Cessation and resuming of alglucosidase alfa in Pompe disease: a retrospective analysis.

Enzyme replacement therapy (ERT) with recombinant human alglucosidase alfa (rhGAA) in late-onset Pompe disease is moderately effective. Little is known about the clinical course after treatment termination and the resumption of ERT. In Switzerland, rhGAA therapy for Pompe disease was temporarily withdrawn after the federal court judged that the treatment costs were greatly out of proportion compared to the benefits. Re-treatment was initiated after the therapy was finally licensed. We retrospectively analysed seven Pompe patients, who underwent cessation and resumption of ERT (median age 43 years). The delay from first symptoms to final diagnosis ranged from 4 to 20 years. The demographics, clinical characteristics, assessments with the 6-min walking test (6-MWT), the predicted forced vital capacity (FVC) and muscle strength were analysed. Before initiation of ERT, all patients suffered from proximal muscle weakness of the lower limbs; one was wheelchair-bound and two patients received night-time non-invasive ventilation. Initial treatment stabilised respiratory function in most patients and improved their walking performance. After treatment cessation, upright FVC declined in most and the 6-MWT declined in all patients. Two patients needed additional non-invasive ventilatory support. Twelve months after resuming ERT, the respiratory and walking capacity improved again in most patients. However, aside for one patient, none of the patients reached the same level of respiratory function or distance walked in 6 min, as at the time of ERT withdrawal. We conclude that cessation of ERT in Pompe disease causes a decline in clinical function and should be avoided. Resuming treatment only partially recovers respiratory function and walking capacity.

Prognostic factors and risk groups in T1G3 non-muscle-invasive bladder cancer patients initially treated with Bacillus Calmette-Guérin: results of a retrospective multicenter study of 2451 patients

BACKGROUND The impact of prognostic factors in T1G3 non-muscle-invasive bladder cancer (BCa) patients is critical for proper treatment decision making. OBJECTIVE To assess prognostic factors in patients who received bacillus Calmette-Guérin (BCG) as initial intravesical treatment of T1G3 tumors and to identify a subgroup of high-risk patients who should be considered for more aggressive treatment. DESIGN, SETTING, AND PARTICIPANTS Individual patient data were collected for 2451 T1G3 patients from 23 centers who received BCG between 1990 and 2011. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Using Cox multivariable regression, the prognostic importance of several clinical variables was assessed for time to recurrence, progression, BCa-specific survival, and overall survival (OS). RESULTS AND LIMITATIONS With a median follow-up of 5.2 yr, 465 patients (19%) progressed, 509 (21%) underwent cystectomy, and 221 (9%) died because of BCa. In multivariable analyses, the most important prognostic factors for progression were age, tumor size, and concomitant carcinoma in situ (CIS); the most important prognostic factors for BCa-specific survival and OS were age and tumor size. Patients were divided into four risk groups for progression according to the number of adverse factors among age ≥ 70 yr, size ≥ 3 cm, and presence of CIS. Progression rates at 10 yr ranged from 17% to 52%. BCa-specific death rates at 10 yr were 32% in patients ≥ 70 yr with tumor size ≥ 3 cm and 13% otherwise. CONCLUSIONS T1G3 patients ≥ 70 yr with tumors ≥ 3 cm and concomitant CIS should be treated more aggressively because of the high risk of progression. PATIENT SUMMARY Although the majority of T1G3 patients can be safely treated with intravesical bacillus Calmette-Guérin, there is a subgroup of T1G3 patients with age ≥ 70 yr, tumor size ≥ 3 cm, and concomitant CIS who have a high risk of progression and thus require aggressive treatment.

A retrospective comparative exploratory study on two methylentetrahydrofolate reductase (MTHFR) polymorphisms in esophagogastric cancer: the A1298C MTHFR polymorphism is an independent prognostic factor only in neoadjuvantly treated gastric cancer patients.

BACKGROUND Methylentetrahydrofolate reductase (MTHFR) plays a major role in folate metabolism and consequently could be an important factor for the efficacy of a treatment with 5-fluorouracil. Our aim was to evaluate the prognostic and predictive value of two well characterized constitutional MTHFR gene polymorphisms for primarily resected and neoadjuvantly treated esophagogastric adenocarcinomas. METHODS 569 patients from two centers were analyzed (gastric cancer: 218, carcinoma of the esophagogastric junction (AEG II, III): 208 and esophagus (AEG I): 143). 369 patients received neoadjuvant chemotherapy followed by surgery, 200 patients were resected without preoperative treatment. The MTHFR C677T and A1298C polymorphisms were determined in DNA from peripheral blood lymphozytes. Associations with prognosis, response and clinicopathological factors were analyzed retrospectively within a prospective database (chi-square, log-rank, cox regression). RESULTS Only the MTHFR A1298C polymorphisms had prognostic relevance in neoadjuvantly treated patients but it was not a predictor for response to neoadjuvant chemotherapy. The AC genotype of the MTHFR A1298C polymorphisms was significantly associated with worse outcome (p = 0.02, HR 1.47 (1.06-2.04). If neoadjuvantly treated patients were analyzed based on their tumor localization, the AC genotype of the MTHFR A1298C polymorphisms was a significant negative prognostic factor in patients with gastric cancer according to UICC 6th edition (gastric cancer including AEG type II, III: HR 2.0, 95% CI 1.3-2.0, p = 0.001) and 7th edition (gastric cancer without AEG II, III: HR 2.8, 95% CI 1.5-5.7, p = 0.003), not for AEG I. For both definitions of gastric cancer the AC genotype was confirmed as an independent negative prognostic factor in cox regression analysis. In primarily resected patients neither the MTHFR A1298C nor the MTHFR C677T polymorphisms had prognostic impact. CONCLUSIONS The MTHFR A1298C polymorphisms was an independent prognostic factor in patients with neoadjuvantly treated gastric adenocarcinomas (according to both UICC 6th or 7th definitions for gastric cancer) but not in AEG I nor in primarily resected patients, which confirms the impact of this enzyme on chemotherapy associated outcome.

An epidemiological evaluation of pediatric long bone fractures - a retrospective cohort study of 2716 patients from two Swiss tertiary pediatric hospitals.

BACKGROUND Children and adolescents are at high risk of sustaining fractures during growth. Therefore, epidemiological assessment is crucial for fracture prevention. The AO Comprehensive Injury Automatic Classifier (AO COIAC) was used to evaluate epidemiological data of pediatric long bone fractures in a large cohort. METHODS Data from children and adolescents with long bone fractures sustained between 2009 and 2011, treated at either of two tertiary pediatric surgery hospitals in Switzerland, were retrospectively collected. Fractures were classified according to the AO Pediatric Comprehensive Classification of Long Bone Fractures (PCCF). RESULTS For a total of 2716 patients (60% boys), 2807 accidents with 2840 long bone fractures (59% radius/ulna; 21% humerus; 15% tibia/fibula; 5% femur) were documented. Children's mean age (SD) was 8.2 (4.0) years (6% infants; 26% preschool children; 40% school children; 28% adolescents). Adolescent boys sustained more fractures than girls (p < 0.001). The leading cause of fractures was falls (27%), followed by accidents occurring during leisure activities (25%), at home (14%), on playgrounds (11%), and traffic (11%) and school accidents (8%). There was boy predominance for all accident types except for playground and at home accidents. The distribution of accident types differed according to age classes (p < 0.001). Twenty-six percent of patients were classed as overweight or obese - higher than data published by the WHO for the corresponding ages - with a higher proportion of overweight and obese boys than in the Swiss population (p < 0.0001). CONCLUSION Overall, differences in the fracture distribution were sex and age related. Overweight and obese patients seemed to be at increased risk of sustaining fractures. Our data give valuable input into future development of prevention strategies. The AO PCCF proved to be useful in epidemiological reporting and analysis of pediatric long bone fractures.

Is clipping the preferable technique to perform sympathicotomy? A retrospective study and review of the literature

PURPOSE Thoracoscopic sympathetic surgery is nowadays a broadly accepted technique in the treatment of primary hyperhidrosis as well as facial blushing. The objective of this study was to compare the two currently most commonly used methods for thoracic sympathicotomy: transection (ETS) and clipping (ETC.). METHODS This is a retrospective study on a total of 63 patients, who underwent rib-oriented sympathicotomy, either by transection (n = 36, 57 %) or by clipping (n = 27, 43 %). Moreover, the up-to-date international literature is reviewed concerning which level(s) of the sympathetic trunk should be addressed, depending on the patients underlying condition. Furthermore, the highly controversial topic of reversibility of sympathetic clipping is debated. RESULTS Our results confirm that clipping is at least as effective as transection of the sympathetic chain in the treatment of hyperhidrosis and facial blushing. Furthermore, the analysis of all larger studies on unclipping in humans shows a surprisingly high reported reversal rate between 48 and 77 %. CONCLUSIONS Depending on the symptoms of the patient, different levels of the sympathetic chain should be addressed. When a higher rib level such as R2 is approached, which more likely will result in moderate to severe compensatory sweating, clipping should be preferred as it seems that this technique has indeed a potential for reversibility. As demonstrated, this method is at least as effective as an irreversible transection of the sympathetic chain.

Sinus floor elevation: comparison of the presurgical ridge height of different techniques - a retrospective analysis.

Purpose: Radiographic evaluation of the vertical presurgical ridge height (PRH) of implants, placed using the transcrestal or lateral window sinus floor elevation (SFE) technique in edentulous and partially dentate patients. The 5-year implant survival rate and the prosthetic restoration following the SFE procedure were also evaluated. Methods: Radiographs of 83 tapered implants placed in 53 patients were available for analysis. 31 implants were placed by the transcrestal and 52 were placed by the lateral window technique. In the lateral window technique 21 implants were placed simultaneously, 31 in a staged approach. The PRH, the implant survival rate after five years and the prosthetic restoration were evaluated with respect to the chosen SFE procedure. Results: The PRH was significantly higher for the transcrestal than both lateral window techniques, mean values: 8.0 ± 2.7 mm (transcrestal); 4.2 ± 2.6 mm (lateral simultaneous); 4.5 ± 2.8 mm (lateral staged). There was no significant difference of PRH between the edentulous and partially dentate patients. All loaded implants were stable, resulting in a 100% implant survival rate after 5 years. There was a small overproportion of single crown restorations in the transcrestal SFE technique group. Conclusion: This study confirms that the transcrestal technique is chosen, when a higher PRH is available. The choice of a simultaneous or staged lateral window approach is mainly dependent on the expected primary stability of the implant and not only on the PRH. SFE procedures are a safe and predictable treatment option to place implants in the vertical atrophic maxilla.

Clinically relevant quality measures for risk factor control in primary care: a retrospective cohort study

BACKGROUND Assessment of the proportion of patients with well controlled cardiovascular risk factors underestimates the proportion of patients receiving high quality of care. Evaluating whether physicians respond appropriately to poor risk factor control gives a different picture of quality of care. We assessed physician response to control cardiovascular risk factors, as well as markers of potential overtreatment in Switzerland, a country with universal healthcare coverage but without systematic quality monitoring, annual report cards on quality of care or financial incentives to improve quality. METHODS We performed a retrospective cohort study of 1002 randomly selected patients aged 50-80 years from four university primary care settings in Switzerland. For hypertension, dyslipidemia and diabetes mellitus, we first measured proportions in control, then assessed therapy modifications among those in poor control. "Appropriate clinical action" was defined as a therapy modification or return to control without therapy modification within 12 months among patients with baseline poor control. Potential overtreatment of these conditions was defined as intensive treatment among low-risk patients with optimal target values. RESULTS 20% of patients with hypertension, 41% with dyslipidemia and 36% with diabetes mellitus were in control at baseline. When appropriate clinical action in response to poor control was integrated into measuring quality of care, 52 to 55% had appropriate quality of care. Over 12 months, therapy of 61% of patients with baseline poor control was modified for hypertension, 33% for dyslipidemia, and 85% for diabetes mellitus. Increases in number of drug classes (28-51%) and in drug doses (10-61%) were the most common therapy modifications. Patients with target organ damage and higher baseline values were more likely to have appropriate clinical action. We found low rates of potential overtreatment with 2% for hypertension, 3% for diabetes mellitus and 3-6% for dyslipidemia. CONCLUSIONS In primary care, evaluating whether physicians respond appropriately to poor risk factor control, in addition to assessing proportions in control, provide a broader view of the quality of care than relying solely on measures of proportions in control. Such measures could be more clinically relevant and acceptable to physicians than simply reporting levels of control.

Validation of the IMPACT-III quality of life questionnaire in Swiss children with inflammatory bowel disease

BACKGROUND AND AIMS Inflammatory bowel disease (IBD) frequently manifests during childhood and adolescence. For providing and understanding a comprehensive picture of a patients' health status, health-related quality of life (HRQoL) instruments are an essential complement to clinical symptoms and functional limitations. Currently, the IMPACT-III questionnaire is one of the most frequently used disease-specific HRQoL instrument among patients with IBD. However, there is a lack of studies examining the validation and reliability of this instrument. METHODS 146 paediatric IBD patients from the multicenter Swiss IBD paediatric cohort study database were included in the study. Medical and laboratory data were extracted from the hospital records. HRQoL data were assessed by means of standardized questionnaires filled out by the patients in a face-to-face interview. RESULTS The original six IMPACT-III domain scales could not be replicated in the current sample. A principal component analysis with the extraction of four factor scores revealed the most robust solution. The four factors indicated good internal reliability (Cronbach's alpha=.64-.86), good concurrent validity measured by correlations with the generic KIDSCREEN-27 scales and excellent discriminant validity for the dimension of physical functioning measured by HRQoL differences for active and inactive severity groups (p<.001, d=1.04). CONCLUSIONS This study with Swiss children with IBD indicates good validity and reliability for the IMPACT-III questionnaire. However, our findings suggest a slightly different factor structure than originally proposed. The IMPACT-III questionnaire can be recommended for its use in clinical practice. The factor structure should be further examined in other samples.

Early co-occurrence of a neurologic-psychiatric disease pattern in Niemann-Pick type C disease: a retrospective Swiss cohort study

BackgroundNiemann-Pick disease type C (NP-C) is a rare autosomal recessive disorder of lysosomal cholesterol transport. The objective of this retrospective cohort study was to critically analyze the onset and time course of symptoms, and the clinical diagnostic work-up in the Swiss NP-C cohort.MethodsClinical, biochemical and genetic data were assessed for 14 patients derived from 9 families diagnosed with NP-C between 1994 and 2013. We retrospectively evaluated diagnostic delays and period prevalence rates for neurological, psychiatric and visceral symptoms associated with NP-C disease. The NP-C suspicion index was calculated for the time of neurological disease onset and the time of diagnosis.ResultsThe shortest median diagnostic delay was noted for vertical supranuclear gaze palsy (2y). Ataxia, dysarthria, dysphagia, spasticity, cataplexy, seizures and cognitive decline displayed similar median diagnostic delays (4¿5y). The longest median diagnostic delay was associated with hepatosplenomegaly (15y). Highest period prevalence rates were noted for ataxia, dysarthria, vertical supranuclear gaze palsy and cognitive decline. The NP-C suspicion index revealed a median score of 81 points in nine patients at the time of neurological disease onset which is highly suspicious for NP-C disease. At the time of diagnosis, the score increased to 206 points.ConclusionA neurologic-psychiatric disease pattern represents the most characteristic clinical manifestation of NP-C and occurs early in the disease course. Visceral manifestation such as isolated hepatosplenomegaly often fails recognition and thus highlights the importance of a work-up for lysosomal storage disorders. The NP-C suspicion index emphasizes the importance of a multisystem evaluation, but seems to be weak in monosymptomatic and infantile NP-C patients.

Impact of Team Familiarity in the Operating Room on Surgical Complications

BACKGROUND: The quality of surgical performance depends on the technical skills of the surgical team as well as on non-technical skills, including teamwork. The present study evaluated the impact of familiarity among members of the surgical team on morbidity in patients undergoing elective open abdominal surgery. METHODS: A retrospective analysis was performed to compare the surgical outcomes of patients who underwent major abdominal operations between the first month (period I) and the last month (period II) of a 6-month period of continuous teamwork (stable dyads of one senior and one junior surgeon formed every 6 months). Of 117 patients, 59 and 58 patients underwent operations during period I and period II, respectively, between January 2010 and June 2012. Team performance was assessed via questionnaire by specialized work psychologists; in addition, intraoperative sound levels were measured. RESULTS: The incidence of overall complications was significantly higher in period I than in period II (54.2 vs. 34.5 %; P = 0.041). Postoperative complications grade <3 were significantly more frequently diagnosed in patients who had operations during period I (39.0 vs. 15.5 %; P = 0.007), whereas no between-group differences in grade ≥3 complications were found (15.3 vs. 19.0 %; P = 0.807). Concentration scores from senior surgeons were significantly higher in period II than in period I (P = 0.033). Sound levels during the middle third part of the operations were significantly higher in period I (median above the baseline 8.85 dB [range 4.5-11.3 dB] vs. 7.17 dB [5.24-9.43 dB]; P < 0.001). CONCLUSIONS: Team familiarity improves team performance and reduces morbidity in patients undergoing abdominal surgery.

Prospective Memory, Retrospective Memory, Executive Functions, and Metacognition: How they are linked longitudinally in young elementary school children

Succeeding in everyday activities often requires executive functioning (EF), metacognitive abilities (MC) and memory skills such as prospective memory (PM) and retrospective memory (RM). These cognitive abilities seem to gradually develop in childhood, possibly influencing each other during development. From a theoretical point of view, it is likely that they are closely interrelated, especially in children. Their empirical relation, however, is less clear. A model that links these cognitive abilities can help to better understand the relation between PM and RM and other cognitive processes. In this project we studied the longitudinal development of PM, RM, EF, and MC in 7-8 year old elementary school children across half a year. 119 second graders (MT1 = 95 months, SDT1, = 4.8 months) completed the same PM, RM, EF and MC tasks twice with a time-lag of 7 months. The developmental progression was analysed using paired t-tests, the longitudinal relationships were analysed using confirmatory factor analysis and all fit indices are in accordance with Hu and Bentler (1998). In general, performance improved significantly (ps < .001) and effect sizes ranged from .45 to .62 (Cohen’s d). CFA revealed a good model fit, c2(227, 119) = 242.56, p = .23, TLI = .973, CFI = .979, RMSEA = .024. At T1, significant cross-sectional links were found between PM T1 and RM T1, between PM T1 and EF T1, and between EF T1 and MC T1. Moreover, significant longitudinal links were found between EFT1 and PMT2 and between EFT1 and MCT2; EF T1 and RM T2 were marginally linked. Results underline previous findings showing that PM, RM, EF, and MC develop significantly during childhood, even within this short time period. Results also indicate that these cognitive abilities are linked not only cross-sectionally, but longitudinally. Most relevant, however, is the predictive role of EF for both metacognition and memory.

Ein Vergleich verschiedener Kurzversionen des Depressive Experiences Questionnaire (DEQ) zur Erhebung von Selbstkritik und Abhängigkeit

Der Depressive Experiences Questionnaire (DEQ) ist ein Fragebogen zur Erfassung der Persönlichkeitsmerkmale Selbstkritik und Abhängigkeit, die als Vulnerabilitätsfaktoren für Depression gelten. Aufgrund seiner Länge und seiner komplexen Auswertungsprozedur wurden im englischsprachigen Raum verschiedene Kurzversionen des DEQ entwickelt. Das Ziel dieser Studie war die psychometrische Überprüfung der verschiedenen DEQ-Versionen in deutscher Sprache sowie die Validierung einer geeigneten Kurzversion. An insgesamt 708 Personen (404 Patienten und 304 nicht-klinische Personen) wurden die psychometrischen Eigenschaften der verschiedenen Versionen verglichen. Es zeigte sich, dass der Theoretische Depressive Experiences Questionnaire–12 Item Version (TDEQ-12) insbesondere aufgrund seiner faktoriellen Validität die besten psychometrischen Eigenschaften aufwies. Zusätzliche Hinweise für die Validität und Reliabilität des TDEQ-12 konnten in vier weiteren Stichproben (436 nicht-klinische Personen, 23 nicht-depressive Personen, 64 depressive Patienten, 74 Studierende) gewonnen werden. Die vorliegende Studie legt nahe, dass der TDEQ-12 eine reliable, valide und ökonomische Alternative zum DEQ für die Erfassung von Selbstkritik und Abhängigkeit darstellt.

Exploring the validity and reliability of a questionnaire for evaluating virtual patient design with a special emphasis on fostering clinical reasoning

Background: Virtual patients (VPs) are increasingly used to train clinical reasoning. So far, no validated evaluation instruments for VP design are available. Aims: We examined the validity of an instrument for assessing the perception of VP design by learners. Methods: Three sources of validity evidence were examined: (i) Content was examined based on theory of clinical reasoning and an international VP expert team. (ii) The response process was explored in think-aloud pilot studies with medical students and in content analyses of free text questions accompanying each item of the instrument. (iii) Internal structure was assessed by exploratory factor analysis (EFA) and inter-rater reliability by generalizability analysis. Results: Content analysis was reasonably supported by the theoretical foundation and the VP expert team. The think-aloud studies and analysis of free text comments supported the validity of the instrument. In the EFA, using 2547 student evaluations of a total of 78 VPs, a three-factor model showed a reasonable fit with the data. At least 200 student responses are needed to obtain a reliable evaluation of a VP on all three factors. Conclusion: The instrument has the potential to provide valid information about VP design, provided that many responses per VP are available.

The association of childhood trauma and personality disorder with adult chronic depression. A cross-sectional study in depressed outpatients

Objective: Chronic depression has often been associated with childhood trauma. There may, however, be an interaction between personality pathology, childhood trauma, and chronic depression. This interaction has not yet been studied. Method: This retrospective analysis is based on 279 patients contacted for a randomized trial in an outpatient psychotherapy center over a period of 18 months from 2010 to 2012. Current diagnoses of a personality disorder and presence of chronic depression were systematically assessed using the Structured Clinical Interview for DSM-IV. Retrospective reports of childhood trauma were collected using the short form of the Childhood Trauma Questionnaire (CTQ-SF). DSM-IV–defined chronic depression was the primary outcome. The association between chronic depression, childhood trauma, and personality disorders was analyzed using correlations. Variables that had at least a small effect on correlation analysis were entered into a series of logistic regression analyses to determine the predictors of chronic depression and the moderating effect of childhood trauma. Results: The presence of avoidant personality disorder, but no CTQ-SF scale, was associated with the chronicity of depression (odds ratio [OR] = 2.20, P = .015). The emotional abuse subscale of the CTQ-SF did, however, correlate with avoidant personality disorder (OR = 1.15, P = .000). The level of emotional abuse had a moderating effect on the effect of avoidant personality disorder on the presence of chronic depression (OR = 1.08, P = .004). Patients who did not suffer from avoidant personality disorder had a decreased rate of chronic depression if they retrospectively reported more severe levels of emotional abuse (18.9% vs 39.7%, respectively). Conclusions: The presence of avoidant personality pathology may interact with the effect of childhood trauma in the development of chronic depression. This has to be confirmed in a prospective study.