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Background: RASopathies account for nearly 20% of cases of childhood hypertrophic cardiomyopathy (HCM). Sudden cardiac death (SCD) occurs in patients with RASopathy-associated HCM, but the risk factors for SCD have not been systematically evaluated., Aim: To validate the HCM Risk-Kids SCD risk prediction model in children with RASopathy-associated HCM and investigate potential specific SCD predictors in this population., Methods: Validation of HCM Risk-Kids was performed in a retrospective cohort of 169 patients with a RASopathy-associated HCM from 15 international paediatric cardiology centres. Multiple imputation by chained equations was used for missing values related to the HCM Risk-Kids parameters., Results: Eleven patients (6.5%) experienced a SCD or equivalent event at a median age of 12.5 months (IQR 7.7-28.64). The calculated SCD/equivalent event incidence was 0.78 (95% CI 0.43-1.41) per 100 patient years. Six patients (54.54%) with an event were in the low-risk category according to the HCM Risk-Kids model. Harrell's C index was 0.60, with a sensitivity of 9.09%, specificity of 63.92%, positive predictive value of 1.72%, and negative predictive value of 91%; with a poor distinction between the different risk groups. Unexplained syncope (HR 42.17, 95% CI 10.49-169.56, p < 0.001) and non-sustained ventricular tachycardia (HR 5.48, 95% CI 1.58-19.03, p < 0.007) were predictors of SCD on univariate analysis., Conclusion: Unexplained syncope and the presence of NSVT emerge as predictors for SCD in children with RASopathy-associated HCM. The HCM Risk-Kids model may not be appropriate to use in this population, but larger multicentre collaborative studies are required to investigate this further., Competing Interests: Declaration of Competing Interest Wolf CM: consultancy with Day One Biopharmaceuticals, Inc., BioMarin Pharmaceuticals, Adrenomed AG, and Pliant Therapeutics; ownership interest: Preventage Therapeutics. Zenker M: consultancy with Day One Biopharmaceuticals, Inc. and Novo Nordisk., (Copyright © 2023. Published by Elsevier B.V.)

Subspecialty consultation is an increasingly used resource in inpatient medicine. Teaching the primary team is an important element of effective consultation and has many potential benefits. However, within academic medical centers many barriers to effective consultation and the consult learning environment exist. High workload, burnout, inexperience, lack of familiarity between teams, quality of the consult requests, and pushback may impede teaching and learning. Herein, the authors review the role of teaching and learning during consultation, challenges to effective consultation facing fellows, and interventions that can enhance primary team-fellow interactions and learning., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: This study evaluates whether the instauration of a heroin prescription trial ('NAOMI') generated an impact on the occurrence of crime and disorder in surrounding areas. The clinical trial was initiated in Vancouver and Montreal in 2005, with the aim of assessing the benefits of heroin-assisted treatment (HAT) in Canada. While experiences from other jurisdictions where HAT trials have been implemented clearly demonstrate substantial crime reduction effects for trial participants, there is overall concern that HAT clinics - similar to other interventions aiming at problematic street drug users - may induce a 'honeypot' effect, leading to increases in crime and/or disorder problems in the vicinity of interventions. It has been argued that HAT clinics will attract undesirable behaviour associated with cultures of street drug use and thereby produce negative impacts on the community., Methods: This study examined the incidence of crime and disorder in the Vancouver and Montreal sites before and during the NAOMI trial (2002-2006), using police calls for service and arrest data. Data were analysed by autoregression analyses., Results: The analysis suggested that most indicators remained stable during the pre- and implementation phase of the NAOMI trial in both sites., Conclusion: While the attribution of observed crime and disorder trends to the specific clinical interventions in Montreal and Vancouver is difficult and many extrinsic factors may play a role, this study has not generated any clear evidence from institutional police data to suggest increases or decreases in community-based problems associated with HAT programs in Canada.

Background: A supervised injection facility (SIF) has been established in North America: Insite, in Vancouver, British Columbia. The purpose of this paper is to conduct a cost-effectiveness and cost-benefit analysis of this SIF using secondary data gathered and analysed in 2008. In using these data we seek to determine whether the facility's prevention of infections and deaths among injecting drug users (IDUs) is of greater or lesser economic cost than the cost involved in providing this service - Insite - to this community., Methods: Mathematical modelling is used to estimate the number of new HIV infections and deaths prevented each year. We use the number of these new HIV infections and deaths prevented, in conjunction with estimated lifetime public health care costs of a new HIV infection, and the value of a life, in order to calculate an identifiable portion of the societal benefits of Insite. The annual costs of operating the SIF are used to measure the social costs of Insite. In using this information, we calculate cost-effectiveness and benefit-cost ratios for the SIF., Results: Through the use of conservative estimates, Vancouver's SIF, Insite, on average, prevents 35 new cases of HIV and almost 3 deaths each year. This provides a societal benefit in excess of $6 million per year after the programme costs are taken into account, translating into an average benefit-cost ratio of 5.12:1., Conclusion: Vancouver's SIF appears to be an effective and efficient use of public health care resources, based on a modelling study of only two specific and measurable benefits-HIV infection and overdose death.

Riboswitches are complex folded RNA domains found in noncoding regions of mRNA that regulate gene expression upon small molecule binding. Recently, Breaker and coworkers reported a tandem aptamer riboswitch (VCI-II) that binds glycine cooperatively. Here, we use hydroxyl radical footprinting and small-angle X-ray scattering (SAXS) to study the conformations of this tandem aptamer as a function of Mg(2+) and glycine concentration. We fit a simple three-state thermodynamic model that describes the energetic coupling between magnesium-induced folding and glycine binding. Furthermore, we characterize the structural conformations of each of the three states: In low salt with no magnesium present, the VCI-II construct has an extended overall conformation, presumably representing unfolded structures. Addition of millimolar concentrations of Mg(2+) in the absence of glycine leads to a significant compaction and partial folding as judged by hydroxyl radical protections. In the presence of millimolar Mg(2+) concentrations, the tandem aptamer binds glycine cooperatively. The glycine binding transition involves a further compaction, additional tertiary packing interactions and further uptake of magnesium ions relative to the state in high Mg(2+) but no glycine. Employing density reconstruction algorithms, we obtain low resolution 3-D structures for all three states from the SAXS measurements. These data provide a first glimpse into the structural conformations of the VCI-II aptamer, establish rigorous constraints for further modeling, and provide a framework for future mechanistic studies.

The Ontario Familial Breast Cancer Registry (OFBCR) is one of six international sites of the Cooperative Familial Registry for Breast Cancer Studies collecting family history, epidemiologic information, and blood samples from families (with various patterns of familial risk) for the purpose of studying the etiology of breast cancer. To invite 2361 female breast cancer patients residing in Ontario to take part in the Registry, a package was sent that included a Family History Questionnaire. Several variations of mailing and follow-up strategies were employed. Overall, the response rate was 67%. The best response (74%) was achieved by following up our introductory package of information with a postcard 10 days later and a telephone call several weeks thereafter. Given the design of the project, which involves a considerable commitment on the part of both patients and their family members, we are impressed by the positive response of these women.

We tested the hypothesis that the fracture location of scaphoid nonunions relates to the fracture displacement, development of dorsal intercalated segment instability (DISI) deformity, and changes in the contact area of the bones in the radiocarpal joint. Eleven patients with scaphoid nonunions were examined with 3-dimensional computed tomography and a new method of proximity mapping. Two different patterns of displacement of scaphoid nonunions were demonstrated, 1 volar and 1 dorsal. All patients with a volar pattern scaphoid nonunion had a DISI deformity. Only a few of the patients with a dorsal pattern scaphoid nonunion, mostly in longstanding nonunions, had a DISI deformity. The fracture line was generally distal to the dorsal apex of the ridge of the scaphoid in the volar-type fractures and proximal in the dorsal displaced fractures. The proximity map of the distal fragment of the scaphoid on the radius in the volar type shifts radial compared with normal; in the distal type it shifts dorsal. Neither of the patterns showed any significant changes of the proximity map in the radiocarpal joint at the proximal scaphoid fragment and the lunate. Whether the fracture line passes distal or proximal to the dorsal apex of the ridge of the scaphoid appears to determine the likelihood of subsequent fracture displacement, DISI deformity, and contact area of the bones in the radiocarpal joint.

The purpose of this study was to examine the anatomy and mechanical properties of the dorsal radiocarpal (DRC) and dorsal intercarpal (DIC) ligaments of the wrist and to better understand the functional design of the dorsal ligaments. The DRC ligament was consistently found to originate from the dorsal margin of the distal radius and extended ulnar obliquely and distally. Its radial fibers attached to the lunate and lunotriquetral interosseous ligament. The DRC ligament then inserted onto the dorsal tubercle of the triquetrum. The DIC ligament originated from the triquetrum and extended radially and attached onto the lunate, inserted into the dorsal groove of the scaphoid, and then extended to the trapezium. The DRC and DIC ligaments together, in their lateral V configuration, act effectively as a dorsal radioscaphoid ligament that has the ability to vary its length by changing the angle between the 2 arms of the V. The DRC-DIC ligaments' lateral V configuration allows normal carpal kinematics while maintaining its indirect dorsal stabilizing effect on the scaphoid throughout the range of motion of the wrist.

This study tested the ability of a self-administered food frequency questionnaire (FFQ) to identify women with low fat intakes. FFQs were completed by 95 control participants of a dietary trial at a mean 2.9 +/- 0.8 years post-randomization. Subjects were selected in approximately equal numbers from women who were low-fat eaters (< or = 30% of energy from fat) and high-fat eaters (> 30% of energy from fat). Percentage energy from fat derived from food records and FFQ were similar in both the low- and high-fat eaters. Percentage of energy from carbohydrate and total grams of carbohydrate (low-fat eaters only) were slightly higher measured by FFQ than by food records, and percentage of energy from protein was slightly lower. The correlation between nutrient intake measured by FFQ and food records for the whole group was 0.74 for percentage of energy from fat, 0.50 for total fat, 0.59 for percentage of energy from carbohydrate, 0.43 for total carbohydrate, 0.53 for percentage of energy from protein, 0.27 for total protein, and 0.32 for energy intake. Correlations were slightly lower when the low- and high-fat eaters were examined separately. The area under the receiver operating characteristic (ROC) curve, 0.83, was significantly above 0.5 (p < < 0.001), indicating that the FFQ discriminated between low- and high-fat eaters significantly better than chance. The FFQ cutoff point of 30% of energy from fat had a true positive rate of 0.63 and false positive rate of 0.24. The use of this cutoff point for screening would result in the loss of 36% of potential subjects and an estimated increase in baseline percentage of energy from fat intake of 2.3 percentage points.

The accuracy of estimates of usual energy intake derived from food records in participants of a long-term dietary-intervention trial was studied in a subset of 29 women aged 48.7+/-5.0 y and weighing 61.9+/-6.5 kg. This sample was similar to the population in the whole trial (n=715), from which it was selected in terms of age, weight, body mass index (BMI), and reported energy and fat intakes. During the validation study, reported energy intake was derived from 7 consecutive days of food records, and total energy expenditure was measured by the doubly labeled water method over 13 d. Reported energy intake (6.98+/-1.58 MJ/d) was significantly lower than energy expenditure (9.00+/-2.08MJ/d) and represented 79.8+/-17.6% of expenditure. The correlation between reported energy intake and expenditure was 0.46 (P=0.01, 95% CI: 0.15, 0.71). Body weight, BMI, height, length of time in the dietary trial, and percentage of energy from fat and carbohydrate were not significantly associated with the accuracy of reporting. These results indicate that energy intake derived from food records is an imprecise measure that substantially underestimates energy intake in middle-aged women participating in a long-term dietary-intervention trial.

The palatal gingiva and intermolar mucosa from normal hamsters and from hamsters that had received N-methyl-N-nitrosourea (NMU) intraperitoneally were examined by scanning electron microscopy over a 22-week period. The normal gingiva and rostral two-thirds of the intermolar mucosa were covered by flat polygonal cells that had a regular honeycomb surface pattern of interconnecting micro-ridges, distinct cell boundaries and imprints of cells that had been desquamated. The caudal third of the intermolar mucosa in normal and NMU-treated hamsters was covered by soft-palate type mucosa whose smooth surfaced cells surrounded scattered fungiform-like papillae. In NMU-treated hamsters changes were more common in the rostral two-thirds of the intermolar mucosa than in the gingiva. At 10 weeks there were sessile and conical surface projections and saucer-shaped and conical epithelial-lined depressions. At 16 weeks these projections and depressions were larger and more numerous, and groups of conical projections formed papillomatous-like lesions. At 22 weeks the projections and depressions were further increased in number and size and there were distinct papillomas. At 10 and 16 weeks the entire epithelium showed cells, cell boundaries and cell imprints resembling those in the controls, except that there were defects or dilated intercellular spaces at the base of the conical depressions and some of the cells were thicker. Much of the 22-week epithelial had a similar structure, but in some areas that did not show the projections or depressions the cells varied in size and shape and were covered by elongated micro-ridges. Here the surface was irregular as were the cell boundaries. Examination of sections by light microscopy, both from these irregular areas and from areas that appeared normal by scanning electron microscopy, revealed that the deeper epithelial strata could be either normal, dysplastic or at times malignant. However, scanning electron microscopy failed to reveal dysplastic or malignant epithelium.

Previous research has indicated the presence of a reciprocal relationship between food intake and opioid-mediated analgesia. We believe the cellular candidate most likely acting as a common mediator of both ingestive and nociceptive behaviors is the ATP-sensitive K+ channel (K+ATP). This ion channel appears to be opened by mu and delta 1 opioid receptor agonists in the service of analgesia, and closed as cellular ATP availability rises. To further examine the role of the K+ATP in the relationship between feeding and opioid function, we administered 80 nmol of glybenclamide (a K+ATP antagonist) to male SD rats via the lateral ventricle. Chow consumption in the treated animals was significantly reduced over the following 48 h (F = 2.62, p < 0.013), with the peak effect (78% of control) occurring at 6 h. In the tail-flick test, 4 mg/kg morphine sulfate provided analgesia of 42.38 +/- 8.4% and 18.89 +/- 7.67% in vehicle and treated animals, respectively (p < 0.05, n = 8/group, one-tailed t-test). These results support the hypothesis that food intake and analgesia are reciprocally modulated through activity at the K+ATP.

We have examined the feasibility of carrying out a randomized controlled trial of dietary fat reduction in women at increased risk for breast cancer. The randomization was either to a control group who were taught the principles of balanced nutrition, but were not counselled to change their fat intake, or to an intervention group who were taught to reduce their dietary fat intake to 15% of total calories from a baseline average of 35% of calories. Potentially eligible subjects were women attending a breast diagnostic clinic who had the mammographic pattern of dysplasia. Subjects were recruited by letter from their referring surgeon followed by a telephone call. Subjects interested in participating in the study then entered by one of two phases. In Phase I, the study was explained, informed consent sought and willing subjects randomized to the intervention or control group. Using this procedure 227 subjects were randomized and 48 (21%) dropped out of the study in the 12 months following randomization. (A drop out was defined as a subject who persistently failed to keep appointments and provide nutrient data.) Of these drop outs, 30 (63%) occurred at or soon after randomization. A modified procedure of entry was then adopted in which subjects interested in the study were first taught the procedures involved, including keeping food records and clinic appointments, and were then asked to provide consent and randomized. Two hundred and eighty subjects were enrolled using this modified procedure and 25 (9%) have dropped out in the 12 months following randomization.(ABSTRACT TRUNCATED AT 250 WORDS)

The appearance of the breast parenchyma as seen on mammography is known to vary between individuals. The evidence is reviewed that some of the sources of this variation, namely, the densities referred to as "dysplasia", are related to breast cancer risk. We have carried out a meta-analysis of the published literature to determine the magnitude of the risk of breast cancer associated with mammographic densities by calculating summary odds ratios for studies grouped according to their design and the method used to classify mammographic parenchymal patterns. This has shown that subjects with mammographic densities have an increased risk of breast cancer relative to those without densities. Of the studies that used Wolfe's method of classification, cohort studies (n = 8) had a summary odds ratio of 5.19 (95% CI, 3.6 to 7.48); case control studies (n = 13) had a summary odds ratio of 1.8 (95% CI, 1.5 to 2.13); and prevalence surveys had a summary odds ratio of 0.54 (95% CI, 0.4 to 0.7). Other methods of classification, using quantitative estimates of the proportion of the breast occupied by densities, gave substantially higher odds ratios than Wolfe's system. The ability to recognize individuals within the population at different risks for breast cancer could be exploited in studies of potential etiological factors.

We compared observed and predicted changes in serum cholesterol in women with mammographic dysplasia who participated for 12 mo in a randomized, controlled trial of a low-fat, high-carbohydrate diet, in which total fat intake was reduced from an average of 37% of calories to 21% and carbohydrate intake increased from 44% to 52% of calories. Changes observed in serum cholesterol were greater than those predicted (by the formulas of Hegsted and Keys) for subjects with initial serum cholesterol values in the upper tertile of the population, were not significantly different from those predicted for subjects with baseline values in the middle tertile, and were significantly less than those predicted for subjects with initial values in the lower tertile. These results show that the usefulness of serum cholesterol as a marker of change in dietary fat intake in women depends on the distribution of serum cholesterol values in the population studied.

During the course of an attempt to purify the substance P (SP) receptor from horse salivary glands by substance P-affinity chromatography, a polypeptide of Mr = 78,000 was isolated. The first fifteen amino acid residues at the amino terminus were determined and, unexpectedly, were found to be identical with the amino terminus of a glucose-regulated protein (GRP) of the same molecular weight, a protein that has been identified as a member of the heat shock protein family. This finding raises the intriguing possibility that SP may interact in vivo with GRPs and other members of the heat shock protein family and play a role in modulating their biological activities.

Metastatic breast cancer cannot be cured with currently available therapeutic agents, and the objectives of treatment must, therefore, be directed towards other goals that include the relief of symptoms and the preservation or restoration of function. The main objective of the study reported here was to examine the relative importance of 28 items concerned with general health or with disease and treatment to a group of patients with metastatic breast cancer. All items concerned aspects of quality of life whose relevance and importance to patients with metastatic breast cancer had been shown in previous work. Patients rated items according to importance using two methods, a Q sort and a linear analogue rating. General health items, notably self-care, mobility, and physical activity, appetite, sleep, and family relationships were ranked in the upper quartile of the group of items rated. By contrast, items concerned directly with the common side-effects of chemotherapy were given lower rankings. The ratings were shown to be reproducible. These results emphasize the importance of including in clinical trials of therapy that are palliative in intent, endpoints that include those aspects of quality of life that are of greatest importance to patients.

We have assessed the validity of a method of measurement for describing the clinical status of patients with breast cancer. One hundred and nine patients with breast cancer assigned numerical values to their own state of health using linear analogue scales. We have shown previously that this method of measurement is reliable and corresponds well with other methods of assessment. Validity was assessed in this study by examining the ability of measurements to distinguish between groups of patients who differed either in the presence of metastatic disease or in the treatments they were receiving. All patients completed the same set of 29 linear analogue scales that enquired about the severity of health related problems and symptoms. In general, patients with metastatic disease were clearly distinguished from patients without metastases by their scores on items related to physical function. Patients receiving chemotherapy were distinguished from those not receiving chemotherapy by their scores on treatment related toxicities. Measures of psychological and social health were similar in patients receiving chemotherapy regardless of disease status. These results provide further support for the validity of measurement of clinical status with linear analogue scales scored by patients.

We have evaluated three methods of assessing patients with cyclical breast symptoms (cyclical mastopathy--CM). One method, a screening questionnaire, was used to identify women with CM, and two others, a symptom severity questionnaire and a daily diary, were used prospectively to record the severity of symptoms in relation to the menstrual cycle. The screening questionnaire was assessed for test-retest reliability and for agreement between the recalled severity of symptoms and those recorded during prospective measurement. The symptom severity questionnaire and diary were assessed by examining their ability to discriminate between pre- and postmenstrual phases of the menstrual cycle, differences in symptom severity at these times being the cardinal feature of CM. Test-retest reliability of premenstrual symptoms by the screening questionnaire gave correlation coefficients over 0.70 for 9 of the 11 items assessed. The symptom severity questionnaire showed significant differences between pre- and post-menstrual scores for 8 of the 11 items assessed and the diary for each of the 2 items assessed. Comparison of symptom severity as recalled and as prospectively recorded showed only modest agreement. These results show that the instruments used to assess symptom severity performed satisfactorily but that the screening questionnaire used to identify women with CM, although reliable, correlated only moderately well with prospective measurement.

Studying the association between diet and disease requires reliable and valid methods for the assessment of diet. The authors reviewed the literature concerned with the assessment of these aspects of the measurement of dietary intake. Studies were examined for the stated purpose and scope of the dietary instrument, for a description of the instrument itself, for any methods employed to train individuals in its use and for the methods used to assess its reliability and validity. Of the 59 studies reviewed, 54% described fully the dietary method used. Of the 39 studies that described the results using questionnaires, 51% gave specific information on questions asked and only 18% included the questionnaire itself. Reliability was assessed in 26 studies and 74% (19) used the test-retest reliability and 22% (6) used proxies to assess reliability. Validity was assessed in 46 studies and 83% (38) used indirect methods that compared the results of one dietary method (e.g. 24 hr recall) with another more extensive one (e.g. diet history). Thirty five percent (16) used biochemical and 15% (7) used other methods. This review suggests several directions that might be usefully followed in conducting and reporting further research in the development of methods to assess diet.

A nitrocellulose-gel transfer technique has been adapted to study the interaction of a polypeptide ligand with individual receptor subunits. The acetylcholine receptor isolated from Torpedo californica has been separated into its subunits by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and transferred in a renaturing environment to nitrocellulose sheets. The sheets were incubated with 125I-alpha-bungarotoxin and autoradiographed. A single receptor polypeptide, the alpha subunit (40K) bound the labeled toxin. This binding was demonstrated to be both saturable and specific, although the affinity of 125I-alpha-bungarotoxin (KD, 165 nM) and the potency of d-tubocurarine to displace this binding (IC50, 1 mM) were both reduced by several orders of magnitude when compared to the native receptor.

The authors have investigated the diagnostic accuracy of computed tomography (CT) of the abdomen and pelvis in the assessment of patients prior to second-look laparotomy for advanced ovarian cancer. CT studies (read independently by three radiologists) and laparotomy findings were analyzed in 50 patients. Sensitivity varied from 0.30 to 0.65 among the radiologists, specificity from 0.44 to 0.89, positive predictive value from 0.50 to 0.73, and negative predictive value from 0.60 to 0.70. Receiver operator curve analysis of the data indicated poor performance of CT as a diagnostic test. The authors also examined some problems in interpreting their data and that of others in the literature, in particular, the influence of potential sources of bias.

Covalently linked soluble immune complexes were prepared with a 2-stage bifunctional reagent. Complexes with antigen-antibody ratio 2 : 1 were purified and characterized. The covalent linkage and antigenic characteristics of the complexes were demonstrated.

21 patients with severe persistent cyclical mastopathy of at least 5 years' duration were randomised to a control group who received general dietary advice or to an intervention group who were taught how to reduce the fat content of their diet to 15% of calories while increasing complex carbohydrate consumption to maintain caloric intake. Both groups were followed for 6 months with food records and measurement of plasma hormone and lipid levels. Severity of symptoms was recorded with daily diaries and patients were assessed at the beginning and end of the study by a physician who was unaware of their dietary regimen. After 6 months there was a significant reduction in the intervention group in the severity of premenstrual breast tenderness and swelling. Physical examination showed reduced breast swelling, tenderness, and nodularity in 6 of 10 patients in the intervention group and 2 of 9 patients in the control group.

Ammonium sulphate, DEAE ion exchange chromatography, and polyethylene glycol (PEG) were compared for their ability to isolate and purify large quantities of immunoglobulins from severely haemolysed plasma. PEG, which produced the highest yield and purity, proved to be the only method which completely removed the haemoglobin.

Dietary compliance was studied in 57 women participating for 1 y in a randomized clinical trial of dietary fat reduction. Nutrient analysis of food records, collected at 0, 6, and 12 mo, was compared with changes observed in lipid profiles and with chemical analysis of duplicate diets. Both food records and duplicate meals showed a significant decrease in fat intake (from 36 to 23% of total calories, p less than 0.0001) and a significant increase in carbohydrate (from 43 to 56% of total calories, p less than 0.0001) in the intervention group. The calculated nutrient intake from food records tended to overestimate the intake of protein, fat, and carbohydrate compared with the chemically analyzed method. The mean level of plasma cholesterol in the intervention group was significantly reduced (7.3%, p less than 0.01) in the first 6 mo after a reduction in dietary fat but the levels observed did not differ significantly between the groups at any time.