deconstructSigs: delineating mutational processes in single tumors distinguishes DNA repair deficiencies and patterns of carcinoma evolution

BACKGROUND: Analysis of somatic mutations provides insight into the mutational processes that have shaped the cancer genome, but such analysis currently requires large cohorts. We develop deconstructSigs, which allows the identification of mutational signatures within a single tumor sample. RESULTS: Application of deconstructSigs identifies samples with DNA repair deficiencies and reveals distinct and dynamic mutational processes molding the cancer genome in esophageal adenocarcinoma compared to squamous cell carcinomas. CONCLUSIONS: deconstructSigs confers the ability to define mutational processes driven by environmental exposures, DNA repair abnormalities, and mutagenic processes in individual tumors with implications for precision cancer medicine

A novel observation of pubic osteomyelitis due to Streptococcus viridans after dental extraction: a case report

<p>Abstract</p> <p>Introduction</p> <p>Pubic osteomyelitis should be suspected in athletic individuals with sudden groin pain, painful restriction of hip movements and fever. It is an infrequent and confusing disorder, which is often heralded by atypical gait disturbance and diffuse pain in the pelvic girdle. The most common pathogen is <it>Staphylococcus aureus </it>but, on occasions, efforts to identify infectious agents sometimes prove negative. Pubic osteomyelitis due to <it>Streptococcus viridans </it>has not been reported previously in the literature.</p> <p>Case presentation</p> <p>We describe the case of a fit 24-year-old athlete, who had a wisdom tooth extracted 2 weeks prior to the presentation, which could have served as a port of entry and predisposed the patient to transient bacteraemia.</p> <p>Conclusion</p> <p><it>S. viridans </it>is well known for causing infective endocarditis of native damaged heart valves, but to the best of the authors' knowledge it has not been reported previously as a cause of pubic osteomyelitis. We believe that this case should alert physicians to the association between dental procedures and osteomyelitis of the pubis secondary to <it>S. viridans</it>.</p

Core components for effective infection prevention and control programmes: new WHO evidence-based recommendations

Abstract Health care-associated infections (HAI) are a major public health problem with a significant impact on morbidity, mortality and quality of life. They represent also an important economic burden to health systems worldwide. However, a large proportion of HAI are preventable through effective infection prevention and control (IPC) measures. Improvements in IPC at the national and facility level are critical for the successful containment of antimicrobial resistance and the prevention of HAI, including outbreaks of highly transmissible diseases through high quality care within the context of universal health coverage. Given the limited availability of IPC evidence-based guidance and standards, the World Health Organization (WHO) decided to prioritize the development of global recommendations on the core components of effective IPC programmes both at the national and acute health care facility level, based on systematic literature reviews and expert consensus. The aim of the guideline development process was to identify the evidence and evaluate its quality, consider patient values and preferences, resource implications, and the feasibility and acceptability of the recommendations. As a result, 11 recommendations and three good practice statements are presented here, including a summary of the supporting evidence, and form the substance of a new WHO IPC guideline

Enzyme‐assisted aqueous extraction of Kalahari melon seed oil: optimization using response surface methodology

Enzymatic extraction of oil from Kalahari melon seeds was investigated and evaluated by response surface methodology (RSM). Two commercial protease enzyme products were used separately: Neutrase® 0.8 L and Flavourzyme® 1000 L from Novozymes (Bagsvaerd, Denmark). RSM was applied to model and optimize the reaction conditions namely concentration of enzyme (20–50 g kg−1 of seed mass), initial pH of mixture (pH 5–9), incubation temperature (40–60 °C), and incubation time (12–36 h). Well fitting models were successfully established for both enzymes: Neutrase 0.8 L (R 2 = 0.9410) and Flavourzyme 1000 L (R 2 = 0.9574) through multiple linear regressions with backward elimination. Incubation time was the most significant reaction factor on oil yield for both enzymes. The optimal conditions for Neutrase 0.8 L were: an enzyme concentration of 25 g kg−1, an initial pH of 7, a temperature at 58 °C and an incubation time of 31 h with constant shaking at 100 rpm. Centrifuging the mixture at 8,000g for 20 min separated the oil with a recovery of 68.58 ± 3.39%. The optimal conditions for Flavourzyme 1000 L were enzyme concentration of 21 g kg−1, initial pH of 6, temperature at 50 °C and incubation time of 36 h. These optimum conditions yielded a 71.55 ± 1.28% oil recovery

Hydroxychloroquine in rheumatic autoimmune disorders and beyond

Initially used as antimalarial drugs, hydroxychloroquine (HCQ) and, to a lesser extent, chloroquine (CQ) are currently being used to treat several diseases. Due to its cost-effectiveness, safety and efficacy, HCQ is especially used in rheumatic autoimmune disorders (RADs), such as systemic lupus erythematosus, primary Sjögren's syndrome and rheumatoid arthritis. Despite this widespread use in the clinic, HCQ molecular modes of action are still not completely understood. By influencing several cellular pathways through different mechanisms, CQ and HCQ inhibit multiple endolysosomal functions, including autophagy, as well as endosomal Toll-like receptor activation and calcium signalling. These effects alter several aspects of the immune system with the synergistic consequence of reducing pro-inflammatory cytokine production and release, one of the most marked symptoms of RADs. Here, we review the current knowledge on the molecular modes of action of these drugs and the circumstances under which they trigger side effects. This is of particular importance as the therapeutic use of HCQ is expanding beyond the treatment of malaria and RADs

Non-monotonic changes in clonogenic cell survival induced by disulphonated aluminum phthalocyanine photodynamic treatment in a human glioma cell line

<p>Abstract</p> <p>Background</p> <p>Photodynamic therapy (PDT) involves excitation of sensitizer molecules by visible light in the presence of molecular oxygen, thereby generating reactive oxygen species (ROS) through electron/energy transfer processes. The ROS, thus produced can cause damage to both the structure and the function of the cellular constituents resulting in cell death. Our preliminary investigations of dose-response relationships in a human glioma cell line (BMG-1) showed that disulphonated aluminum phthalocyanine (AlPcS₂) photodynamically induced loss of cell survival in a concentration dependent manner up to 1 μM, further increases in AlPcS₂concentration (>1 μM) were, however, observed to decrease the photodynamic toxicity. Considering the fact that for most photosensitizers only monotonic dose-response (survival) relationships have been reported, this result was unexpected. The present studies were, therefore, undertaken to further investigate the concentration dependent photodynamic effects of AlPcS₂.</p> <p>Methods</p> <p>Concentration-dependent cellular uptake, sub-cellular localization, proliferation and photodynamic effects of AlPcS₂were investigated in BMG-1 cells by absorbance and fluorescence measurements, image analysis, cell counting and colony forming assays, flow cytometry and micronuclei formation respectively.</p> <p>Results</p> <p>The cellular uptake as a function of extra-cellular AlPcS₂concentrations was observed to be biphasic. AlPcS₂was distributed throughout the cytoplasm with intense fluorescence in the perinuclear regions at a concentration of 1 μM, while a weak diffuse fluorescence was observed at higher concentrations. A concentration-dependent decrease in cell proliferation with accumulation of cells in G₂+M phase was observed after PDT. The response of clonogenic survival after AlPcS₂-PDT was non-monotonic with respect to AlPcS₂concentration.</p> <p>Conclusions</p> <p>Based on the results we conclude that concentration-dependent changes in physico-chemical properties of sensitizer such as aggregation may influence intracellular transport and localization of photosensitizer. Consequent modifications in the photodynamic induction of lesions and their repair leading to different modes of cell death may contribute to the observed non-linear effects.</p

Key issues in the design of pay for performance programs

Pay for performance (P4P) is increasingly being used to stimulate healthcare providers to improve their performance. However, evidence on P4P effectiveness remains inconclusive. Flaws in program design may have contributed to this limited success. Based on a synthesis of relevant theoretical and empirical literature, this paper discusses key issues in P4P-program design. The analysis reveals that designing a fair and effective program is a complex undertaking. The following tentative conclusions are made: (1) performance is ideally defined broadly, provided that the set of measures remains comprehensible, (2) concerns that P4P encourages "selection" and "teaching to the test" should not be dismissed, (3) sophisticated risk adjustment is important, especially in outcome and resource use measures, (4) involving providers in program design is vital, (5) on balance, group incentives are preferred over individual incentives, (6) whether to use rewards or penalties is context-dependent, (7) payouts should be frequent and low-powered, (8) absolute targets are generally preferred over relative targets, (9) multiple targets are preferred over single targets, and (10) P4P should be a permanent component of provider compensation and is ideally "decoupled" form base payments. However, the design of P4P programs should be tailored to the specific setting of implementation, and empirical research is needed to confirm the conclusions

The health disparities cancer collaborative: a case study of practice registry measurement in a quality improvement collaborative

<p>Abstract</p> <p>Background</p> <p>Practice registry measurement provides a foundation for quality improvement, but experiences in practice are not widely reported. One setting where practice registry measurement has been implemented is the Health Resources and Services Administration's Health Disparities Cancer Collaborative (HDCC).</p> <p>Methods</p> <p>Using practice registry data from 16 community health centers participating in the HDCC, we determined the completeness of data for screening, follow-up, and treatment measures. We determined the size of the change in cancer care processes that an aggregation of practices has adequate power to detect. We modeled different ways of presenting before/after changes in cancer screening, including count and proportion data at both the individual health center and aggregate collaborative level.</p> <p>Results</p> <p>All participating health centers reported data for cancer screening, but less than a third reported data regarding timely follow-up. For individual cancers, the aggregate HDCC had adequate power to detect a 2 to 3% change in cancer screening, but only had the power to detect a change of 40% or more in the initiation of treatment. Almost every health center (98%) improved cancer screening based upon count data, while fewer (77%) improved cancer screening based upon proportion data. The aggregate collaborative appeared to increase breast, cervical, and colorectal cancer screening rates by 12%, 15%, and 4%, respectively (p < 0.001 for all before/after comparisons). In subgroup analyses, significant changes were detectable among individual health centers less than one-half of the time because of small numbers of events.</p> <p>Conclusions</p> <p>The aggregate HDCC registries had both adequate reporting rates and power to detect significant changes in cancer screening, but not follow-up care. Different measures provided different answers about improvements in cancer screening; more definitive evaluation would require validation of the registries. Limits to the implementation and interpretation of practice registry measurement in the HDCC highlight challenges and opportunities for local and aggregate quality improvement activities.</p