HEREDITARY ENDOCRINE TUMOURS: CURRENT STATE-OF-THE-ART AND RESEARCH OPPORTUNITIES: MEN1-related pancreatic NETs: identification of unmet clinical needs and future directives.

The PanNET Working Group of the 16th International Multiple Endocrine Neoplasia Workshop (MEN2019) convened in Houston, TX, USA, 27-29 March 2019 to discuss key unmet clinical needs related to PanNET in the context of MEN1, with a special focus on non-functioning (nf)-PanNETs. The participants represented a broad range of medical scientists as well as representatives from patient organizations, pharmaceutical industry and research societies. In a case-based approach, participants addressed early detection, surveillance, prognostic factors and management of localized and advanced disease. For each topic, after a review of current evidence, key unmet clinical needs and future research directives to make meaningful progress for MEN1 patients with nf-PanNETs were identified. International multi-institutional collaboration is needed for adequately sized studies and validation of findings in independent datasets. Collaboration between basic, translational and clinical scientists is paramount to establishing a translational science approach. In addition, bringing clinicians, scientists and patients together improves the prioritization of research goals, assures a patient-centered approach and maximizes patient involvement. It was concluded that collaboration, research infrastructure, methodologic and reporting rigor are essential to any translational science effort. The highest priority for nf-PanNETs in MEN1 syndrome are (1) the development of a data and biospecimen collection architecture that is uniform across all MEN1 centers, (2) unified strategies for diagnosis and follow-up of incident and prevalent nf-PanNETs, (3) non-invasive detection of individual nf-PanNETs that have an increased risk of metastasis, (4) chemoprevention clinical trials driven by basic research studies and (5) therapeutic targets for advanced disease based on biologically plausible mechanisms.

Inter- and intra-individual variability of active glucagon-like peptide 1 among healthy adults.

Objective: To determine whether sex, age, and body mass index are correlated with active glucagon-like-peptide 1 concentrations and to investigate glucagon-like-peptide 1 reproducibility during repeated oral glucose tolerance tests. Methods: Sixty-one healthy volunteers underwent four 2-hour repeated oral glucose tolerance tests approximately 1 week apart. Because this randomized same-subject crossover trial was designed to investigate effects of non-nutritive sweeteners, participants received 355 mL (12 ounces) of water or a beverage containing non-nutritive sweeteners 10 minutes prior to each oral glucose tolerance test. Blood samples were collected 10 minutes before, and 0, 10, 20, 30, 60, 90, and 120 minutes following ingestion of 75 grams of glucose. Results: Basal active glucagon-like-peptide 1, peak glucagon-like-peptide 1, and glucagon-like-peptide 1 area-under-the-curve were higher in men than women (all p ≤0.04), adjusting for body mass index and age. Fasting and stimulated active glucagon-like-peptide 1 results were highly reproducible with little within-subject variability (between-subjects to within-subject variability ratio 4.2 and 3.5 for fasting glucagon-like-peptide 1 and glucagon-like-peptide 1 area-under-the-curve). Conclusion: Men had higher active glucagon-like-peptide 1 concentrations than women. In contrast to considerable inter-individual variability of basal and stimulated active glucagon-like-peptide 1 concentrations, intra-individual variability was low, consistent with tight physiological regulation.

Anti-microbial stewardship: antibiotic use in well-appearing term neonates born to mothers with chorioamnionitis.

OBJECTIVE: To determine if implementation of a protocol based on a neonatal early-onset sepsis (EOS) calculator developed by Kaiser Permanente would safely reduce antibiotic use in well-appearing term infants born to mothers with chorioamnionitis in the unique setting of an Observation Nursery. STUDY DESIGN: Data obtained from a retrospective chart review of well-appearing term infants born between 2009 and 2016 were entered into the EOS calculator to obtain management recommendations. RESULTS: Three hundred and sixty-two infants met the study criteria. Management according to the EOS calculator would reduce antibiotic use from 99% to 2.5% (P<0.0001) of patients. Average length of therapy would also decrease from 2.08 to 0.05 days (P<0.0001). One infant, who remained asymptomatic, had Enterococcus bacteremia and received a 7-day course of broad-spectrum antibiotics. CONCLUSIONS: Culture-positive sepsis in asymptomatic neonates born to mothers with chorioamnionitis is rare. Management according to the EOS calculator would markedly reduce the potential complications of antibiotic use. These data should initiate re-examination of existing protocols for management of this cohort of patients.

Evaluation of critical congenital heart defects screening using pulse oximetry in the neonatal intensive care unit.

OBJECTIVE: To evaluate the implementation of early screening for critical congenital heart defects (CCHDs) in the neonatal intensive care unit (NICU) and potential exclusion of sub-populations from universal screening. STUDY DESIGN: Prospective evaluation of CCHD screening at multiple time intervals was conducted in 21 NICUs across five states (n=4556 infants). RESULTS: Of the 4120 infants with complete screens, 92% did not have prenatal CHD diagnosis or echocardiography before screening, 72% were not receiving oxygen at 24 to 48 h and 56% were born ⩾2500 g. Thirty-seven infants failed screening (0.9%); none with an unsuspected CCHD. False positive rates were low for infants not receiving oxygen (0.5%) and those screened after weaning (0.6%), yet higher among infants born at <28 weeks (3.8%). Unnecessary echocardiograms were minimal (0.2%). CONCLUSION: Given the majority of NICU infants were ⩾2500 g, not on oxygen and not preidentified for CCHD, systematic screening at 24 to 48 h may be of benefit for early detection of CCHD with minimal burden.

Normal and Delayed Fracture Healing: Symphony and Cacophony.

The incidence of any fracture in the US is estimated to be 2 704 fractures per 100,000 person-years. Approximately 10 percent of these fractures develop complications of healing. The processes that occur during fracture healing mimic the processes that take place in the growth plate during development. The study of fracture healing represents a window to enhance our understanding of the processes of growth and development of bones and its reparative biology. This review is aimed for clinicians evaluating non-unions as an overview of different factors that inhibit fracture healing.

Long-term immunosuppression after solitary islet transplantation is associated with preserved C-peptide secretion for more than a decade.

We report on two patients with type 1 diabetes (T1D) after solitary islet transplantation in 2001. They received steroid-sparing immunosuppression (daclizumab, sirolimus, and tacrolimus according to the Edmonton protocol). Both patients became insulin independent for 2 years: Patient A, a 42-year-old female with a 12-year history of T1D, received two islet infusions; patient B, a 53-year-old female with a 40-year T1D history, received one islet infusion. Pretransplant, both had undetectable C-peptide concentrations and frequent and severe hypoglycemia. Pretransplant, hemoglobin A1c (HbA1c) was 7.8% and 8.8% and insulin requirements were 0.47 and 0.33 units/kg/day, respectively. Posttransplant, C-peptide levels remained detectable while immunosuppression was continued, but decreased over time. Insulin was re-started 2 years posttransplant in both patients. Since patient A's glycemia and insulin requirements trended toward pretransplant levels, immunosuppression was discontinued after 13 years. This resulted in a sudden cessation of C-peptide secretion. Patient B continues on immunosuppression, has better HbA1c, and half the insulin requirement compared to pretransplant. Both patients no longer experience severe hypoglycemia. Herein, we document blood glucose concentrations over time (>30 000 measurements per patient) and ß cell function based on C-peptide secretion. Despite renewed insulin dependence, both patients express satisfaction with having undergone the procedure.

Cost-effectiveness of pneumococcal conjugate vaccination in Georgia.

OBJECTIVE: Financial support from the Global Alliance for Vaccines and Immunization (GAVI) to introduce the 10-valent pneumococcal conjugate vaccine (PCV10) into the routine childhood immunization schedule in Georgia is ending in 2015. As a result, the Interagency Coordination Committee (ICC) decided to carry out a cost-effectiveness analysis to gather additional evidence to advocate for an appropriate evidence-based decision after GAVI support is over. The study also aimed to strengthen national capacity to conduct cost-effectiveness studies, and to introduce economic evaluations into Georgia's decision-making process. METHODOLOGY: A multidisciplinary team of national experts led by a member of the ICC carried out the analysis that compared two scenarios: introducing PCV10 vs no vaccination. The TRIVAC model was used to evaluate 10 cohorts of children over the period 2014-2023. National data was used to inform demographics, disease burden, vaccine coverage, health service utilization, and costs. Evidence from clinical trials and the scientific literature was used to estimate the impact of the vaccine. A 3+0 schedule and a vaccine price increasing to US$ 3.50 per dose was assumed for the base-case scenario. Alternative univariate and multivariate scenarios were evaluated. RESULTS: Over the 10-year period, PCV10 was estimated to prevent 7170 (8288 undiscounted) outpatient visits due to all-cause acute otitis media, 5325 (6154 undiscounted) admissions due to all-cause pneumonia, 87 (100 undiscounted) admissions due to pneumococcal meningitis, and 508 (588 undiscounted) admissions due to pneumococcal non-pneumonia and non-meningitis (NPNM). In addition, the vaccine was estimated to prevent 41 (48 undiscounted) deaths. This is equivalent to approximately 5 deaths and 700 admissions prevented each year in Georgia. Over the 10-year period, PCV10 would cost the government approximately US$ 4.4 million ($440,000 per year). However, about half of this would be offset by the treatment costs prevented. The discounted cost-effectiveness ratio was estimated to be US$ 1599 per DALY averted with scenarios ranging from US$ 286 to US$ 7787. DISCUSSION: This study led to better multi-sectoral collaboration and improved national capacity to perform economic evaluations. Routine infant vaccination against Streptococcus pneumoniae would be highly cost-effective in Georgia. The decision to introduce PCV10 was already made some time before the study was initiated but it provided important economic evidence in support of that decision. There are several uncertainties around many of the parameters used, but a multivariate scenario analysis with several conservative assumptions (including no herd effect in older individuals) shows that this recommendation is robust. This study supports the decision to introduce PCV10 in Georgia.

Cost-effectiveness of pneumococcal conjugate vaccination in Croatia.

OBJECTIVE: Pneumococcus is a known cause of meningitis, pneumonia, sepsis, and acute otitis media in children and adults globally. Two new vaccines for children have the potential to prevent illness, disability, and death, but these vaccines are expensive. The Croatian Ministry of Health has considered introducing the vaccine in the past, but requires economic evidence to ensure that the limited funds available for health care will be used in the most effective way. METHODOLOGY: Croatia appointed a multidisciplinary team of experts to evaluate the cost-effectiveness of introducing pneumococcal conjugate vaccination (PCV) into the national routine child immunization program. Both 10-valent and 13-valent PCV (PCV10 and PCV13) were compared to a scenario assuming no vaccination. The TRIVAC decision-support model was used to estimate cost-effectiveness over the period 2014-2033. We used national evidence on demographics, pneumococcal disease incidence and mortality, the age distribution of disease in children, health service utilization, vaccine coverage, vaccine timeliness, and serotype coverage. Vaccine effectiveness was based on evidence from the scientific literature. Detailed health care costs were not available from the Croatian Institute for Health Insurance at the time of the analysis so assumptions and World Health Organization (WHO) estimates for Croatia were used. We assumed a three-dose primary vaccination schedule, and an initial price of US$ 30 per dose for PCV10 and US$ 35 per dose for PCV13. We ran univariate sensitivity analyses and multivariate scenario analyses. RESULTS: Either vaccine is estimated to prevent approximately 100 hospital admissions and one death each year in children younger than five in Croatia. Compared to no vaccine, the discounted cost-effectiveness of either vaccine is estimated to be around US$ 69,000-77,000 per disability-adjusted life-years (DALYs) averted over the period 2014-2033 (from the government or societal perspective). Only two alternative scenarios were borderline cost-effective (US$ per DALY averted less than 3×GDP per capita of approximately US$ 40,000). The first was a scenario based primarily on the WHO 2008 pneumococcal disease burden estimates for Croatia. The second was a scenario that assumed a fairly dramatic drop in the price of the vaccine over the period. Both vaccines would need to be priced at approximately US$ 20 per dose or less to be considered cost-effective under base-case assumptions. PCV10 would be more cost-effective than PCV13 with base-case assumptions, but this is sensitive to the price of each vaccine. CONCLUSION: Based on estimated health and economic benefits in children alone, PCV is unlikely to be cost-effective in Croatia. Both vaccines would need to be priced at less than US$ 20 per dose to be considered cost-effective for children. Further analyses should be conducted to estimate the health and economic burden of pneumococcal disease in older age groups, and to assess the influence on cost-effectiveness results when short-term and long-term indirect effects are included for older individuals. While there are important uncertainties around the price and effectiveness of both vaccines, our analysis suggests there is insufficient evidence to warrant a significant difference in the price of the two vaccines.

Note: An adhesion measurement setup for bioinspired fibrillar surfaces using flat probes.

Current adhesion measurement setups designed for experiments on bioinspired fibrillar surfaces, either commercial or constructed in-house, do not allow adhesion measurements with in situ visualization, high resolution, high force range, and controlled alignment at the same time. In this paper a new adhesion tester is presented, which enables contact experiments with controlled tilt angle (accuracy of ±0.02°). This allows the use of flat probes and thus greatly simplifies the determination of experimental parameters such as pull-off strength or Young's modulus. The deflection of a double-clamped glass beam is measured by laser interferometry with an accuracy of ±60 nm, which yields a precise force measurement over three orders of magnitude force range without changing the glass beam. Contact formation and detachment events can be visualized in situ. The current adhesion tester is designed for force measurements in the range of 1 µN to 1 N and fills the gap between macroscopic tests and atomic force microscopy measurements.

What is there left to learn about the Drosophila clock?

Circadian rhythms offer probably the best understanding of how genes control behavior, and much of this understanding has come from studies in Drosophila. More recently, genetic manipulation of clock neurons in Drosophila has helped identify how daily patterns of activity are programmed by different clock neuron groups. Here, we review some of the more recent findings on the fly molecular clock and ask what more the fly model can offer to circadian biologists.

Ponytail headache: a pure extracranial headache.

Fifty of 93 females experienced headache from wearing a ponytail. Pain was experienced only at the site of the hair tie in 10 subjects, extending in others, forwards to the vertex (n = 5) or forehead (n = 7), laterally to the parietal region (n = 8) or temples (n = 3), downwards to the neck (n = 5), or to other areas (n = 12). Loosening the hair relieved pain immediately in 4 subjects, within half an hour in 32, and within an hour in 5 subjects; the remaining 9 subjects were uncertain of pain duration. This headache was preventable by wearing the ponytail more loosely tied. Ponytail headache, well known to females, is not described in the medical literature because the remedy is obvious, therefore those affected do not seek medical advice. This seemingly common headache provides an example of a pure extracranial headache arising from pericranial muscle fascia and tendon traction. Males almost certainly have similar experiences, but were not questioned in this study. Distinguishing intracranial from extracranial headache is essential in diagnosis and treatment. Further research on ponytail and other extracranial headaches could shed light on the mechanism of tension-type headache.

The Drosophila circadian clock: what we know and what we don't know.

Circadian rhythms are regulated by endogenous body clocks, which are formed by rhythmic cycles of clock gene expression. Almost all reviews of the Drosophila circadian clock state that the intracellular oscillator is based on a simple negative feedback loop. However, not many 'simple' feedback loops in biology last for 24 h. Instead, the Drosophila clock is a series of precisely timed steps that are deliberately slow. In this paper, I will discuss the current model for how the Drosophila clock is regulated, and ask what questions remain to be answered.

Death and taxes are more than just a certainty.

This article discusses a tax provision referenced under Internal Revenue Code Section 691(a) known as "Income in Respect of a Decedent" (IRD) and includes many circumstances applicable to physicians. "IRD" refers to income that accrued to the decedent but was not included in taxable income.

Your money should be working harder: the power of compound interest.

In light of the recent stock market volatility, many physicians may feel compelled to re-evaluate the progress they've made toward their goal of financial independence. Those who have planned proactively understand the importance of accumulating assets in order to have a specific amount available at the time of retirement capable of generating sufficient income over their lifetime. Regardless of whether that magic number is $1.5 million, $4 million or somewhere in between, it is critical to understand the methods of wealth accumulation that will allow you to achieve your specific goal in the quickest and most efficient manner. While we have no control over the performance of the various equity (stock) and fixed income (bond) markets, we do have control as to the methods used to accumulate funds for any given objective. These methods, when properly applied, will enable physicians to reach their goals with the minimum investment.

Cycling vrille expression is required for a functional Drosophila clock.

We identified a novel regulatory loop within Drosophila's circadian clock. A screen for clock-controlled genes recovered vrille (vri), a transcription factor essential for embryonic development. vri is expressed in circadian pacemaker cells in larval and adult brains. vri RNA levels oscillate with a circadian rhythm. Cycling is directly regulated by the transcription factors dCLOCK and CYCLE, which are also required for oscillations of period and timeless RNA. Eliminating the normal vri cycle suppresses period and timeless expression and causes long-period behavioral rhythms and arrhythmicity, indicating that cycling vri is required for a functional Drosophila clock. We also show that dCLOCK and VRI independently regulate levels of a neuropeptide, pigment dispersing factor, which appears to regulate overt behavior.