A survey of factors influencing career preference in new-entrant and exiting medical students from four UK medical schools.
Workforce planning is a central issue for service provision and has consequences for medical education. Much work has been examined the career intentions, career preferences and career destinations of UK medical graduates but there is little published about medical students career intentions. How soon do medical students formulate careers intentions? How much do these intentions and preferences change during medical school? If they do change, what are the determining factors? Our aim was to compare medical students' career preferences upon entry into and exit from undergraduate medical degree programmes. This was a cross-sectional questionnaire survey. Two cohorts [2009-10, 2010-11] of first and final year medical students at the four Scottish graduating medical schools took part in career preference questionnaire surveys. Questions were asked about demographic factors, career preferences and influencing factors. The response rate was 80.9% [2682/3285]. Significant differences were found across the four schools, most obviously in terms of student origin [Scotland, rest of UK or overseas], age group, and specialty preferences in Year 1 and Year 5. Year 1 and Year 5 students' specialty preferences also differed within each school and, while there were some common patterns, each medical school had a different profile of students' career preferences on exit. When the analysis was adjusted for demographic and job-related preferences, specialty preferences differed by gender, and wish for work-life balance and intellectual satisfaction. This is the first multi-centre study exploring students' career preferences and preference influences upon entry into and exit from undergraduate medical degree programmes. We found various factors influenced career preference, confirming prior findings. What this study adds is that, while acknowledging student intake differs by medical school, medical school itself seems to influence career preference. Comparisons across medical school populations must therefore control for differences in input [the students] as well as context and process [the medical school] when looking at output [e.g., performance]. A robust, longitudinal study is required to explore how medical students' career preferences change as they progress through medical school and training to understand the influence of the learning environment on training choice and outcomes.


Light-evoked contraction of the photosensitive iris of the frog.
Smooth muscle cells of the frog iris sphincter contain rhodopsin and contract in response to light. The mechanism of light-evoked contraction was studied with particular attention paid to the role of calcium. The contractile proteins of the sphincter smooth muscle cell can be activated by an increase in intracellular calcium. Light-evoked contraction, however, is not accompanied by a measurable change in membrane potential and occurs in the absence of extracellular Na+ and/or Ca2+, as well as in the presence of isotonic KCI. Maximum light-evoked tension is reduced by exposure to Ca2+-free solutions containing EGTA and high K+ and is restored by incubation in solutions containing Ca2+. The restored response, which persists after return to Ca2+-free solution, depends on the concentration of Ca2+ in the incubating solution and on the duration of the incubation. The results support the conclusion that light produces contraction of the iris sphincter by causing the release of Ca2+ from an intracellular storage site.


Vulnerability in the context of HIV and syphilis infection in a population of men who have sex with men (MSM) in Salvador, Bahia State, Brazil.
Social, individual, and programmatic vulnerability of men who have sex with men (MSM) in the context of the HIV epidemic and other sexually transmitted infections (STI) is a reality in many countries. The survey Behavior, Attitudes, Practices, and Prevalence of HIV and Syphilis in Men Who Have Sex with Men in 10 Brazilian Cities selected 383 MSM in the city of Salvador, Bahia State, Brazil, using the respondent driven sampling (RDS) technique. Individual vulnerability early sexual initiation (51%), average of eight sex partners, and unprotected receptive anal sex with casual (32%) and steady partners (45%) and positive rapid tests HIV (6.5%) and syphilis (9%). Social vulnerability young adults (80%), black race/skin color (91%), mean monthly family income of BRL 1,000.00, and personal history of discrimination (57%). Programmatic factors no previous HIV test (63%) and no access to lubricant gel (88%). The study showed a profile of vulnerability and the urgent need for interventions and STI prevention in the MSM population in Salvador, in addition to high prevalence rates for HIV and syphilis.


Association of Daily Intellectual Activities With Lower Risk of Incident Dementia Among Older Chinese Adults.
Associations between late-life participation in intellectual activities and decreased odds of developing dementia have been reported. However, reverse causality and confounding effects due to other health behaviors or problems have not been adequately addressed. To examine whether late-life participation in intellectual activities is associated with a lower risk of incident dementia years later, independent of other lifestyle and health-related factors. A longitudinal observational study was conducted at all Elderly Health Centres of the Department of Health of the Government of Hong Kong among 15 582 community-living Chinese individuals age 65 years or older at baseline who were free of dementia, with baseline evaluations performed January 1 to June 30, 2005, and follow-up assessments performed from January 1, 2006, to December 31, 2012. Statistical analysis was performed from January 1, 2015, to December 31, 2016. The main outcome was incident dementia as diagnosed by geriatric psychiatrists in accordance with the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, or a Clinical Dementia Rating of 1 to 3. At baseline and follow-up interviews, self-reported information on participation in intellectual activities within 1 month before assessment was collected. Examples of intellectual activities, which were described by a local validated classification system, were reading books, newspapers, or magazines; playing board games, Mahjong, or card games; and betting on horse racing. Other important variables including demographics (age, sex, and educational level), physical and psychiatric comorbidities (cardiovascular risks, depression, visual and hearing impairments, and poor mobility), and lifestyle factors (physical exercise, adequate fruit and vegetable intake, smoking, and recreational and social activities) were also assessed. Of the 15 582 individuals in the study, 9950 (63.9%) were women, and the median age at baseline was 74 years (interquartile range, 71-77 years). A total of 1349 individuals (8.7%) developed dementia during a median follow-up period of 5.0 years. Multivariable logistic regression analysis showed that the estimated odds ratio for incident dementia was 0.71 (95% CI, 0.60-0.84; P < .001) for those with intellectual activities at baseline, after excluding those who developed dementia within 3 years after baseline and adjusting for health behaviors, physical and psychiatric comorbidities, and sociodemographic factors. Active participation in intellectual activities, even in late life, might help delay or prevent dementia in older adults.


Recent advances in the direct functionalization of quinoxalin-2(1H)-ones.
The direct C3-functionalization of quinoxalin-2(1H)-ones via C-H bond activation has recently attracted considerable attention, due to their diverse biological activities and chemical properties. This review will focus on the recent achievements, mainly including arylation, alkylation, acylation, alkoxycarbonylation, amination, amidation and phosphonation of quinoxalin-2(1H)-ones. Their mechanisms are also discussed.


Essential fatty acids and their role in the treatment of impulsivity disorders.
Essential fatty acids (EFAs) have been shown to benefit patients with depression, schizophrenia and dementia. More recently, their role in disorders characterised by impulsivity has attracted some attention. The psychiatric conditions of attention-deficit hyperactivity disorder and borderline personality disorder as well as the phenomena of deliberate self-harm and violence have been ameliorated by the supplementation of EFAs in a number of recent clinical trials. This paper summarises the burgeoning clinical and basic research indicating the existence of significant deficits of EFAs in impulsivity disorders and the supplementation studies of EFAs in these diverse conditions, all of which remain a major therapeutic challenge.


Independent and Joint Use of Statins and Metformin by Elderly Patients With Diabetes and Overall Survival Following HCC Diagnosis.
To investigate associations of prediagnosis and postdiagnosis use of statins and metformin on overall survival of patients with diabetes who later developed HCC. Statins and metformin have received considerable interest as potential chemopreventive agents against hepatocellular carcinoma (HCC) development in individuals with type 2 diabetes mellitus (T2DM); however, their impact on overall survival of patients with T2DM who later develop HCC (diabetic HCC patients) is unclear. Data on 2499 elderly diabetic HCC patients obtained from the SEER-Medicare program (2009 to 2013) were analyzed. Patients were categorized based on use of statins only, metformin only, both, or neither (reference for all comparisons). The patients were further categorized based on: (1) metformin dose: ≤1500 or >1500 mg/d; (2) statins functional form: hydrophilic (pravastatin and rosuvastatin) or lipophilic (atorvastatin, fluvastatin, lovastatin, and simvastatin); (3) statins potency: high (atorvastatin, rosuvastatin, and simvastatin) or low (fluvastatin, lovastatin, and pravastatin); and (4) individual statins type. Multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (CIs) were calculated using Cox proportional hazard models. Prediagnosis use of metformin dose ≤1500 mg/d was associated with lower risk of death after HCC diagnosis in patients with T2DM (HR, 0.72; 95% CI, 0.58-0.91), adjusting for postdiagnosis metformin dose, diabetes severity, Charlson comorbidity index, tumor characteristics, and other relevant factors. No association was found for prediagnosis metformin dose >1500 mg/d or postdiagnosis metformin use. Further, no association was found for either prediagnosis or postdiagnosis statins use. Prediagnosis use of metformin dose ≤1500 mg/d is associated with longer overall survival of elderly diabetic HCC patients.


Transfection of live, tick derived sporozoites of the protozoan Apicomplexan parasite Theileria parva.
Theileria parva is an important veterinary protozoan causing the tick-borne disease East Coast fever. Transfection of Theileria parasites will facilitate the investigation of many aspects of this apicomplexan infection and its unique host-parasite interaction. The pathogen has the extraordinary capacity of transforming B and T cells into clonally dividing cancerous cell lines in a reversible way. Sequence data of the entire T. parva genome are available and in vitro infected cell lines can easily be generated, thereby eliminating the use of animals in the evaluation of the evolution of the transfected sporozoites. Here we report, for the first time, on experiments towards successful transient transfection of T. parva sporozoites, making use of a new generation transfection device. Plasmid DNA containing the strong EF-1α promoter and an Azami Green reporter gene were integrated by nucleofection into freshly purified T. parva sporozoites. Expression of Azami Green was detected with a fluorescence microscope and confirmed by counter staining with a monoclonal directed against a sporozoite protein. Despite the fact that transfection efficiencies are still low, this is the first step towards a stable infection method of T. parva parasites. In the long run, transfected parasites might become an alternative way to induce immunity without clinical signs.


Topical NSAIDs for acute musculoskeletal pain in adults.
Use of topical NSAIDs to treat acute musculoskeletal conditions has become widely accepted because they can provide pain relief without associated systemic adverse events. This review is an update of 'Topical NSAIDs for acute pain in adults' originally published in Issue 6, 2010. To determine the efficacy and safety of topically applied NSAIDs in acute musculoskeletal pain in adults. We searched the Cochrane Register of Studies Online, MEDLINE, and EMBASE to February 2015. We sought unpublished studies by asking personal contacts and searching online clinical trial registers and manufacturers websites. For the earlier review, we also searched our own in-house database and contacted manufacturers. We included randomised, double-blind, active or placebo (inert carrier)-controlled trials in which treatments were administered to adults with acute pain resulting from strains, sprains or sports or overuse-type injuries (twisted ankle, for instance). There had to be at least 10 participants in each treatment arm, with application of treatment at least once daily. Two review authors independently assessed studies for inclusion, and extracted data. We used numbers of participants achieving each outcome to calculate the risk ratio and numbers needed to treat for an additional beneficial outcome (NNT) or additional harmful outcome (NNH) compared with placebo or other active treatment. We reported 95% confidence intervals (CI). We were particularly interested to compare different formulations (gel, cream, plaster) of individual NSAIDs. For this update we added 14 new included studies (3489 participants), and excluded four studies. We also identified 20 additional reports of completed or ongoing studies that have not been published in full. The earlier review included 47 studies.This update included 61 studies. Most compared topical NSAIDs in the form of a gel, spray, or cream with a similar topical placebo; 5311 participants were treated with a topical NSAID, 3470 with placebo, and 220 with an oral NSAID. This was a 63% increase in the number of included participants over the previous version of this review. We also identified a number of studies in clinical trial registries with unavailable results amounting to about 5900 participants for efficacy and 5300 for adverse events.Formulations of topical diclofenac, ibuprofen, ketoprofen, piroxicam, and indomethacin demonstrated significantly higher rates of clinical success (more participants with at least 50% pain relief) than matching topical placebo (moderate or high quality data). Benzydamine did not. Three drug and formulation combinations had NNTs for clinical success below 4. For diclofenac, the Emulgel® formulation had the lowest NNT of 1.8 (95% CI 1.5 to 2.1) in two studies using at least 50% pain intensity reduction as the outcome. Diclofenac plasters other than Flector® also had a low NNT of 3.2 (2.6 to 4.2) based on good or excellent responses in some studies. Ketoprofen gel had an NNT of 2.5 (2.0 to 3.4), from five studies in the 1980s, some with less well defined outcomes. Ibuprofen gel had an NNT of 3.9 (2.7 to 6.7) from two studies with outcomes of marked improvement or complete remission. All other drug and formulation combinations had NNT values above 4, indicating lesser efficacy.There were insufficient data to compare reliably individual topical NSAIDs with each other or the same oral NSAID.Local skin reactions were generally mild and transient, and did not differ from placebo (high quality data). There were very few systemic adverse events (high quality data) or withdrawals due to adverse events (low quality data). Topical NSAIDs provided good levels of pain relief in acute conditions such as sprains, strains and overuse injuries, probably similar to that provided by oral NSAIDs. Gel formulations of diclofenac (as Emugel®), ibuprofen, and ketoprofen, and some diclofenac patches, provided the best effects. Adverse events were usually minimal.Since the last version of this review, the new included studies have provided additional information. In particular, information on topical diclofenac is greatly expanded. The present review supports the previous review in concluding that topical NSAIDs are effective in providing pain relief, and goes further to demonstrate that certain formulations, mainly gel formulations of diclofenac, ibuprofen, and ketoprofen, provide the best results. Large amounts of unpublished data have been identified, and this could influence results in updates of this review.


Pharmacogenetics of antiangiogenic and antineovascular therapies of age-related macular degeneration.
Age-related macular degeneration (AMD), the most common age-related disease causing irreversible visual loss in industrialized countries, is a complex and multifactorial illness. Researchers have found components of the complement alternative pathway inside drusen and Bruch's membrane of AMD patients, underlying a possible important role of complement factor H in the pathogenesis of AMD. The neovascular (wet) AMD is the most destructive form and it is characterized by invasion of new blood vessels into subretinal spaces with subsequent exudation and bleeding, resulting in scarring of the macular region and loss of the central vision. The hallmark of the neovascular form is the choroidal neovascularization, where VEGF-A has an important role in the pathogenesis of the disease. SNPs of these genes have recently been investigated as potential pharmacogenetic markers of the antiangiogenic and antineovascular therapy of AMD, which includes verteporfin photodynamic therapy and anti-VEGF-A drugs, such as pegaptanib, bevacizumab and ranibizumab. The CFH rs1061170 CT and TT genotypes have been associated with an improvement of visual acuity in bevacizumab or ranibizumab treated patients, whereas patients harboring VEGF-A rs699946 G allele responded better to bevacizumab-based therapy if compared with patients carrying the A allele. In conclusion, the discovery of pharmacogenetic markers for the personalization of the antiangiogenic and/or antineovascular therapy could be, in the future, a key issue in ophthalmology to obtain a personalization of the therapy and to avoid unnecessary costs and adverse drug reactions.


Deleterious Effects of Molting on the Morpho-physiology of Japanese Quail Layers (Coturnix japonica).
Molting is a natural physiological phenomenon involving the periodic replacement of old feathers with new ones in the avian species. During mid-November an extensive loss of feathers in Japanese quail was observed in our breeding colony. The cause of molting could not be established, however, lower ambient temperatures may have played a major role and the decrease in day length could not be ruled out as a contributing factor. This study was conducted to correlate some aspects of the molting process using various physiological and morphometric parameters. Forty healthy 125-days old layers, hatch-mates, of approximately similar body weights (130.0±3.9 g) and in peak production were used for cohort evaluation of the molting process. Most of the birds lost feathers extensively from the cervical, thorax and dorsum areas, while some did not molt and continued laying eggs as usual, serving as a premolting control group. The molting birds drastically lost body weight weighing on average 117.5 g compared to 130.0 g in the control group and ceased egg production completely. There was a significant increase in blood glucose (293.03 mg/dL vs. 222.11 mg/dL), an increase in PCV values (47.14% vs. 41.43%) and a decrease in total plasma proteins (3.5 g/dl vs. 5.56 g/dl) and oviducts (1.55 g vs. 5.78 g, a decrease of 73.2%). Ovarian follicles underwent atresia and resorption. Birds that recovered from the molt resumed egg production and regained their body weights showing similar morpho-physiological measures of the control values, which changed during the molting phase. Scientists working with Japanese quail should be fully aware of the physiology of the molting process and its impact on on-going studies involving growth, physiology, endocrinology, nutrition, reproduction and toxicology.


[Arterial vascularization of the sino-auricular node of the heart in dogs].
In order to study the arterial blood supply of the sinus atrial node in the Dog, the authors have performed the post-mortem injection of the arterial branches going to this node. They observed 65 cases and they came to the following conclusions: in 31 cases (47.7%) the sinus atrial node is supplied by the artery of the sinus atrial node and by the anterior atrial artery, branch of the circumflex; in 20 cases (30.8%) besides the two arteries already mentioned there was also the anterior branch from the first portion of the right coronary artery; in 13 cases (20%) the sinus atrial node was exclusively supplied by the artery of the sinus atrial node and in one case (1.5%) it was supplied only by the first anterior atrial branch of the circumflex artery. Their findings are different from those of other authors and they attribute the failure in provoking experimental ischemia of the sinus atrial node in the Dog, to the rich blood supply of this node and to the different origins of the vessels supplying it.


Orchidectomy and oestrogen therapy revisited.
Over the past 20 years therapeutic options for prostate cancer have increased. Nevertheless, there may still be a role for long-established treatments such as orchidectomy and oestrogens. Orchidectomy is a simple surgical procedure, and patient survival is comparable with other treatments involving androgen ablation. However, loss of libido and sexual function is an expected outcome and hot flushes occur in about 50% of patients. Osteoporosis, loss of muscle mass, and the psychological impact associated with orchidectomy are of concern, particularly with increasing treatment periods. Nevertheless, orchidectomy is indicated when an immediate reduction of testosterone levels is required, or the patient does not comply with other treatments or objects to the cost of medical therapy. Oestrogen therapy may be superior to castration in terms of efficacy, but orally administered oestrogens are associated with gynaecomastia, loss of sexual function and unacceptable cardiovascular toxicity. Low dose oestrogens in combination with antiandrogens or antithrombotic agents may be better tolerated treatments. The route of administration is a crucial factor in the genesis of cardiovascular toxicity and parenterally administered oestrogens may not entail the same risk. Further research in this area is warranted.


Multifactorial Causation of Alzheimer's Disease Due to COVID-19.
There are several implications of the surge in the incidence of pandemics and epidemics in the last decades. COVID-19 being the most remarkable one, showed the vulnerability of patients with neurodegenerative diseases like Alzheimer's disease (AD). This review studies the pathological interlinks and triggering factors between the two illnesses and proposes a multifactorial pathway of AD causation due to COVID-19. The article evaluates and describes all the postulated hypotheses which explain the etiology and possible pathogenesis of the disease in four domains: Inflammation & Neurobiochemical interactions, Oxidative Stress, Genetic Factors, and Social Isolation. We believe that a probable hypothesis of an underlying cause of AD after COVID-19 infection could be the interplay of all these factors.


Integrated analysis from multi-center studies identities m7G-derived modification pattern and risk stratification system in skin cutaneous melanoma.
The m7G modification has been proven to play an important role in RNA post-transcriptional modification and protein translation. However, the potential role of m7G modification patterns in assessing the prognosis of Skin cutaneous melanoma (SKCM) and tumor microenvironment (TME) has not been well studied. In this study, we investigated and finally identified 21 available m7G-related genes. We used hierarchical clustering (K-means) to classify 743 SKCM patients into three m7G-modified subtypes named m7G/gene cluster-A, B, C. We found that both m7G cluster B and gene cluster B exhibited higher prognosis and higher immune cell infiltration in TME compared to other subtypes. EIF4E3 and IFIT5, two m7G related genes, were both markedly elevated in Cluster B. Then, we constructed an m7G score system utilizing principal component analysis (PCA) in order to evaluate the patients' prognosis. High m7G score subtype was associated with better survival prognosis and active immune response. Overall, this article revealed that m7G modification patterns were involved in the development of the tumor microenvironment. Evaluating patients' m7G modification patterns will enhance our understanding of TME characteristics and help to guide personal treatment in clinics in the future.


Current and emerging techniques in gastrointestinal imaging.
This review is devoted to current and emerging techniques in gastrointestinal (GI) imaging. It is divided into three sections focusing on areas that are both interesting and challenging: imaging of the small bowel and appendix, imaging of the colon and rectum and finally liver and pancreas in the upper abdomen. The first section covers cross-sectional imaging of the small bowel using the techniques of multidetector computed tomography (MDCT) (including CT enterography) and magnetic resonance imaging (MRI). The evaluation of mesenteric ischemia and GI tract bleeding using MDCT angiography is also reviewed. Current imaging practice in the evaluation of appendix is also reviewed and illustrated. The second section reviews CT and MR colonography and imaging of the rectum. It describes CT virtual colonoscopy (CTVC) with emphasis on the advantages and disadvantages of the technique with discussion of the role of CTVC in screening. The intriguing topic of MR colonography (MRC) is also reviewed. Imaging of the rectum with emphasis on imaging of rectal cancer is described with the roles of CT, MR, endoluminal ultrasound and positron emission tomography scanning discussed. The final section reviews current and emerging techniques in liver imaging with the role of ultrasound including contrast ultrasound, MDCT and MR (including contrast agents) discussed. The new developments and applications of imaging of pancreatic disease are discussed with emphasis on the role of MDCT and MRI with gadolinium. This review highlights the current role and advancement of imaging techniques with new diagnostic and prognostic information pertinent to gastrointestinal disease continuing to emerge.


Fixed-density boundary conditions in overdamped Langevin simulations of diffusion in channels.
We consider the numerical integration of Langevin equations for particles in a channel, in the presence of boundary conditions fixing the concentration values at the ends. This kind of boundary condition appears, for instance, when considering the diffusion of ions in molecular channels, between the different concentrations at both sides of the cellular membrane. For this application the overdamped limit of Brownian motion (leading to a first order Langevin equation) is most convenient, but in previous works some difficulties associated with this limit were found for the implementation of the boundary conditions. We derive here an algorithm that, unlike previous attempts, does not require the simulation of particle reservoirs or the consideration of velocity variables or adjustable parameters. Simulations of Brownian particles in simple cases show that results agree perfectly with theory, both for the local concentration values and for the resulting particle flux in nonequilibrium situations. The algorithm is appropriate for the modeling of more complex ionic channels and, in general, for the treatment of analogous boundary conditions in other physical models using first order Langevin equations.


Role of immune activation in HIV pathogenesis.
T-cell activation has long been considered a central mediator of HIV pathogenesis. High T-cell activation levels predict more rapid disease progression in untreated patients and decreased treatment-mediated CD4+ T-cell gains during antiretroviral therapy, independent of plasma HIV RNA levels, and may be the primary feature distinguishing pathogenic from nonpathogenic primate models of HIV infection. Studies in animal models and individuals with HIV infection continue to enhance our understanding of how T-cell activation causes immunodeficiency during HIV infection. The goal of these studies is to identify specific mechanisms that can be targeted by novel immune-based therapies for patients who have thus far been unable to recover normal immune function despite years of antiretroviral therapy. Although most immune-based therapies targeting T-cell activation have been unsuccessful to date, recent scientific developments have focused attention on specific pathways that may be exploited by future generations of immune-based therapies.


Immunologic studies with ethylene oxide-treated human serum.
The antigenicity of an ethylene oxide-treated human serum in humans has been studied. The immune response to the material had many of the characteristics of a delayed cellular skin reaction. Even after repeated immunizations by intradermal skin testing over a period of 1(1/2) years, no detectable antibody could be found in the sera. The antigenicity has been shown to be associated with drastic alteration of the homologous serum proteins as evidenced by (a) the formation of new proteins, and (b) the poor cross-reactions of the modified serum proteins with antisera against normal human serum albumin and normal human gamma globulin. The delayed hypersensitivity was transferable to normal recipients by either viable or killed leukocytes. The implications of these findings have been discussed with respect to the problem of sterilization of sera, the tuberculin reaction, and autoimmune phenomena.


Planctomicrobium piriforme gen. nov., sp. nov., a stalked planctomycete from a littoral wetland of a boreal lake.
An aerobic, budding, non-pigmented and rosette-forming bacterium was isolated from a littoral wetland of a boreal lake located in Valaam Island, northern Russia, and designated strain P3(T). Ellipsoidal to pear-shaped cells of this bacterium were covered with crateriform pits and possessed stalks suggesting a planctomycete morphotype. 16S rRNA gene sequence analysis confirmed that strain P3(T) was a member of the order Planctomycetales and belonged to a phylogenetic lineage defined by the genus Planctomyces , with 89 and 86% sequence similarity to Planctomyces brasiliensis and Planctomyces maris , respectively. Strain P3(T) was a mildly acidophilic, mesophilic organism capable of growth at pH values between pH 4.2 and 7.1 (with an optimum at pH 6.0-6.5) and at temperatures between 10 and 30 °C (optimum at 20-28 °C). Most sugars, a number of polysaccharides and several organic acids were the preferred growth substrates. Compared with Planctomyces brasiliensis and Planctomyces maris , which require NaCl for growth, strain P3(T) was salt-sensitive and did not develop at NaCl concentrations above 0.5% (w/v). The major fatty acids were C16 : 0 and C16 : 1ω7c; the cells also contained significant amounts of C18 : 1ω7c and C18 : 0. The major intact polar lipids were diacylglycerol-O-(N,N,N-trimethyl)homoserine (DGTS) lipids; the major neutral lipids were long-chain 1,(ω-1)-diols and C31 : 9 hydrocarbon. The quinone was MK-6, and the G+C content of the DNA was 59.0 mol%. Strain P3(T) differed from Planctomyces brasiliensis and Planctomyces maris by cell morphology, substrate utilization pattern and a number of physiological characteristics. Based on these data, the novel isolate should be considered as representing a novel genus and species of planctomycetes, for which the name Planctomicrobium piriforme gen. nov., sp. nov., is proposed. The type strain is P3(T) ( =DSM 26348(T) =VKM B-2887(T)).


Arteriovenous fistula and skin flaps.
An experimental study was done in a rat groin flap model to assess the possible effects of arteriovenous fistulas (AVF) on the viability of skin flaps. The animals were randomly divided into three groups. In Group 1, an island flap, and in Groups 2 and 3, peninsular flaps, including the superficial epigastric artery and vein, were elevated. In Group 2, the base of the peninsula was on the rectus side of the flap; in Group 3, the base of the peninsula was located on the lower extremity side. After elevation of the flap and following arteriovenotomy, an A-V fistula was produced by side-to-side anastomosis proximal to the pedicle at the level of the common femoral vessels. Then the flaps were sutured back into their beds. All the island groin flaps with the AVF failed to survive. In Group 3, there was a severe reduction of blood flow in the flap and no flaps survived; however, all the flaps in Group 2 survived totally with no problem. It was concluded that island skin flap circulation is negatively affected by an AVF proximal to the flap pedicle. If the flap and AVF are treated as in Group 2, then flap necrosis caused by reduced blood flow can be overcome in this model.


Challenges in managing patients in Australia with chronic hepatitis B: the General Practitioners' perspective.
General Practitioners (GPs) are essential to reducing the impact of chronic hepatitis B (CHB) given their clinical management role where only 56% of people with the infection in Australia have been diagnosed. This qualitative study aimed to identify the challenges GPs face in effectively responding to CHB. Semi-structured interviews were conducted with 26 GPs self-identifying as having a 'high caseload' of patients and/or a particular interest in CHB. Participants were recruited from five jurisdictions and came from diverse ethnicities, clinical experience and practice profile. Interview data were analysed according to the principles of grounded theory. Patient and GP knowledge, a lack of community awareness, and language and cultural diversity impeded the GP response to CHB. Communication with specialists was reported as challenging with unclear referral pathways, limited feedback from specialists after referral, and poor liaison and support for managing people living with CHB. Regulations restricting GPs capacity to respond included the lack of prescribing opportunities, fear of Medicare auditing for screening the populations most at risk, and inadequate financial support given the complexity of CHB and the communities most affected by the infection. General Practitioners require additional skills and resources to support the effective management of people with CHB. These include improved awareness and knowledge about the infection, adequate financial resources to support patient management, and effective referral pathways and support.


Exploiting tumor-specific defects in the interferon pathway with a previously unknown oncolytic virus.
Interferons are circulating factors that bind to cell surface receptors, activating a signaling cascade, ultimately leading to both an antiviral response and an induction of growth inhibitory and/or apoptotic signals in normal and tumor cells. Attempts to exploit the ability of interferons to limit the growth of tumors in patients has met with limited results because of cancer-specific mutations of gene products in the interferon pathway. Although interferon-non-responsive cancer cells may have acquired a growth/survival advantage over their normal counterparts, they may have simultaneously compromised their antiviral response. To test this, we used vesicular stomatitis virus (VSV), an enveloped, negative-sense RNA virus exquisitely sensitive to treatment with interferon. VSV rapidly replicated in and selectively killed a variety of human tumor cell lines even in the presence of doses of interferon that completely protected normal human primary cell cultures. A single intratumoral injection of VSV was effective in reducing the tumor burden of nude mice bearing subcutaneous human melanoma xenografts. Our results support the use of VSV as a replication-competent oncolytic virus and demonstrate a new strategy for the treatment of interferon non-responsive tumors.


A method for evaluating patient care and auditing skills of family practice residents.
A system of chart review is presented which develops both auditing skills and patient care skills. The model suggested is a flexible one, applicable at various levels of training in both inpatient and outpatient settings. Its application to family practice resident training is shown by comparing the performances of residents at the beginning and end of a demonstration period.


Learning in certainty-factor-based multilayer neural networks for classification.
The computational framework of rule-based neural networks inherits from the neural network and the inference engine of an expert system. In one approach, the network activation function is based on the certainty factor (CF) model of MYCIN-like systems. In this paper, it is shown theoretically that the neural network using the CF-based activation function requires relatively small sample sizes for correct generalization. This result is also confirmed by empirical studies in several independent domains.


Mouse Model of Loeys-Dietz Syndrome Shows Elevated Susceptibility to Periodontitis via Alterations in Transforming Growth Factor-Beta Signaling.
Loeys-Dietz syndrome (LDS) is a syndromic connective tissue disorder caused by a heterozygous missense mutation in genes that encode transforming growth factor (TGF)-β receptor (TGFBR) 1 and 2. We encountered a patient with LDS, who had severe periodontal tissue destruction indicative of aggressive periodontitis. The patient had a missense mutation in the glycine and serine-rich domain of TGFBR1 exon 3. This G-to-T mutation at base 563 converted glycine to valine. We established an LDS model knock-in mouse that recapitulated the LDS phenotype. Homozygosity of the mutation caused embryonic lethality and heterozygous knock-in mice showed distorted and ruptured elastic fibers in the aorta at 24 weeks of age and died earlier than wildtype (WT) mice. We stimulated mouse embryonic fibroblasts (MEFs) from the knock-in mouse with TGF-β and examined their responses. The knock-in MEFs showed downregulated Serpine 1 mRNA expression and phosphorylation of Smad2 to TGF-β compared with WT MEFs. To clarify the influence of TGF-β signaling abnormalities on the pathogenesis or progression of periodontitis, we performed pathomolecular analysis of the knock-in mouse. There were no structural differences in periodontal tissues between WT and LDS model mice at 6 or 24 weeks of age. Micro-computed tomography revealed no significant difference in alveolar bone resorption between WT and knock-in mice at 6 or 24 weeks of age. However, TGF-β-related gene expression was increased significantly in periodontal tissues of the knock-in mouse compared with WT mice. Next, we assessed a mouse periodontitis model in which periodontal bone loss was induced by oral inoculation with the bacterial strain Porphyromonas gingivalis W83. After inoculation, we collected alveolar bone and carried out morphometric analysis. P. gingivalis-induced alveolar bone loss was significantly greater in LDS model mice than in WT mice. Peritoneal macrophages isolated from Tgfbr1 G188V/+ mice showed upregulation of inflammatory cytokine mRNA expression induced by P. gingivalis lipopolysaccharide compared with WT macrophages. In this study, we established an LDS mouse model and demonstrated that LDS model mice had elevated susceptibility to P. gingivalis-induced periodontitis, probably through TGF-β signal dysfunction. This suggests that TGF-β signaling abnormalities accelerate the pathogenesis or progression of periodontitis.


[Brace effect in scoliosis in the sagittal plane - an MRI study].
Using magnetic resonance (MR) imaging we studied the brace effect in scoliosis in the sagittal plane. In 38 patients with idiopathic scoliosis (mean age 13.4 years) MR total spine imaging was carried out to investigate the immediate effect of bracing in the sagittal plane. There were 19 thoracic, 13 S-shaped and 6 lumbar scoliosis. On conventional radiographs the mean Cobb angle of the thoracic curves was 31 degrees and of the lumbar curves 26 degrees. MR imaging was performed in the supine position with and without the brace in direct sequence. On the sagittal MR projection the Cobb angle was measured between T 4 and T 12 and between T 12 and L 5. On the coronal MR images the mean correction with brace was 23 % of the thoracic curves and 29 % of the lumbar curves. The mean, sagittal Cobb angle (T 4 - T 12) was 14 degrees without brace and 12 degrees with brace. For the lumbar curves the mean sagittal Cobb angle (T 12 - L 5) was 32 degrees without brace and 31 degrees with brace. In the paired t-test these differences were significant. Using MR total spine imaging the brace effect in scoliosis could be depicted in the sagittal plane. In the thoracic spine a correction of the lordotic deformity could not be observed.


Low mammalian species richness is associated with Kyasanur Forest disease outbreak risk in deforested landscapes in the Western Ghats, India.
Kyasanur forest disease virus (KFDV) is a rapidly expanding tick-borne zoonotic virus with natural foci in the forested region of the Western Ghats of South India. The Western Ghats is one of the world's most important biodiversity hotspots and, like many such areas of high biodiversity, is under significant pressure from anthropogenic landscape change. The current study sought to quantify mammalian species richness using ensemble models of the distributions of a sample of species extant in the Western Ghats and to explore its association with KFDV outbreaks, as well as the modifying effects of deforestation on this association. Species richness was quantified as a composite of individual species' distributions, as derived from ensembles of boosted regression tree, random forest, and generalised additive models. Species richness was further adjusted for the potential biotic constraints of sympatric species. Both species richness and forest loss demonstrated strong positive associations with KFDV outbreaks, however forest loss substantially modified the association between species richness and outbreaks. High species richness was associated with increased KFDV risk but only in areas of low forest loss. In contrast, lower species richness was associated with increased KFDV risk in areas of greater forest loss. This relationship persisted when species richness was adjusted for biotic constraints at the taluk-level. In addition, the taluk-level species abundances of three monkey species (Macaca radiata, Semnopithecus hypoleucus, and Semnopithecus priam) were also associated with outbreaks. These results suggest that increased monitoring of wildlife in areas of significant habitat fragmentation may add considerably to critical knowledge gaps in KFDV epidemiology and infection ecology and should be incorporated into novel One Health surveillance development for the region. In addition, the inclusion of some primate species as sentinels of KFDV circulation into general wildlife surveillance architecture may add further value.


Fire-safe unsaturated polyester resin nanocomposites based on MAX and MXene: a comparative investigation of their properties and mechanism of fire retardancy.
Recently, MXene, as a novel graphene-like nanomaterial, has been found to bestow good flame-retardant and smoke-suppression properties to polymers mainly due to the physical barrier effect of its 2D nanosheets. However, a comprehensive investigation of its chemical components as an important factor for these properties has not been conducted to date. To address this issue, herein, MXene (Ti3C2Tx) and MAX (Ti3AlC2) were introduced into unsaturated polyester resin (UPR) at same amounts (2.0 wt%). Their structures are different (multilayer for MXene and bulk for MAX), but the chemical components are similar; therefore, it is important to study the influence of the chemical components of MXene on the fire-safety properties of polymers. In this study, 2 wt% MAX was added to the UPR, and the peak heat release rate (PHRR), the total smoke production (TSP), and carbon monoxide production (COP) of the resulting material were reduced by 11.04%, 19.08%, and 15.79%, respectively; these findings demonstrate the important role of the chemical components of MAX: Ti exerts a catalytic attenuation effect on the UPR nanocomposites during combustion. Moreover, a better fire-safety property of the MXene/UPR nanocomposites (reduction of PHRR by 29.56%, TSP by 25.26%, and COP by 31.58%) than that of the MAX/UPR nanocomposites was achieved, which was due to the physical barrier effect of the MXene nanosheets. This study verifies that in addition to the physical barrier effect, the chemical components play a very important role in the fire safety enhancement of MXene-based nanocomposites.


Natural toxic impact and thyroid signalling interplay orchestrates riverine adaptive divergence of salmonid fish.
Adaptive radiation in fishes has been actively investigated over the last decades. Along with numerous well-studied cases of lacustrine radiation, some examples of riverine sympatric divergence have been recently discovered. In contrast to the lakes, the riverine conditions do not provide evident stability in the ecological gradients. Consequently, external factors triggering the radiation, as well as developmental mechanisms underpinning it, remain unclear. Herein, we present the comprehensive study of external and internal drivers of the riverine adaptive divergence of the salmonid fish Salvelinus malma. In the Kamchatka River, north-east Asia, this species splits in the reproductively isolated morphs that drastically differ in ecology and morphology: the benthivorous Dolly Varden (DV) and the piscivorous stone charr (SC). To understand why and how these morphs originated, we performed a series of field and experimental work, including common-garden rearing, comparative ontogenetic, physiological and endocrinological analyses, hormonal 'engineering' of phenotypes and acute toxicological tests. We revealed that the type of spawning ground acts as the decisive factor driving the radiation of S. malma. In contrast to DV spawning in the leaf krummholz zone, SC reproduces in the zone of coniferous forest, which litter has a toxic impact on developing fishes. SC enhances resistance to the toxicants via metabolism acceleration provided by the elevated thyroid hormone expenditure. These physiological changes lead to the multiple heterochronies resulting in a specific morphology and ecology of SC. Salvelinus malma represents a notable example of how the thyroid axis contributes to the generation of diverse phenotypic outcomes underlying the riverine sympatric divergence. Our findings, along with the paleoecology data concerning spruce forest distribution during the Pleistocene, provide an opportunity to reconstruct a scenario of S. malma divergence. Taken together, obtained results with the data of the role of thyroid hormones in the ontogeny and diversification of fishes contribute a resource to consider the thyroid axis as a prime director orchestrating the phenotypic plasticity promoting evolutionary diversification under the changing environmental conditions.


Influence of infection intensity on predilection sites in swine trichinellosis.
The muscular distribution of Trichinella spiralis or T. britovi was studied by digestion in 59 experimentally infected pigs and seven wild boars. Crus muscle was the predilection site in 89.3% of 28 heavily infected swine with 146-3634 larvae per gram (lpg), but in 51.6% of middle to light infections (0.005-59 lpg) the basis of the tongue showed higher larval densities than the crus muscle. The basis of the tongue was also the predilection site in 71.4% of wild boars. Highest counts in other muscles were found only in lightly infected pigs. The influence of intensity of infection, host species, and Trichinella species on muscle distribution is discussed.


Vibrational spectroscopic force field studies of dimethyl sulfoxide and hexakis(dimethyl sulfoxide)scandium(III) iodide, and crystal and solution structure of the hexakis(dimethyl sulfoxide)scandium(III) ion.
Hexakis(dimethyl sulfoxide)scandium(III) iodide, [Sc(OS(CH(3))(2))(6)]I(3) contains centrosymmetric hexasolvated scandium(III) ions with an Sc-O bond distance of 2.069(3) angstroms. EXAFS spectra yield a mean Sc-O bond distance of 2.09(1) angstroms for solvated scandium(III) ions in dimethyl sulfoxide solution, consistent with six-coordination. Raman and infrared absorption spectra have been recorded, also of the deuterated compound, and analysed by means of normal coordinate methods, together with spectra of dimethyl sulfoxide. The effects on the vibrational spectra of the weak intermolecular C-H...O interactions and of the dipole-dipole interactions in liquid dimethyl sulfoxide have been evaluated, in particular for the S-O stretching mode. The strong Raman band at 1043.6 cm(-1) and the intense IR absorption at 1062.6 cm(-1) have been assigned as the S-O stretching frequencies of the dominating species in liquid dimethyl sulfoxide, evaluated as centrosymmetric dimers with antiparallel polar S-O groups. The shifts of vibrational frequencies and force constants for coordinated dimethyl sulfoxide ligands in hexasolvated trivalent metal ion complexes are discussed. Hexasolvated scandium(iii) ions are found in dimethyl sulfoxide solution and in [Sc(OSMe(2))(6)]I(3). The iodide ion-dipole attraction shifts the methyl group C-H stretching frequency for (S-)C-H...I(-) more than for the intermolecular (S-)C-H...O interactions in liquid dimethyl sulfoxide.


Rapid shape detection signals in area V4.
Vision in foveate animals is an active process that requires rapid and constant decision-making. For example, when a new object appears in the visual field, we can quickly decide to inspect it by directing our eyes to the object's location. We studied the contribution of primate area V4 to these types of rapid foveation decisions. Animals performed a reaction time task that required them to report when any shape appeared within a peripherally-located noisy stimulus by making a saccade to the stimulus location. We found that about half of the randomly sampled V4 neurons not only rapidly and precisely represented the appearance of this shape, but they were also predictive of the animal's saccades. A neuron's ability to predict the animal's saccades was not related to the specificity with which the cell represented a single type of shape but rather to its ability to signal whether any shape was present. This relationship between sensory sensitivity and behavioral predictiveness was not due to global effects such as alertness, as it was equally likely to be observed for cells with increases and decreases in firing rate. Careful analysis of the timescales of reliability in these neurons implies that they reflect both feedforward and feedback shape detecting processes. In approximately 7% of our recorded sample, individual neurons were able to predict both the delay and precision of the animal's shape detection performance. This suggests that a subset of V4 neurons may have been directly and causally contributing to task performance and that area V4 likely plays a critical role in guiding rapid, form-based foveation decisions.


Comparative proteomic analysis of rat aorta in a subtotal nephrectomy model.
Although accelerated atherosclerosis and arteriosclerosis are the main causes of cardiovascular morbidity and mortality in chronic kidney disease (CKD) patients, the molecular pathogenesis remains largely obscure. Our study of the aortic function in a typical CKD model of subtotal nephrectomy (SNX) rats demonstrated phenotypes that resemble CKD patients with aortic stiffness. The 2-DE analysis of rat aortas followed by MS identified 29 up-regulated and 53 down-regulated proteins in SNX rats. Further Western blot and immunohistochemistry analyses validated the decreased HSP27 and increased milk fat globule epidermal growth factor-8 (MFG-E8) in SNX rats. Functional classification of differential protein profiles using KOGnitor revealed that the two major categories involved in aortic stiffness are posttranslational modification, protein turnover, chaperones (23%) and cytoskeleton (21%). Ingenuity Pathway Analysis highlighted cellular assembly and organization, and cardiovascular system development and function as the two most relevant pathways. Among the identified proteins, the clinical significance of the secreted protein MFG-E8 was confirmed in 50 CKD patients, showing that increased serum MFG-E8 level is positively related to aortic stiffness and renal function impairment. Drug interventions with an inhibitor of the angiotensin converting enzyme, enalapril, in SNX rats improved aortic stiffness and decreased MFG-E8 depositions. Together, our studies provide a repertoire of potential biomarkers related to the aortic stiffness in CKD.


SarA based novel therapeutic candidate against Staphylococcus aureus associated with vascular graft infections.
Staphylococcus aureus is a common pathogen seen in prosthetic vascular graft, leading to high morbidity and mortality. The virulence genes for severity of infections are under the control of global regulators. Staphylococcal accessory regulator A (SarA) a known master controller of biofilm formation is an attractive target for the drug development. A structure based screening of lead compounds was employed for the identification of novel small molecule inhibitors targeted to interact to the DNA binding domain of the transcriptional activator, SarA and hinder its response over the control of genes that up-regulate the phenotype, biofilm. The top-hit SarA selective inhibitor, 4-[(2,4-diflurobenzyl)amino] cyclohexanol (SarABI) was further validated in-vitro for its efficacy. The SarABI was found to have MBIC50value of 200 μg/ml and also down-regulated the expression of the RNA effector, (RNAIII), Hemolysin (hld), and fibronectin-binding protein (fnbA). The anti-adherence property of SarABI on S. aureus invasion to the host epithelial cell lines (Hep-2) was examined where no significant attachment of S. aureus was observed. The SarABI inhibits the colonization of MDR S. aureus in animal model experiment significantly cohere to the molecular docking studies and in vitro experiments. So, we propose that the SarABI could be a novel substitute to overcome a higher degree of MDR S. aureus colonization on vascular graft.


Trends in breast reduction technique.
There are two main approaches to breast reduction surgery today: the traditional long scar ("Wise-pattern") technique and the more recent short ("vertical") scar technique, which is becoming more popular. During the last two decades there has been a gradual shift between the two techniques, including at our institute. To evaluate the evidence behind this obvious trend. We retrospectively collected data fromarchived hospital charts of all patients who underwent breast reduction surgery during the period 1995-2007. Epidemicological, clinical and postoperative data were analyzed and compared between patients in whom the short scar vs. the long scar techniques was used. During the study period 91 patients underwent breast reduction surgery in our department: 34 with the Wise-pattern breast reduction technique and 57 with the short-scar procedure. There was no significant difference in operative and postoperative data, including length of hospital stay. In some of the categories there was even a slight advantage (but not statistically significant) to the former. The only significant difference was the size of reduction, with a tendencyto prefer the long scar technique for larger reductions; however, with experience gained the limit for short scar reductions was gradually extended to a maximum of 1470 g. We noticed a sharp increase in the safe and uneventful practice of the short scar technique in breast reduction of < or = 1400 g--especially in young women without extreme ptosis. This observation, together with other advantages, namely, reduced scar length, prolonged shape preservation and better breast projection, support the use of this technique.


Self-biasing photoelectrochemical cell for spontaneous overall water splitting under visible-light illumination.
A self-biasing photoelectrochemical (PEC) cell that could work for spontaneous overall water splitting in a neutral solution was established based on the mismatched Fermi levels between the photoelectrodes. A Pt-catalyst-decorated crystalline silicon photovoltaic cell (Pt/PVC) was prepared and employed as an effective photocathode. This was coupled with a poly(ethylene glycol)-directed WO3/W photoanode prepared by a hydrothermal process. Both of the photoelectrodes showed a response to visible light. The WO3/W photoanode had a positively located valence band edge, the energy level of which was enough for water oxidation, and the Pt/PVC photocathode possessed a negatively located conduction band edge, which was capable of water reduction. More importantly, the Fermi level of the WO3/W photoanode was more positive than that of the Pt/PVC photocathode because of the p-n junction of the PVC that decoupled the band bending and enlarged the photovoltage. Under visible-light irradiation, the WO3/W photoanode provided a negative bias for the Pt/PVC photocathode, and the Pt/PVC photocathode provided a positive bias for the WO3/W photoanode. An interior bias was generated that could relax the strict criteria of overall water splitting by cooperatively separating the hole-electron pairs at both photoelectrodes. In this system, the short-circuit current and the open-circuit voltage increased with increasing light intensity (AM 1.5 illumination) to reach 121 μA cm(-2) and 0.541 V, respectively, at a light intensity of 100 mW cm(-2). Such a combination provides a promising method for the fabrication of self-driven devices for solar-energy storage.


Parathyroid Hormone-Related Changes of Bone Structure.
Parathyroid hormone (PTH) increases the release of serum calcium through osteoclasts, which leads to bone resorption. Primary, PTH stimulates osteoblasts leading to increase RANKL (receptor activator for nuclear factor kappa-B ligand) expression and thus differentiation of osteoclasts. In kidneys, PTH increases calcium and decrease phosphate reabsorption. In kidneys, PTH stimulates 1alpha-hydroxylase to synthesize active vitamin D. Primary hyperparathyroidism (PHPT) is characterized by skeletal or renal complications. Nowadays, the classical form of PHPT is less seen and asymptomatic or subclinical (oligo symptomatic) forms are more frequent. Previously, it was thought that cortical bone is preferably affected by PHPT and that predispose bones to fracture at sites with a higher amount of cortical bone. However, an increased risk of vertebral fractures has been found by most of the studies showing that also trabecular bone is affected. Bone Mass measurement (BMD) at all skeletal sites is advised, but another specific tool for fracture assessment is needed. Trabecular bone score (TBS), an indirect measure of trabecular bone, maybe a useful method to estimate fracture risk. TBS is associated with vertebral fractures in PHPT regardless of BMD, age, BMI and gender. Furthermore, there is an association between TBS and high resolution peripheral quantitative computed tomography (HR-pQCT) parameters in the trabecular and cortical compartment. However, studies considering the effect of PHPT treatment on TBS are more conflicting. Secondary hyperparathyroidism caused by vitamin D deficiency was associated with impaired bone microarchitecture in all age categories, as measured by TBS and Hr-pQCT with further improvement after treatment with vitamin D.


Comparison of ciclopirox olamine 1% cream with ciclopirox 1%-hydrocortisone acetate 1% cream in the treatment of inflamed superficial mycoses.
The hydroxypyridone antifungal agent ciclopirox olamine cream 1% has been shown to be as effective in the treatment of inflamed, superficial fungal infections as a formulation in which ciclopirox 1% and hydrocortisone acetate 1% were combined. In a randomized, double-blind, parallel group comparison study, 138 patients with culture-confirmed superficial fungal diseases applied their assigned medication twice daily for 21 days. Clinical assessments were made at the baseline visit; at visits on days 4, 7, 14, and 21 during treatment; and on day 28 (one week posttreatment). Specimens for cultures were taken at baseline and on day 28. There were no differences for the 69 patients in either treatment group at any visit with respect to improvement in the signs/symptoms evaluated; mycological cures in the two treatment groups also were not significantly different.


Hazards and Control Measures among Artisanal and Small-Scale Gold Miners in Zimbabwe.
In 2017 around 14-19 million miners were exposed to multiple hazards in artisanal and small-scale gold mining (ASGM). ASGM is characterized by basic and compromised mining methods with either very limited control of hazards or none at all. There is little knowledge about health and safety among artisanal and small-scale gold miners in Zimbabwe. This study explores the interaction between hazards, control measures, and health and safety in Zimbabwe's ASGM. Triangulation and mixed methods were applied using standardized questionnaires, Hazard Identification and Risk Assessment (HIRA), focus group discussions (FGDs), and summary notes from in-depth interviews (IDIs). Data were analyzed using descriptive statistics, regression analysis, and thematic analysis. Quantitative data were collected through HIRA, which was conducted on 34 mining sites. 401 participants, selected through multi-stage sampling, were assessed through standardized questionnaires. Qualitative data was collected through six FGDs, and existing summary notes from 84 IDIs. The most prioritized hazards from the questionnaires were silica dust, noise, and workplace violence as indicated by 238 (62.0%), 107 (26.8%), and 104 (26.7%) respondents (respectively). HIRA identified noise, dust, unsafe shafts, violence, poor sanitation, and poor hygiene as key hazards requiring urgent attention. A key finding of this study was the poor application of the hierarchy of controls in managing workplace hazards. After adjusting for confounders, association with experiencing health and safety challenges was working underground (AOR = 2.0, p = 0.03), workplace violence (AOR = 3.3, p = 0.002), and long working hours (AOR = 2.8, p = 0.019). Injuries and fatalities were common without mitigation strategies. ASGM in Zimbabwe is characterized by underground mining, long working hours, and workplace violence. The poor application of the hierarchy of controls is characterized by increased workplace injuries and fatalities. We recommend following the hierarchy of control measures in ASGM: elimination, substitution, engineering, administrative, and personal protective equipment.


Effects of structural parameters and rigidity of driving diaphragm on flow characteristics of micro valveless pump.
The structure and operating principle of micro valveless pump were investigated theoretically and experimentally. The mathematical model of pressure and flow rate within the micro nozzle/diffuser was established to analyze the effects of nozzle/diffuser parameters on the output flow rate of the micro valveless pump. The experiments were carried out with different structural parameters, driving frequencies, vibration amplitudes and stiffness of the driving diaphragms. Effects of the structural parameters and driving conditions on the operation performance of the pump are discussed in detail. The work provides useful reference for structure optimization selection of the driving diaphragm of micro valveless pump.


A Q-Modulation Technique for Efficient Inductive Power Transmission.
A fully-integrated power management ASIC for efficient inductive power transmission has been presented capable of automatic load transformation using a method, called Q-modulation. Q-modulation is an adaptive scheme that offers load matching against a wide range of loading (RL ) and coupling distance (d23 ) variations in inductive links to maintain high power transfer efficiency (PTE). It is suitable for inductive powering implantable microelectronic devices (IMDs), recharging mobile electronics, and electric vehicles. In Q-modulation, the zero-crossings of the induced current in the receiver (Rx) LC-tank are detected and a low-loss switch chops the Rx LC-tank for part of the power carrier cycle to form a high-Q LC-tank and store the maximum energy, which is then transferred to RL by opening the switch. By adjusting the duty cycle (D), the loaded-Q of the Rx LC-tank can be dynamically modulated to compensate for variations in RL . A Q-modulation power management (QMPM) prototype chip was fabricated in a 0.35-μm standard CMOS process, occupying 4.8 mm2. In a 1.45 W wireless power transfer setup, using a class-E power amplifier (PA) operating at 2 MHz, the QMPM successfully increased the inductive link PTE and the overall power efficiency by 98.5% and 120.7% at d23 = 8 cm, respectively, by compensating for 150 Ω variation in RL at D = 45%.


Ligament Repair Method for Sports Dancers Based on Health Monitoring.
In sports dance training, the injury rate of athletes' ligaments is higher than that of ordinary ones. Careful study of ligament repair methods can better prolong the sports life of sports dance athletes. The purpose of this paper is to investigate how to analyze ligament repair in sports dancers based on health monitoring. This paper proposes a deep learning algorithm based on health monitoring and a neural network algorithm, both of which have the function of prediction. The experimental results of this paper show that the common injuries in sports dance include ankle ligament injury, medial and lateral knee ligament strain, lumbar muscle strain, toe joint strain, shoulder deltoid strain and other injuries. Among them, the number of ankle ligament injuries is the largest, with 36 people, accounting for 30%. The number of people with medial and lateral ligament strains in the knee joint ranks second with 32 people, accounting for 26%. The total proportion of two kinds of ligament strains is 56%, accounting for more than half. It can be seen that ligament strains are the most common in sports dance injuries, so it is of great research significance to repair the ligaments of sports dancers based on health monitoring.


Association between bone, body composition and strength in premenarcheal girls and postmenopausal women.
The study examined whether associations between bone, body composition and strength are age dependent. Two age levels (premenarcheal girls and postmenopausal women on HRT) were studied in a 10-month follow-up. Bone, lean and fat mass were measured by dual-energy X-ray absorptiometry (DXA), and strength was measured using an isokinetic dynamometer. In girls, significant correlations were found between mass (lean, fat and body mass), strength and most bone characteristics (r = 0.15-0.93). At the proximal femur changes in bone mineral density (BMD) were moderately related to changes in body composition. In the women, body mass and lean mass were significantly correlated with most bone characteristics (r = 0.34-0.82). Low to moderate correlations were observed between changes in bone and changes in body composition. After controlling for lean mass the relation between strength and bone was no longer significant. In premenarcheal girls, bone is partly determined by mass, with lean mass the most important predictor at the femoral sites. In postmenopausal women, lean mass is an important determinant of bone mineral content (BMC) and BMD, but changes in BMD are related to changes in fat. The relation between strength and BMD is mainly attributable to the relation between lean mass and BMD. The contributory effects of soft tissue to bone change over different life periods.


An optimized lanthanide-chlorophyll nanocomposite for dual-modal imaging-guided surgery navigation and anti-cancer theranostics.
In this research, an optimized phosphor combined with naturally green chlorophyll (Phosphor-Chlorophyll, denoted as Ph-chl) was designed for dual-modal luminescence-guided anti-tumor surgery and photodynamic therapy (PDT). A genetic algorithm (GA) is used to solve the "low up-conversion luminescence (UCL) and short-wavelength infrared (SWIR) intensity" problem by coding the proportions of elements in the phosphor in order to find the optimal phosphor with enhanced red UCL emission and SWIR luminescence using Yb/Er in the core and Yb/Nd in the shell. Moreover, when phosphors with different emission light colors (blue and green) are combined with chlorophyll as the control, the results indicate that phosphors with red emission as the energy donor have high PDT efficiency to activate the chlorophyll for reactive oxygen species (ROS) production. Additionally, due to the enhanced penetration and retention (EPR) effect, the as-synthesized Ph-chl could be used for surgery navigation with a higher SWIR imaging effect focusing on cancer rather than normal tissues and paracancerous tissue. Thus, the high dual-modal luminescence guided surgery properties of the final optimized phosphor will promote its further use in minimally-invasive endoscopic clinical surgery navigation.


Antigen-specific and MHC-restricted Plasmodium falciparum-induced human T lymphocyte clones.
We established and analyzed human T lymphocyte clones induced by crude Plasmodium falciparum antigens of schizont-enriched asexual blood stages. Peripheral blood mononuclear cells (PBMC) were stimulated for 6 days with antigen, and the T cell blasts were separated and were transferred to limiting dilution cultures with antigen, irradiated PBMC, and recombinant interleukin 2. The following observations were made. Malaria antigen (M.Ag) induced similar proportions of T blasts in PBMC from infected individuals and noninfected controls, and the M.Ag-dependent clone frequencies (1/79 to 1/216) obtained with the blasts were similar. The majority of established clones derived from infected and noninfected subjects specifically recognized M.Ag and would not proliferate in response to red blood cells or autologous PBMC alone. They also required HLA class II determinant-compatible antigen-presenting (E-) cells. With three clones from one malaria patient, DR 1 or DR 5 specificities correlated with antigen presentation. Although T4+ and T8+ blasts were induced by M.Ag in PBMC, only T4 (Leu-3+) clones were obtained in our culture system. These clones secreted IL 2 in response to M.Ag. 4) Differential patterns of reactivity to native M.Ag, heat-stable antigens, and heat-precipitated antigens were exhibited by T cell clones, and the tested clones did not recognize Plasmodium berghei antigen. In conclusion, it is important with regard to previous observations on apparently nonspecific, mitogen-like effects of M.Ag in bulk T cell cultures that our results demonstrate specific recognition of P. falciparum by human T cells. The T cell clones obtained will be an important tool in the quest for a better understanding of the mechanisms involved in resistance to malaria infection.


Spinal analgesia improves surgical outcome after open nephrectomy for renal cell carcinoma: a randomized controlled study.
This study evaluated whether more effective perioperative analgesia can be part of a multimodal approach to minimizing morbidity and improving postoperative management after the open surgical approaches frequently used in the treatment of renal cell carcinoma (RCC). The aim of the study was to determine whether spinal anesthesia with clonidine can enhance postoperative analgesia, speed up mobilization and reduce the length of hospital stay (LOS). Between 2012 and 2015, 135 patients with RCC were randomized, in addition to general anesthesia, to receive either spinal analgesia with clonidine or epidural analgesia, stratified to surgical technique. Inclusion criteria were American Society of Anesthesiologists (ASA) score of III or less, age over 18 years and no chronic pain medication or cognitive disorders. The median LOS was 4 days for patients in the spinal group and 6 days in the epidural group (p = 0.001). There were no differences regarding duration of surgery, blood loss, RENAL score, tumor size or complications between the given analgesia methods. A limitation was that different anesthesiologists were responsible for administering spinal or epidural anesthesia, as in a real-world clinical situation. In this randomized controlled study, spinal analgesia with clonidine was superior to continuous epidural analgesia in patients operated on with open nephrectomy, based on shorter LOS. A shorter LOS in the study group indicates faster mobilization and improved analgesia. Spinal analgesia did not carry more complications than epidural analgesia.


Genome-Wide Screening in Human Embryonic Stem Cells Highlights the Hippo Signaling Pathway as Granting Synthetic Viability in ATM Deficiency.
ATM depletion is associated with the multisystemic neurodegenerative syndrome ataxia-telangiectasia (A-T). The exact linkage between neurodegeneration and ATM deficiency has not been established yet, and no treatment is currently available. In this study, we aimed to identify synthetic viable genes in ATM deficiency to highlight potential targets for the treatment of neurodegeneration in A-T. We inhibited ATM kinase activity using the background of a genome-wide haploid pluripotent CRISPR/Cas9 loss-of-function library and examined which mutations confer a growth advantage on ATM-deficient cells specifically. Pathway enrichment analysis of the results revealed the Hippo signaling pathway as a major negative regulator of cellular growth upon ATM inhibition. Indeed, genetic perturbation of the Hippo pathway genes SAV1 and NF2, as well as chemical inhibition of this pathway, specifically promoted the growth of ATM-knockout cells. This effect was demonstrated in both human embryonic stem cells and neural progenitor cells. Therefore, we suggest the Hippo pathway as a candidate target for the treatment of the devastating cerebellar atrophy associated with A-T. In addition to the Hippo pathway, our work points out additional genes, such as the apoptotic regulator BAG6, as synthetic viable with ATM-deficiency. These genes may help to develop drugs for the treatment of A-T patients as well as to define biomarkers for resistance to ATM inhibition-based chemotherapies and to gain new insights into the ATM genetic network.


Common mental disorders during the COVID-19 pandemic in Hong Kong: Age-related differences and implications for dementia risk.
The COVID-19 pandemic has imposed a profound negative impact on the mental health and wellbeing of societies and individuals worldwide. Older adults may be more vulnerable to the mental health effects of the pandemic, either directly from the infection itself or indirectly through the preventive measures. However, the existing literature on mental health in the older age groups has not been consistent so far. The aim of this study was therefore to assess the prevalence of common mental disorders (CMD; including depression and anxiety disorders) given their association with dementia risk, and to further examine age-related differences between older (≥60 years old) and younger (18-59 years old) adult's psychological status during the COVID-19 pandemic. This was a secondary analysis of a cross-sectional survey-study conducted during the second wave of COVID-19 pandemic in Hong Kong. The survey was disseminated through different social media platforms to the general population and included sociodemographic questions, self-reported physical health, and previous encounter with SARS or COVID-19. CMD was the primary outcome and was assessed using the 6-item Kessler Scale. A total of 1030 adults fulfilled inclusion criteria. The prevalence of CMD during the pandemic was 16.1%. Compared to younger adults, older adults were significantly less likely to have a CMD (unadjusted OR = 0.07, 95% CI = 0.02-0.30, p < 0.001), with 18.1% of younger adults having CMD compared to 1.6% in the older cohort. Age differences remained significant after controlling for sociodemographic factors, physical health, and previous encounter with SARS or COVID-19 (adjusted OR = 0.12, 95% CI = 0.02-0.57, p = 0.008). Common mental disorders are highly prevalent during the COVID-19 pandemic in Hong Kong, though older adults appeared to be less affected mentally. Present findings highlight the urgent need to implement measures and strategies to mitigate the mental health problems, with particular attention to the younger cohort. Given their association with higher dementia risk, early detection and treatment of depression and anxiety disorders will be of critical importance in providing some relief to the already pressurized dementia burden in the longer term.


Semiparametric Bayesian inference for phage display data.
We discuss inference for a human phage display experiment with three stages. The data are tripeptide counts by tissue and stage. The primary aim of the experiment is to identify ligands that bind with high affinity to a given tissue. We formalize the research question as inference about the monotonicity of mean counts over stages. The inference goal is then to identify a list of peptide-tissue pairs with significant increase over stages. We use a semiparametric Dirichlet process mixture of Poisson model. The posterior distribution under this model allows the desired inference about the monotonicity of mean counts. However, the desired inference summary as a list of peptide-tissue pairs with significant increase involves a massive multiplicity problem. We consider two alternative approaches to address this multiplicity issue. First we propose an approach based on the control of the posterior expected false discovery rate. We notice that the implied solution ignores the relative size of the increase. This motivates a second approach based on a utility function that includes explicit weights for the size of the increase.


Characterization of transplanted green fluorescent protein+ bone marrow cells into adipose tissue.
Following transplantation of green fluorescent protein (GFP)-labeled bone marrow (BM) into irradiated, wild-type Sprague-Dawley rats, propagated GFP(+) cells migrate to adipose tissue compartments. To determine the relationship between GFP(+) BM-derived cells and tissue-resident GFP(-) cells on the stem cell population of adipose tissue, we conducted detailed immunohistochemical analysis of chimeric whole fat compartments and subsequently isolated and characterized adipose-derived stem cells (ASCs) from GFP(+) BM chimeras. In immunohistochemistry, a large fraction of GFP(+) cells in adipose tissue were strongly positive for CD45 and smooth muscle actin and were evenly scattered around the adipocytes and blood vessels, whereas all CD45(+) cells within the blood vessels were GFP(+). A small fraction of GFP(+) cells with the mesenchymal marker CD90 also existed in the perivascular area. Flow cytometric and immunocytochemical analyses showed that cultured ASCs were CD45(-)/CD90(+)/CD29(+). There was a significant difference in both the cell number and phenotype of the GFP(+) ASCs in two different adipose compartments, the omental (abdominal) and the inguinal (subcutaneous) fat pads; a significantly higher number of GFP(-)/CD90(+) cells were isolated from the subcutaneous depot as compared with the abdominal depot. The in vitro adipogenic differentiation of the ASCs was achieved; however, all cells that had differentiated were GFP(-). Based on phenotypical analysis, GFP(+) cells in adipose tissue in this rat model appear to be of both hematopoietic and mesenchymal origin; however, infrequent isolation of GFP(+) ASCs and their lack of adipogenic differentiation suggest that the contribution of BM to ASC generation might be minor.


On the impact of episode sensitization on the course of recurrent affective disorders.
Sensitization of an organism by recurrent disease episodes is postulated as a key mechanism governing the progressive long-term course of affective disorders. The particular significance is that episode sensitization could underly the transition from externally triggered disease episodes to autonomous episode generation. Functionally, this transition might be explained by positive feedback between a disease episode and the activity state of an organism which includes the introduction of a memory trace for generated disease episodes. Here we consider the functional consequences of episode sensitization for the course of recurrent affective disorders. We use a computational approach and extend our previously introduced model for the course of affective disorders by a feedback mechanism for episode sensitization. Depending on sensitization timescale and amount, triggered episodes leave the model in a sustained sensitized state or induce autonomous disease progression. Runaway activation can end in saturation. Remarkably, however, over a broad parametric range the progression ends in intermediate states with fluctuating disease patterns. This behavior results from the model's nonlinear dynamics and represents a situation where the feedback intermittently changes between positive and negative directions. Our simulations strongly support episode sensitization as an important disease mechanism for affective disorders. From a nonlinear standpoint, this mechanism offers an explanation not only for autonomous disease progression but also for occurence and stability of irregular rapid-cycling disease states.


Transgenerational fitness effects of lifespan extension by dietary restriction in Caenorhabditis elegans.
Dietary restriction (DR) increases lifespan in a broad variety of organisms and improves health in humans. However, long-term transgenerational consequences of dietary interventions are poorly understood. Here, we investigated the effect of DR by temporary fasting (TF) on mortality risk, age-specific reproduction and fitness across three generations of descendants in Caenorhabditis elegans. We show that while TF robustly reduces mortality risk and improves late-life reproduction of the individuals subject to TF (P0), it has a wide range of both positive and negative effects on their descendants (F1-F3). Remarkably, great-grandparental exposure to TF in early life reduces fitness and increases mortality risk of F3 descendants to such an extent that TF no longer promotes a lifespan extension. These findings reveal that transgenerational trade-offs accompany the instant benefits of DR, underscoring the need to consider fitness of future generations in pursuit of healthy ageing.


Benzene-extracted components are important for the major activity of diesel exhaust particles: effect on interleukin-8 gene expression in human bronchial epithelial cells.
Epidemiologic and experimental studies suggest that diesel exhaust particles (DEPs) may be related to increasing respiratory mortality and morbidity. We have shown that DEPs augmented the production of inflammatory cytokines by human airway epithelial cells in vitro. To better understand the mechanisms of their proinflammatory activities, we studied the effects of several components extracted from DEPs on interleukin (IL)-8 expression in human bronchial epithelial cell line BEAS-2B and normal human airway epithelial cells obtained from very peripheral airways by an ultrathin bronchoscope. We used several agents active on signal transduction pathways in cytokine expression, such as the protein kinase C inhibitor staurosporin, antioxidant agents including N-acetyl cysteine (NAC) and pyrrolidine dithiocarbamate (PDTC), and p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580. Benzene-extracted components showed effects mimicking DEPs on IL-8 gene expression, release of several cytokines (IL-8; granulocyte macrophage colony-stimulating factor; and regulated on activation, normal T cells expressed and secreted) and nuclear factor (NF)-kappa B activation. We also found that NAC, PDTC, and SB203580 suppressed the activities of DEPs and their benzene extracts, suggesting the roles of oxidants-mediated NF-kappa B activation and p38MAPK pathways. Finally, benzo[a]pyrene, one of the important compounds included in the benzene component, replicated the activities shown by DEPs.


Nuclear Rho kinase, ROCK2, targets p300 acetyltransferase.
Rho-associated coiled-coil protein kinase (ROCK) is an effector for the small GTPase Rho and plays a pivotal role in diverse cellular activities, including cell adhesion, cytokinesis, and gene expression, primarily through an alteration of actin cytoskeleton dynamics. Here, we show that ROCK2 is localized in the nucleus and associates with p300 acetyltransferase both in vitro and in cells. Nuclear ROCK2 is present in a large protein complex and partially cofractionates with p300 by gel filtration analysis. By immunofluorescence, ROCK2 partially colocalizes with p300 in distinct insoluble nuclear structures. ROCK2 phosphorylates p300 in vitro, and nuclear-restricted expression of constitutively active ROCK2 induces p300 phosphorylation in cells. p300 acetyltransferase activity is dependent on its phosphorylation status in cells, and p300 phosphorylation by ROCK2 results in an increase in its acetyltransferase activity in vitro. These observations suggest that nucleus-localized ROCK2 targets p300 for phosphorylation to regulate its acetyltransferase activity.


Cannabis, More Than the Euphoria: Its Therapeutic Use in Drug-Resistant Epilepsy.
A significant number of epilepsy patients are refractory to conventional antiepileptic drugs. These patients experience considerable neurocognitive impairments that impact their quality of life and ability to function independently. This need for alternative treatment has generated increased interest in cannabis use as a therapeutic option in these patients. This review seeks to analyze data presented on the pharmacology, safety, and efficacy of cannabis use in patients with drug-resistant epilepsy (DRE) and to propose any future recommendations regarding its use. PubMed was used to retrieve all published studies and articles which evaluated the use of cannabis in epilepsy. The two foremost phytocannabinoids of cannabis showing anticonvulsant properties are tetrahydrocannabinol (THC) and cannabidiol (CBD). Due to the psychoactive properties of THC, most studies focused on CBD use in these patients. The use of CBD as an adjunct resulted in decreased seizure frequency, and secondary benefits observed included improvement in mood, alertness and sleep. Adverse events (AEs) reported were drowsiness, diarrhea, increased transaminases and worsening of seizures. It can safely be concluded that there is a significant benefit in DRE patients using CBD as adjunctive therapy. However, further controlled and adequately powered studies are needed to assess the pharmacokinetics and impact of the long-term use of cannabis.


Association of serum carotenoid levels with N-terminal pro-brain-type natriuretic peptide: a cross-sectional study in Japan.
Several epidemiologic studies have reported an inverse association between serum levels of carotenoids and cardiovascular disease risk. However, no studies have reported an association between serum carotenoids and N-terminal pro-brain-type natriuretic peptide (NT-proBNP) in the general population. In this cross-sectional study, we investigated whether serum carotenoids were associated with serum NT-proBNP in 1056 Japanese subjects (390 men, 666 women) who attended a health examination. Serum levels of carotenoids were separately determined by high-performance liquid chromatography. Serum NT-proBNP level was measured by electrochemiluminescence immunoassay. Serum NT-proBNP was elevated (≥55 pg/ml) in 31.8% of men and 48.2% of women. Multivariate logistic regression analyses adjusted for confounding factors showed a significant association between the highest quartile of serum α-carotene and elevated NT-proBNP in men (odds ratio [OR] = 0.40, 95% CI = 0.19-0.82, P for trend = 0.005) and women (OR = 0.62, 95% CI = 0.39-0.99, P for trend = 0.047). In women, moreover, elevated serum NT-proBNP was significantly associated with serum canthaxanthin (OR = 0.57, 95% CI = 0.36-0.90 for highest quartile, P for trend = 0.026) and β-cryptoxanthin (OR = 0.53, 95% CI = 0.32-0.85 for highest quartile, P for trend = 0.026), after adjusting for potential confounders. Higher levels of serum carotenoids were associated with lower risk of elevated serum NT-proBNP levels after adjusting for possible confounders, which suggests that a diet rich in carotenoids could help prevent cardiac overload in the Japanese population.


Prevalence of chlamydial eye infection in patients attending an eye clinic, a VD clinic, and in healthy persons.
Chlamydial eye infection was detected in 28 of 983 ophthalmological patients with conjunctivitis or keratoconjunctivitis, with a peak frequency of over 9% in patients aged 16-20 years and with decreasing frequency thereafter. In patients aged 1 to 15 years chlamydial conjunctivitis was not observed. Chlamydial eye infection could not be detected in patients at a venereal diseases clinic, though chlamydial genital infection was rather frequent in these patients. Nor was Chlamydia trachomatis found in the eyes of healthy young adults. In patients with proved chlamydial conjunctivitis unilateral symptoms were the rule. Pseudoptosis was the most conspicuous presentation in two cases. A prolonged course can be expected in chlamydial eye infection if the condition is unrecognised and effective treatment delayed. The venereal background of the condition must also influence the management.


Automated evaluation of physical therapy exercises using multi-template dynamic time warping on wearable sensor signals.
We develop an autonomous system to detect and evaluate physical therapy exercises using wearable motion sensors. We propose the multi-template multi-match dynamic time warping (MTMM-DTW) algorithm as a natural extension of DTW to detect multiple occurrences of more than one exercise type in the recording of a physical therapy session. While allowing some distortion (warping) in time, the algorithm provides a quantitative measure of similarity between an exercise execution and previously recorded templates, based on DTW distance. It can detect and classify the exercise types, and count and evaluate the exercises as correctly/incorrectly performed, identifying the error type, if any. To evaluate the algorithm's performance, we record a data set consisting of one reference template and 10 test executions of three execution types of eight exercises performed by five subjects. We thus record a total of 120 and 1200 exercise executions in the reference and test sets, respectively. The test sequences also contain idle time intervals. The accuracy of the proposed algorithm is 93.46% for exercise classification only and 88.65% for simultaneous exercise and execution type classification. The algorithm misses 8.58% of the exercise executions and demonstrates a false alarm rate of 4.91%, caused by some idle time intervals being incorrectly recognized as exercise executions. To test the robustness of the system to unknown exercises, we employ leave-one-exercise-out cross validation. This results in a false alarm rate lower than 1%, demonstrating the robustness of the system to unknown movements. The proposed system can be used for assessing the effectiveness of a physical therapy session and for providing feedback to the patient.


Genetic mapping of a second myotonic dystrophy locus.
We report the mapping of a second myotonic dystrophy locus, myotonic dystrophy type 2 (DM2). Myotonic dystrophy (DM) is a multi-system disease and the most common form of muscular dystrophy in adults. In 1992, DM was shown to be caused by an expanded CTG repeat in the 3' untranslated region of the dystrophia myotonica-protein kinase gene (DMPK) on chromosome 19 (refs 2-6). Although several theories have been put forth to explain how the CTG expansion causes the broad spectrum of clinical features associated with DM, it is not understood how this mutation, which does not alter the protein-coding region of a gene, causes an affect at the cellular level. We have identified a five-generation family (MN1) with a genetically distinct form of myotonic dystrophy. Affected members exhibit remarkable clinical similarity to DM (myotonia, proximal and distal limb weakness, frontal balding, cataracts and cardiac arrhythmias) but do not have the chromosome-19 D CTG expansion. We have mapped the disease locus (DM2) of the MN1 family to a 10-cM region of chromosome 3q. Understanding the common molecular features of two different forms of the disease should shed light on the mechanisms responsible for the broad constellation of seemingly unrelated clinical features present in both diseases.


Is soluble mesothelin-related protein an upfront predictive marker of pleural mesothelioma? A prospective study on Italian workers exposed to asbestos.
Soluble mesothelin-related peptide (SMRP) may be useful in the diagnosis and detection of early stage mesothelioma. We investigated the SMRP upfront predictive role for mesothelioma in asbestos-exposed workers. A total of 1,715 subjects underwent a first visit and were invited for a follow-up after 1 and 2 years, with a clinical examination and blood sampling. SMRP was measured by an ELISA assay. Median SMRP at the first visit was 0.45 [interquartile range (IQR) i.e. 25th-75th percentile: 0.30-0.67 nmol/l]. In all, 1,676 subjects (97.8%) were followed up for a median period of 47.1 months. SMRP was measured at the first visit and at both follow-up visits in 1,536 subjects. At follow-up, 3 subjects were diagnosed with an epithelioid mesothelioma. In these cases, SMRP at the first visit ranged from 0.17 to 0.52 nmol/l. Malignant pleural mesothelioma was diagnosed 9-17 months after the last SMRP evaluation. No SMRP variation was observed during the follow-up. Other 61 miscellaneous cancers were diagnosed (median SMRP at first visit: 0.50 nmol/l, IQR: 0.34-0.71 nmol/l). Our results did not support the usefulness of SMRP as an early marker for the detection of the disease for a time interval of 1 year.


Assessment of a Digital Symptom Checker Tool's Accuracy in Suggesting Reproductive Health Conditions: Clinical Vignettes Study.
Reproductive health conditions such as endometriosis, uterine fibroids, and polycystic ovary syndrome (PCOS) affect a large proportion of women and people who menstruate worldwide. Prevalence estimates for these conditions range from 5% to 40% of women of reproductive age. Long diagnostic delays, up to 12 years, are common and contribute to health complications and increased health care costs. Symptom checker apps provide users with information and tools to better understand their symptoms and thus have the potential to reduce the time to diagnosis for reproductive health conditions. This study aimed to evaluate the agreement between clinicians and 3 symptom checkers (developed by Flo Health UK Limited) in assessing symptoms of endometriosis, uterine fibroids, and PCOS using vignettes. We also aimed to present a robust example of vignette case creation, review, and classification in the context of predeployment testing and validation of digital health symptom checker tools. Independent general practitioners were recruited to create clinical case vignettes of simulated users for the purpose of testing each condition symptom checker; vignettes created for each condition contained a mixture of condition-positive and condition-negative outcomes. A second panel of general practitioners then reviewed, approved, and modified (if necessary) each vignette. A third group of general practitioners reviewed each vignette case and designated a final classification. Vignettes were then entered into the symptom checkers by a fourth, different group of general practitioners. The outcomes of each symptom checker were then compared with the final classification of each vignette to produce accuracy metrics including percent agreement, sensitivity, specificity, positive predictive value, and negative predictive value. A total of 24 cases were created per condition. Overall, exact matches between the vignette general practitioner classification and the symptom checker outcome were 83% (n=20) for endometriosis, 83% (n=20) for uterine fibroids, and 88% (n=21) for PCOS. For each symptom checker, sensitivity was reported as 81.8% for endometriosis, 84.6% for uterine fibroids, and 100% for PCOS; specificity was reported as 84.6% for endometriosis, 81.8% for uterine fibroids, and 75% for PCOS; positive predictive value was reported as 81.8% for endometriosis, 84.6% for uterine fibroids, 80% for PCOS; and negative predictive value was reported as 84.6% for endometriosis, 81.8% for uterine fibroids, and 100% for PCOS. The single-condition symptom checkers have high levels of agreement with general practitioner classification for endometriosis, uterine fibroids, and PCOS. Given long delays in diagnosis for many reproductive health conditions, which lead to increased medical costs and potential health complications for individuals and health care providers, innovative health apps and symptom checkers hold the potential to improve care pathways.