Cholesterol testing on a smartphone.
Home self-diagnostic tools for blood cholesterol monitoring have been around for over a decade but their widespread adoption has been limited by the relatively high cost of acquiring a quantitative test-strip reader, complicated procedure for operating the device, and inability to easily store and process results. To address this we have developed a smartphone accessory and software application that allows for the quantification of cholesterol levels in blood. Through a series of human trials we demonstrate that the system can accurately quantify total cholesterol levels in blood within 60 s by imaging standard test strips. In addition, we demonstrate how our accessory is optimized to improve measurement sensitivity and reproducibility across different individual smartphones. With the widespread adoption of smartphones and increasingly sophisticated image processing technology, accessories such as the one presented here will allow cholesterol monitoring to become more accurate and widespread, greatly improving preventive care for cardiovascular disease.


A 26-hour system of highly sensitive whole genome sequencing for emergency management of genetic diseases.
While the cost of whole genome sequencing (WGS) is approaching the realm of routine medical tests, it remains too tardy to help guide the management of many acute medical conditions. Rapid WGS is imperative in light of growing evidence of its utility in acute care, such as in diagnosis of genetic diseases in very ill infants, and genotype-guided choice of chemotherapy at cancer relapse. In such situations, delayed, empiric, or phenotype-based clinical decisions may meet with substantial morbidity or mortality. We previously described a rapid WGS method, STATseq, with a sensitivity of >96 % for nucleotide variants that allowed a provisional diagnosis of a genetic disease in 50 h. Here improvements in sequencing run time, read alignment, and variant calling are described that enable 26-h time to provisional molecular diagnosis with >99.5 % sensitivity and specificity of genotypes. STATseq appears to be an appropriate strategy for acutely ill patients with potentially actionable genetic diseases.


Neuromelanin is an immune stimulator for dendritic cells in vitro.
Parkinson's disease (PD) is characterized at the cellular level by a destruction of neuromelanin (NM)-containing dopaminergic cells and a profound reduction in striatal dopamine. It has been shown recently that anti-melanin antibodies are increased in sera of Parkinson patients, suggesting that NM may act as an autoantigen. In this study we tested whether NM is being recognized by dendritic cells (DCs), the major cell type for inducing T- and B-cell responses in vivo. This recognition of NM by DCs is a prerequisite to trigger an adaptive autoimmune response directed against NM-associated structures. Murine DCs were treated with NM of substantia nigra (SN) from human subjects or with synthetic dopamine melanin (DAM). DCs effectively phagocytized NM and subsequently developed a mature phenotype (CD86(high)/MHCII(high)). NM-activated DCs secreted the proinflammatory cytokines IL-6 and TNF-α. In addition, they potently triggered T cell proliferation in a mixed lymphocyte reaction, showing that DC activation was functional to induce a primary T cell response. In contrast, DAM, which lacks the protein and lipid components of NM but mimics the dopamine-melanin backbone of NM, had only very little effect on DC phenotype and function. NM is recognized by DCs in vitro and triggers their maturation. If operative in vivo, this would allow the DC-mediated transport and presentation of SN antigens to the adaptive immune system, leading to autoimmmunity in susceptible individuals. Our data provide a rationale for an autoimmune-based pathomechanism of PD with NM as the initial trigger.


Patterns of health-related quality of life and associated factors in Chinese patients undergoing haemodialysis.
Haemodialysis (HD) is a life-saving but burdensome therapy for patients with end-stage renal disease (ESRD) which can have a detrimental impact on patients' quality of life and outcomes. There is currently little data on the health related quality of life (HRQOL) of Chinese ESRD patients undergoing HD and this study sought to examine the patterns of HRQOL and its associated factors within this population, as well as in comparison with the general local population. A cross-sectional study of 244 ESRD patients receiving HD in the hospital and in the community in Hong Kong was conducted using the Short Form-12 Health Survey version 2 (SF-12v2). All study subjects were one-to-one matched with subjects in a Hong Kong general population database by sex and exact age. Independent t-tests were performed to compare the mean SF-12v2 scores between HD patients and the general population, followed by one-way analysis of variance with post hoc Tukey's HSD tests to compare community-based haemodialysis, hospital-based haemodialysis and the general population. Multiple linear regressions were used to identify the factors (socio-demographic, clinical characteristics and comorbidities) associated with the HRQOL scores of ESRD patients receiving HD. The SF-12v2 Physical Functioning, Role Physical, Bodily Pain, General Health and Physical Component Summary scores of HD patients were significantly lower than the age-sex adjusted general population. However, the SF-12v2 Mental Health and Mental Component Summary scores of HD patients were significantly higher than the corresponding general population. Poorer HRQOL was associated with being female, smoking, unemployment and hospital-based haemodialysis. HD patients had substantially poorer physical HRQOL but better mental HRQOL than the age-sex adjusted general population. Patients receiving HD in the community setting had better HRQOL. Reasons for these observations will need to be further investigated. Those patients who are female, smokers and unemployed may warrant more attention as their poorer HRQOL may be associated with poorer outcomes.


Early-life determinants of overweight and obesity: a review of systematic reviews.
The aim of this paper was to review the evidence for early-life (from conception to 5 years of age) determinants of obesity. The design is review of published systematic reviews. Data sources included Medline, Embase, Web of Science, Cochrane Library, CINAHL, PsycINFO. Identification of 22 eligible reviews from a database of 12,021 independent publications. Quality of selected reviews assessed using the Assessment of Multiple Systematic Reviews score. Articles published after the reviews were used to confirm results. No review was classified as high quality, 11 as moderate and 11 as low. Factors associated with later overweight and obesity: maternal diabetes, maternal smoking, rapid infant growth, no or short breastfeeding, obesity in infancy, short sleep duration, <30 min of daily physical activity, consumption of sugar-sweetened beverages. Other factors were identified as potentially relevant, although the size of their effect is difficult to estimate. Maternal smoking, breastfeeding, infant size and growth, short sleep duration and television viewing are supported by better-quality reviews. It is difficult to establish a causal association between possible determinants and obesity, and the relative importance of each determinant. Future research should focus on early-life interventions to confirm the role of protective and risk factors and to tackle the high burden obesity represents for present and future generations.


Measuring variation in use of the WHO surgical safety checklist in the operating room: a multicenter prospective cross-sectional study.
Full implementation of safety checklists in surgery has been linked to improved outcomes and team effectiveness; however, reliable and standardized tools for assessing the quality of their use, which is likely to moderate their impact, are required. This was a multicenter prospective study. A standardized observational instrument, the "Checklist Usability Tool" (CUT), was developed to record precise characteristics relating to the use of the WHO's surgical safety checklist (SSC) at "time-out" and "sign-out" in a representative sample of 5 English hospitals. The CUT was used in real-time by trained assessors across general surgery, urology, and orthopaedic cases, including elective and emergency procedures. We conducted 565 and 309 observations of the time-out and sign-out, respectively. On average, two-thirds of the items were checked, team members were absent in more than 40% of cases, and they failed to pause or focus on the checks in more than 70% of cases. Information sharing could be improved across the entire operating room (OR) team. Sign-out was not completed in 39% of cases, largely due to uncertainty about when to conduct it. Large variation in checklist use existed between hospitals, but not between surgical specialties or between elective and emergency procedures. Surgical safety checklist performance was better when surgeons led and when all team members were present and paused. We found large variation in WHO checklist use in a representative sample of English ORs. Measures sensitive to checklist practice quality, like CUT, will help identify areas for improvement in implementation and enable provision of comprehensive feedback to OR teams.


Association of Low-Value Testing With Subsequent Health Care Use and Clinical Outcomes Among Low-risk Primary Care Outpatients Undergoing an Annual Health Examination.
The association of low-value testing with downstream care and clinical outcomes among primary care outpatients is unknown to date. To assess the association of low-value testing with subsequent care among low-risk primary care outpatients undergoing an annual health examination (AHE). This population-based retrospective cohort study used administrative health care claims from Ontario, Canada, for primary care outpatients undergoing an AHE between April 1, 2012, and March 31, 2016, to identify individuals who could be placed into one (or more) of the following 3 cohorts: adult patients (18 years or older) at low risk for cardiovascular and pulmonary disease, adult patients at low risk for cardiovascular disease, and female patients (aged 13-20 years or older than 69 years) at low risk for cervical cancer. The dates of analysis were June 3 to September 12, 2019. Low-value screening tests were defined per cohort as (1) a chest radiograph within 7 days, (2) an electrocardiogram (ECG) within 30 days, or (3) a Papanicolaou test within 7 days after an AHE. Subsequent specialist visits, diagnostic tests, and procedures within 90 days after a low-value test (if the patient had a chest radiograph, ECG, or Papanicolaou test) or end of the exposure observation window (if not tested). Included in the chest radiograph, ECG, and Papanicolaou test cohorts of propensity score-matched pairs were 43 532 patients (mean [SD] age, 47.5 [14.4] years; 38.5% female), 245 686 patients (mean [SD] age, 49.9 [13.7] years; 51.1% female), and 29 194 patients (mean [SD] age, 45.5 [27.1] years; 100% female), respectively. At 90 days, chest radiographs in low-risk patients were associated with an additional 0.87 (95% CI, 0.69-1.05) and 1.96 (95% CI, 1.71-2.22) patients having an outpatient pulmonology visit or an abdominal or thoracic computed tomography scan per 100 patients, respectively, and ECGs in low-risk patients were associated with an additional 1.92 (95% CI, 1.82-2.02), 5.49 (95% CI, 5.33-5.65), and 4.46 (95% CI, 4.31-4.61) patients having an outpatient cardiologist visit, a transthoracic echocardiogram, or a cardiac stress test per 100 patients, respectively. At 180 days, Papanicolaou testing in low-risk patients was associated with an additional 1.31 (95% CI, 0.84-1.78), 52.8 (95% CI, 51.9-53.6), and 0.84 (95% CI, 0.66-1.01) patients having an outpatient gynecology visit, a follow-up Papanicolaou test, or colposcopy per 100 patients, respectively. Observed associations in this population-based cohort study suggest that testing in low-risk patients as part of an AHE increases the likelihood of subsequent specialist visits, diagnostic tests, and procedures.


Quality Assessment of the Preanalytical Workflow in Liquid Biobanking: Taurine as a Serum-Specific Quality Indicator for Preanalytical Process Variations.
The scientific impact of translational biomedical research largely depends on the availability of high-quality biomaterials. However, evidence-based and robust quality indicators (QIs) covering the most relevant preanalytical variations are still lacking. The aim of this study was to identify and validate a QI suitable for assessing time-to-centrifugation (TTC) delays in human liquid biospecimens originating from both healthy and diseased individuals. Serum and plasma samples with varying TTCs were analyzed by liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) in a pilot cohort of healthy individuals to identify a suitable QI candidate. Taurine (TAU), as a TTC QI candidate, was validated in healthy individuals and patients with rheumatologic and cardiologic diseases, considering the (1) preanalytical handling temperature, (2) platelet count, and (3) postcentrifugation delay. For discrimination of high TTC (TTC >60 minutes) from low TTC serum specimens, a probability calculation tool was developed (Triple-T-cutoff-model). TTC-dependent changes in healthy individuals were observed for amino acids, particularly TAU. Validation of the TAU levels in an independent cohort of healthy individuals revealed a time-dependent increase in serum, but not in plasma, for a TTC delay of 30-240 minutes. TAU increases were dependent on the handling temperature and platelet count and volume. By contrast, no changes in TAU concentrations were observed for additional postcentrifugation delays. Validation of TAU and the Triple-T-cutoff-model, in rheumatologic/cardiologic patient collectives, allowed the discrimination of samples with TTC ≤60 min/>60 min with estimated AUROC (area under the receiver operating characteristic curve) values of 89% [78%-100%]/86% [71%-100%] and 91% [79%-100%]/84% [68%-100%], respectively. Considering the preanalytical handling temperature and platelet count and volume, TAU and the Triple-T-cutoff-model represent reliable QIs for TTC >60 minutes in serum samples from healthy individuals and selected rheumatologic/cardiologic patients. However, further studies in larger patient collectives with various diseases are needed to assess the robustness and potential of the QIs presented in this article as biobanking quality assurance/quality control tools to support high-quality biomedical research.


Design and application of a data-independent precursor and product ion repository.
The functional design and application of a data-independent LC-MS precursor and product ion repository for protein identification, quantification, and validation is conceptually described. The ion repository was constructed from the sequence search results of a broad range of discovery experiments investigating various tissue types of two closely related mammalian species. The relative high degree of similarity in protein complement, ion detection, and peptide and protein identification allows for the analysis of normalized precursor and product ion intensity values, as well as standardized retention times, creating a multidimensional/orthogonal queryable, qualitative, and quantitative space. Peptide ion map selection for identification and quantification is primarily based on replication and limited variation. The information is stored in a relational database and is used to create peptide- and protein-specific fragment ion maps that can be queried in a targeted fashion against the raw or time aligned ion detections. These queries can be conducted either individually or as groups, where the latter affords pathway and molecular machinery analysis of the protein complement. The presented results also suggest that peptide ionization and fragmentation efficiencies are highly conserved between experiments and practically independent of the analyzed biological sample when using similar instrumentation. Moreover, the data illustrate only minor variation in ionization efficiency with amino acid sequence substitutions occurring between species. Finally, the data and the presented results illustrate how LC-MS performance metrics can be extracted and utilized to ensure optimal performance of the employed analytical workflows.


Multiple K-ras codon 12 mutations in cholangiocarcinomas demonstrated with a sensitive polymerase chain reaction technique.
By using a modified polymerase chain reaction strategy, we have devised an approach to detect a K-ras oncogene mutated at codon 12 in the presence of 1000 normal alleles. This is a considerable improvement in sensitivity on previous assays. Application of this assay to 15 cholangiocarcinomas showed that all contained a K-ras mutation to codon 12 and that nine of the tumors contained two or more mutations. In 11 cases, mutations were present in less than 10% of the cells in the sample. In common with pancreatic adenocarcinomas, in which 75 to 95% of cases contain a mutation in K-ras, cholangiocarcinomas show a very high frequency of ras gene mutation, but within a tumor only a fraction of cells contain a ras mutation. The presence of multiple mutations and the low frequency of mutant alleles in the samples argue against K-ras mutations being the initiating genetic lesion in this tumor, but suggest that ras gene mutation is involved in the stepwise progression of neoplastic cells to full malignancy.


Maximally Localized Radial Profiles for Tight Steerable Wavelet Frames.
A crucial component of steerable wavelets is the radial profile of the generating function in the frequency domain. In this paper, we present an infinite-dimensional optimization scheme that helps us find the optimal profile for a given criterion over the space of tight frames. We consider two classes of criteria that measure the localization of the wavelet. The first class specifies the spatial localization of the wavelet profile, and the second that of the resulting wavelet coefficients. From these metrics and the proposed algorithm, we construct tight wavelet frames that are optimally localized and provide their analytical expression. In particular, one of the considered criterion helps us finding back the popular Simoncelli wavelet profile. Finally, the investigation of local orientation estimation, image reconstruction from detected contours in the wavelet domain, and denoising indicate that optimizing wavelet localization improves the performance of steerable wavelets, since our new wavelets outperform the traditional ones.


Varicella: complications and costs.
Varicella (chickenpox) has long been considered a benign, inevitable disease of childhood. Complications are generally mild and rarely severe, and virtually every individual is infected by adulthood. Infection is associated, however, with a high risk of serious complications in certain high-risk groups, such as leukemic children. Concerns about the severity of varicella in this population have led to the development and testing of a live, attenuated vaccine. Because of the favorable results thus far available, the vaccine may soon be licensed for use in high-risk individuals. The fact that a vaccine may soon be available has led to an increased interest in the potential benefits of a childhood varicella vaccine program. The costs associated with varicella infection in normal persons without a varicella vaccination program have been estimated to be approximately $400 million, 95% of which is the cost of caring for a child at home. Vaccination of normal 15-month-old children with a safe and effective vaccine with long-lasting immunity could reduce the cost by 66% and result in a savings of $7 for every dollar spent on the vaccination program. This assumes that vaccine would be administered only once with measles, mumps, and rubella vaccine, that there would be no increase in the number of varicella cases in older persons who are at increased risk for complications, and that there would be no deleterious effect on the occurrence and severity of herpes zoster.(ABSTRACT TRUNCATED AT 250 WORDS)


Evaluation of acetylcholinesterase and carbonic anhydrase inhibition profiles of 1,2,3,4,6-pentasubstituted-4-hydroxy-cyclohexanes.
Carbonic anhydrase (CA; EC 188.8.131.52) is used for remedial purposes for several years, as there is significant focus on expanding more new activators (CAAs) and high affinity inhibitors. Alzheimer's disease and other similar ailments such as dementia and vascular dementia with Lewy bodies reduce cholinergic activity in the important areas involved in cognition and memory. Prevalent drugs for the symptomatic therapy of dementia are significant in increasing the associated cholinergic deficiency by inhibiting acetylcholinesterase (AChE). These six-membered carbocycles showed nice inhibitory action against AChE and human carbonic anhydrase (hCA) II and I isoforms. The hCA I, II, and AChE were efficiently inhibited by these molecules, with Ki values in the range of 6.70-35.85 nM for hCA I, 18.77-60.84 nM for hCA II, and 0.74-4.60 for AChE, respectively.


Interim results of sentinel node biopsy during laparoscopic gastrectomy: possible role in function-preserving surgery for early cancer.
Intraoperative detection of sentinel nodes (SNs) has been used clinically to predict regional lymph node (LN) metastasis in patients with breast cancer and malignant melanoma. Intraoperative lymphatic mapping and SN biopsy can potentially be combined with minimally invasive surgery. However, few reports have demonstrated the validity of SN biopsy during laparoscopic gastrectomy. The aim of this study was to investigate the feasibility and accuracy of laparoscopic lymphatic mapping in predicting LN status in patients with gastric cancer. A total of 35 patients with gastric cancer diagnosed preoperatively as T1, N0 were enrolled. Endoscopic injection of technetium-99m-radiolabeled tin colloid was completed 16 hours before surgery, and radioactive SNs were identified with a gamma probe intraoperatively. Isosulfan blue dye was injected endoscopically during the operation. Laparoscopy-assisted gastrectomy with LN dissection was performed. All resected LNs were evaluated by routine pathology examination. SNs were detected in 33 (94.3%) of 35 patients. The mean number of SNs was 3.9, and the diagnostic accuracy according to SN status was 97.0% (32/33), as one patient with a false-negative result was observed. The patient with the false-negative specimen was finally diagnosed as having advanced gastric cancer with invasion into the proper muscular layer and severe lymphatic vessel invasion, causing destruction of normal lymphatic flow by the tumor. Radio-guided SN mapping during laparoscopic gastrectomy is an accurate diagnostic tool for detecting lymph node metastasis in patients with early-stage gastric cancer. Validation of this method requires further studies on technical issues, including indications, tracers, methods of lymph node retrieval, and diagnostic modalities of metastasis.


Effects of misestimated far-end boundary values on two common lidar inversion solutions.
Solutions of the lidar equation in both the Klett [Appl. Opt. 20, 211 (1981)] and the Fernald [Appl. Opt. 23, 652 (1984)] approaches include the effect of errors in the estimated boundary value at the far end. In the present study an attempt is made to formulate the effect of the error in the boundary value on the solution of the lidar equation. Using a modified extinction coefficient, we can simplify and unify the error expression of the lidar inversion solution. From the unified error expression and numerical experiments, we found that (a) in the case of overestimation of the boundary value, the discrepancy between the estimated value and the real value decreases near the lidar more rapidly than in the case of underestimation; and (b) the error for the Fernald solution converges to zero more rapidly than the error for the Klett solution, but the convergence of the Fernald solution sometimes shows oscillatory behavior, whereas the convergence of the Klett solution is always monotonic.


The effect of medication samples on self-reported prescribing practices: a statewide, cross-sectional survey.
The pharmaceutical industry spends billions of dollars annually to encourage clinicians to prescribe their medications. Small studies have demonstrated that one of the marketing strategies, the distribution of free sample medications, is associated with increased use of brand name medication over generic medication. To determine the relationship between the presence of drug samples in primary care clinics and prescription of preferred drug treatments. Cross-sectional survey. Primary care prescribers in the state of Vermont. Prescribers were presented with two clinical vignettes and asked to provide the name of the medication they would prescribe in each case. We compared the responses of prescribers with and without samples in their clinics. Two hundred six prescribers out of the total population of 631 returned the survey and met the eligibility criteria. Seventy-two percent of prescribers had sample closets in their clinics. Seventy percent of clinicians with samples would prescribe a thiazide diuretic for hypertension compared to 91% in those without samples (P<0.01). For managing depression 91% of prescribers with samples would have provided a generic medication in a patient with no health insurance, compared to 100% of those without samples in their clinic (P=0.02). Clinicians with samples in their clinics were less likely to prescribe preferred medications for hypertension and depression.


Physics and biology of mobile telephony.
Although safety guidelines--to which mobile telephones and their base-stations conform--do protect against excessive microwave heating, there is evidence that the low intensity, pulsed radiation currently used can exert subtle non-thermal influences. If these influences entail adverse health consequences, current guidelines would be inadequate. This review will focus on this possibility. The radiation used is indeed of very low intensity, but an oscillatory similitude between this pulsed microwave radiation and certain electrochemical activities of the living human being should prompt concern. However, being so inherently dependent on aliveness, non-thermal effects cannot be expected to be as robust as thermal ones, as is indeed found; nor can everyone be expected to be affected in the same way by exposure to the same radiation. Notwithstanding uncertainty about whether the non-thermal influences reported do adversely affect health, there are consistencies between some of these effects and the neurological problems reported by some mobile-telephone users and people exposed longterm to base-station radiation. These should be pointers for future research.


The false alarm hypothesis: Food allergy is associated with high dietary advanced glycation end-products and proglycating dietary sugars that mimic alarmins.
The incidence of food allergy has increased dramatically in the last few decades in westernized developed countries. We propose that the Western lifestyle and diet promote innate danger signals and immune responses through production of "alarmins." Alarmins are endogenous molecules secreted from cells undergoing nonprogrammed cell death that signal tissue and cell damage. High molecular group S (HMGB1) is a major alarmin that binds to the receptor for advanced glycation end-products (RAGE). Advanced glycation end-products (AGEs) are also present in foods. We propose the "false alarm" hypothesis, in which AGEs that are present in or formed from the food in our diet are predisposing to food allergy. The Western diet is high in AGEs, which are derived from cooked meat, oils, and cheese. AGEs are also formed in the presence of a high concentration of sugars. We propose that a diet high in AGEs and AGE-forming sugars results in misinterpretation of a threat from dietary allergens, promoting the development of food allergy. AGEs and other alarmins inadvertently prime innate signaling through multiple mechanisms, resulting in the development of allergic phenotypes. Current hypotheses and models of food allergy do not adequately explain the dramatic increase in food allergy in Western countries. Dietary AGEs and AGE-forming sugars might be the missing link, a hypothesis supported by a number of convincing epidemiologic and experimental observations, as discussed in this article.


Technical Note: Nanometric organic photovoltaic thin film detectors for dose monitoring in diagnostic x-ray imaging.
To fabricate organic photovoltaic (OPV) cells with nanometric active layers sensitive to ionizing radiation and measure their dosimetric characteristics in clinical x-ray beams in the diagnostic tube potential range of 60-150 kVp. Experiments were designed to optimize the detector's x-ray response and find the best parameter combination by changing the active layer thickness and the area of the electrode. The OPV cell consisted of poly (3-hexylthiophene-2,5-diyl): [6,6]-phenyl C61 butyric acid methyl ester photoactive donor and acceptor semiconducting organic materials sandwiched between an aluminum electrode as an anode and an indium tin oxide electrode as a cathode. The authors measured the radiation-induced electric current at zero bias voltage in all fabricated OPV cells. The net OPV current as a function of beam potential (kVp) was proportional to kVp(-0.5) when normalized to x-ray tube output, which varies with kVp. Of the tested configurations, the best combination of parameters was 270 nm active layer thicknesses with 0.7 cm(2) electrode area, which provided the highest signal per electrode area. For this cell, the measured current ranged from approximately 0.7 to 2.4 nA/cm(2) for 60-150 kVp, corresponding to about 0.09 nA-0.06 nA/mGy air kerma, respectively. When compared to commercial amorphous silicon thin film photovoltaic cells irradiated under the same conditions, this represents 2.5 times greater sensitivity. An additional 40% signal enhancement was observed when a 1 mm layer of plastic scintillator was attached to the cells' beam-facing side. Since both OPVs can be produced as flexible devices and they do not require external bias voltage, they open the possibility for use as thin film in vivo detectors for dose monitoring in diagnostic x-ray imaging.


Cost-effectiveness of childhood cancer treatment in Egypt: Lessons to promote high-value care in a resource-limited setting based on real-world evidence.
Childhood cancer in low-and middle-income countries is a global health priority, however, the perception that treatment is unaffordable has potentially led to scarce investment in resources, contributing to inferior survival. In this study, we analysed real-world data about the cost-effectiveness of treating 8886 children with cancer at a large resource-limited paediatric oncology setting in Egypt, between 2013 and 2017, stratified by cancer type, stage/risk, and disease status. Childhood cancer costs (USD 2019) were calculated from a health-system perspective, and 5-year overall survival was used to represent clinical effectiveness. We estimated cost-effectiveness as the cost per disability-adjusted life-year (cost/DALY) averted, adjusted for utility decrement for late-effect morbidity and mortality. For all cancers combined, cost/DALY averted was $1384 (0.5 × GDP/capita), which is very cost-effective according to WHO-CHOICE thresholds. Ratio of cost/DALY averted to GDP/capita varied by cancer type/sub-type and disease severity (range: 0.1-1.6), where it was lowest for Hodgkin lymphoma, and retinoblastoma, and highest for high-risk acute leukaemia, and high-risk neuroblastoma. Treatment was cost-effective (ratio <3 × GDP/capita) for all cancer types/subtypes and risk/stage groups, except for relapsed/refractory acute leukaemia, and relapsed/progressive patients with brain tumours, hepatoblastoma, Ewing sarcoma, and neuroblastoma. Treatment cost-effectiveness was affected by the high costs and inferior survival of advanced-stage/high-risk and relapsed/progressive cancers. Childhood cancer treatment is cost-effective in a resource-limited setting in Egypt, except for some relapsed/progressive cancer groups. We present evidence-based recommendations and lessons to promote high-value in care delivery, with implications on practice and policy. Egypt Cancer Network; NIHR School for Primary Care Research; ALSAC.


[Study on quality of life of asymptomatic HIV infected persons with traditional Chinese medicine].
Study on quality of life of asymptomatic HIV infected persons with traditional Chinese medical, which can provide the clinical basis for improving the quality of life. This study applied a randomized, double-blind, and placeb-parallel control designed method to select 1 200 persons in the asymptomatic period of HIV infection as the subjects. The subjects were randomly divided into the treatment group and the control group at the ratio of about 2:1. According to the results of monthly differential diagnosis of TCM, the test group and the control group were given homologue Chinese drugs preparations and model Chinese drugs. The total study period was 18 months. Using PRO scale and the world health organization AIDS determination of quality of life short scale form (WHOQOL-HIV-BREF) to investigate asymptomatic HIV infected persons, according to different times, we calculated the total score and each domain score of quality of life of the treatment group and control group, we did statistical analysis. Form the PRO scale,we can see that the treatment group showed a trend of stability, compared with the control group with significant statistical difference (P < 0.05) after 6 months; from the WHOQOL-HIV scale analysis, we can see that compared with before treatment, the quality of life of the treatment group was increased, the difference was significant (P < 0.05), but the quality of life of the control quality of life was decreased, the differences was significant (P < 0.05). Dialectical therapy of Chinese medicine can significantly improve the patient's quality of life, which can provide the basis for the prevention and control policy formulation and implementation with asymptomatic HIV infected persons.


Skills, division of labour and economies of scale among Amazonian hunters and South Indian honey collectors.
In foraging and other productive activities, individuals make choices regarding whether and with whom to cooperate, and in what capacities. The size and composition of cooperative groups can be understood as a self-organized outcome of these choices, which are made under local ecological and social constraints. This article describes a theoretical framework for explaining the size and composition of foraging groups based on three principles: (i) the sexual division of labour; (ii) the intergenerational division of labour; and (iii) economies of scale in production. We test predictions from the theory with data from two field contexts: Tsimane' game hunters of lowland Bolivia, and Jenu Kuruba honey collectors of South India. In each case, we estimate the impacts of group size and individual group members' effort on group success. We characterize differences in the skill requirements of different foraging activities and show that individuals participate more frequently in activities in which they are more efficient. We evaluate returns to scale across different resource types and observe higher returns at larger group sizes in foraging activities (such as hunting large game) that benefit from coordinated and complementary roles. These results inform us that the foraging group size and composition are guided by the motivated choice of individuals on the basis of relative efficiency, benefits of cooperation, opportunity costs and other social considerations.


Revision arthroplasty for periprosthetic femoral fracture using an uncemented modular tapered conical stem.
Periprosthetic femoral fracture (PFF) is a potentially devastating complication after total hip arthroplasty, with historically high rates of complication and failure because of the technical challenges of surgery, as well as the prevalence of advanced age and comorbidity in the patients at risk. This study describes the short-term outcome after revision arthroplasty using a modular, titanium, tapered, conical stem for PFF in a series of 38 fractures in 37 patients. The mean age of the cohort was 77 years (47 to 96). A total of 27 patients had an American Society of Anesthesiologists grade of at least 3. At a mean follow-up of 35 months (4 to 66) the mean Oxford Hip Score (OHS) was 35 (15 to 48) and comorbidity was significantly associated with a poorer OHS. All fractures united and no stem needed to be revised. Three hips in three patients required further surgery for infection, recurrent PFF and recurrent dislocation and three other patients required closed manipulation for a single dislocation. One stem subsided more than 5 mm but then stabilised and required no further intervention. In this series, a modular, tapered, conical stem provided a versatile reconstruction solution with a low rate of complications.


Effects of progesterone and norethindrone on female fathead minnow (Pimephales promelas) steroidogenesis.
As knowledge of contaminants capable of adversely modulating endocrine functions increases, attention is focused on the effects of synthetic progestins as environmental endocrine disrupters. In the present study, effects of exposure to a synthetic progestin (norethindrone, 168 ± 7.5 ng/L) and endogenous progestogen (progesterone, 34 ± 4.1 ng/L) on steroidogenesis in adult female fathead minnows were examined. In vivo exposure to either compound lowered expression (nonsignificant) of luteinizing hormone (LHβ) levels in the brain along with significantly down-regulating the beta isoform of membrane progesterone receptor (mPRβ) in ovary tissue. The correspondence between lowered LHβ levels in the brain and mPRβ in the ovary is suggestive of a possible functional association as positive correlations between LHβ and mPR levels have been demonstrated in other fish species. In vitro exposure of ovary tissue to progesterone resulted in significantly elevated progestogen (pregnenolone, 17α-hydroxyprogesterone, and 17α,20β-dihydroxypregnenone) and androgen (testosterone) production. Whereas in vitro exposure to norethindrone did not significantly impact steroid hormone production but showed decreased testosterone production relative to solvent control (however this was not significant). Overall, this study showed that exposure to a natural progestogen (progesterone) and synthetic progestin (norethindrone), was capable of modulating LHβ (in brain) and mPRβ expression (in ovary).


Algorithms for phylogenetic footprinting.
Phylogenetic footprinting is a technique that identifies regulatory elements by finding unusually well conserved regions in a set of orthologous noncoding DNA sequences from multiple species. We introduce a new motif-finding problem, the Substring Parsimony Problem, which is a formalization of the ideas behind phylogenetic footprinting, and we present an exact dynamic programming algorithm to solve it. We then present a number of algorithmic optimizations that allow our program to run quickly on most biologically interesting datasets. We show how to handle data sets in which only an unknown subset of the sequences contains the regulatory element. Finally, we describe how to empirically assess the statistical significance of the motifs found. Each technique is implemented and successfully identifies a number of known binding sites, as well as several highly conserved but uncharacterized regions. The program is available at http://bio.cs.washington.edu/software.html.


The effectiveness and cost-effectiveness of diversion and aftercare programmes for offenders using class A drugs: a systematic review and economic evaluation.
The societal costs of problematic class A drug use in England and Wales exceed £15B; drug-related crime accounts for almost 90% of costs. Diversion plus treatment and/or aftercare programmes may reduce drug-related crime and costs. To assess the effectiveness and cost-effectiveness of diversion and aftercare for class A drug-using offenders, compared with no diversion. Adult class A drug-using offenders diverted to treatment or an aftercare programme for their drug use. Programmes to identify and divert problematic drug users to treatment (voluntary, court mandated or monitored services) at any point within the criminal justice system (CJS). Aftercare follows diversion and treatment, excluding care following prison or non-diversionary drug treatment. Thirty-three electronic databases and government online resources were searched for studies published between January 1985 and January 2012, including MEDLINE, PsycINFO and ISI Web of Science. Bibliographies of identified studies were screened. The UK Drug Data Warehouse, the UK Drug Treatment Outcomes Research Study and published statistics and reports provided data for the economic evaluation. Included studies evaluated diversion in adult class A drug-using offenders, in contact with the CJS. The main outcomes were drug use and offending behaviour, and these were pooled using meta-analysis. The economic review included full economic evaluations for adult opiate and/or crack, or powder, cocaine users. An economic decision analytic model, estimated incremental costs per unit of outcome gained by diversion and aftercare, over a 12-month time horizon. The perspectives included the CJS, NHS, social care providers and offenders. Probabilistic sensitivity analysis and one-way sensitivity analysis explored variance in parameter estimates, longer time horizons and structural uncertainty. Sixteen studies met the effectiveness review inclusion criteria, characterised by poor methodological quality, with modest sample sizes, high attrition rates, retrospective data collection, limited follow-up, no random allocation and publication bias. Most study samples comprised US methamphetamine users. Limited meta-analysis was possible, indicating a potential small impact of diversion interventions on reducing drug use [odds ratio (OR) 1.68, 95% confidence interval (CI) 1.12 to 2.53 for reduced primary drug use, and OR 2.60, 95% CI 1.70 to 3.98 for reduced use of other drugs]. The cost-effectiveness review did not identify any relevant studies. The economic evaluation indicated high uncertainty because of variance in data estimates and limitations in the model design. The primary analysis was unclear whether or not diversion was cost-effective. The sensitivity analyses indicated some scenarios where diversion may be cost-effective. Nearly all participants (99.6%) in the effectiveness review were American (Californian) methamphetamine users, limiting transfer of conclusions to the UK. Data and methodological limitations mean it is unclear whether or not diversion is effective or cost-effective. High-quality evidence for the effectiveness and cost-effectiveness of diversion schemes is sparse and does not relate to the UK. Importantly this research identified a range of methodological limitations in existing evidence. These highlight the need for research to conceptualise, define and develop models of diversion programmes and identify a core outcome set. A programme of feasibility, pilot and definitive trials, combined with process evaluation and qualitative research is recommended to assess the effectiveness and cost-effectiveness of diversionary interventions in class A drug-using offenders. The National Institute for Health Research Health Technology Assessment programme.


Laparoscopic nephron-sparing surgery for the small exophytic renal mass.
Nephron-sparing surgery has emerged as the treatment of choice for the incidentally detected small renal mass, especially those less than 4 cm in size. We describe our technique and experience with the laparoscopic excision of these lesions. Between June 2001 and October 2003, 20 patients underwent nephron-sparing surgery at our institution. Twenty-one laparoscopic partial nephrectomy procedures were performed. All tumors were detected incidentally by cross-sectional imaging. All patients had a solid renal mass or a complex cystic renal mass of Bosniak category III or greater. All solid tumors were exophytic and less than 4cm in diameter. Both transperitoneal and retroperitoneal approaches were used. Hemostasis was achieved without hilar control in 20 of the 21 cases. Twenty renal units were approached transperitoneally, and 1 retroperitoneally. Mean tumor size was 2.6 cm (range, 1.2 to 4). Mean estimated blood loss was 211 mL (range, 50 to 500), and mean operative time was 165 minutes. Pathology revealed renal cell carcinoma in 14 (70%). No intraoperative complications occurred. Two patients required blood transfusions postoperatively. Carefully selected patients with small, exophytic renal masses can safely undergo laparoscopic excision. When achievable, this procedure can be a more logical alternative to ablative techniques for the minimally invasive management of such lesions.


Peripheral blood cell-specific cytokines in persons with untreated HIV infection in Malawi, Africa.
Human immunodeficiency virus (HIV) infection is the primary cause of morbidity and mortality in Malawi, Africa, because of its many effects on the immune system. Immune cells communicate through cytokines; therefore, we examined the relationships between HIV serostatus and cell-specific cytokine production for 40 asymptomatic, employed adults and 312 acutely ill, hospitalized patients in Malawi. We also measured the plasma HIV-1 RNA levels of 13 asymptomatic persons and 83 patients found to be HIV(+). We incubated peripheral whole blood with brefeldin-A +/- phorbol 12-myristate 13-acetate and ionomycin and then permeabilized, fixed, fluorescently stained, and examined the mononuclear cells with four-color, six-parameter flow cytometry. The percentage of lymphocytes expressing CD4 did not differ significantly between the HIV(+) and HIV(-) healthy adults (medians, 35.2 vs. 40.8%, respectively), but a wide array of cytokine parameters were lower in the HIV(+) than in the HIV(-) asymptomatic persons, for example, median percentages of T cells producing induced interleukin 2 (IL-2) (8.7 vs. 16.5%, respectively) and spontaneously producing IL-6 (0.7 vs. 11.0%, respectively). Also, four T cell parameters reflecting type 2-to-type 1 cytokine balances (T2/T1) were higher in the HIV(+), versus HIV(-), asymptomatic persons. Unlike the healthy adults, for patients with mycobacteremia/fungemia or malaria, the HIV(+) patients had higher median percentages of T cells and CD8(+) T cells producing induced interferon gamma than did the HIV(-) PATIENTS: For both asymptomatic and acutely ill persons, HIV-1 plasma levels were positively correlated with T2/T1 parameters. Cell-specific cytokine effects of HIV infection may precede measurable effects on CD4 expression. Cytokine therapies, even beyond periodic administration of IL-2, may improve the responses of HIV-infected persons to both HIV and coinfections.


Use of plant colonizing bacteria as chassis for transfer of N₂-fixation to cereals.
Engineering cereal crops that are self-supported by nitrogen fixation has been a dream since the 1970s when nitrogenase was transferred from Klebsiella pneumoniae to Escherichia coli. A renewed interest in this area has generated several new approaches with the common aim of transferring nitrogen fixation to cereal crops. Advances in synthetic biology have afforded the tools to rationally engineer microorganisms with traits of interest. Nitrogenase biosynthesis has been a recent target for the application of new synthetic engineering tools. Early successes in this area suggest that the transfer of nitrogenase and other supporting traits to microorganisms that already closely associate with cereal crops is a logical approach to deliver nitrogen to cereal crops.


Epithelial IL-33 appropriates exosome trafficking for secretion in chronic airway disease.
IL-33 is a key mediator of chronic airway disease driven by type 2 immune pathways, yet the nonclassical secretory mechanism for this cytokine remains undefined. We performed a comprehensive analysis in human airway epithelial cells, which revealed that tonic IL-33 secretion is dependent on the ceramide biosynthetic enzyme neutral sphingomyelinase 2 (nSMase2). IL-33 is cosecreted with exosomes by the nSMase2-regulated multivesicular endosome (MVE) pathway as surface-bound cargo. In support of these findings, human chronic obstructive pulmonary disease (COPD) specimens exhibited increased epithelial expression of the abundantly secreted IL33Δ34 isoform and augmented nSMase2 expression compared with non-COPD specimens. Using an Alternaria-induced airway disease model, we found that the nSMase2 inhibitor GW4869 abrogated both IL-33 and exosome secretion as well as downstream inflammatory pathways. This work elucidates a potentially novel aspect of IL-33 biology that may be targeted for therapeutic benefit in chronic airway diseases driven by type 2 inflammation.


Uptake of HIV testing and outcomes within a Community-based Therapeutic Care (CTC) programme to treat severe acute malnutrition in Malawi: a descriptive study.
In Malawi and other high HIV prevalence countries, studies suggest that more than 30% of all severely malnourished children admitted to inpatient nutrition rehabilitation units are HIV-infected. However, clinical algorithms designed to diagnose paediatric HIV are neither sensitive nor specific in severely malnourished children. The present study was conducted to assess : i) whether HIV testing can be integrated into Community-based Therapeutic Care (CTC); ii) to determine if CTC can improve the identification of HIV infected children; and iii) to assess the impact of CTC programmes on the rehabilitation of HIV-infected children with Severe Acute Malnutrition (SAM). This community-based cohort study was conducted in Dowa District, Central Malawi, a rural area 50 km from the capital, Lilongwe. Caregivers and children admitted in the Dowa CTC programme were prospectively (Prospective Cohort = PC) and retrospectively (Retrospective Cohort = RC) admitted into the study and offered HIV testing and counseling. Basic medical care and community nutrition rehabilitation was provided for children with SAM. The outcomes of interest were uptake of HIV testing, and recovery, relapse, and growth rates of HIV-positive and uninfected children in the CTC programme. Student's t-test and analysis of variance were used to compare means and Kruskall Wallis tests were used to compare medians. Dichotomous variables were compared using Chi2 analyses and Fisher's exact test. Stepwise logistic regression with backward elimination was used to identify predictors of HIV infection (alpha = 0.05). 1273 and 735 children were enrolled in the RC and PC. For the RC, the average age (SD) at CTC admission was 30.0 (17.2) months. For the PC, the average age at admission was 26.5 (13.7) months. Overall uptake of HIV testing was 60.7% for parents and 94% for children. HIV prevalence in severely malnourished children was 3%, much lower than anticipated. 59% of HIV-positive and 83% of HIV-negative children achieved discharge Weight-For-Height (WFH) > or = 80% of the NCHS reference median (p = 0.003). Clinical algorithms for diagnosing HIV in SAM children had poor sensitivity and specificity. CTC is a potentially valuable entry point for providing HIV testing and care in the community to HIV infected children with SAM.


Mutant TDP-43 does not impair mitochondrial bioenergetics in vitro and in vivo.
Mitochondrial dysfunction has been linked to the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Functional studies of mitochondrial bioenergetics have focused mostly on superoxide dismutase 1 (SOD1) mutants, and showed that mutant human SOD1 impairs mitochondrial oxidative phosphorylation, calcium homeostasis, and dynamics. However, recent reports have indicated that alterations in transactivation response element DNA-binding protein 43 (TDP-43) can also lead to defects of mitochondrial morphology and dynamics. Furthermore, it was proposed that TDP-43 mutations cause oxidative phosphorylation impairment associated with respiratory chain defects and that these effects were caused by mitochondrial localization of the mutant protein. Here, we investigated the presence of bioenergetic defects in the brain of transgenic mice expressing human mutant TDP-43 (TDP-43A315T mice), patient derived fibroblasts, and human cells expressing mutant forms of TDP-43. In the brain of TDP-43A315T mice, TDP-43 mutant fibroblasts, and cells expressing mutant TDP-43, we tested several bioenergetics parameters, including mitochondrial respiration, ATP synthesis, and calcium handling. Differences between mutant and control samples were evaluated by student t-test or by ANOVA, followed by Bonferroni correction, when more than two groups were compared. Mitochondrial localization of TDP-43 was investigated by immunocytochemistry in fibroblasts and by subcellular fractionation and western blot of mitochondrial fractions in mouse brain. We did not observe defects in any of the mitochondrial bioenergetic functions that were tested in TDP-43 mutants. We detected a small amount of TDP-43A315T peripherally associated with brain mitochondria. However, there was no correlation between TDP-43 associated with mitochondria and respiratory chain dysfunction. In addition, we observed increased calcium uptake in mitochondria from TDP-43A315T mouse brain and cells expressing A315T mutant TDP-43. While alterations of mitochondrial morphology and dynamics in TDP-43 mutant neurons are well established, the present study did not demonstrate oxidative phosphorylation defects in TDP-43 mutants, in vitro and in vivo. On the other hand, the increase in mitochondrial calcium uptake in A315T TDP-43 mutants was an intriguing finding, which needs to be investigated further to understand its mechanisms and potential pathogenic implications.


THE ROLE OF TURNING POINTS IN ESTABLISHING BASELINE DIFFERENCES BETWEEN PEOPLE IN DEVELOPMENTAL AND LIFE-COURSE CRIMINOLOGY.
Turning points, between-person differences, and within-person changes have all been linked to desistance from crime. Nevertheless, the means through which between- person differences are frequently captured in life-course criminology makes them intertwined with, and perhaps confounded by, turning points in life. We propose that a new way of capturing the between-person effect-the baseline between-person difference-could benefit theoretically informed tests of developmental and life-course issues in criminology. Because they occur at one time point immediately preceding a turning point in life, we demonstrate that baseline between-person differences establish meaningful theoretical connections to behavior and the way people change over time. By using panel data from the Serious and Violent Offender Reentry Initiative, we estimate models capturing within-person change and baseline between-person differences in social bonds (family support) and differential association (peer criminality) at the time of release from prison. The results demonstrate that baseline levels of family support protect people from postrelease substance use but not from crime. Baseline between- person differences and within-person changes in peer criminality, however, are robustly related to crime and substance use. Collectively, baseline between-person differences seem critical for behavior and within-person change over time, and the results carry implications for reentry-based policy as well as for theory testing in developmental criminology more broadly.


Brain Network Response to Acupuncture Stimuli in Experimental Acute Low Back Pain: An fMRI Study.
Most neuroimaging studies have demonstrated that acupuncture can significantly modulate brain activation patterns in healthy subjects, while only a few studies have examined clinical pain. In the current study, we combined an experimental acute low back pain (ALBP) model and functional magnetic resonance imaging (fMRI) to explore the neural mechanisms of acupuncture analgesia. All ALBP subjects first underwent two resting state fMRI scans at baseline and during a painful episode and then underwent two additional fMRI scans, once during acupuncture stimulation (ACUP) and once during tactile stimulation (SHAM) pseudorandomly, at the BL40 acupoint. Our results showed that, compared with the baseline, the pain state had higher regional homogeneity (ReHo) values in the pain matrix, limbic system, and default mode network (DMN) and lower ReHo values in frontal gyrus and temporal gyrus; compared with the OFF status, ACUP yielded broad deactivation in subjects, including nearly all of the limbic system, pain status, and DMN, and also evoked numerous activations in the attentional and somatosensory systems; compared with SHAM, we found that ACUP induced more deactivations and fewer activations in the subjects. Multiple brain networks play crucial roles in acupuncture analgesia, suggesting that ACUP exceeds a somatosensory-guided mind-body therapy for ALBP.


A Clathrate Crystalline Form of Silica.
The low-density cubic form of silica (impure), melanophlogite, has a clathrate-type structure that incorporates organic molecules, including long straight-chain hydrocarbons. The structure is analogous to that of the clathrate crystalline hydrates of composition 6X.46H(2)O or 8X.46H(2)O. This is the first known example of a silicate framework structure with the pentagonal dodecahedron as a framework element.


Effectiveness of Digital Interventions for Reducing Behavioral Risks of Cardiovascular Disease in Nonclinical Adult Populations: Systematic Review of Reviews.
Digital health interventions are increasingly being used as a supplement or replacement for face-to-face services as a part of predictive prevention. They may be offered to those who are at high risk of cardiovascular disease and need to improve their diet, increase physical activity, stop smoking, or reduce alcohol consumption. Despite the popularity of these interventions, there is no overall summary and comparison of the effectiveness of different modes of delivery of a digital intervention to inform policy. This review aims to summarize the effectiveness of digital interventions in improving behavioral and health outcomes related to physical activity, smoking, alcohol consumption, or diet in nonclinical adult populations and to identify the effectiveness of different modes of delivery of digital interventions. We reviewed articles published in the English language between January 1, 2009, and February 25, 2019, that presented a systematic review with a narrative synthesis or meta-analysis of any study design examining digital intervention effectiveness; data related to adults (≥18 years) in high-income countries; and data on behavioral or health outcomes related to diet, physical activity, smoking, or alcohol, alone or in any combination. Any time frame or comparator was considered eligible. We searched MEDLINE, Embase, PsycINFO, Cochrane Reviews, and gray literature. The AMSTAR-2 tool was used to assess review confidence ratings. We found 92 reviews from the academic literature (47 with meta-analyses) and 2 gray literature items (1 with a meta-analysis). Digital interventions were typically more effective than no intervention, but the effect sizes were small. Evidence on the effectiveness of digital interventions compared with face-to-face interventions was mixed. Most trials reported that intent-to-treat analysis and attrition rates were often high. Studies with long follow-up periods were scarce. However, we found that digital interventions may be effective for up to 6 months after the end of the intervention but that the effects dissipated by 12 months. There were small positive effects of digital interventions on smoking cessation and alcohol reduction; possible effectiveness in combined diet and physical activity interventions; no effectiveness for interventions targeting physical activity alone, except for when interventions were delivered by mobile phone, which had medium-sized effects; and no effectiveness observed for interventions targeting diet alone. Mobile interventions were particularly effective. Internet-based interventions were generally effective. Digital interventions have small positive effects on smoking, alcohol consumption, and in interventions that target a combination of diet and physical activity. Small effects may have been due to the low efficacy of treatment or due to nonadherence. In addition, our ability to make inferences from the literature we reviewed was limited as those interventions were heterogeneous, many reviews had critically low AMSTAR-2 ratings, analysis was typically intent-to-treat, and follow-up times were relatively short. PROSPERO International Prospective Register of Systematic Reviews CRD42019126074; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=126074.


Optical forced oscillation for the study of lectin-glycoprotein interaction at the cellular membrane of a Chinese hamster ovary cell.
We report the application of a set of twin optical tweezers to trap and oscillate a ConA (lectin)- coated polystyrene particle and to measure its interaction with glycoprotein receptors at the cellular plasma membrane of a Chinese hamster ovary (CHO) cell. The particle was trapped between two quadratic potential wells defined by a set of twin optical tweezers and was forced to oscillate by chopping on and off one of the trapping beams. We tracked the oscillatory motion of the particle via a quadrant photodiode and measured with a lock-in amplifier the amplitude of the oscillation as a function of frequency at the fundamental component of the driving frequency over a frequency range from 10Hz to 600Hz. By analyzing the amplitude as a function of frequency for a free particle suspended in buffer solution without the presence of the CHO cell and compared with the corresponding data when the particle was interacting with the CHO cell, we deduced the transverse force constant associated with the optical trap and that associated with the interaction by treating both the optical trap and the interaction as linear springs. The force constants were determined to be approximately 2.15pN/mum for the trap and 2.53pN/mum for the lectin-glycoprotein interaction. When the CHO cell was treated with lantrunculin A, a drug that is known to destroy the cytoskeleton of the cell, the oscillation amplitude increased with time, indicating the softening of the cellular membrane, until a steady state with a smaller force constant was reached. The steady state value of the force constant depended on the drug concentration.


Changing sexual behavior among gay male repeat testers for HIV: a randomized, controlled trial of a single-session intervention.
High-risk sexual behavior is increasingly prevalent among men who have sex with men (MSM) and among men with a history of repeat testing for HIV. The study assessed whether one counseling intervention session focusing on self-justifications (thoughts, attitudes, or beliefs that allow the participant to engage in high-risk sexual behaviors) at most recent unprotected anal intercourse (UAI) is effective in reducing future high-risk behaviors among HIV-negative men. A randomized, controlled, counseling intervention trial was conducted at an anonymous testing site in San Francisco, California, between May 1997 and January 2000. Participants were 248 MSM with a history of at least one previous negative HIV test result and self-reported UAI (receptive or insertive) in the previous 12 months with partners of unknown or discordant HIV status. Two intervention groups received standard HIV test counseling plus a cognitive-behavioral intervention, and two control groups received only standard HIV test counseling. Follow-up evaluation was at 6 and 12 months. Number of episodes of UAI with nonprimary partners (of unknown or discordant HIV status) in the 90 days preceding the interview was measured via self-report during face-to-face interview. A novel counseling intervention focusing on self-justifications significantly decreased the proportion of participants reporting UAI with nonprimary partners of unknown or discordant HIV status at 6 and 12 months (from 66% to 21% at 6 months and to 26% at 12 months, p =.002; p <.001) as compared with a control group when added to standard client-centered HIV counseling and testing. A specific, single-session counseling intervention focusing on a reevaluation of a person's self-justifications operant during a recent occasion of high-risk behavior may prove useful in decreasing individual risk behavior and thus limiting community-level HIV transmission.


Wilms' tumor--lessons and outcomes--a 25-year single center UK experience.
Wilms' tumor (WT) is a common childhood renal cancer. A 25-year single center UK experience is reported. During 1985-2010, 97 children underwent immediate nephrectomy or delayed resection of tumor after chemotherapy. Survival, morbidity, and late effects following treatment are described. Tumor distribution was: Stage I, 25.7% (n = 25); Stage II, 24.7% (n = 24); Stage III, 26.8% (n = 26); Stage IV, 17.5% (n = 17); and Stage V, 5.2% (n = 5). Immediate nephrectomy was performed in 39% (n = 38) patients with elective delayed resection in 61% (n = 59) cases. Ten patients had cavotomy to excise tumor involving vena cava territory. Two cases required cardiopulmonary bypass. Tumor rupture was recorded in eight (8.5%) total operated cases-after immediate (n = 5/37), 13.5% vs delayed nephrectomy-(n = 3/57), 5.2%; X(2) P = .154. From 2001 onwards, one case of tumor rupture was recorded at this center after the universal adoption of UKW3 and SIOP guidelines advocating preoperative chemotherapy and delayed nephrectomy for all WT. Three treatment-related deaths occurred-hepatic veno-occlusive disease (n = 2) with actinomycin D and a single WT fatality due to vascular injury. Overall survival was 84.5% (82/97 cases). Two patients developed "late malignancies" -thyroid cancer and a basal cell carcinoma. This study demonstrates excellent survival for WT comparable with national outcomes and international cooperative studies. Adverse events with chemotherapy and surgery, including "late onset," second malignancies deserve special consideration.


Incidence, Characteristics and Implications of Thromboembolic Events in Patients with Muscle Invasive Urothelial Carcinoma of the Bladder Undergoing Neoadjuvant Chemotherapy.
Neoadjuvant chemotherapy and pelvic surgery are significant risk factors for thromboembolic events. Our study objectives were to investigate the timing, incidence and characteristics of thromboembolic events during and after neoadjuvant chemotherapy and subsequent radical cystectomy in patients with muscle invasive bladder cancer. We performed a multi-institutional retrospective analysis of 761 patients who underwent neoadjuvant chemotherapy and radical cystectomy for muscle invasive bladder cancer from 2002 to 2014. Median followup from diagnosis was 21.4 months (range 3 to 272). Patient characteristics included the Khorana score, and the incidence and timing of thromboembolic events (before vs after radical cystectomy). Survival was calculated using the Kaplan-Meier method. The log rank test and multivariable Cox proportional hazards regression were used to compare survival between patients with vs without thromboembolic events. The Khorana score indicated an intermediate thromboembolic event risk in 88% of patients. The overall incidence of thromboembolic events in patients undergoing neoadjuvant chemotherapy was 14% with a wide variation of 5% to 32% among institutions. Patients with thromboembolic events were older (67.6 vs 64.6 years, p = 0.02) and received a longer neoadjuvant chemotherapy course (10.9 vs 9.7 weeks, p = 0.01) compared to patients without a thromboembolic event. Of the thromboembolic events 58% developed preoperatively and 72% were symptomatic. On multivariable regression analysis the development of a thromboembolic event was not significantly associated with decreased overall survival. However, pathological stage and a high Khorana score were adverse risk factors for overall survival. Thromboembolic events are common in patients with muscle invasive bladder cancer who undergo neoadjuvant chemotherapy before and after radical cystectomy. Our results suggest that a prospective trial of thromboembolic event prophylaxis during neoadjuvant chemotherapy is warranted.


Opposing effects of bacterial endophytes on biomass allocation of a wild donor and agricultural recipient.
Root endophytes are a promising tool for increasing plant growth, but it is unclear whether they perform consistently across plant hosts. We characterized the blue grama (Bouteloua gracilis) root microbiome using two sequencing methods, quantified the effects of root endophytes in the original host (blue grama) and an agricultural recipient, corn (Zea mays), under drought and well-watered conditions and examined in vitro mechanisms for plant growth promotion. 16S rRNA amplicon sequencing revealed that the blue grama root microbiome was similar across an elevation gradient, with the exception of four genera. Culturing and Sanger sequencing revealed eight unique endophytes belonging to the genera Bacillus, Lysinibacillus and Pseudomonas. All eight endophytes colonized corn roots, but had opposing effects on aboveground and belowground biomass in each plant species: they increased blue grama shoot mass by 45% (19) (mean +/- SE) while decreasing corn shoot mass by 10% (19), and increased corn root:shoot by 44% (7), while decreasing blue grama root:shoot by 17% (7). Furthermore, contrary to our expectations, endophytes had stronger effects on plant growth under well-watered conditions rather than drought conditions. Collectively, these results suggest that ecological features, including host identity, bacterial traits, climate conditions and morphological outcomes, should be carefully considered in the design and implementation of agricultural inocula.


Loss of hSef promotes metastasis through upregulation of EMT in prostate cancer.
We have previously reported that the negative signaling regulator Similar Expression to FGF (hSef) is downregulated in prostate cancer and its loss is associated with clinical metastasis. Here, we explored the mechanistic basis of this finding. We first confirmed our clinical observation by testing hSef manipulation in an in vivo metastasis model. hSef stable expressing cells (PC3M-hSef) or empty vector controls (PC3M-EV) were injected subcutaneously into the lateral thoracic walls of NOD-SCID gamma mice and lungs were harvested at autopsy. In this model, 6/7 PC3M-EV xenografts had definitive lung micro-metastasis whilst only 1/6 PC3M-hSef xenografts exhibited metastasis recapitulating the clinical scenario (p = 0.03). Gene expression studies revealed key perturbations in genes involved in cell motility and epithelial to mesenchymal transition (EMT) along with alterations in cognate signaling pathways. These results were validated in an EMT specific PCR array whereby hSef over-expression and silencing reciprocally altered E-Cadherin expression (p = <0.001) amongst other EMT markers. Immunohistochemistry of excised tumors from the xenografts also confirmed the effect of hSef in suppressing E-Cadherin expression at the protein level. Phosphokinase arrays further demonstrated a role for hSef in attenuating signaling of not only ERK-MAPK but also the JNK and p38 pathways as well. Taken together, these data suggest evidence that loss of hSef may be a critical event facilitating tumor dissemination of prostate cancer through alteration of EMT. Detection of downregulated hSef, along with other negative regulators, may therefore be a useful biomarker heralding a transition to a metastatic phenotype and warrants further exploration in this context.


Effects of Beauveria bassiana on survival, blood-feeding success, and fecundity of Aedes aegypti in laboratory and semi-field conditions.
The fungus Beauveria bassiana reduces Aedes aegypti longevity in laboratory conditions, but effects on survival, blood-feeding behavior, and fecundity in realistic environmental conditions have not been tested. Adult, female Ae. aegypti infected with B. bassiana (FI-277) were monitored for blood-feeding success and fecundity in the laboratory. Fungal infection reduced mosquito-human contact by 30%. Fecundity was reduced by (mean ± SD) 29.3 ± 8.6 eggs per female per lifetime in the laboratory; egg batch size and viability were unaffected. Mosquito survival, blood-feeding behavior, and fecundity were also tested in 5 meter × 7 meter × 4 meter semi-field cages in northern Queensland, Australia. Fungal infection reduced mosquito survival in semi-field conditions by 59-95% in large cages compared with 61-69% in small cages. One semi-field cage trial demonstrated 80% reduction in blood-feeding; a second trial showed no significant effect. Infection did not affect fecundity in large cages. Beauveria bassiana can kill and may reduce biting of Ae. aegypti in semi-field conditions and in the laboratory. These results further support the use of B. bassiana as a potential biocontrol agent against Ae. aegypti.


Photocrosslinking using linear polyols in xanthene dye-doped polyvinyl alcohol plates.
A simple and highly efficient system for holographic recording based on a polyvinyl alcohol matrix is presented. A linear polyol is added to the solution made with the polymer and a xanthene dye in order to increase the photoinduced crosslinking rate. The optimization of the film fabrication process is determined experimentally. It is found that the length of the assistant unit, the position and the number of the attached hydroxyl groups is related with the saturation level and the shelf lifetime of the holographic planar grating. Also, host matrix and photoinitiator attributes are significant in the photosensitive medium response.


Alpha-oximono-esters as precursors to heterocycles--generation of oxazinone N-oxides and cycloaddition to alkene dipolarophiles.
Preparation of a series of terminally and internally substituted delta-alkenyl and delta-alkynyl esters 6, 7 and 9, potential precursors to oxazin-2-one nitrones, has been attempted. Condensation between pyruvic or benzoylformic acid and the appropriate alcohol proceeded smoothly in some cases whilst allylic transposition was a major feature in other cases--most especially during reactions with alpha-vinylbenzyl alcohol. Oximation of pyruvic acid derivatives furnished E-oxime isomers whilst benzoylformic acid derivatives afforded mixed geometrical isomers. The E-oxime of 4a1 carrying an internal Me group undergoes facile thermal cyclisation affording nitrones 1c and 1d in good yield. Oximes E-5a,b with a terminal methyl substituent on the alkene moiety furnish nitrone only under the influence of an external electrophile [PhSeBr/AgBF4]. A terminal Ph substituent on 5c,d prohibits formation of the cyclic dipole irrespective of reaction conditions, and whilst 5d reacts to afford a bicyclic isoxazolofuranone 13 by an IOOC reaction (intramolecular oxime olefin cyclisation) 5c remains thermally inert. Finally delta-alkynyl oximes 9c,d also failed to cyclise. The regio- and stereochemical characteristics of the cycloadditions between the new dipoles and electron poor olefinic dipolarophiles have been investigated. The conditions needed for reaction were rather forcing since the dipoles are somewhat stabilised by the adjacent alkoxycarbonyl group. All reactions proceeded regiospecifically to give adducts with 5-substituted isoxazolidine rings whilst diastereoselectivity varied with the choice of dipolarophile and the steric demands of the nitrone substituents. The phenylselenyl dipole 10a could not be trapped by any dipolarophiles bar dimethyl acetylenedicarboxylate.


Doing synchronous online focus groups with young people: methodological reflections.
Although online focus groups are emerging as a worthwhile methodological approach for qualitative researchers, reporting has been constrained in several ways. The majority of studies report asynchronous groups, whereas others employ synchronous exchanges, the efficacy of which with young people has seldom been explored. Considering the popularity of the Internet as a communication tool for young people, this missed opportunity is surprising. Based on a series of synchronous online focus groups with young people, the authors explore why this approach might be an effective way of engaging young people with appearance-related concerns in research. In this article, they discuss the process of hosting and moderating synchronous online focus groups, highlighting some of the ethical, pragmatic, and personal challenges that might face researchers using this method. Through a reflexive approach, they intend to inform and encourage qualitative researchers to consider alternative ways of engaging young people in research.


Whey protein concentrate (WPC) and glutathione modulation in cancer treatment.
The glutathione (GSH) antioxidant system is foremost among the cellular protective mechanisms. Depletion of this small molecule is a common consequence of increased formation of reactive oxygen species during increased cellular activities. This phenomenon can occur in the lymphocytes during the development of the immune response and in the muscular cells during strenuous exercise. It is not surprising that so much research has been done, and is still being done on this small tripeptide molecule. Whey protein concentrate has been shown to represent an effective and safe cysteine donor for GSH replenishment during GSH depletion in immune deficiency states. Cysteine is the crucial limiting amino acid for intracellular GSH synthesis. Animal experiments showed that the concentrates of whey proteins also exhibit anti-carcinogenesis and anticancer activity. They do this via their effect on increasing GSH concentration in relevant tissues, and may have anti-tumor effect on low volume of tumor via stimulation of immunity through the GSH pathway. It is considered that oxygen radical generation is frequently a critical step in carcinogenesis, hence the effect of GSH on free radicals as well as carcinogen detoxification, could be important in inhibiting carcinogenesis induced by a number of different mechanisms. Case reports are presented which strongly suggest an anti-tumor effect of a whey protein dietary supplement in some urogenital cancers. This non toxic dietary intervention, which is not based on the principles of current cancer chemotherapy, will hopefully attract the attention of laboratory and clinical oncologists.


Assaulted and Unheard: Violence Against Healthcare Staff.
Healthcare workers regularly face the risk of violent physical, sexual, and verbal assault from their patients. To explore this phenomenon, a collaborative descriptive qualitative study was undertaken by university-affiliated researchers and a union council representing registered practical nurses, personal support workers, and other healthcare staff in Ontario, Canada. A total of fifty-four healthcare workers from diverse communities were consulted about their experiences and ideas. They described violence-related physical, psychological, interpersonal, and financial effects. They put forward such ideas for prevention strategies as increased staffing, enhanced security, personal alarms, building design changes, "zero tolerance" policies, simplified reporting, using the criminal justice system, better training, and flagging. They reported such barriers to eliminating risks as the normalization of violence; underreporting; lack of respect from patients, visitors, higher status professionals, and supervisors; poor communication; and the threat of reprisal for speaking publicly. Inadequate postincident psychological and financial support compounded their distress.


Reverse micelles as a platform for dynamic nuclear polarization in solution NMR of proteins.
Despite tremendous advances in recent years, solution NMR remains fundamentally restricted due to its inherent insensitivity. Dynamic nuclear polarization (DNP) potentially offers significant improvements in this respect. The basic DNP strategy is to irradiate the EPR transitions of a stable radical and transfer this nonequilibrium polarization to the hydrogen spins of water, which will in turn transfer polarization to the hydrogens of the macromolecule. Unfortunately, these EPR transitions lie in the microwave range of the electromagnetic spectrum where bulk water absorbs strongly, often resulting in catastrophic heating. Furthermore, the residence times of water on the surface of the protein in bulk solution are generally too short for efficient transfer of polarization. Here we take advantage of the properties of solutions of encapsulated proteins dissolved in low viscosity solvents to implement DNP in liquids. Such samples are largely transparent to the microwave frequencies required and thereby avoid significant heating. Nitroxide radicals are introduced into the reverse micelle system in three ways: attached to the protein, embedded in the reverse micelle shell, and free in the aqueous core. Significant enhancements of the water resonance ranging up to ∼-93 at 0.35 T were observed. We also find that the hydration properties of encapsulated proteins allow for efficient polarization transfer from water to the protein. These and other observations suggest that merging reverse micelle encapsulation technology with DNP offers a route to a significant increase in the sensitivity of solution NMR spectroscopy of proteins and other biomolecules.


Reversal of autophagy dysfunction in the TgCRND8 mouse model of Alzheimer's disease ameliorates amyloid pathologies and memory deficits.
Autophagy, a major degradative pathway for proteins and organelles, is essential for survival of mature neurons. Extensive autophagic-lysosomal pathology in Alzheimer's disease brain contributes to Alzheimer's disease pathogenesis, although the underlying mechanisms are not well understood. Here, we identified and characterized marked intraneuronal amyloid-β peptide/amyloid and lysosomal system pathology in the Alzheimer's disease mouse model TgCRND8 similar to that previously described in Alzheimer's disease brains. We further establish that the basis for these pathologies involves defective proteolytic clearance of neuronal autophagic substrates including amyloid-β peptide. To establish the pathogenic significance of these abnormalities, we enhanced lysosomal cathepsin activities and rates of autophagic protein turnover in TgCRND8 mice by genetically deleting cystatin B, an endogenous inhibitor of lysosomal cysteine proteases. Cystatin B deletion rescued autophagic-lysosomal pathology, reduced abnormal accumulations of amyloid-β peptide, ubiquitinated proteins and other autophagic substrates within autolysosomes/lysosomes and reduced intraneuronal amyloid-β peptide. The amelioration of lysosomal function in TgCRND8 markedly decreased extracellular amyloid deposition and total brain amyloid-β peptide 40 and 42 levels, and prevented the development of deficits of learning and memory in fear conditioning and olfactory habituation tests. Our findings support the pathogenic significance of autophagic-lysosomal dysfunction in Alzheimer's disease and indicate the potential value of restoring normal autophagy as an innovative therapeutic strategy for Alzheimer's disease.


Shaping the surface of Borofloat 33 glass with ultrashort laser pulses and a spatial light modulator.
We demonstrate an application of a liquid-crystal-based spatial light modulator (LC-SLM) for the parallel generation of optically smooth structured surfaces on Borofloat 33 glass. In this work, the picosecond laser beam intensity profile of wavelength 515 nm is spatially altered by a LC-SLM, and then delivered to the workpiece in order to generate surface deformations whose shape corresponds to the image generated by the LC display. To ensure that localized melting occurs without ablation, the glass surface is covered by a thin layer of graphite prior to laser treatment to provide increased linear absorption of the laser light. After laser treatment the residual graphite layer is removed using methanol and the whole sample is annealed for 1 h at a temperature of 560 °C, making the laser-induced surface deformations optically smooth.


Sequences adjacent to oriP improve the persistence of Epstein-Barr virus-based episomes in B cells.
Epstein-Barr virus (EBV) oriP and the EBV nuclear antigen 1 (EBNA-1) protein allow persistence of EBV-based episomes. A nuclear matrix attachment region (MAR) spans oriP and the adjacent region of the EBV genome containing the EBV-expressed RNAs. Here, we show that episomes with the MAR are retained significantly more efficiently in EBV-positive B cells than episomes containing oriP alone.


Identifying strategy use in category learning tasks: a case for more diagnostic data and models.
The strength of conclusions about the adoption of different categorization strategies-and their implications for theories about the cognitive and neural bases of category learning-depend heavily on the techniques for identifying strategy use. We examine performance in an often-used "information-integration" category structure and demonstrate that strategy identification is affected markedly by the range of models under consideration, the type of data collected, and model-selection techniques. We use a set of 27 potential models that represent alternative rule-based and information-integration categorization strategies. Our experimental paradigm includes the presentation of nonreinforced transfer stimuli that improve one's ability to discriminate among the predictions of alternative models. Our model-selection techniques incorporate uncertainty in the identification of individuals as either rule-based or information-integration strategy users. Based on this analysis we identify 48% of participants as unequivocally using an information-integration strategy. However, adopting the standard practice of using a restricted set of models, restricted data, and ignoring the degree of support for a particular strategy, we would typically conclude that 89% of participants used an information-integration strategy. We discuss the implications of potentially erroneous strategy identification for the security of conclusions about the categorization capabilities of various participant and patient groups.


Low levels of population genetic structure in Pinus contorta (Pinaceae) across a geographic mosaic of co-evolution.
Population genetic analyses provide information on the population context in which evolutionary processes operate and are important for understanding the evolution of geographically variable traits. Earlier studies showed that cone structure of lodgepole pine in the Rocky Mountains diverged among populations because of geographic variation in coevolutionary interactions involving mammalian and avian seed predators. Analyses of population genetic variation are needed to determine whether this divergence has arisen despite extensive gene flow and whether populations to the east and west of the Rocky Mountains have evolved convergent phenotypes independently. We investigated genetic structuring across 22 stands of lodgepole pine in the central Rocky Mountains and in isolated peripheral populations that experience different seed predators and exhibit parallel divergence in cone traits using a set of nine simple sequence repeats and 235 AFLP loci. Our analyses reveal high levels of genetic diversity within and low genetic differentiation among populations. Nonetheless, geographic and genetic distances were correlated, and isolated populations to the east and west of the Rocky Mountains had higher levels of differentiation than did populations in the central part of the range. These data indicate not only that adaptive divergence of cone traits across a geographic mosaic of coevolution has occurred despite minimal genetic differentiation, but also that isolated populations to the east and west of the Rocky Mountains have evolved distinctive cones independently and in parallel. The population structure quantified here will inform future research aimed at detecting genetic variants associated with divergent adaptive traits.


Vitamin D3 administration induces nuclear p27 accumulation, restores differentiation, and reduces tumor burden in a mouse model of metastatic follicular thyroid cancer.
We have previously demonstrated in vitro that 1alpha,25-dihydroxyvitamin D3 (calcitriol) treatment increases p27 expression and decreases cell proliferation in cultured thyroid carcinoma cell lines. We hypothesized that in vivo treatment with calcitriol would have a beneficial effect on thyroid carcinoma growth and progression. Five x 10(6) WRO (human thyroid follicular carcinoma derived) cells were implanted in the neck in 4- to 5-wk-old female SCID mice in an orthotopic xenograft model. Animals (n = 15) were treated i.p. three times a week for 21 d with 0.75 microg/kg calcitriol or vehicle. Mice were killed 21 d after tumor implantation, tumor volume was measured, and excised tumor tissue was examined by light microscopy and immunohistochemistry for p27 and thyroglobulin reactivity. Average tumor volume in control mice after 21 d of vehicle treatment was 2002 +/- 207 mm3 compared with a mean tumor volume of 1241 +/- 115 mm3 in animals receiving calcitriol, reflecting a 38% reduction in tumor volume size (P < 0.003). Tumors from vehicle-treated animals demonstrated morphological features of epithelial malignancies with characteristics of insular carcinoma and multiple metastases to the lungs. Tumors excised from calcitriol-treated animals demonstrated signs of differentiation with restoration of thyroglobulin staining. This was associated with a marked accumulation of p27 immunoreactivity in the nuclear compartment. These studies demonstrate that in vivo calcitriol administration can effectively restore p27 accumulation in thyroid carcinoma cells, an effect associated with appreciably enhanced cellular differentiation, reduction in tumor burden, and prevention of metastatic growth.


Clinical interpretation: the hermeneutics of medicine.
I argue that clinical medicine can best be understood not as a purified science but as a hermeneutical enterprise: that is, as involved with the interpretation of texts. The literary critic reading a novel, the judge asked to apply a law, must arrive at a coherent reading of their respective texts. Similarly, the physician interprets the 'text' of the ill person: clinical signs and symptoms are read to ferret out their meaning, the underlying disease. However, I suggest that the hermeneutics of medicine is rendered uniquely complex by its wide variety of textual forms. I discuss four in turn: the "experiential text" of illness as lived out by the patient; the "narrative text" constituted during history-taking; the "physical text" of the patient's body as objectively examined; the "instrumental text" constructed by diagnostic technologies. I further suggest that certain flaws in modern medicine arise from its refusal of a hermeneutic self-understanding. In seeking to escape all interpretive subjectivity, medicine has threatened to expunge its primary subject--the living, experiencing patient.


Extended bronchoplasty for locally advanced left lower lobe lung cancer: surgical technique and outcomes.
Extended bronchoplasty combined with left lower lobectomy plus lingulectomy can be indicated for some locally advanced left lower lobe cancers to avoid pneumonectomy, but its outcome has not been well studied. We retrospectively analysed the surgical outcomes of 10 patients since 2008, when we introduced this procedure. The median age was 67 years (range 42-80). Squamous cell carcinoma was the most common histology. The indication for this procedure was bulky or extranodal metastasis in an interlobar node in 9 patients and massive tumour invasion to the lingula in 1 patient. Bronchoplasty was performed by a sleeve (n = 7) or deep-wedge (n = 3) resection of the left main and superior division bronchi, according to the type of tumour extension. One of the sleeve cases resulted in anastomotic kinking and was converted to left pneumonectomy intraoperatively, but no postoperative morbidity or mortality was observed. Locoregional recurrence was not found with a median follow-up of 31 months (range 13-83). This type of extended bronchoplasty can be a safe alternative to left pneumonectomy for left lower lobe cancers invading an interlobar node or lingula in which R0 resection is difficult by a simple or standard sleeve left lower lobectomy.


Acetylcholine receptor clustering and nuclear movement in muscle fibers in culture.
We have studied the formation of acetylcholine receptor (AChR) clusters and the behavior of myonuclei in rat and chick skeletal muscle cells grown in cell culture. These cells were treated with a factor derived from Torpedo electric extracellular matrix, which causes a large increase in their number of AChR clusters. We found that these clusters were located preferentially in membrane regions above myonuclei. This cluster-nucleus colocalization is explained by our finding that most of the nuclei near clusters remain relatively stationary, while most of those away from clusters are able to translocate throughout the myotube. In some cases, clusters clearly formed first, then nuclei migrated underneath and became immobilized. If clustered AChRs later dispersed, their associated nuclei resumed moving. These results suggest that AChR clustering initiates an extensive cytoskeletal rearrangement that causes the subcluster localization of organelles, potentially providing a stable source of newly synthesized AChRs for insertion into the cluster.


Exploring sources of variability in adherence to guidelines across hospitals in low-income settings: a multi-level analysis of a cross-sectional survey of 22 hospitals.
Variability in processes of care and outcomes has been reported widely in high-income settings (at geographic, hospital, physician group and individual physician levels); however, such variability and the factors driving it are rarely examined in low-income settings. Using data from a cross-sectional survey undertaken in 22 hospitals (60 case records from each hospital) across Kenya that aimed at evaluating the quality of routine hospital services, we sought to explore variability in four binary inpatient paediatric process indicators. These included three prescribing tasks and use of one diagnostic. To examine for sources of variability, we examined intra-class correlation coefficients (ICC) and their changes using multi-level mixed models with random intercepts for hospital and clinician levels and adjusting for patient and clinician level covariates. Levels of performance varied substantially across indicators and hospitals. The absolute values for ICCs also varied markedly ranging from a maximum of 0.48 to a minimum of 0.09 across the models for HIV testing and prescription of zinc, respectively. More variation was attributable at the hospital level than clinician level after allowing for nesting of clinicians within hospitals for prescription of quinine loading dose for malaria (ICC = 0.30), prescription of zinc for diarrhoea patients (ICC = 0.11) and HIV testing for all children (ICC = 0.43). However, for prescription of correct dose of crystalline penicillin, more of the variability was explained by the clinician level (ICC = 0.21). Adjusting for clinician and patient level covariates only altered, marginally, the ICCs observed in models for the zinc prescription indicator. Performance varied greatly across place and indicator. The variability that could be explained suggests interventions to improve performance might be best targeted at hospital level factors for three indicators and clinician factors for one. Our data suggest that better understanding of performance and sources of variation might help tailor improvement interventions although further data across a larger set of indicators and sites would help substantiate these findings.


Deletion of the Pseudorabies Virus gE/gI-US9p complex disrupts kinesin KIF1A and KIF5C recruitment during egress, and alters the properties of microtubule-dependent transport in vitro.
During infection of neurons by alphaherpesviruses including Pseudorabies virus (PRV) and Herpes simplex virus type 1 (HSV-1) viral nucleocapsids assemble in the cell nucleus, become enveloped in the cell body then traffic into and down axons to nerve termini for spread to adjacent epithelia. The viral membrane protein US9p and the membrane glycoprotein heterodimer gE/gI play critical roles in anterograde spread of both HSV-1 and PRV, and several models exist to explain their function. Biochemical studies suggest that PRV US9p associates with the kinesin-3 motor KIF1A in a gE/gI-stimulated manner, and the gE/gI-US9p complex has been proposed to recruit KIF1A to PRV for microtubule-mediated anterograde trafficking into or along the axon. However, as loss of gE/gI-US9p essentially abolishes delivery of alphaherpesviruses to the axon it is difficult to determine the microtubule-dependent trafficking properties and motor-composition of Δ(gE/gI-US9p) particles. Alternatively, studies in HSV-1 have suggested that gE/gI and US9p are required for the appearance of virions in the axon because they act upstream, to help assemble enveloped virions in the cell body. We prepared Δ(gE/gI-US9p) mutant, and control parental PRV particles from differentiated cultured neuronal or porcine kidney epithelial cells and quantitated the efficiency of virion assembly, the properties of microtubule-dependent transport and the ability of viral particles to recruit kinesin motors. We find that loss of gE/gI-US9p has no significant effect upon PRV particle assembly but leads to greatly diminished plus end-directed traffic, and enhanced minus end-directed and bidirectional movement along microtubules. PRV particles prepared from infected differentiated mouse CAD neurons were found to be associated with either kinesin KIF1A or kinesin KIF5C, but not both. Loss of gE/gI-US9p resulted in failure to recruit KIF1A and KF5C, but did not affect dynein binding. Unexpectedly, while KIF5C was expressed in undifferentiated and differentiated CAD neurons it was only found associated with PRV particles prepared from differentiated cells.