Defining minimum volume thresholds to increase quality of care: a new patient-oriented approach using mixed integer programming

A positive relationship between treatment volume and outcome quality has been demonstrated in the literature and is thus evident for a variety of procedures. Consequently, policy makers have tried to translate this so-called volume–outcome relationship into minimum volume regulation (MVR) to increase the quality of care—yet with limited success. Until today, the effect of strict MVR application remains unclear as outcome quality gains cannot be estimated adequately and restrictions to application such as patient travel time and utilization of remaining hospital capacity are not considered sufficiently. Accordingly, when defining MVR, its effectiveness cannot be assessed. Thus, we developed a mixed integer programming model to define minimum volume thresholds balancing utility in terms of outcome quality gain and feasibility in terms of restricted patient travel time and utilization of hospital capacity. We applied our model to the German hospital sector and to four surgical procedures. Results showed that effective MVR needs a minimum volume threshold of 125 treatments for cholecystectomy, of 45 and 25 treatments for colon and rectum resection, respectively, of 32 treatments for radical prostatectomy and of 60 treatments for total knee arthroplasty. Depending on procedure type and incidence as well as the procedure’s complication rate, outcome quality gain ranged between 287 (radical prostatectomy) and 977 (colon resection) avoidable complications (11.7% and 11.9% of all complications). Ultimately, policy makers can use our model to leverage MVR’s intended benefit: concentrating treatment delivery to improve the quality of care.

     

Fibroblast growth factor receptors in cancer: genetic alterations,diagnostics, therapeutic targets and mechanisms of resistance

Fibroblast growth factor receptors (FGFRs) are aberrantly activated through single-nucleotide variants, gene fusions and copy number amplifications in 5–10% of all human cancers, although this frequency increases to 10–30% in urothelial carcinoma and intrahepatic cholangiocarcinoma. We begin this review by highlighting the diversity of FGFR genomic alterations identified in human cancers and the current challenges associated with the development of clinical-grade molecular diagnostic tests to accurately detect these alterations in the tissue and blood of patients. The past decade has seen significant advancements in the development of FGFR-targeted therapies, which include selective, non-selective and covalent small-molecule inhibitors, as well as monoclonal antibodies against the receptors. We describe the expanding landscape of anti-FGFR therapies that are being assessed in early phase and randomised controlled clinical trials, such as erdafitinib and pemigatinib, which are approved by the Food and Drug Administration for the treatment of FGFR3-mutated urothelial carcinoma and FGFR2-fusion cholangiocarcinoma, respectively. However, despite initial sensitivity to FGFR inhibition, acquired drug resistance leading to cancer progression develops in most patients. This phenomenon underscores the need to clearly delineate tumour-intrinsic and tumour-extrinsic mechanisms of resistance to facilitate the development of second-generation FGFR inhibitors and novel treatment strategies beyond progression on targeted therapy.Subject terms: Cancer, Cancer     

Metastatic adult-type non-rhabdomyosarcoma soft tissue sarcomas in children and adolescents: A cohort study from the European paediatric Soft tissue sarcoma Study Group

Background

Limited data exist on the clinical behavior of pediatric non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) with distant metastases at onset, and a clear standard of care has not yet been defined.

Methods

This cohort study reports on pediatric adult-type metastatic NRSTS enrolled in two concurrent prospective European studies, i.e., the randomized BERNIE study and the single-arm MTS 2008 study developed by the European paediatric Soft tissue sarcoma Study Group. Treatment programs were originally designed for patients with metastatic rhabdomyosarcoma, i.e., nine courses of multidrug chemotherapy (with or without bevacizumab in the BERNIE study), followed by 12 cycles of maintenance therapy, whereas radiotherapy and/or surgery (on primary tumor and/or metastases) were delayed until after seven courses of chemotherapy had been administered.

Results

The study included 61 patients <21 years old treated from July 2008 to December 2016. The lung was the site of metastases in 75% of the cases. All patients received multi-agent chemotherapy, 44% had local therapy to primary tumor, and 18% had treatment of metastases. Median time to progression/relapse was 6 months. A high rate of tumor progression was observed during the initial part of the chemotherapy program. With a median follow-up of 41.5 months (range, 2–111 months), 3-year event-free survival and overall survival were 15.4% (95% confidence interval [CI], 7.6–25.7) and 34.9% (95% CI, 22.7–47.5), respectively. There were no statistically significant differences in outcome depending on the type of treatment administered.

Conclusions

The study confirmed the overall poor outcome for patients with metastatic NRSTS, whose treatment remains a challenge.

Plain Language Summary

• Pediatric non-rhabdomyosarcoma soft tissue sarcomas form a heterogeneous group of rare tumors.
• Although recent international studies have defined the standard of care for patients with localized disease, limited data are available on the clinical behavior of patients with distant metastases.
• This study on 61 metastatic cases treated on two prospective European protocols confirms that the chances of survival of such patients are often dismal and a standard treatment is still lacking.

     

Gaming-Gambling Convergence: Trends,Emerging Risks,and Legislative Responses

A convergence of gaming and gambling products, services, and platforms is presently drawing considerable policy debate. This convergence may be giving rise to a critical area of consumer vulnerability given the addictive potential of gaming and gambling. While some convergence aspects are gaining research attention, the broader contexts of the phenomenon have not been adequately examined. In light of this, the present study aimed to inform four key enquiry areas pertaining to gaming-gambling convergence—contexts and drivers, definitions and framings, risk and harm, and legislative response. Using a narrative review method, 108 articles from the academic and grey literature were examined and thematically summarised to provide an overview of the convergence phenomenon. Findings indicate convergence in multiple overlapping contexts (gaming elements in gambling, games incorporating gambling elements, gambling on games, free simulated online gambling, and social media games and gambling) driven by technological advances and commercial interests. Findings related to definitions and framing include the industry’s strategic use of the term gaming to reduce negative connotations associated with gambling, and community perceptions of gaming as legitimate and harmless entertainment. Potential risks include transitions from games (without money) to real-money gambling, and problem co-existence. Legislative responses are beginning to emerge with the greatest focus being on loot boxes in games. However, the limited evidence of risk and harm has led to hesitancies in legislative actions to regulate gaming-gambling hybrids in some jurisdictions. Considering that convergence is supported by rapid advances in technology and is taking place largely on the Internet (accessible 24 h), harms for consumers could manifest quickly and spread broadly across societies before their existence and severity are established. Based on the Precautionary Principle, the present evidence base call for harm prevention policies and regulations in addition to changes in the definition of money (including digital currency and microtransaction) in gaming and gambling laws.

     

Reflecting on exchange students’ learning: Structure,objectives and supervision

Abstract

Background and aim: The increasing opportunities for medical students to participate in international electives may improve students’ professionalism and cultural competence. However, the students’ overall experiences may be unpredictable, unstructured and lack supervision. There is scant evidence with respect to their learning outcomes. These reflections demonstrate that short-term supervised elective can provide students with structured learning experiences to achieve specific learning objectives.

Methods: We carried out daily debriefs and a weekly summary with seven Curtin Medical School students from Perth, Australia during an 18-days supervised elective in the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. The daily debriefs and the weekly summary in different disciplines become the content of the reflections discussed in this article.

Results: The main themes identified in the feedback were as follows: Skills in history taking and physical examination; clinical reasoning; diagnosis and management of diseases rarely seen in Australia; awareness of clinical ethics; merits and demerits of different systems of healthcare; sensitivity to issues in doctor-patient relationships; work ethics; enhancement of cultural competence; and personal development.

Conclusions: These reflections provide insight into how overseas electives may be structured to improve students’ clinical reasoning skills in this hospital. These students achieved their learning outcomes under joint supervision from both institutions. The clinical skills learned from these experiences enhanced the students’ professionalism and cultural competence, giving students the opportunities to appreciate the multitude healthcare model of bio-psycho-social-political-economical-spiritual dimensions.     

P2Y13 and P2X7 receptors modulate mechanically induced adenosine triphosphate release from mast cells

Subcutaneous mast cells (MCs) are vulnerable to mechanical stimulation from external environment. Thus, MCs immune function could be modulated by their mechanosensitivity. This property has been identified as the trigger mechanism of needling acupuncture, a traditional oriental therapy. Previously we have demonstrated the release of adenosine triphosphate (ATP), a stress-responsive signalling molecule, from mechanical-perturbed MCs. The current work explores its underlying mechanisms. We noticed that propagation of intracellular free Ca²⁺ occurred among HMC-1 cells in response to 50% hypotonic shock. Additionally, amplifying cascade of ATP-induced ATP release was observed in RBL-2H3 cells stimulated by medium displacement, which could be mimicked by exogenous ATP (exoATP). Secondary ATP liberation induced by low level (50 nmol/L) of exoATP was reduced by inhibiting ecto-ATPase-dependent ADP production with ARL67156, or blocking P2 receptors with suramin or PPADS, or with specific P2Y₁₃ receptor antagonist MRS2211, or siRNA. Secondary ATP release induced by higher dose (200 μmol/L) of exoATP, sufficient to stimulate P2X₇ receptor, was attenuated by suramin, PPADS or specific P2X₇ receptor antagonist BBG, or siRNA. Finally, RT-PCR confirmed mRNA expression of P2Y₁₃ and P2X₇ in RBL-2H3 cells. Additionally, such secondary ATP release was attenuated by DPCPX, specific antagonist of adenosine A1 receptor, but not by MRS2179, specific inhibitor of P2Y₁ receptor. In summary, mechanosensitive ATP release from MCs is facilitated by paracrine/autocrine stimulation of P2Y₁₃ and P2X₇ receptors. This multi-receptor combination could mediate transmission of information from a local site to distal areas, enabling communication with multiple surrounding cells to coordinate and synchronize their function.     

Dysfunction of mouse cerebral arteries during early aging

Aging leads to a gradual decline in the fidelity of cerebral blood flow (CBF) responses to neuronal activation, resulting in an increased risk for stroke and dementia. However, it is currently unknown when age-related cerebrovascular dysfunction starts or which vascular components and functions are first affected. The aim of this study was to examine the function of microcirculation throughout aging in mice. Microcirculation was challenged by inhalation of 5% and 10% CO₂ or by forepaw stimulation in 6-week, 8-month, and 12-month-old FVB/N mice. The resulting dilation of pial vessels and increase in CBF was measured by intravital fluorescence microscopy and laser Doppler fluxmetry, respectively. Neurovascular coupling and astrocytic endfoot Ca²⁺ were measured in acute brain slices from 18-month-old mice. We did not reveal any changes in CBF after CO₂ reactivity up to an age of 12 months. However, direct visualization of pial vessels by in vivo microscopy showed a significant, age-dependent loss of CO₂ reactivity starting at 8 months of age. At the same age neurovascular coupling was also significantly affected. These results suggest that aging does not affect cerebral vessel function simultaneously, but starts in pial microvessels months before global changes in CBF are detectable.     

Dexamethasone as an adjuvant for peripheral nerve blockade: a randomised,triple-blinded crossover study in volunteers

Background

The efficacy of dexamethasone in extending the duration of local anaesthetic block is uncertain. In a randomised controlled triple blind crossover study in volunteers, we tested the hypothesis that neither i.v. nor perineurally administered dexamethasone prolongs the sensory block achieved with ropivacaine.