary study at the 1-month follow-up visit. Research staff will interview women that consent to participate at the 3-month follow-up visit. Primary outcomes are depression, sexual dysfunction and menstrual disturbances. The Beck Depression Inventory will be used to assess depression and the Arizona Sexual Experiences Scale to assess sexual dysfunction. Participants will also be asked to prospectively complete a 28-day symptom diary. The required sample size is 522 participants. Depression scores will be analysed as continuous and categorical variables. Analysis will be by intention to treat.

Ethics and dissemination

The ancillary study protocol received ethical approval from the University of the Witwatersrand Committee for Research on Human Subjects on 17 February 2016 (reference no. 14112). The results will be disseminated in a peer-reviewed open-access journal.

Trial registration number

PACTR201706001651380.

http://ift.tt/2i9fxxt

Improving best practise for patients receiving hospital discharge letters: a realist review protocol

Introduction

Discharge documents are important for transferring information from hospitals to the referring clinician; in the UK and many countries, this is often the patient's general practitioner or family physician. However, patients may or may not receive their discharge letters, and whether patients should routinely receive discharge letters remains unclear.

Methods and analysis

The review will consolidate evidence on patients receiving discharge letters through the theory-driven approach of a realist review.

The review will be conducted systematically and seek to explain how, why, for whom and in what contexts does this practice 'work'. The review will specifically explore whether there are benefits of this practice and if so what are the important contexts for triggering the mechanisms associated with these outcome benefits. Negative effects will also be considered.

Several steps will occur: devising initial rough programme theory, searching the evidence, selecting relevant documents, extracting data, synthesising and finally programme theory refinement. As the process is viewed as iterative, this cycle of steps may be repeated as many times as is necessary to reach theoretical saturation and may not be linear.

The initial programme theory will be tested and refined throughout the review process and by stakeholder involvement of National Health Service (NHS) policy makers, practitioners and service users.

Ethics and dissemination

Formal ethical review is not required. The resulting programme theory is anticipated to explain how the intervention of patients receiving written discharge communication may work in practice, for whom and in what contexts; this will inform best practice of patients receiving discharge communication. The review findings will be disseminated in a peer-reviewed journal and presentations and discussions with relevant organisations and stakeholders. While the review will be from the perspective of the UK NHS, its findings should be relevant to other healthcare systems.

PROSPERO registration number

CRD42017069863.

http://ift.tt/2i9Oe67

National citation patterns of NEJM, The Lancet, JAMA and The BMJ in the lay press: a quantitative content analysis

Objectives

To analyse the total number of newspaper articles citing the four leading general medical journals and to describe national citation patterns.

Design

Quantitative content analysis.

Setting/sample

Full text of 22 general newspapers in 14 countries over the period 2008–2015, collected from LexisNexis. The 14 countries have been categorised into four regions: the USA, the UK, Western World (European countries other than the UK, and Australia, New Zealand and Canada) and Rest of the World (other countries).

Main outcome measure

Press citations of four medical journals (two American: NEJM and JAMA; and two British: The Lancet and The BMJ) in 22 newspapers.

Results

British and American newspapers cited some of the four analysed medical journals about three times a week in 2008–2015 (weekly mean 3.2 and 2.7 citations, respectively); the newspapers from other Western countries did so about once a week (weekly mean 1.1), and those from the Rest of the World cited them about once a month (monthly mean 1.1). The New York Times cited above all other newspapers (weekly mean 4.7). The analysis showed the existence of three national citation patterns in the daily press: American newspapers cited mostly American journals (70.0% of citations), British newspapers cited mostly British journals (86.5%) and the rest of the analysed press cited more British journals than American ones. The Lancet was the most cited journal in the press of almost all Western countries outside the USA and the UK. Multivariate correspondence analysis confirmed the national patterns and showed that over 85% of the citation data variability is retained in just one single new variable: the national dimension.

Conclusion

British and American newspapers are the ones that cite the four analysed medical journals more often, showing a domestic preference for their respective national journals; non-British and non-American newspapers show a common international citation pattern.

http://ift.tt/2i8xFYg

Reading Emotion From Mouse Cursor Motions: Affective Computing Approach

Abstract

Affective computing research has advanced emotion recognition systems using facial expressions, voices, gaits, and physiological signals, yet these methods are often impractical. This study integrates mouse cursor motion analysis into affective computing and investigates the idea that movements of the computer cursor can provide information about emotion of the computer user. We extracted 16–26 trajectory features during a choice-reaching task and examined the link between emotion and cursor motions. Participants were induced for positive or negative emotions by music, film clips, or emotional pictures, and they indicated their emotions with questionnaires. Our 10-fold cross-validation analysis shows that statistical models formed from "known" participants (training data) could predict nearly 10%–20% of the variance of positive affect and attentiveness ratings of "unknown" participants, suggesting that cursor movement patterns such as the area under curve and direction change help infer emotions of computer users.

http://ift.tt/2hv3Y6r

Models of Chinese Reading: Review and Analysis

Abstract

Our understanding of the cognitive processes involved in reading has been advanced by computational models that simulate those processes (e.g., see Reichle, 2015). Unfortunately, most of these models have been developed to explain the reading of English and other alphabetic languages, with relatively fewer efforts to examine whether or not the assumptions of these models also explain what has been learned from other languages and, in particular, non-alphabetic writing systems like Chinese (e.g., see Li, Zang, Liversedge, & Pollatsek, 2015). In this article, we will review those computational models that have been developed to explain the reading of Chinese, with the goal of comparing their theoretical assumptions to those of models that explain the reading of English. Our analysis indicates that there are both points of convergence and divergence between the theoretical assumptions of Chinese versus English models, suggesting that the cognitive systems supporting reading may be differentially influenced by features of the languages and/or writing systems, or that certain theoretical assumptions developed to explain the reading of one language might be adapted to explain the reading of others.

http://ift.tt/2jpUsT2

Neurosyphilis is an easily missed cause of encephalopathy [Letters]

http://ift.tt/2jlGiSI

Validation of the Ottawa Subarachnoid Hemorrhage Rule in patients with acute headache [Research]

BACKGROUND:

We previously derived the Ottawa Subarachnoid Hemorrhage Rule to identify subarachnoid hemorrhage (SAH) in patients with acute headache. Our objective was to validate the rule in a new cohort of consecutive patients who visited an emergency department.

METHODS:

We conducted a multicentre prospective cohort study at 6 university-affiliated tertiary-care hospital emergency departments in Canada from January 2010 to January 2014. We included alert, neurologically intact adult patients with a headache peaking within 1 hour of onset. Treating physicians in the emergency department explicitly scored the rule before investigations were started. We defined subarachnoid hemorrhage as detection of any of the following: subarachnoid blood visible upon computed tomography of the head (from the final report by the local radiologist); xanthochromia in the cerebrospinal fluid (by visual inspection); or the presence of erythrocytes (> 1 x 10⁶/L) in the final tube of cerebrospinal fluid, with an aneurysm or arteriovenous malformation visible upon cerebral angiography. We calculated sensitivity and specificity of the Ottawa SAH Rule for detecting or ruling out subarachnoid hemorrhage.

RESULTS:

Treating physicians enrolled 1153 of 1743 (66.2%) potentially eligible patients, including 67 with subarachnoid hemorrhage. The Ottawa SAH Rule had 100% sensitivity (95% confidence interval [CI] 94.6%–100%) with a specificity of 13.6% (95% CI 13.1%–15.8%), whereas neuroimaging rates remained similar (about 87%).

INTERPRETATION:

We found that the Ottawa SAH Rule was sensitive for identifying subarachnoid hemorrhage in otherwise alert and neurologically intact patients. We believe that the Ottawa SAH Rule can be used to rule out this serious diagnosis, thereby decreasing the number of cases missed while constraining rates of neuroimaging.

http://ift.tt/2hunEaX

Delivering more equitable primary health care in Northern Canada [Commentary]

http://ift.tt/2jkvZ19

Diagnosis and management of low-back pain in primary care [Review]

http://ift.tt/2huYeJV

Gairdner recipient improved stroke treatment globally [News]

http://ift.tt/2jp6iwJ

Autosomal dominant polycystic kidney disease [Practice]

http://ift.tt/2hubP4m

Fish processing and human infection [Letters]

http://ift.tt/2huTunW

Dermal leishmaniasis in a 25-year-old Syrian refugee [Practice]

http://ift.tt/2jmEFUP

Gairdner award winner recognized for sharing his techniques [News]

http://ift.tt/2hyrJKZ

A feminist in the academy [Humanities]

http://ift.tt/2jmEx7N

Electronic health records contributing to physician burnout [News]

http://ift.tt/2hubvma

Restrictive or Liberal Red-Cell Transfusion for Cardiac Surgery

The avoidance of unnecessary blood transfusion is a high priority; therefore, determining safe thresholds for transfusion is imperative. Among the highest recipients of red-cell transfusion are patients undergoing cardiac surgery, with a substantial proportion of the total blood supply used by this…

http://ift.tt/2i8BkFz

Molecular testing on endobronchial ultrasound (EBUS) fine needle aspirates (FNA): Impact of triage

Abstract

Background

Endobronchial ultrasound (EBUS)-guided fine needle aspiration (FNA) is performed to diagnose and stage lung cancer. Multiple studies have described the value of Rapid On-Site Evaluation (ROSE), but often the emphasis is upon diagnosis than adequacy for molecular testing (MT). The aim was to identify variable(s), especially cytology-related, that can improve MT.

Methods

A search for EBUS-FNAs with ROSE was conducted for lung adenocarcinomas or when this diagnosis could not be excluded. All such cases underwent reflex MT on cell blocks. The impact of cytology-related variables [i.e., number of pass(es), dedicated pass(es) directly into media, cytotechnologist (CT), laboratory technician (LT) and triage with 1 or >1 cytologist] was evaluated. The latter category was divided into Group A [ROSE, triage and slide preparation by cytopathologist (CP) and CT at start of the procedure] and Group B (ROSE only by CT or by CT/CP after start of procedure; triage and slide preparation by CT or clinical staff). The impact of all these variables on MT was assessed.

Results

A total of 100 cases were identified, and 79 had sufficient tissue for MT. Of all variables evaluated, MT was positively affected by performing a direct dedicated pass (P = 0.013) and ROSE by Group A (P = 0.033).

Conclusions

ROSE with appropriate triage, including performing a dedicated pass and proper slide preparation, improves MT, and this is enhanced by having >1 cytologist at the start of the procedure. In the era of personalized medicine, "adequate" should denote sufficient tissue for diagnosis and MT.

http://ift.tt/2AzwlEu

Cytologic findings of an adult rhabdomyoma in the parapharyngeal space: A report of a case and review of the literature

Adult extracardiac rhabdomyomas are rare benign mesenchymal tumor arising from skeletal muscle. While they are often located in the larynx and pharynx, the incidence in the parapharyngeal area is extremely rare with only 1 documented cytology case report to date. We report a case of an adult extracardiac rhabdomyoma in the parapharyngeal space diagnosed cytologically with subsequent histologic confirmation. The patient is a 57-year-old man with history of weight loss, hematuria, dysphagia, and airway encroachment. Computerized tomography of his abdomen showed a large left renal mass. While the patient was in the operating room for the resection of his renal mass, a fine-needle aspiration from left the parapharyngeal mass was performed. The smears showed uniform bland polygonal cells with abundant eosinophilic cytoplasm and peripherally located nuclei. Immunohistochemical stains performed on the cell block showed the tumor cells were desmin positive and negative for S-100 and PAX-8, supporting the diagnosis of an adult rhabdomyoma. Subsequent resection of the mass confirmed the diagnosis of an adult extracardiac rhabdomyoma.

http://ift.tt/2i9keai

Ischemia reperfusion injury in aged livers - the energy metabolism, inflammatory response and autophagy

Abstract Due to the lack of adequate organs, the number of patients with end-stage liver diseases, acute liver failure or hepatic malignancies waiting for liver transplantation is constantly increasing. Accepting aged liver grafts is one of the strategies expanding the donor pool to ease the discrepancy between the growing demand and the limited supply of donor organs. However, recipients of organs from old donors may show an increased post-transplantation morbidity and mortality due to enhanced ischemia reperfusion injury. Energy metabolism, inflammatory response and autophagy are three critical processes which are involved in the ageing progress as well as in hepatic ischemia reperfusion injury. Compared to young liver grafts, impairment of energy metabolism in aged liver grafts leads to lower ATP production and an enhanced generation of free radicals, both aggravating the inflammatory response. The aggravated inflammatory response determines the extent of hepatic ischemia reperfusion injury and augments the liver damage. Autophagy protects cells by removal of damaged organelles including dysfunctional mitochondria, a process impaired in ageing and involved in ischemia reperfusion related apoptotic cell death. Furthermore, autophagic degradation of cellular compounds relieves intracellular ATP level for the energy depressed cells. Strategies targeting the mechanisms involved in energy metabolism, inflammatory response and autophagy might be especially useful to prevent the increased risk for ischemia reperfusion injury in aged livers after major hepatic surgery. CORRESPONDING AUTHOR: Uta Dahmen, M.D., Experimental Transplantation Surgery, Department of General, Visceral, and Vascular Surgery, Friedrich Schiller University of Jena, Drackendorfer Straße 1, 07747 Jena, Germany. Telephone: +49-03641-932 5350; FAX: +49-03641-932 5352; E-mail: Uta.Dahmen@med.uni-jena.de AUTHORSHIP Kan C. (Chunyi.Kan@med.uni-jena.de) contributed to conception and design as well as participated in writing the article; Ungelenk L. (Luisa.Ungelenk@med.uni-jena.de) participated in the critical revision of the article; Lupp A. (Amelie.Lupp@med.uni-jena.de) participated in the critical revision of the article; Dirsch O. (Olaf.Dirsch@gmail.com) contributed to conception, design and obtain funding as well as participated in the critical revision of the article. Dahmen U. (Uta.Dahmen@med.uni-jena.de) contributed to conception, design and obtain funding as well as participated in the critical revision of the article. DISCLOSURE The authors disclose no conflicts of interest. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

http://ift.tt/2huP5Bi

A patient with acquired factor X deficiency and metastatic transitional cell carcinoma of the bladder: is there a link between metastasis and factor deficiency in solid tumors?

http://ift.tt/2iRGPbf

Is Lipidomic the Answer to the Search of a Biomarker for Organ Preservation Protocol in Head and Neck Squamous Cell Carcinoma?

Abstract

In the last decade organ preservation protocols based on chemoradiotherapy (CRT) has been showing the possibility of preserving function without jeopardizing survival for locally advanced head and neck squamous cell carcinoma (HNSCC). Still, only a percentage of the patients will benefit from this approach and, to date, no biomarkers are known to correctly predict these patients. More recently, modern mass spectrometry method has been used to determine metabolic profiles, and lipidomics, in particular, emerged as a new field of study in oncology and other diseases. This study aimed to analyze the lipid profile on saliva from patients undergoing to a prospective, single center, open-label, non-randomized phase II trial for organ preservation on HNSCC. The lipid analysis was performed using matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF-MS). Multivariate statistical analyses based on principal component analysis and orthogonal partial least square-discriminant analysis were applied to MALDI-TOF-MS data to visualize differences between the lipid profiles and identify potential biomarkers. The results assisted on distinguishing complete responders from non-responders to the treatment protocol. In conclusion, we demonstrated that a group of lipids is differentially abundant in saliva from HNSCC patients submitted to an organ preservation protocol, being able to differentiate responders from non-responders. These results suggest the potential use of lipid biomarkers to identify patients who may benefit from this treatment. Also, we showed that saliva testing might be routinely used in clinical practice, for being a non-invasive alternative to blood testing, besides inexpensive and easy to obtain.

http://ift.tt/2zyr1og

Restrictive or Liberal Red-Cell Transfusion for Cardiac Surgery

The avoidance of unnecessary blood transfusion is a high priority; therefore, determining safe thresholds for transfusion is imperative. Among the highest recipients of red-cell transfusion are patients undergoing cardiac surgery, with a substantial proportion of the total blood supply used by this…

http://ift.tt/2i8BkFz

Nutritional value of raw Canavalia ensiformis and its utilization as partial replacement for soybean meal in the diet of Clarias gariepinus (Burchell, 1822) fingerlings

Abstract

The nutritional value of raw Jack bean meal (Canavalia ensiformis) as a partial substitute for soybeans meal was investigated in this study. Preliminary investigation on nutrient composition revealed that lysine, histidine, and phenylalanine were significantly higher in C. ensiformis seed meal compared to soybean meal. However, crude protein and other essential amino acids were significantly lower. Feeding trial was then conducted to investigate the effect of replacing about 40% soybeans meal (at 58.8% inclusion) with C. ensiformis in the diet of Clarias gariepinus. The result obtained after 56 days revealed that fingerlings could tolerate up to 20% replacement without significant effect on growth and nutrient utilization. Beyond this, growth was significantly reduced. Survivals of the fish also follow a similar trend as stated above. It was concluded that dietary inclusion of raw C. ensiform meal should not be beyond 11% (or 20% replacement for soybeans meal included at 58.8%) in the diet of C. gariepinus.

This study shows that Canavalia ensiformis can tolerate up to 20% replacement without significant effect on growth and nutrient utilization of African catfish Clarias gariepinus.

http://ift.tt/2zwyhkv

Antioxidant, Antiglycation, and Hypoglycaemic Effect of Seriphium plumosum Crude Plant Extracts

Diabetes is a severely debilitating metabolic disorder characterised by chronic hyperglycaemia. Traditional medicinal plants provide an important avenue for the development of novel antidiabetic agents. The antidiabetic potential of the methanol, acetone, and hexane extracts of S. plumosum was assessed using different parameters. These included secondary metabolite quantification, hypoglycaemic, cytotoxic effects, and GLUT4 translocation augmentation on C2C12 cells. The methanol extract contained the highest amount of total phenolic and flavonoid compounds and showed enhanced antioxidant activity. The methanol extracts had the best DPPH scavenging (EC50 = 0.72 mg/ml) and ferric reducing powers (EC50 = 2.31 mg/ml). The hexane extract resulted in the highest glucose uptake activity of 35, 77% with respect to all other treatments after a 6-hour exposure period. Immunocytochemistry technique further revealed that the increased glucose utilisation may be due to increased membrane fused GLUT4 molecules in C2C12 cells. The hexane extract was also shown to upregulate the phosphorylation of p70 S6 kinase and Akt1/2. The study highlights a probable insulin-mimetic activity of the hexane extract via the augmentation of Akt1/2 phosphorylation which is involved in the GLUT4 translocation pathway. Furthermore, the study represents the first report on the cytotoxic effect, GLUT4 translocation, and glucose uptake potential of S. plumosum.

http://ift.tt/2iRJMIz

Ethnopharmacological Evaluation of Breu Essential Oils from Protium Species Administered by Inhalation

Background. Breu is an aromatic oleoresin which has been used by Amazonian traditional communities as a remedy for headaches and migraines by burning and inhaling the smoke produced during its combustion. This study evaluated the antinociceptive and sedative activities of formulations containing breu essential oils administered by inhalation. Methods. Five different formulations (A–E) containing breu essential oils were evaluated for their sedative and antinociceptive activities in mice. They were delivered for 20 minutes using an inhalation chamber coupled with a nebulizer and the air inside was collected by static headspace and analyzed by GC-FID. Results. All nebulized formulations had similar chemical compositions and major compounds as the original essential oils. None of them resulted in significant increase in response time during the hot plate test. In the formalin test, Formulation E showed a significant inhibition of licking responses in the early (46.8%) and late (60.2%) phases. Formulation B was effective (36.9%) in the first phase and Formulation D (37.9%) in the second. None of the formulations presented sedative effects. Conclusion. Breu essential oils, when inhaled, may present antinociceptive and anti-inflammatory properties without sedation. Additionally, nebulization proved to be an efficient method for administration of formulations containing these essential oils.

http://ift.tt/2iQCp4k

Patent processus vaginalis as a conduit for tumoral seeding: a rare presentation of port site metastasis

http://ift.tt/2ABwFCy

Impact of web-based clinical practice guidelines on paediatric fracture clinics

Background

In an effort to standardize management and reduce over-treatment of uncomplicated paediatric fractures, the Victorian Pediatric Orthopaedic Network and the Royal Children's Hospital, Melbourne, created publically available web-based paediatric fracture pathways. The aim of this study was to determine the impact of web-based fracture pathways on the clinic volume at a tertiary-care paediatric fracture clinic.

Methods

A comparative retrospective review was performed at a large, urban, tertiary-care children's hospital. Fracture clinic data from two 12-week periods before and after implementation of the fracture pathways were compared. For each study period, data collected included: total number of emergency department visits, number of fracture clinic visits, number of fracture clinic visits for patients that presented with upper extremity fractures for which web-based fracture pathways were available, number of radiology department visits for X-rays, and number of fracture clinic visits for patients requiring orthopaedic intervention in the operating room (closed or open reductions).

Results

The number of fracture clinic visits for patients with upper extremity fractures decreased 12% post-pathway implementation, from 954 visits to 842 visits. The number of radiology department visits for patients with upper extremity fractures decreased 24% post-pathway implementation, from 714 to 544 visits.

Conclusion

The implementation of web-based fracture pathways for upper extremity paediatric fractures was associated with a decrease in clinic resource utilization at a tertiary-care children's hospital.

http://ift.tt/2i8aLQQ

How to do breast reconstruction using free flaps with short pedicles: a stepwise technique for easier, safer anastomoses

http://ift.tt/2ABwAie

Out of sight, out of mind: perforated distal stump appendicitis

http://ift.tt/2i8LkP3

Quinke's triad: haemobilia secondary to hepatic artery aneurysm

http://ift.tt/2ABwuHo

Malting and fermentation effects on antinutritional components and functional characteristics of sorghum flour

Abstract

The research was aimed to observe the effect of malting and fermentation on antinutritional component and functional characteristics of sorghum flour. For whole sorghum flour, cleaned sorghum grain was milled to pass through 40 mesh sieve. For malting, cleaned sorghum grain was steeped in 0.2% calcium hydroxide solution for 24 hr and then germinated for 48 hr at 90% RH and 27 ± 2°C. Sprout was removed, dried in hot air oven at 50 ± 2°C for 24 hr and milled to pass through 40 mesh sieve. For fermented sorghum flour, 13.3 mg% diastase and 2 mg % pepsin (on the basis of whole sorghum flour weight) was added to cooked (88 ± 2°C) sorghum flour and left for 1 hr. Lactobacillus plantarum (10⁷ cfu/g) was inoculated and incubated at temperature 30 ± 2°C for 48 hr. The fermented slurry was dried at 50 ± 2°C in hot air oven for 24 hr and milled to pass through 40 mesh sieve. The lower yield of sorghum flour was obtained compared to whole and malted sorghum flour. Germination of sorghum reduced phytate, tannin, and oxalate by 40%, 16.12% and 49.1%, respectively, whereas fermentation of sorghum flour reduced above by 77%, 96.7% and 67.85%, respectively. There was no significant change in hydrogen cyanide in malted sorghum flour compared to whole sorghum flour, but fermentation of sorghum flour reduced hydrogen cyanide by 52.3%. Bulk density and viscosity was significantly reduced by the malting and fermentation, whereas water absorption capacity and oil absorption capacity was markedly increased by the malting and fermentation. Fermented flour was good due to reduced ANF and improved functional property despite of lower yield.

The research aimed to study the effect of malting and fermentation on antinutritional factors (ANF) and functional property of sorghum flour. Fermented flour was good due to reduced ANF and improved functional property despite of lower yield.

http://ift.tt/2jntE5D

Binding of volatile aroma compounds to can linings with different polymeric characteristics

Abstract

Flavor compounds have been shown to interact with packaging materials either by scalping, the movement of flavorings from the food product to the package, or by flavor release, movement of flavorings from the package to the food. Work has elucidated the parameters important for the scalping of flavor compounds to polyolefin packaging materials, but very little work has been conducted examining the scalping of flavor compounds by can lining materials. Can linings composed of three different polymers, polyolefin, acrylic, epoxy, were studied for binding of volatile flavor compounds (octanal, nonanal, decanal, eugenol, d-limonene) at room temperature over a 2-week period. Solid phase microextraction (SPME) was used with gas chromatography mass spectrometry to identify and quantify volatile compounds. Flavor compounds were studied at concentrations around 4–1,000 ppb. Fourier transform infrared spectroscopy was used to verify can lining polymer chemistry. Almost complete binding of all five of the volatile compounds studied was observed over 9–14 days at room temperature for each of the can lining chemistries. The number of time data points limited our ability to determine the order and rate constants of binding. This model system appears to be a valuable for investigating flavor binding of polymeric can lining materials.

Binding of flavor compounds with polymeric can lining materials was studied. Compounds were completely bound by can lining polymers within 9–14 days. All polymers examined (polyolefin, epoxy, acrylic) bound flavors.

http://ift.tt/2htW7X9

Effects of Electrostatic Field on Osteoblast Cells for Bone Regeneration Applications

Many external stimulations have been shown to promote bone regeneration. The effects of an alternating current (AC) electrostatic field, one of external stimulations, generated from a device with high voltage and low current output on human osteoblastic cell line have been investigated in this study. We investigated how human osteoblasts responded to an AC electrostatic field, and the output parameters were set as 1 kV and 160 μA. Our results showed that, under such condition, the AC electrostatic field had a downregulation effect on the production ability of alkaline phosphatase and type 1 collagen expression. However, the expression of osteocalcin gene was elevated on the end of EFID treatment suggesting that AC electrostatic field might be a potential stimulation for accelerating the differentiation of osteoblastic cells.

http://ift.tt/2iSkVV9

Protective Effects of Genistein against Mono-(2-ethylhexyl) Phthalate-Induced Oxidative Damage in Prepubertal Sertoli Cells

Mono-(2-ethylhexyl) phthalate (MEHP) and genistein are two of the most prevalent endocrine-disrupting chemicals (EDCs) that present in the environment and food. However, how these two EDCs would affect prepubertal Sertoli cells development was rarely studied. In this study, primary prepubertal Sertoli cells were isolated from 22-day-old Sprague Dawley rats and exposed to MEHP at 1 μmol/L, 10 μmol/L, and 100 μmol/L (M1, M10, and M100), genistein at 10 μmol/L (G), and their combination (G + M1, G + M10, and G + M100). Cell proliferation inhibition rate, apoptosis and necrosis rate, and cellular redox state were evaluated. Our results revealed that MEHP could significantly increase cell proliferation inhibition rate, apoptosis rate, necrosis rate, and intracellular reactive oxidative species level. However, coadministration of genistein could partially alleviate MEHP-induced prepubertal Sertoli cells oxidative injuries via enhancement of testicular antioxidative enzymes activities and upregulation of Nrf2 and HO-1, indicating that genistein could partially attenuate MEHP-induced prepubertal Sertoli cells damage through antioxidative action and may have promising future on its curative role for attenuating other EDCs-induced reproductive disorders.

http://ift.tt/2zF26wM

Clarion call for histopathological clot analysis in “cryptogenic” ischemic stroke: implications for diagnosis and treatment

Abstract

Diagnosis, treatment, and secondary management of cryptogenic stroke patients pose a formidable challenge. The scenario is further complicated in patients with native and prosthetic valvular heart disease. We present a case study of a 36-year-old man who received intravenous thrombolysis (IV-tPA) and endovascular thrombectomy (EVT) for presumed "cryptogenic" complete middle cerebral artery infarction who made a surprisingly excellent clinical recovery despite poor baseline and postintervention neuroimaging. Retrospective gram stain of his clot confirmed a diagnosis of infective endocarditis. This raises an important issue regarding need for more routine histopathological analysis of clot retrieved after EVT in "cryptogenic" stroke patients particularly those with valvular heart disease.

http://ift.tt/2zTt7zs

Everolimus for treatment of tuberous sclerosis complex-associated neuropsychiatric disorders

Abstract

Objective

To evaluate if short-term treatment with everolimus was safe and could improve neurocognition and behavior in children with TSC.

Methods

This was a prospective, double-blind randomized, placebo-controlled two-center phase II study. Participants diagnosed with TSC and age 6–21 years were treated with 4.5 mg/m² per day of oral everolimus (n = 32) or matching placebo (n = 15) taken once daily for 6 months. For efficacy, a comprehensive neurocognitive and behavioral evaluation battery was performed at baseline, 3 months, and 6 months. For safety, adverse events recorded continuously via patient diary were categorized and graded per NCI Common Toxicity Criteria for Adverse Events, version 3.0 (CTCAE 3.0). Analyses were performed on the intention-to-treat population (n = 47).

Results

Nearly all assessment measures failed to demonstrate significant differences between the two groups at the end of 6 months. Only one measure each of executive function (Cambridge Neuropsychological Test Automated Battery Stockings of Cambridge) favoring placebo (P = 0.025) and social cognition (Social Responsiveness Scale Social Cognition Subscale) favoring everolimus (P = 0.011) was observed. A total of 473 adverse events (AE) were reported. The average number of total AE per subject was similar for both placebo and everolimus. Most were mild or moderate in severity and serious AE were rare.

Interpretation

While safe, oral everolimus administered once daily for 6 months did not significantly improve neurocognitive functioning or behavior in children with TSC.

http://ift.tt/2zy2Mqe

Issue Information

http://ift.tt/2zRNbC6

In situ production of active vitamin B12 in cereal matrices using Propionibacterium freudenreichii

Abstract

The in situ production of active vitamin B12 was investigated in aqueous cereal-based matrices with three strains of food-grade Propionibacterium freudenreichii. Matrices prepared from malted barley flour (33% w/v; BM), barley flour (6%; BF), and wheat aleurone (15%; AM) were fermented. The effect of cobalt and the lower ligand 5,6-dimethylbenzimidazole (DMBI) or its natural precursors (riboflavin and nicotinamide) on active B12 production was evaluated. Active B12 production was confirmed by UHPLC–UV–MS analysis. A B12 content of 12–37 μg·kg⁻¹ was produced in BM; this content increased 10-fold with cobalt and reached 940–1,480 μg·kg⁻¹ with both cobalt and DMBI. With riboflavin and nicotinamide, B12 production in cobalt-supplemented BM increased to 712 μg·kg⁻¹. Approximately, 10 μg·kg⁻¹ was achieved in BF and AM and was increased to 80 μg·kg⁻¹ in BF and 260 μg·kg⁻¹ in AM with cobalt and DMBI. The UHPLC and microbiological assay (MBA) results agreed when both cobalt and DMBI or riboflavin and nicotinamide were supplemented. However, MBA gave ca. 20%–40% higher results in BM and AM supplemented with cobalt, indicating the presence of human inactive analogues, such as pseudovitamin B12. This study demonstrates that cereal products can be naturally fortified with active B12 to a nutritionally relevant level by fermenting with P. freudenreichii.

This study demonstrates that plant-based foods can naturally be fortified with active vitamin B12 at a nutritionally relevant level by fermentation, using food-grade microorganisms.

http://ift.tt/2AEpcUc

Visual evaluation of sliced Italian salami by image analysis

Abstract

Visual inspection is an important part of quality control not only for manufacturers but also for retailers and consumers. The object of this investigation was to determine fat content in sliced salami by means of image analysis. The image analysis procedure is applied to digital images of sliced Italian salami produced in 16 different salami factories (A–P). The image analysis method described in this work is nondestructive and the necessary equipment is cheap. It extracts directly interpretable parameters of fat particle morphology (e.g., area, roundness) and number of fat particles from 15 digital images for each sample (A–P). The correlations between the fat features extracted from the images with the chemical fat content measured on the samples were also studied. Good relationships were found between the fat particle characteristics measured by image analysis procedure and the percentage of chemically extractable fat by correlation (R²=0.75) and principal component analysis.

Image Analysis (IA) as method to characterize typical Italian salami. Image Analysis protocol for quantification of fat content and distribution in salami. PCA on the chemical and IA parameters pointed out the potential of technique.

http://ift.tt/2yvRZJe

Pomegranate seed clustering by machine vision

Abstract

Application of new procedures for reliable and fast recognition and classification of seeds in the agricultural industry is very important. Recent advances in computer image analysis made applicable the approach of automated quantitative analysis in order to group cultivars according to minor differences in seed traits that would be indiscernible in ocular inspection. In this work, in order to cluster 20 cultivars of pomegranate seed, nine image features and 21 physicochemical properties of them were extracted. The aim of this study was to evaluate if the information extracted from image of pomegranate seeds could be used instead of time-consuming and partly expensive experiments of measuring their physicochemical properties. After data reduction with principal component analysis (PCA), different kinds of overlapping between these two types of data were controlled. The results showed that clustering base on all variables of image features contain more similar cultivars with clustering base on physicochemical properties (66.67% for cluster 1, 75% for cluster 2, and 50% for cluster 3). Therefore, by applying image analysis technique, the seeds almost were placed in different pomegranate clusters without spending time and additional costs.

Application of new procedures for reliable and fast recognition and classification of seeds. Automated quantitative analysis in order to group cultivars according to minor differences in seed traits. Clustering of different cultivars of pomegranate seed. The information extracted from image of pomegranate seeds could be used instead of time-consuming and partly expensive experiments of measuring their physicochemical properties.

http://ift.tt/2ADvEuJ

Surveillance and diagnosis of zoonotic foodborne parasites

Abstract

Foodborne parasites are a source of human parasitic infection. Zoonotic infections of humans arise from a variety of domestic and wild animals, including sheep, goats, cattle, camels, horses, pigs, boars, bears, felines, canids, amphibians, reptiles, poultry, and aquatic animals such as fishes and shrimp. Therefore, the implementation of efficient, accessible, and controllable inspection policies for livestock, fisheries, slaughterhouses, and meat processing and packaging companies is highly recommended. In addition, more attention should be paid to the education of auditors from the quality control (QC) and assurance sectors, livestock breeders, the fishery sector, and meat inspection veterinarians in developing countries with high incidence of zoonotic parasitic infections. Furthermore, both the diagnosis of zoonotic parasitic infections by inexpensive, accessible, and reliable identification methods and the organization of effective control systems with sufficient supervision of product quality are other areas to which more attention should be paid. In this review, we present some examples of successful inspection policies and recent updates on present conventional, serologic, and molecular diagnostic methods for zoonotic foodborne parasites from both human infection and animal-derived foods.

Foodborne parasites can be transmitted from a variety of domestic and wild animals to human. Therefore, the implementation of efficient, accessible, and controllable inspection policies for livestock, fisheries, slaughterhouses, and meat processing and packaging companies is highly recommended. In addition, more attention should be paid to the education of auditors from the quality control (QC) and assurance sectors, livestock breeders, the fishery sector, and meat inspection veterinarians as well as designing novel cost-benefit diagnosis methods for detection of foodborne parasites such as molecular-based detection assays.

http://ift.tt/2yvSCT9

Effect of isolation techniques on the characteristics of pigeon pea (Cajanus cajan) protein isolates

Abstract

In this study, the effect of different isolation techniques on the isolated proteins from pigeon pea was investigated. Water, methanol, ammonium sulfate, and acetone were used for the precipitation of proteins from pigeon pea. Proximate composition, and antinutritional and functional properties of the pigeon pea flour and the isolated proteins were measured. Data generated were statistically analyzed. The proximate composition of the water-extracted protein isolate was moisture 8.30%, protein 91.83%, fat 0.25%, ash 0.05%, and crude fiber 0.05%. The methanol-extracted protein isolate composition was moisture 7.87%, protein 91.83%, fat 0.17%, and ash 0.13%, while crude fiber and carbohydrates were not detected. The composition of the ammonium sulfate-extracted protein isolate was moisture 7.73%, protein 91.73%, fat 0.36, ash 0.13%, and crude fiber 0.67%. The acetone-extracted protein isolate composition was moisture 8.03%, protein 91.50%, ash 0.67%, and fat 0.30%, but crude fiber and carbohydrates were not detected. The isolate precipitated with ammonium sulfate displayed the highest foaming capacity (37.63%) and foaming stability (55.75%). Isolates precipitated with methanol and acetone had the highest water absorption capacity (160%). Pigeon pea protein isolates extracted with methanol and ammonium sulfate had the highest oil absorption capacity of 145%. Protein isolates recovered through acetone and methanol had the highest emulsifying capacity of 2.23% and emulsifying stability of 91.47%, respectively. The proximate composition of the recovered protein isolates were of high purity. This shows the efficiency of the extraction techniques. The isolates had desirable solubility index. All the isolation techniques brought significant impact on the characteristics of the isolated pigeon pea protein.

Water, methanol, ammonium sulfate, and acetone were used for the precipitation of protein from pigeon pea. Proximate composition, and antinutritional and functional properties of the pigeon pea flour and the isolated proteins were measured. Data generated were statistically analyzed.

http://ift.tt/2ABpOdf

EMCrit Podcast 212 – Thoughts on Deliberate Practice and Expertise

My thoughts on the recent interview with Anders Ericcson

EMCrit by Scott Weingart.

http://ift.tt/2zRxk6y

Investigating antenatal nutrition education preferences in South-East Queensland, including Maori and Pasifika women

Publication date: Available online 12 November 2017
Source:Women and Birth
Author(s): Andrea Cruickshank, Helen E. Porteous, Michelle A. Palmer
BackgroundLittle is reported about the nutrition-related needs and preferences of women seeking maternity services, particularly Maori and Pasifika (M&P) women who have higher chronic disease rates in Queensland.AimNutrition-related knowledge, needs, behaviours and education preferences were compared between women of M&P ancestry and non-Maori and Pasifika women (NMP).MethodWomen (≥18 years) admitted to the postnatal ward were surveyed. Anthropometry, dietary quality, nutrition education preferences, country of birth and ancestry were collected. Analysis included chi-squared and t-tests.FindingsThe survey was completed by 399 eligible women. Country of birth data suggested 4% of respondents were Pasifika and failed to separately identify New Zealand Maori, whereas 18% of respondents (n=73) reported M&P ancestry. Descriptors were similar between groups (28±5 years; 91% any breastfeeding; 18% gestational diabetes mellitus; p>0.05). However M&P women were less often university educated (M&P:6(9%); NMP:71(22%), p<0.01) and more likely had >2 children (M&P: 30(54%); NMP:70(30%), p<0.01). M&P women reported heavier weight at conception (M&P:79.0±20.2kg, 29.2±7.5kg/m²; NMP:71.3±18.9kg, 26.3±6.5kg/m², p<0.01), and were more likely to report excess gestational weight gain (M&P:30(56%), NMP:96(36%), p<0.05). Most (>75%) women did not know their recommended weight gain. Many respondents reported inadequate intake of vegetables (95%), fruit (29%) and dairy (69%) during pregnancy. Two-fifths (38–41%) reported interest in perinatal nutrition education, with topics including healthy eating postpartum.DiscussionFindings enable targeted service delivery according to women's preferences.ConclusionCollecting ancestral and maternal data to facilitate the provision of appropriate nutrition education may be critical for achieving optimal maternal outcomes in Maori and Pasifika women.



http://ift.tt/2zBByOQ

Dissection of Human Retina and RPE-Choroid for Proteomic Analysis

The human retina is composed of functionally and molecularly distinct regions, including the fovea, macula, and peripheral retina. Here, we describe a method using punch biopsies and manual removal of tissue layers from a human eye to dissect and collect these distinct retinal regions for downstream proteomic analysis.

http://ift.tt/2i9WEdT

Advanced Confocal Microscopy Techniques to Study Protein-protein Interactions and Kinetics at DNA Lesions

Laser microirradiation is a useful tool for studies of DNA repair in living cells. A methodological approach for the use of UVA lasers to induce various DNA lesions is shown. We have optimized a method for local microirradiation that maintains the normal cell cycle; thus, irradiated cells proceed through mitosis.

http://ift.tt/2jkQlr8

Familial choreoathetosis due to novel heterozygous mutation in PDE10A

PDE10A encodes a dual cAMP-cGMP phosphodiesterase that is enriched in the medium spiny neurons of the corpus striatum in the brain and plays an important role in basal ganglia circuitry. Three unrelated patients with childhood onset chorea and striatal abnormalities on MRI brain with heterozygous de novo variants in PDE10A have been described previously. Two families with eight affected individuals with biallelic mutations in PDE10A have also been described previously. We report a family with multiple affected individuals with childhood onset chorea, striatal abnormalities, and a novel heterozygous mutation, c.1001T>G(p.F334C) in PDE10A which was identified by exome sequencing.

http://ift.tt/2AxYxHS

DOCK3-related neurodevelopmental syndrome: Biallelic intragenic deletion of DOCK3 in a boy with developmental delay and hypotonia

Dedicator of cytokinesis (DOCK) family are evolutionary conserved guanine nucleotide exchange factors (GEFs) for the Rho GTPases, Rac, and Cdc42. DOCK3 functions as a GEF for Rac1, and plays an important role in promoting neurite and axonal growth by stimulating actin dynamics and microtubule assembly pathways in the central nervous system. Here we report a boy with developmental delay, hypotonia, and ataxia due to biallelic DOCK3 deletion. Chromosomal single nucleotide polymorphism (SNP) microarray analysis detected a 170 kb homozygous deletion including exons 6–12 of the DOCK3 gene at 3p21.2. Symptoms of our proband resembles a phenotype of Dock3 knockout mice exhibiting sensorimotor impairments. Furthermore, our proband has clinical similarities with two siblings with compound heterozygous loss-of-function mutations of DOCK3 reported in [Helbig, Mroske, Moorthy, Sajan, and Velinov (); http://ift.tt/2AyB7SX]. Biallelic DOCK3 mutations cause a neurodevelopmental disorder characterized by unsteady gait, hypotonia, and developmental delay.

http://ift.tt/2i9uzDv

In reply to “Mast Cell Disorders in Ehlers–Danlos Syndrome”

http://ift.tt/2AxRdff

Expanding the phenotypic spectrum of TP63-related disorders including the first set of monozygotic twins

Individuals with Tumor Protein P63 (TP63)-related disorders are known to present with a range of phenotypic features, including ectrodactyly, ectodermal dysplasia, cleft lip/palate, Rapp-Hodgkin, Hay–Wells, and limb-mammary syndromes. We present six individuals from three families, including a set of monozygotic twins, with pathogenic TP63 variants who had novel clinical findings. The twins were discordant for cleft lip and palate, and the type of hand malformations, but concordant for choanal atresia, and bilateral volar nail. Both failed newborn screening for severe combined immunodeficiency (SCID) due to T-cell lymphopenia. The second family included three family members across two generations. Two of these three family members had orofacial clefting, but the remaining child had a laryngeal web and hydrocele with no clefting or hand anomalies, highlighting the variable expressivity in TP63-related disorders. The individual from the third family had unilateral cleft lip and palate, hydronephrosis, and bilateral volar nails. Together, these cases illustrate that: there is significant familial variability, including discordant major but concordant minor anomalies in the first ever reported set of molecularly confirmed monozygotic twins with pathogenic variants in TP63; pathogenic variants in TP63 should be considered in individuals with volar nail, which was previously only strongly associated with 4q34 deletion syndrome; and failed SCID newborn screening due to abnormal immune functioning may be part of the phenotypic spectrum of TP63-related disorders, as it was reported in one prior individual and two of the individuals in our case series.

http://ift.tt/2i7gar9

How chromosomal deletions can unmask recessive mutations? Deletions in 10q11.2 associated with CHAT or SLC18A3 mutations lead to congenital myasthenic syndrome

A congenital myasthenia was suspected in two unrelated children with very similar phenotypes including several episodes of severe dyspnea. Both children had a 10q11.2 deletion revealed by Single Nucleotide Polymorphisms array or by Next Generation Sequencing analysis. The deletion was inherited from the healthy mother in the first case. These deletions unmasked a recessive mutation at the same locus in both cases, but in two different genes: CHAT and SLC18A3.

http://ift.tt/2AxRcId

Co-occurring medical conditions in adults with Down syndrome: A systematic review toward the development of health care guidelines

Adults with Down syndrome (DS) represent a unique population who are in need of clinical guidelines to address their medical care. The United States Preventive Service Task Force (USPSTF) has developed criteria for prioritizing conditions of public health importance with the potential for providing screening recommendations to improve clinical care. The quality of existing evidence needed to inform clinical guidelines has not been previously reviewed. Using the National Library of Medicine (NLM) database PubMed, we first identified 18 peer reviewed articles that addressed co-occurring medical conditions in adults with DS. Those conditions discussed in over half of the articles were prioritized for further review. Second, we performed detailed literature searches on these specific conditions. To inform the search strategy and review process a series of key questions were formulated a priori. The quality of available evidence was then graded and knowledge gaps were identified. The number of participating adults and the design of clinical studies varied by condition and were often inadequate for answering all of our key questions. We provide data on thyroid disease, cervical spine disease, hearing impairment, overweight-obesity, sleep apnea, congenital heart disease, and osteopenia-osteoporosis. Minimal evidence demonstrates massive gaps in our clinical knowledge that compromises clinical decision-making and management of these medically complex individuals. The development of evidence-based clinical guidance will require an expanded clinical knowledge-base in order to move forward.

http://ift.tt/2i7t3Sf

A homozygous deleterious CDK10 mutation in a patient with agenesis of corpus callosum, retinopathy, and deafness

The primary cilium is a key organelle in numerous physiological and developmental processes. Genetic defects in the formation of this non-motile structure, in its maintenance and function, underlie a wide array of ciliopathies in human, including craniofacial, brain and heart malformations, and retinal and hearing defects. We used exome sequencing to study the molecular basis of disease in an 11-year-old female patient who suffered from growth retardation, global developmental delay with absent speech acquisition, agenesis of corpus callosum and paucity of white matter, sensorineural deafness, retinitis pigmentosa, vertebral anomalies, patent ductus arteriosus, and facial dysmorphism reminiscent of STAR syndrome, a suspected ciliopathy. A homozygous variant, c.870_871del, was identified in the CDK10 gene, predicted to cause a frameshift, p.Trp291Alafs*18, in the cyclin-dependent kinase 10 protein. CDK10 mRNAs were detected in patient cells and do not seem to undergo non-sense mediated decay. CDK10 is the binding partner of Cyclin M (CycM) and CDK10/CycM protein kinase regulates ciliogenesis and primary cilium elongation. Notably, CycM gene is mutated in patients with STAR syndrome. Following incubation, the patient cells appeared less elongated and more densely populated than the control cells suggesting that the CDK10 mutation affects the cytoskeleton. Upon starvation and staining with acetylated-tubulin, γ-tubulin, and Arl13b, the patient cells exhibited fewer and shorter cilia than control cells. These findings underscore the importance of CDK10 for the regulation of ciliogenesis. CDK10 defect is likely associated with a new form of ciliopathy phenotype; additional patients may further validate this association.

http://ift.tt/2AxR9w1

Short rib syndrome Beemer–Langer type, a short history

http://ift.tt/2i7t20D

Calvarial mass as a presenting feature of neurofibromatosis type 2 in a pediatric patient

http://ift.tt/2AxR6QR

Further delineation of the GDF6 related multiple synostoses syndrome

A mutation in GDF6 was recently found to underlie a multiple synostoses syndrome. In this report, we describe the second family with GDF6-related multiple synostoses syndrome (SYNS4), caused by a novel c.1287C>A/p.Ser429Arg mutation in GDF6. In addition to synostoses of carpal and/or tarsal bones, at least 6 of 10 affected patients in this family have been diagnosed with mild to moderate hearing loss. In four of them otosclerosis was said to be present, one patient had hearing loss due to severe stapes fixation at the age of 6 years, providing evidence that hearing loss in the GDF6-related multiple synostoses syndrome can be present in childhood. Two others had surgery for stapes fixation at adult age. We hypothesize that, identical to the recently published GDF6-related multiple synostoses family, the p.Ser429Arg mutation also leads to a gain of function. The previously reported c.1330T>A/pTyr444Asn mutation was located in a predicted Noggin and receptor I interacting domain and the gain of function was partly due to resistance of the mutant GDF6 to the BMP-inhibitor Noggin. The results in our family show that mutations predicting to affect the type II receptor interface can lead to a similar phenotype and that otosclerosis presenting in childhood can be part of the GDF6-related multiple synostoses syndrome.

http://ift.tt/2i7t091

Interstitial microdeletion of 17q11.2 is associated with hypotonia, fatigue, intellectual disability, and a subtle facial phenotype in three unrelated patients

Over the past decade chromosomal microarray analysis (array CGH) has allowed the discovery of many novel disease-causing recurrent microdeletion and microduplication syndromes. Here we present three unrelated patients (2F; 1M) from three different countries, with developmental delay, intellectual disability, hypotonia, fatigue, and highly similar dysmorphic facial features. Shared facial features are a broad and wide forehead, similar shape of the eyes with long palpebral fissures, a bulbous tip of the nose and thick lips. Intellectual disabilities range from mild to severe. One female patient and the male patient were investigated in childhood for significant hypotonia thought to be suggestive of a neuromuscular disorder. The two female patients also show excessive fatigue with daytime somnolence. The patients carry overlapping, de novo microdeletions of chromosome 17q11.2, with sizes ranging from 0.97 to 1.18 Mb. The smallest region of overlap (SRO) between the three patients is 863 kb, and contains seven genes, five of which are predicted to exhibit haploinsufficiency (CDK5R1, PSMD11, RHOT1, SUZ12, ZNF207) although none has yet been associated with genetic syndromes. Of these five genes, the brain expressed CDK5R1 gene constitutes a good candidate for the developmental delay, while the RHOT1 gene, involved in mitochondrial trafficking, might underlie the hypotonia and the excessive fatigue.

http://ift.tt/2AyB7Cr