High-dose versus low-dose D-penicillamine in early diffuse systemic sclerosis trial: lessons learned

Objectives

To review important findings, or lessons, that were learned about measures of response, design, conduct, and analysis of a randomized, controlled trial (RCT), even though the trial failed to demonstrate efficacy of d-penicillamine.

Methods

One hundred thirty-four patients with early (≤18 months), diffuse systemic sclerosis (SSc) were entered into an RCT (high-dose [822 mg daily] vs low-dose [120 mg every other day] d-penicillamine) and were followed up regularly for up to 4 years. Because analysis failed to show efficacy for d-penicillamine in early diffuse SSc, all data were pooled for additional secondary analyses.

Results

This RCT showed that trials of potential disease-modifying interventions can be completed in SSc using the American College of Rheumatology guidelines. This RCT used an active control. After analysis, we were not able to tell whether either dose was effective or ineffective. That experience argues in favor of using placebo controls until such time as an active control can be found that truly modifies the disease. Skin score and the disability index of the Health Assessment Questionnaire (HAQ-DI) were valid predictors of outcome. Along with the physician global assessment, they also were valid measures of response.

Conclusions

Even in studies that are therapeutically “negative,” careful evaluation of the data can examine other hypotheses and thereby provide important insights into other aspects of trial design, outcome measures, patient function, and trial conduct.     

Knockdown resistance mutations (kdr) and insecticide susceptibility to DDT and pyrethroids in Anopheles gambiae from Equatorial Guinea

Objectives To determine the frequency of knockdown resistance (kdr) mutations in the malaria vector Anopheles gambiae s.s. from continental Equatorial Guinea; and to relate kdr genotypes with susceptibility to DDT and pyrethroid insecticides in this vector. Methods Female mosquitoes were collected in two villages, Miyobo and Ngonamanga, of mainland Equatorial Guinea. Insecticide susceptibility tests were performed following WHO procedures. Anopheles gambiae complex specimens were identified to species and molecular form by PCR. Genotyping of the kdr locus was performed by allele‐specific PCR and direct sequencing in a subset of samples. Results Both M and S molecular forms of A. gambiae were found in Ngonamanga whereas only the S‐form was identified in Miyobo. The two kdr mutations were detected in S‐form samples of both villages, with a higher frequency of the kdr‐e (Leu‐1014‐Ser) allele (Miyobo: 16%; Ngonamanga: 40%). The kdr‐w (Leu‐1014‐Phe) mutation was also detected in 3% of the M‐form. All individuals tested for pyrethroids were susceptible. A mortality rate of 86% was obtained for DDT. An overall kdr allele frequency (i.e. kdr‐e + kdr‐w) of 22% was detected in DDT resistant individuals, whereas susceptible individuals had a kdr frequency of 6%. Conclusion The co‐occurrence of both kdr mutations and reduced susceptibility to DDT found in A. gambiae highlights the importance of implementing efficient surveillance of insecticide resistance in Equatorial Guinea.     

Time trends of incidence rates of thyroid cancer in Israel: what might explain the sharp increase.

Background: Worldwide changes in the incidence, histological type, and prognosis of thyroid cancer (TC) have been observed. Regional differences in the spectrum of TC may be related to genetic factors, ionizing radiation, lifestyle, and nutritional iodine, as well as to the availability of medical services. Methods: Analysis of records of 5864 TC patients (diagnosed between 1982 and 2001), retrieved from the Israel National Cancer Registry. Results: The age-standardized incidence rate (ASR per 100,000 persons) of TC among Jewish women in 2001 was 12.45 (higher than generally reported in the world) and 3.68 among Jewish men. There was a significant increase in the ASR for TC between 1982 and 2001 in the Jewish population (by 101% among women and by 25% among men, p < 0.01 for both), mainly due to papillary carcinoma. TC incidence increased in the non-Jewish population from 2.33 to 6.02 in women (p < 0.05) and from 1.13 to 2.49 in men (p > 0.05). TC incidence was similar among immigrants from Europe and America arriving in Israel before 1990 or after 1990 for both genders. An improved 5-year survival was noted in patients diagnosed between 1992 and 1996 in comparison to patients diagnosed earlier: 1982-1986 (86% versus 78%, p < 0.01). Conclusions: A marked increase in TC incidence over the last two decades (mainly due to papillary carcinoma) has been noted in different Israeli subpopulations, being the highest in Jewish women. The increase trends were similar regardless of gender or ethnicity. The reasons for this rise in TC incidence and improvement in the survival are probably multifactorial and may relate partly to increased diagnostic vigilance and changes in clinical practice.     

Vascular complications after transcatheter aortic valve implantation (TAVI): risk and long-term results

Vascular complications are the main safety limitations of transcatheter aortic valve implantation (TAVI). The aim of the study was to assess the incidents, predictors, and the impact of early vascular complications on prognosis after TAVI. This was a single-center analysis of vascular complications related to TAVI. Early vascular complications were defined as incidents within 30 days after TAVI and comprised complications related to transvascular: transfemoral/transsubclavian ,and transapical bioprosthesis implantation. Evaluated risk factors were: (1) clinical characteristics, (2) TAVI route, and (3) center experience. In patients with transvascular TAVI the impact of: (1) diameters of access arteries, vascular sheathes and difference between them, (2) arterial wall calcification, and (3) ProStar devices used for access site closure were assessed. Arterial wall calcification and arteries diameters were measured by 64-slice computer tomography. Arterial wall calcification was graded according to 5° scale. Results: between 2009–2011; follow-up 1–23 months (12 ± 15.55), 83 consecutive patients, and 62–91 (81.10 ± 7.20) years, underwent TAVI: 67 (80.72 %) patients had transvascular, and 16 (19.27 %) patients had transapical bioprosthesis implantation. We noted 44 (53.01 %) early vascular complications: 17 (20.48 %) were major and 27 (32.53 %) were minor incidents. Independent predictors of early vascular complications were: history of anaemia (OR 3.497: 95 % CI [1.276–9.581]; p = 0.014), diabetes (OR 0.323: 95 % CI [0.108–0.962]; p = 0.042), percutaneous coronary intervention performed as preparation for TAVI (OR 4.809: 95 % CI [1.172–19.736]; p = 0.029), and arterial wall calcification (OR 1.945: 95 % CI [1.063–3.558]; p = 0.03). Of 6 (7.22 %) in-hospital and 10 (12.98 %) late deaths: 5 (83.33 %) patients and 8 (80 %) patients respectively had post-procedural vascular complications. Vascular complications, which occurred in 30-days after TAVI, predict late mortality (p = 0.036). Conclusions derived were: (1) TAVI patients with history of anaemia and diabetes required careful monitoring for early vascular complications. (2) If coronary intervention before TAVI is required, it should be performed in the time allowing vascular injuries to heal. (3) Calcification of access arteries is an independent predictor of post-procedural vascular complications; therefore, its estimation should be a regular element of preceding computer tomography. (4) Vascular complications seem to be predictors of late mortality after TAVI.     

Heritable and Environmental Factors in the Causation of Clinical Vertebral Fractures

Vertebral fractures are common osteoporotic fractures, and their incidence is greater in Scandinavia than in other European regions. Vertebral fractures are strongly associated with low bone mineral density, which has a predominant genetic etiology. The heritability of radiological vertebral deformities has been estimated in one recent family study. The objective of our study was to determine the genetic liability to clinical vertebral fractures and to what extent individual-specific environmental factors can explain the variance of these fractures. Participants were ascertained from the Swedish Twin Registry. Twin pairs born 1896-1944 formed the study base, a total of 33,432 subjects. Vertebral fractures after the age of 50 years were identified in the National Patient Register (n = 1,037) or by self-report (n = 35). The age-adjusted heritability for all vertebral fractures was 0.17 (95 % CI 0.00-0.40). Restricting the fracture cases to low-energy causes of injury, the heritability was 0.24 (95 % CI 0.00-0.47). Individual-specific environmental influences were found to explain one-third of the variance in vertebral fracture occurrence before the age of 70 years (0.33, 95 % CI 0.16-0.56), whereas they explained most of the variance among those 80 years of age or older (0.83, 95 % CI 0.61-1.00). We conclude that the occurrence of clinical vertebral fractures is largely explained by environmental influences and not by genetic factors. Individual-specific environmental influences such as lifestyle become more important with increasing age, and it is of importance to identify those environmental factors that cause more fracture cases in Scandinavia than in other European settings.     

Estimation of age at onset of linear enamel hypoplasia. New calculation tool,description and comparison of current methods

Enamel Hypoplasia (EH) is known to be a useful indicator for wide range of detrimental factors in early childhood in past populations, such as nutritional disturbances, mechanical trauma, disease, metabolic, and/or genetic disorders. EH may be divided into three categories: pits, grooves, and lines, where the last two are referred to as “Linear Enamel Hypoplasia” (LEH). The regularity of enamel formation allows retrospective determination of the age of LEH formation. The current article reviews and compares the best-known methods used to estimate age at LEH formation and provides a new computational tool. Growth curves for canines and incisors were developed based on tooth growth tables by previous authors. Optimal models were selected using the Akaike Information Criterion. A Microsoft Excel spreadsheet was created to calculate age at LEH formation using the most common methods. All method results were compared with an archaeological sample (44 teeth of 18 individuals from an early modern cemetery from Wrocław, Poland) and a theoretical model. The results of the methods were compared pairwise with Bland-Altman plots. The current article provides a quick and easy-to-use tool for analyzing LEH chronology and comparing the results of different methods. As shown by the Bland-Altman plots, most methods provide approximately consistent results for LEHs formed at around 2–3 years of age. However, LEHs formed particularly early or late are more prone to discrepancies between different methods. Comparison of the age at LEH formation obtained by different methods should be done carefully - and the new LEH calculation tool with optimized equations provided in this publication can facilitate this process.