Swiss Academy of Medical Sciences

Abstract Two types of host reactivities not requiring immunization in the mouse and not mediated by T lymphocytes were compared: resistance of irradiated and nonirradiated F 1 hybrids to accept parental grafts of normal or malignant hemopoietic cells (Hh system), and the natural killer cell activity against mouse lymphomas (NK system). The effects of six independent variables known to influence resistance to marrow grafts were investigated in the NK system using YAC‐1 lymphoma cells as targets. The following properties were shared: (a) maturation during the fourth week of life; (b) low sensitivity to acute total body irradiation; (c) dependence on the integrity of bone marrow as demonstrated by reduced reactivity in 89 Sr‐treated mice; (d) suppression by a single injection of rabbit anti‐mouse bone marrow serum; (e) suppression by a single injection of the anti‐macrophage agents silica and i‐carrageenan; and (f) suppression by multiple injections of parental spleen cells into F 1 mice. These positive correlations are particularly significant because most of the variables have either opposing or no effect on conventional immunity. F 1 mice rendered specifically unresponsive to parental marrow grafts, could retain NK cell activity, and genetically susceptible mice could be rendered hyporeactive in terms of NK cells, indicating that the specificities of YAC‐1 and Hh‐1 incompatible targets were different. It is extremely unlikely that this remarkable parallelism is fortuitous. These results indicate that either a very similar, or more likely a common mechanism is operative in the two cell‐mediated natural reactivities: effector cells in the NK and Hh systems do not bear B or T lymphocyte markers but are nevertheless endowed with “specificity”. They are dependent for generation in vivo (presumably by maturation or by recruitment) on the interaction with nonlymphoid accessory cells not endowed with specificity, capable of also interacting in vitro with Thy‐1‐positive F 1 hybrid prekiller cells specific for parental targets. Because of thymus independence in vivo and apparent restriction to target cells of the hemopoietic system, these reactivities should be effective in the regulation of hemopoiesis and surveillance over leukemogenesis.

IMPORTANCE: The discontinuation of randomized clinical trials (RCTs) raises ethical concerns and often wastes scarce research resources. The epidemiology of discontinued RCTs, however, remains unclear. OBJECTIVES: To determine the prevalence, characteristics, and publication history of discontinued RCTs and to investigate factors associated with RCT discontinuation due to poor recruitment and with nonpublication. DESIGN AND SETTING: Retrospective cohort of RCTs based on archived protocols approved by 6 research ethics committees in Switzerland, Germany, and Canada between 2000 and 2003. We recorded trial characteristics and planned recruitment from included protocols. Last follow-up of RCTs was April 27, 2013. MAIN OUTCOMES AND MEASURES: Completion status, reported reasons for discontinuation, and publication status of RCTs as determined by correspondence with the research ethics committees, literature searches, and investigator surveys. RESULTS: After a median follow-up of 11.6 years (range, 8.8-12.6 years), 253 of 1017 included RCTs were discontinued (24.9% [95% CI, 22.3%-27.6%]). Only 96 of 253 discontinuations (37.9% [95% CI, 32.0%-44.3%]) were reported to ethics committees. The most frequent reason for discontinuation was poor recruitment (101/1017; 9.9% [95% CI, 8.2%-12.0%]). In multivariable analysis, industry sponsorship vs investigator sponsorship (8.4% vs 26.5%; odds ratio [OR], 0.25 [95% CI, 0.15-0.43]; P < .001) and a larger planned sample size in increments of 100 (-0.7%; OR, 0.96 [95% CI, 0.92-1.00]; P = .04) were associated with lower rates of discontinuation due to poor recruitment. Discontinued trials were more likely to remain unpublished than completed trials (55.1% vs 33.6%; OR, 3.19 [95% CI, 2.29-4.43]; P < .001). CONCLUSIONS AND RELEVANCE: In this sample of trials based on RCT protocols from 6 research ethics committees, discontinuation was common, with poor recruitment being the most frequently reported reason. Greater efforts are needed to ensure the reporting of trial discontinuation to research ethics committees and the publication of results of discontinued trials.

BACKGROUND: The Mayer-Rokitansky-Kuester-Hauser (MRKH) syndrome is a malformation of the female genitals (occurring in one in 4000 female live births) as a result of interrupted embryonic development of the Müllerian (paramesonephric) ducts. This retrospective study examined the issue of associated malformations, subtyping, and the frequency distribution of subtypes in MRKH syndrome. METHODS: Fifty-three MRKH patients were investigated using a newly developed standardized questionnaire. Together with the results of clinical and diagnostic examinations, the patients were classified into the three recognized subtypes [typical, atypical and MURCS (Müllerian duct aplasia, renal aplasia, and cervicothoracic somite dysplasia)]. RESULTS: The typical form was diagnosed in 25 patients (47%), the atypical form in 11 patients (21%), and the most marked form-the MURCS type-in 17 patients (32%). Associated malformations were notably frequent among the patients. Malformations of the renal system were the most frequent type of accompanying malformation, with 23 different malformations in 19 patients, followed by 18 different skeletal changes in 15 patients. CONCLUSIONS: In accordance with the literature, this study shows that associated malformations are present in more than a third of cases. Therefore, new basic guidelines for standard diagnostic classification involving patients with suspected MRKH are presented.

BACKGROUND: It is possible that antiretroviral treatment given early during primary infection with the human immunodeficiency virus (HIV) may reduce acute symptoms, help preserve immune function, and improve the long-term prognosis. METHODS: To assess the effect of early antiviral treatment, we conducted a multicenter, double-blind, placebo-controlled trial in which 77 patients with primary HIV infection were randomly assigned to receive either zidovudine (250 mg twice daily; n = 39) or placebo (n = 38) for six months. RESULTS: The mean time from the onset of symptoms until enrollment in the study was 25.1 days. Among the 43 patients who were still symptomatic at the time of enrollment, there was no appreciable difference in the mean (+/- SE) duration of the retroviral syndrome between the zidovudine group (15.0 +/- 4.1 days) and the placebo group (15.8 +/- 3.6 days). During a mean follow-up period of 15 months, minor opportunistic infections developed in eight patients: oral candidiasis in four, herpes zoster in two, and oral hairy leukoplakia in two. Disease progression was significantly less frequent in the zidovudine group (one opportunistic infection) than in the placebo group (seven opportunistic infections; P = 0.009 by the log-rank test). After adjustment for the base-line CD4 cell count, the patients treated with zidovudine had an average gain of 8.9 CD4 cells per cubic millimeter per month (95 percent confidence interval, -1.4 to 19.1) during the first six months of the study, whereas those receiving placebo had an average loss of 12.0 CD4 cells per cubic millimeter per month (95 percent confidence interval, 5.2 to 18.7), for a between-group difference of 20.9 CD4 cells per cubic millimeter per month (95 percent confidence interval, 8.5 to 33.2; P = 0.001). CONCLUSIONS: Antiretroviral therapy administered during primary HIV infection may improve the subsequent clinical course and increase the CD4 cell count.

We previously reported that acetaldehyde increases the production of type I collagen in cultured rat fat-storing cells. We studied the regulation of this effect by determining the expression of procollagen type I, fibronectin and transforming growth factor-beta 1 messenger RNAs in passage 1 and 2 cultures of fat-storing cells exposed to acetaldehyde for up to 24 hr. By 6 hr, acetaldehyde increased the steady-state levels of alpha 1 procollagen type I messenger RNA 3.2-fold and of fibronectin messenger RNA 2.8-fold above control values. At 24 hr, messenger RNA levels remained elevated. In contrast, transforming growth factor-beta 1 messenger RNA steady-state levels remained unaltered by 6 hr, but increased 1.5-fold by 24 hr. Cycloheximide (0.3 mmol/L) completely inhibited the acetaldehyde effect when added at zero time but was less effective when added at 15 min. The effect of acetaldehyde was not modified when cells were cultured in the presence of the acetaldehyde dehydrogenase inhibitor cyanamide (100 mumol/L). Fat-storing cells were also cultured in the presence of lactate (5, 15 and 25 mmol/L) for 6 hr. At none of these concentrations was any effect seen on either alpha 1(I) procollagen or fibronectin messenger RNAs. In the presence of methylene blue, a scavenger of reducing equivalents, the effect of acetaldehyde on alpha 1(I) procollagen and fibronectin gene expression was totally inhibited. Transcription run-on assay showed that acetaldehyde increased both procollagen type I and fibronectin transcriptional activity threefold and 2.5-fold, respectively. We conclude that acetaldehyde increases alpha 1(I) procollagen and fibronectin gene expression through enhanced transcription by a mechanism dependent on newly synthesized proteins.(ABSTRACT TRUNCATED AT 250 WORDS)

Irreversible and unspecific inhibitors of MAO were the first modern antidepressants, but after an initial success they fell into discredit due to adverse side effects. In the past two decades interest in MAO inhibitors has been renewed because of progress in basic research, a milestone being the finding that there are two subtypes of MAO, MAO-A and MAO-B. These are distinct proteins with high amino acid homology, coded by separate genes both located on the short arm of the human chromosome X. The enzyme subforms show different substrate specificities in vitro and different distributions within the central nervous system and in peripheral organs. In the central nervous system of man MAO-A seems to be mainly involved in the metabolism of 5 HT and noradrenaline, whereas 2-phenylethylamine and probably dopamine are predominantly deaminated by MAO-B. In the intestinal tract tyramine is mainly metabolized by MAO-A. These characteristics indicate distinct physiological functions of the two MAO-subforms. Several irreversible and reversible non-hydrazine inhibitors with relative selectivities for one of the MAO-subforms have been developed. They belong to various chemical classes with different modes of enzyme inhibition. These range from covalent mechanism based interaction (e.g. by propargyl- and allylamine derivatives) to pseudosubstrate inhibition (e.g. by 2-aminoethyl-carboxamides) and non-covalent interaction (e.g. by brofaromine, toloxatone and possibly moclobemide). The most important pharmacological effects of the new types of MAO inhibitors are those observed in neuropsychiatric disorders. The inhibitors of MAO-A show a favorable action in various forms of mental depression. The drugs seem to have about the same activity as other types of antidepressants, including tricyclic and related compounds as well as classical MAO inhibitors. The onset of action of the MAO-A inhibitors is claimed to be relatively fast. Other possible indications of these drugs include disorders with cognitive impairment, e.g. dementia of the Alzheimer type. In subjects with Parkinson's disease the MAO-B inhibitor L-deprenyl exerts a L-dopa-sparing effect, prolongs L-dopa action and seems to have a favorable influence regarding on-off disabilities. The action is in general transitory (months to several years). In addition L-deprenyl has been shown to delay the necessity for L-dopa treatment in patients with early parkinsonism. Whether the drug influence the progression of the disease is still a matter of debate. L-deprenyl also appears to have some antidepressant effect (especially in higher doses) and to exert a beneficial influence in other disorders, e.g. dementia of the Alzheimer type.(ABSTRACT TRUNCATED AT 400 WORDS)

To test the hypothesis that elevated atrial natriuretic peptide (ANP) may be involved in altered fluid homeostasis at high altitude, we examined 25 mountaineers at an altitude of 550 m and 6, 18, and 42 h after arrival at an altitude of 4,559 m, which was climbed in 24 h starting from 3,220 m. In 14 subjects, symptoms of acute mountain sickness (AMS) were absent or mild (group A), whereas 11 subjects had severe AMS (group B). Fluid intake was similar in both groups. In group B, urine flow decreased from 61 +/- 8 (base line) to 36 +/- 3 (SE) ml/h (maximal decrease) (P less than 0.05) and sodium excretion from 7.9 +/- 0.9 to 4.6 +/- 0.7) mmol.l-1.h-1 (P less than 0.05); ANP increased from 31 +/- 4 to 87 +/- 26 pmol/l (P less than 0.001), plasma aldosterone from 191 +/- 27 to 283 +/- 55 pmol/l (P less than 0.01 compared with group A), and antidiuretic hormone (ADH) from 1.0 +/- 0.1 to 2.9 +/- 1.2 pmol/l (P = 0.08 compared with group A). These variables did not change significantly in group A, with the exception of a decrease in plasma aldosterone from 189 +/- 19 to 111 +/- 17 pmol/l (P less than 0.01). There were no measurable effects of elevated ANP on natriuresis, cortisol, or blood pressure. The reduced diuresis in AMS may be explained by increased plasma aldosterone and ADH overriding the expected renal action of ANP. The significance of elevated ANP in AMS remains to be established.(ABSTRACT TRUNCATED AT 250 WORDS)

While 30%-70% of RSV-infected infants develop bronchiolitis, 2% require hospitalization. It is not clear why disease severity differs among healthy, full-term infants; however, virus titers, inflammation, and Th2 bias are proposed explanations. While TLR4 is associated with these disease phenotypes, the role of this receptor in respiratory syncytial virus (RSV) pathogenesis is controversial. Here, we evaluated the interaction between TLR4 and environmental factors in RSV disease and defined the immune mediators associated with severe illness. Two independent populations of infants with RSV bronchiolitis revealed that the severity of RSV infection is determined by the TLR4 genotype of the individual and by environmental exposure to LPS. RSV-infected infants with severe disease exhibited a high GATA3/T-bet ratio, which manifested as a high IL-4/IFN-γ ratio in respiratory secretions. The IL-4/IFN-γ ratio present in infants with severe RSV is indicative of Th2 polarization. Murine models of RSV infection confirmed that LPS exposure, Tlr4 genotype, and Th2 polarization influence disease phenotypes. Together, the results of this study identify environmental and genetic factors that influence RSV pathogenesis and reveal that a high IL-4/IFN-γ ratio is associated with severe disease. Moreover, these molecules should be explored as potential targets for therapeutic intervention.

OBJECTIVE: To determine whether a single oral dose of N-acetylcysteine corrects the deficiency of cysteine and glutathione in plasma and mononuclear cells of HIV-infected patients. DESIGN: Pharmacokinetic and pharmacodynamic study. METHODS: Cysteine and glutathione were measured in plasma and peripheral blood mononuclear cells of patients at different stages of HIV infection before and after a single oral dose of N-acetylcysteine. RESULTS: At baseline, the plasma concentrations of glutathione and cysteine were significantly lower in HIV-infected patients than in healthy controls. The intracellular concentration of glutathione correlated with the absolute CD4 lymphocyte counts: the concentration of glutathione in mononuclear cells was significantly lower in patients with more advanced immunodeficiency. A single oral dose of N-acetylcysteine increased the concentration of cysteine in plasma and mononuclear cells of HIV-infected patients. Four hours after N-acetylcysteine administration, intracellular glutathione concentrations in the patients were moderately higher than at baseline and at 2 h. CONCLUSIONS: Oral N-acetylcysteine transiently increases the concentrations of cysteine and glutathione in mononuclear cells of patients with HIV infection. A sustained increase in intracellular cysteine may be necessary to normalize intracellular glutathione. This may be accomplished by repeat administration of N-acetylcysteine.

Several retrospective and prospective studies confirmed the beneficial effect of dietary protein restriction (DPR) on the downhill course of renal function in chronic kidney disease. The long-term results of this therapeutic modality may be different than the short-term effects. In our nephrology outpatient department, a prospective randomized trial has been in progress since April, 1982. In 1984, we reported a general beneficial effect of our diet after two years of follow-up. Two hundred and forty-eight patients with initial creatinine clearances between 10 and 60 ml/min entered the trial. Patients were stratified for sex, age and degree of renal insufficiency. One hundred and twenty-nine patients were randomly assigned to a DPR-group (0.4 to 0.6 g/kg/day); 118 patients to a control group. Patients on DPR visited the dietitian every three months during the first 24 months of the study; thereafter, as with the controls, the dietitian visits were only for specific needs. Urea excretion decreased significantly in DPR patients as a sign of good compliance and stayed at that level, even without frequent visits to the dietitian. Biochemical parameters showed no signs of malnutrition. Amino acid profiles were related to the degree of renal failure. The diet appeared to have a selective effect on the progression rate of renal failure: only patients with primary glomerular disease responded to the diet. Furthermore, there were striking intersex differences. Males showed a more rapid decline towards end-stage renal failure, but responded in a positive way to the diet, whereas female patients did not benefit from the dietary manipulation at all.(ABSTRACT TRUNCATED AT 250 WORDS)

OBJECTIVE: To identify associations between the characteristics of general practitioners and practices, and patients' evaluations of the availability of general practice. DESIGN: Written surveys completed by patients. SETTING: General practice care in nine European countries: Denmark, Germany, The Netherlands, Norway, UK, Belgium (Flanders and Wallonia), Switzerland, Slovenia and Spain. STUDY PARTICIPANTS: 15996 adult patients consecutively visiting the general practitioner (response rates per country varied between 47 and 89%). MAIN MEASURES: The Europep instrument to assess patients' evaluations of five aspects of the availability of general practice care: (1) getting an appointment, (2) getting through on the phone, (3) being able to speak to the practitioner on the telephone, (4) waiting time in the waiting room, and (5) providing quick services for urgent health problems. Each general practitioner recorded age, sex, number of years in the practice, number of practitioners and other care providers in the practice, and urbanization level of the practice. RESULTS: Patients' more positive evaluations were associated with fewer general practitioners in the practice, except for quick services for urgent health problems (range of conditional overall odds ratios, 1.69-2.02). In addition, a number of significant unconditional overall odds ratios were found, particularly those related to the number of general practitioners' working hours and the number of care providers in the practice. None of the associations was found consistently in all countries. CONCLUSION: Patients favour small practices and full-time general practitioners, which contradicts developments in general practice in many countries. Policy makers should consider how the tensions between patients' views and organizational developments can be solved.

Twenty patients requiring ventilation for acute respiratory failure were studied to determine whether intrapulmonary shunt fraction (Qs/Qt) measured at an inspired oxygen concentration (FIO2) of 1.0 differs from Qs/Qt measured at the clinically indicated FIO2 and, if so, the mechanism by which this occurs. Qs/Qt increased from 15.5 +/- 1.8 per cent (mean +/- SE) at the clinically indicated inspired oxygen fraction (FIO2 0.3-0.6) to 21.7 +/- 2.1 per cent after 20 minutes at FIO2 1.0. Functional residual capacity (FRC) decreased by 6 +/- 6 per cent and total compliance (CT) by 10 +/- 6 per cent. Mean pulmonary arterial pressure fell from 21 +/- 2 to 17 +/- 2 mm Hg, whereas pulmonary capillary wedge pressure (PCWP) and cardiac output remained unchanged. Mixed venous oxygen tension increased from 37 +/- 1 to 45 +/- 2 mm Hg with 100 per cent oxygen. At 90 per cent oxygen, Qs/Qt increased from the value at low FIO2, but FRC and CT did not change. Simultaneous application of 100 per cent oxygen and a positive end-expiratory pressure (6 cm H2O) increased FRC, CT and Qs/Qt. Patients with increased PCWP showed smaller increases in Qs/Qt with 100 per cent oxygen. These findings suggest two mechanisms responsible for the increase in Qs/Qt: 1) redistribution of blood flow to nonventilated areas, resulting from the vasodilating effect of an increased oxygen tension in the vessels of hypoxic lung segments; 2) resorption atelectasis. Of the total change in Qs/Qt observed during ventilation with oxygen, 63 per cent was calculated to be due to factors other than a decrease in FRC. (Key words: Ventilation, positive end-expiratory pressure; Oxygen, pulmonary shunt and; Lung, compliance; Lung, shunts.)

Objective. To determine whether a single oral dose of N-acetylcysteine corrects the deficiency of cysteine and glutathione in plasma and mononuclear cells of HIV-infected patients. Design. Pharmacokinetic and pharmacodynamic study. Methods. Cysteine and glutathione were measured in plasma and peripheral blood mononuclear cells of patients at different stages of HIV infection before and after a single oral dose of N-acetylcysteine. Results. At baseline, the plasma concentrations of glutathione and cysteine were significantly lower in HIV-infected patients than in healthy controls. The intracellular concentration of glutathione correlated with the absolute CD4 lymphocyte counts: the concentration of glutathione in mononuclear cells was significantly lower in patients with more advanced immunodeficiency. A single oral dose of N-acetylcysteine increased the concentration of cysteine in plasma and mononuclear cells of HIV-infected patients. Four hours after N-acetylcysteine administration, intracellular glutathione concentrations in the patients were moderately higher than at baseline and at 2 h. Conclusions. Oral N-acetylcysteine transiently increases the concentrations of cysteine and glutathione in mononuclear cells of patients with HIV infection. A sustained increase in intracellular cysteine may be necessary to normalize intracellular glutathione. This may be accomplished by repeat administration of N-acetylcysteine.

CONTEXT: Pregnant women are often iron deficient, and iron deficiency has adverse effects on thyroid metabolism. Impaired maternal thyroid function during pregnancy may cause neurodevelopmental delays in the offspring. OBJECTIVE: Our objective was to investigate whether maternal iron status is a determinant of TSH and/or total T(4) (TT4) concentrations during pregnancy. DESIGN AND OUTCOME MEASURES: In a representative national sample of Swiss pregnant women (n = 365) in the second and third trimester, samples of urine and blood were collected, and data on maternal characteristics and supplement use were recorded. Concentrations of TSH, TT4, hemoglobin, mean corpuscular volume, serum ferritin, transferrin receptor, and urinary iodine were measured. Body iron stores were calculated and stepwise regressions performed to look for associations. RESULTS: Median urinary iodine was 139 mug/liter (range 30-433). In the third trimester, nearly 40% of women had negative body iron stores, 16% had a TT4 less than 100 nmol/liter, and 6% had a TSH more than 4.0 mU/liter. Compared with the women with positive body iron stores, the relative risk of a TT4 less than 100 nmol/liter in the group with negative body iron stores was 7.8 (95% confidence interval 4.1; 14.9). Of the 12 women with TSH more than 4.0 mU/liter, 10 had negative body iron stores. Serum ferritin, transferrin receptor, and body iron stores were highly significant predictors of TSH (standardized beta: -0.506, 0.602, and -0.589, respectively; all P < 0.0001) and TT4 (standardized beta: 0.679, -0.589, and 0.659, respectively; all P < 0.0001). CONCLUSION: Poor maternal iron status predicts both higher TSH and lower TT4 concentrations during pregnancy in an area of borderline iodine deficiency.

Several studies during the past 15 years have shown that antihypertensive therapy with different types of drugs can reduce microalbuminuria or clinical proteinuria and retard the progression toward end-stage renal failure. However, some authors reported disparate renal protective effects of different antihypertensive drugs in diabetic animals and humans. In an attempt to resolve the controversy surrounding this possibility, previously we reported a meta-analysis of published studies in diabetics with microalbuminuria or overt proteinuria treated with conventional agents, angiotensin-converting enzyme (ACE) inhibitors, or calcium antagonists (Ca2+ antagonists). Here we present an updated meta-analysis of published studies in diabetics with microalbuminuria or clinical proteinuria (UProt), treated during ≥ 4 weeks with ACE inhibitors, Ca2+ antagonists, or conventional therapy (diuretic and/or β-blocker). Despite similar blood pressure (BP) reductions, UProt tended to decrease more on ACE inhibitors (on average -45%) than on conventional therapy (on average -23%) or Ca2+ antagonists other than nifedipine (on average -35%); in contrast, UProt tended to increase slightly on nifedipine (on average 5%, P < .05). On the basis of multiple regression analysis, ACE inhibitor-induced UProt changes correlated with BP changes (r = 0.77, P < .00001), averaged -28% at zero BP change, and varied 1.5% for each percent BP change. On conventional therapy, UProt and BP changes also correlated (r = 0.62, P < .005), but UProt began to decrease only after a BP reduction of >5% and the slope was steeper (4% UProt change per percent BP change) than on ACE inhibitors. On Ca2+ antagonists other than nifedipine, UProt was unchanged at zero BP change, and the regression line for the relationship between changes in UProt (r = 0.55, P < .05) was in an intermediate position between ACE inhibitors and conventional treatment. Seventy reports also contained data on glomerular filtration rate (GFR). On ACE inhibitors, GFR was on average unchanged, but tended to increase slighty with progressive BP reduction (r = -0.55, P < .0001). On conventional therapy or Ca2+.antagonists, variations in GFR were unrelated to changes in BP. As ACE inhibitors exert a specific antiproteinuric effect even without a change in systemic BP, they are superior to other agents in treating microalbuminuria or overt proteinuria in initially normotensive or mildly hypertensive diabetic patients. On the other hand, when systemic BP can be lowered by 20%, as it is desirable in severely hypertensive patients, ACE inhibitors, conventional therapy, and several Ca2+ antagonists all have a distinct antiproteinuric action. In contrast, as the example of nifedipine illustrates, drug-specific intrarenal effects may antagonize a BP-dependent antiproteinuric action and even counteract the effect of lowering systemic pressure. It is of note that ACE inhibitors may, in addition to their antiproteinuric effect, exert a drug-specific beneficial influence on GFR. Am J Hypertens 1994;7:84S-92S

OBJECTIVE: Variations in definitions, scores, and methodologies have created differences in the results and conclusions obtained from studies on mountaineering and climbing sports injuries and illnesses; this has made interstudy comparisons difficult or impossible. To develop a common, simple, and sport-specific scoring system to classify injuries and illnesses in mountaineering and climbing studies; such retrospective scoring would facilitate the analysis and surveillance of their frequencies, severity and fatalities, and outcomes of any treatment. METHODS: The UIAA (The International Mountaineering and Climbing Federation) makes recommendations, sets policy, and advocates on behalf of the climbing and mountaineering community internationally through its various commissions. Using a nominal group consensus model approach, a working group was formed during the UIAA Medical Commission's meeting in Adršpach - Zdoňov, in the Czech Republic, 2008. This group critically examined climbing and other relevant literature for various methodological approaches in measuring injury incident rates and severity, including data sources, and produced a working document that was later edited and ratified by all members of the UIAA Medical Commission. RESULTS: Definitions of injury location, injury classification, and fatality risk are proposed. Case fatality, time-related injury risk, and a standardized metric climbing difficulty scale are also defined. CONCLUSIONS: The medical commission of the UIAA recommends the use of the described criteria and scores for future research in mountaineering and climbing sports in order to enable robust and comprehensive interstudy comparisons and epidemiological analysis.

OBJECTIVE: To investigate the planning of subgroup analyses in protocols of randomised controlled trials and the agreement with corresponding full journal publications. DESIGN: Cohort of protocols of randomised controlled trial and subsequent full journal publications. SETTING: Six research ethics committees in Switzerland, Germany, and Canada. DATA SOURCES: 894 protocols of randomised controlled trial involving patients approved by participating research ethics committees between 2000 and 2003 and 515 subsequent full journal publications. RESULTS: Of 894 protocols of randomised controlled trials, 252 (28.2%) included one or more planned subgroup analyses. Of those, 17 (6.7%) provided a clear hypothesis for at least one subgroup analysis, 10 (4.0%) anticipated the direction of a subgroup effect, and 87 (34.5%) planned a statistical test for interaction. Industry sponsored trials more often planned subgroup analyses compared with investigator sponsored trials (195/551 (35.4%) v 57/343 (16.6%), P<0.001). Of 515 identified journal publications, 246 (47.8%) reported at least one subgroup analysis. In 81 (32.9%) of the 246 publications reporting subgroup analyses, authors stated that subgroup analyses were prespecified, but this was not supported by 28 (34.6%) corresponding protocols. In 86 publications, authors claimed a subgroup effect, but only 36 (41.9%) corresponding protocols reported a planned subgroup analysis. CONCLUSIONS: Subgroup analyses are insufficiently described in the protocols of randomised controlled trials submitted to research ethics committees, and investigators rarely specify the anticipated direction of subgroup effects. More than one third of statements in publications of randomised controlled trials about subgroup prespecification had no documentation in the corresponding protocols. Definitive judgments regarding credibility of claimed subgroup effects are not possible without access to protocols and analysis plans of randomised controlled trials.

Climbing and mountaineering sports are gaining more and more public interest. This chapter reviews scientific studies on injuries and accidents in climbing and mountaineering sports to evaluate the danger of these sports and their specific injuries and preventive measures. An initial PubMed query was performed using the key words 'rock climbing', 'sport climbing', 'mountaineering', 'alpine injuries' and 'climbing injuries'. More than 500 extracted papers were analyzed which gave information on injury, mortality/fatality, prevention and risk factors. Cross-references were also scanned according to the above given criteria. Also the data sources of the UIAA and IFSC Medical Commissions were analyzed. Overall, alpine (traditional) climbing has a higher injury risk than sport climbing, especially indoor climbing. Alpine and ice climbing have more objective dangers which can affect climber safety. Overall injury rates are low, nevertheless fatalities do occur in all climbing disciplines. Altitude-related illnesses/injuries also occur in mountaineering. Most injuries in sport climbing are overstrain injuries of the upper extremity. In alpine climbing, injuries mostly occur through falls which affect the lower extremity. Objective reporting of the injury site and severity varied in most studies according to the injury definition and methodology used. This creates differences in the injury and fatality results and conclusions, which in turn makes inter-study comparisons difficult. In future studies, the UIAA MedCom score for mountain injuries should be used to guarantee inter-study comparability. Evidence in preventive measures is low and further studies must be performed in this field.

OBJECTIVE This study examined reasons for specialty choice among Swiss residents (post graduate doctors training in specialties). METHODS In 2006, a questionnaire was sent to 8626 Swiss residents registered in postgraduate medical training programmes to obtain specialist qualifications. The response rate was 65% (n = 5631). As residents are allowed to decide on the specialty they want to acquire later in the training process, only residents who had already chosen a specific specialty were included (n = 5038). In responding, residents rated the importance of 19 factors in making their choice of specialty. Categorical principal component analysis was conducted to obtain underlying dimensions within the reasons for choice. A two-way analysis of variance was performed for each dimension to compare the mean object scores for the 10 specialties chosen by the most residents and to examine possible interactions by gender and year of graduation. Contrasts between the specialties were analysed with Scheffe post hoc tests. RESULTS Categorical principal component analyses yielded three factors underlying residents' choice of specialty, which explained 40.8% of the variance in responses: work and time-related aspects; career-related aspects, and patient orientation. Women considered work and time-related aspects and patient orientation to be more important factors in their choice, and career-related aspects to be less important, than did men. Career-related aspects became less important with advancing training status. CONCLUSIONS This study showed that reasons for specialty choice differ according to gender, year of graduation and specialty. With progressing training status, gender differences in reasons for choice and specialty choice may become more pronounced, especially regarding career aspects, which may lead to a change in preferred specialty. Therefore, a modular constructed postgraduate training programme might give residents the flexibility to change from one specialty to another.

BACKGROUND: The dramatic rise in chronically ill patients on permanent disability benefits threatens the sustainability of social security in high-income countries. Social insurance organizations have started to invest in promising, but costly return to work (RTW) coordination programmes. The benefit, however, remains uncertain. We conducted a systematic review to determine the long-term effectiveness of RTW coordination compared to usual practice in patients at risk for long-term disability. METHODS AND FINDINGS: Eligible trials enrolled employees on work absence for at least 4 weeks and randomly assigned them to RTW coordination or to usual practice. We searched 5 databases (to April 2, 2012). Two investigators performed standardised eligibility assessment, study appraisal and data extraction independently and in duplicate. The GRADE framework guided our assessment of confidence in the meta-analytic estimates. We identified 9 trials from 7 countries, 8 focusing on musculoskeletal, and 1 on mental complaints. Most trials followed participants for 12 months or less. No trial assessed permanent disability. Moderate quality evidence suggests a benefit of RTW coordination on proportion at work at end of follow-up (risk ratio = 1.08, 95% CI = 1.03 to 1.13; absolute effect = 5 in 100 additional individuals returning to work, 95% CI = 2 to 8), overall function (mean difference [MD] on a 0 to 100 scale = 5.2, 95% CI = 2.4 to 8.0; minimal important difference [MID] = 10), physical function (MD = 5.3, 95% CI = 1.4 to 9.1; MID = 8.4), mental function (MD = 3.1, 95% CI = 0.7 to 5.6; MID = 7.3) and pain (MD = 6.1, 95% CI = 3.1 to 9.2; MID = 10). CONCLUSIONS: Moderate quality evidence suggests that RTW coordination results in small relative, but likely important absolute benefits in the likelihood of disabled or sick-listed patients returning to work, and associated small improvements in function and pain. Future research should explore whether the limited effects persist, and whether the programmes are cost effective in the long term.