The role of the physician in Israel’s maternal child health clinics: surveys of professional and parental perceptions

Background

Preventative health services are a pediatric health care cornerstone, which strives to promote health and prevent illness and injury. In Israel, Maternal Child Health Clinics (MCHC) provide these well child services for ages 0–6 years. MCHC care includes physician visits; however, the physician’s role is not well defined. The study purpose was to provide a basis for setting policies that determine the role of physicians in the provision of MCHC services. To get broad input we included MCHC stakeholders - parents, MCHC physicians, non-MCHC physicians and MCHC nurses, specifically to obtain insights regarding the MCHC physician role and to characterize the stakeholder demographics, service utilization, and practice patterns.

Methods

Professional groups completed self-administered written questionnaires (n = 398). Parents were interviewed during MCHC visits using a structured questionnaire (n = 1052). All provided demographic data, service characteristics and agreement with ten potential MCHC physician roles - Physical Examination, Abnormal Health Condition Detection, Developmental Screening, Anticipatory Guidance, Parent-Child Interaction Counseling, MCHC Staff Advice, Children-at-Risk Detection, Growth Surveillance, Vaccination Counseling, and Inter-physician Communication.

Results

The study findings seem to indicate a true shortage of MCHC physicians. The median age of MCHC physicians was significantly higher than both non-MCHC physicians and MCHC nurses. There was agreement among stakeholders regarding some roles (Physical Examination, Developmental Screening and Detection of Abnormal Health Conditions) but not others. Most parents reported having at least one MCHC physician encounter. Parents who did not visit the physician were younger and had fewer children.

Conclusions

Stakeholders view MCHC physicians as integral to MCHC care. Roles traditionally regarded as part of primary prevention were less likely to be attributed to physicians than screening roles considered secondary prevention.Updating and standardization of the MCHC physician role is needed along with a national strategy to recruit and train MCHC physicians.to ensure optimal pediatric preventive health care in Israel.

     

Evaluation of FGFR3 as a Therapeutic Target in Head and Neck Squamous Cell Carcinoma

Background

Although head and neck squamous cell carcinoma (HNSCC) is the sixth most common tumour entity worldwide, it remains a clinical challenge. Large-scale explorative genomic projects have identified several genes as potential targets for therapy, including fibroblast growth factor receptor 3 (FGFR3).

Aims

The aim of this study was to investigate the biological significance of wild-type and mutated FGFR3 to evaluate its potential as a novel therapeutic target in HNSCC.

Methods

FGFR3 protein expression was analysed in a large HNSCC tissue cohort (n?=?536) and FGFR3 mRNA expression from The Cancer Genome Atlas (TCGA; n?=?520). Moreover, FGFR3 wild-type and mutant versions were overexpressed in vitro, and both proliferation and migration was assessed with and without BGJ398 (a specific FGFR1-3 inhibitor) treatment.

Results

Although FGFR3 expression for both cohorts decreased during tumour progression, high FGFR3 expression levels were observed in a small subset of patients. In vitro, FGFR3 overexpression led to increased proliferation, whereas migration was not altered. Moreover, FGFR3-overexpressing cells were more sensitive to BGJ398. Cells overexpressing FGFR3 mutant versions showed increased proliferation compared to wild-type FGFR3 under serum-reduced conditions and were largely as sensitive as the wild-type protein to BGJ398.

Conclusions

Taken together, the results of this study demonstrate that although FGFR3 expression decreases during HNSSC progression, it plays an important role in tumour cell proliferation and thus may be a potential target for therapy in selected patients suffering from this dismal tumour entity.

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Exercise adherence in a randomized trial of exercise on aromatase inhibitor arthralgias in breast cancer survivors: the Hormones and Physical Exercise (HOPE) study

Purpose

Up to 50 % of postmenopausal breast cancer survivors taking aromatase inhibitors (AIs) experience AI-associated arthralgias, or joint pain, which causes many to stop taking AIs and may inhibit exercise, despite known health benefits. We thus evaluated exercise adherence and factors associated with better exercise adherence in breast cancer survivors experiencing AI-induced arthralgia in the (HOPE) year long randomized controlled trial.

Methods

We included 61 HOPE women randomized to exercise (150 min/week of moderate-intensity aerobic exercise and twice-weekly supervised strength training). Our main outcomes were aerobic exercise measured with daily activity logs, attendance at supervised exercise sessions, and changes in cardiorespiratory fitness, measured maximal oxygen consumption (VO₂max). We examined means and standard deviations (SDs) for exercise adherence by demographic and medical characteristics and used the t test for mean differences. We also examined predictors of adherence using linear regression.

Results

On average, at the end of the year long trial, women reported 119 (SD 78)?min/week of moderate-intensity aerobic exercise and participated in 70 % of supervised exercise training sessions. After adjustment for other factors that influence adherence, at 6 months postrandomization, only baseline VO₂max was associated with higher aerobic exercise levels and at 12 months, only older age predicted better supervised exercise training attendance.

Conclusions

Breast cancer survivors taking AIs and experiencing arthralgia are able to initiate and maintain a year long exercise program, regardless of other factors that influence activity levels.

Implications for Cancer Survivors

Breast cancer survivors can exercise at levels that have been shown to improve AI-associated arthralgia.

     

Body mass index,physical activity,and television time in relation to mortality risk among endometrial cancer survivors in the NIH-AARP Diet and Health Study cohort

Purpose

Endometrial cancer (EC) survivors are the second largest group of female cancer survivors in the USA, with high prevalence of obesity and physical inactivity. While higher pre-diagnosis body mass index (BMI) has been associated with higher all-cause and disease-specific mortality, pre-diagnosis physical activity has shown mixed evidence of an association with mortality. However, the association between BMI, physical activity, and TV viewing measured after diagnosis and mortality risk among EC survivors is unknown.

Methods

We identified 580 women with EC in the NIH-AARP Diet and Health Study who completed a post-diagnosis questionnaire on BMI, leisure time moderate- to vigorous-intensity physical activity (MVPA), and TV viewing. We used Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for mortality.

Results

With a median follow-up time of 7.1 years, we observed 91 total deaths. We found a positive association between BMI (\({\text{HR}}_{{35+\,{\text{ vs.}}\, <25 {\text{kg/m}}^{2} }}\) = 2.14, 95% CI 1.08–4.24 and mortality, and no statistically significant association between TV viewing (HR_{5+ vs. <3 h/day} = 1.46, 95% CI 0.86–2.46) and mortality nor MVPA with mortality (HR_{15+ vs. 0 MET h/week} = 0.72, 95% CI 0.43–1.21) after adjusting for tumor characteristics and demographic factors. Further adjustment for lifestyle and health status attenuated BMI associations (\({\text{HR}}_{{35+\,{\text{ vs.}}\, <25 {\text{kg/m}}^{2} }}\) = 1.47, 95% CI 0.71–3.07), but strengthened the association between TV viewing and mortality (HR_{5+ vs. <3 h/day} = 2.28, 95% CI 1.05–4.95).

Conclusions

Our results suggest that higher post-diagnosis BMI and TV viewing may be associated with higher mortality risk among EC patients, but that there may be complicated interrelationships between lifestyle factors of BMI, PA, and TV viewing and the mediating role of health status that need to be clarified.

     

Cumulative cultural evolution in the laboratory: an experimental approach to the origins of structure in human language

We introduce an experimental paradigm for studying the cumulative cultural evolution of language. In doing so we provide the first experimental validation for the idea that cultural transmission can lead to the appearance of design without a designer. Our experiments involve the iterated learning of artificial languages by human participants. We show that languages transmitted culturally evolve in such a way as to maximize their own transmissibility: over time, the languages in our experiments become easier to learn and increasingly structured. Furthermore, this structure emerges purely as a consequence of the transmission of language over generations, without any intentional design on the part of individual language learners. Previous computational and mathematical models suggest that iterated learning provides an explanation for the structure of human language and link particular aspects of linguistic structure with particular constraints acting on language during its transmission. The experimental work presented here shows that the predictions of these models, and models of cultural evolution more generally, can be tested in the laboratory.     

Maraviroc: in vitro assessment of drug-drug interaction potential

AIMS

To characterize the cytochrome P450 enzyme(s) responsible for the N-dealkylation of maraviroc in vitro, and predict the extent of clinical drug–drug interactions (DDIs).

METHODS

Human liver and recombinant CYP microsomes were used to identify the CYP enzyme responsible for maraviroc N-dealkylation. Studies comprised enzyme kinetics and evaluation of the effects of specific CYP inhibitors. In vitro data were then used as inputs for simulation of DDIs with ketoconazole, ritonavir, saquinavir and atazanvir, using the Simcyp™ population-based absorption, distribution, metabolism and elimination (ADME) simulator. Study designs for simulations mirrored those actually used in the clinic.

RESULTS

Maraviroc was metabolized to its N-dealkylated product via a single CYP enzyme characterized by a K_m of 21 µM and V_max of 0.45 pmol pmol⁻¹ min⁻¹ in human liver microsomes and was inhibited by ketoconazole (CYP3A4 inhibitor). In a panel of recombinant CYP enzymes, CYP3A4 was identified as the major CYP responsible for maraviroc metabolism. Using recombinant CYP3A4, N-dealkylation was characterized by a K_m of 13 µM and a V_max of 3 pmol pmol⁻¹ CYP min⁻¹. Simulations therefore focused on the effect of CYP3A4 inhibitors on maraviroc pharmacokinetics. The simulated median AUC ratios were in good agreement with observed clinical changes (within twofold in all cases), although, in general, there was a trend for overprediction in the magnitude of the DDI.

CONCLUSION

Maraviroc is a substrate for CYP3A4, and exposure will therefore be modulated by CYP3A4 inhibitors. Simcyp™ has successfully simulated the extent of clinical interactions with CYP3A4 inhibitors, further validating this software as a good predictor of CYP-based DDIs.

WHAT IS ALREADY KNOWN ABOUT THE SUBJECT

• Maraviroc is known to undergo oxidative metabolism in vivo and is a substrate for cytochrome P450 (CYP).
• Simcyp™ has recently become more widely used for the prediction of CYP-mediated drug–drug interactions (DDIs) using in vitro metabolism data.

WHAT THIS STUDY ADDS

• Maraviroc has been identified as a CYP3A4 substrate and the kinetic constants characterized.
• The predicted DDIs associated with maraviroc as a CYP3A4 substrate using Simcyp™ have been compared against the clinical data.
• This study demonstrates the value of a reliable Simcyp™ model for prediction of DDIs.

     

Whole-genome sequencing of artificial single-nucleotide variants induced by DNA degradation in biological crime scene traces

The aim of this study was to identify artificial single-nucleotide variants (SNVs) in degraded trace DNA samples. In a preliminary study, blood samples were stored for up to 120 days and whole-genome sequencing was performed using the Snakemake workflow dna-seq-gatk-variant-calling to identify positions that vary between the time point 0 sample and the aged samples. In a follow-up study on blood and saliva samples stored under humid and dry conditions, potential marker candidates for the estimation of the age of a blood stain (= time since deposition) were identified. Both studies show that a general decrease in the mean fragment size of the libraries over time was observed, presumably due to the formation of abasic sites during DNA degradation which are more susceptible to strand breaks by mechanical shearing of DNA. Unsurprisingly, an increase in the number of failed genotype calls (no coverage) was detected over time. Both studies indicated the presence of artificial SNVs with the majority of changes happening at guanine and cytosine positions. This confirms previous studies and can be explained by depurination through hydrolytic attacks which more likely deplete guanine while deamination leads to cytosine to thymine variants. Even complete genotype switches from homozygote 0/0 genotypes to the opposite 1/1 genotypes were observed. While positions with such drastic changes might provide suitable candidate markers for estimating short-term time since deposition (TsD), 11 markers were identified which show a slower gradual change of the relative abundance of the artificial variant in both blood and saliva samples, irrespective of storage conditions.