Pragmatic rules for comparability of biological medicinal products

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A 5-year follow-up study of Alfredson's heel-drop exercise programme in chronic midportion Achilles tendinopathy

Background: Eccentric exercises have the most evidence in conservative treatment of midportion Achilles tendinopathy. Although short-term studies show significant improvement, little is known of the long-term (>3 years) results. Aim: To evaluate the 5-year outcome of patients with chronic midportion Achilles tendinopathy treated with the classical Alfredson's heel-drop exercise programme. Study design: Part of a 5-year follow-up of a previously conducted randomised controlled trial. Methods: 58 patients (70 tendons) were approached 5 years after the start of the heel-drop exercise programme according to Alfredson. At baseline and at 5-year follow-up, the validated Victorian Institute of Sports Assessment-Achilles (VISA-A) questionnaire score, pain status, alternative treatments received and ultrasonographic neovascularisation score were recorded. Results: In 46 patients (58 tendons), the VISA-A score significantly increased from 49.2 at baseline to 83.6 after 5 years (p<0.001) and from the 1-year to 5-year follow-up from 75.0 to 83.4 (p<0.01). 39.7% of the patients were completely pain-free at follow-up and 48.3% had received one or more alternative treatments. The sagittal tendon thickness decreased from 8.05 mm (SD 2.1) at baseline to 7.50 mm (SD 1.6) at the 5-year follow-up (p=0.051). Conclusion: At 5-year follow-up, a significant increase of VISA-A score can be expected. After the 3-month Alfredson's heel-drop exercise programme, almost half of the patients had received other therapies. Although improvement of symptoms can be expected at long term, mild pain may remain

The Taurus Boundary of Stellar/Substellar (TBOSS) Survey II. Disk Masses from ALMA Continuum Observations

We report 885$\mu$m ALMA continuum flux densities for 24 Taurus members spanning the stellar/substellar boundary, with spectral types from M4 to M7.75. Of the 24 systems, 22 are detected at levels ranging from 1.0-55.6 mJy. The two non-detections are transition disks, though other transition disks in the sample are detected. Converting ALMA continuum measurements to masses using standard scaling laws and radiative transfer modeling yields dust mass estimates ranging from $\sim$0.3-20M$_{\oplus}$. The dust mass shows a declining trend with central object mass when combined with results from submillimeter surveys of more massive Taurus members. The substellar disks appear as part of a continuous sequence and not a distinct population. Compared to older Upper Sco members with similar masses across the substellar limit, the Taurus disks are brighter and more massive. Both Taurus and Upper Sco populations are consistent with an approximately linear relationship in $M_{dust}$ to $M_{star}$, although derived power-law slopes depend strongly upon choices of stellar evolutionary model and dust temperature relation. The median disk around early M-stars in Taurus contains a comparable amount of mass in small solids as the average amount of heavy elements in Kepler planetary systems on short-period orbits around M-dwarf stars, with an order of magnitude spread in disk dust mass about the median value. Assuming a gas:dust ratio of 100:1, only a small number of low-mass stars and brown dwarfs have a total disk mass amenable to giant planet formation, consistent with the low frequency of giant planets orbiting M-dwarfs.Comment: 41 pages and 32 figures, with all tables and appendices presented here in their entirety. Accepted for publication in AJ (November 26, 2017

Variant repeats within the DMPK CTG expansion protect function in myotonic dystrophy type 1

Objective: We tested the hypothesis that variant repeat interruptions (RIs) within the DMPK CTG repeat tract lead to milder symptoms compared with pure repeats (PRs) in myotonic dystrophy type 1 (DM1). Methods: We evaluated motor, neurocognitive, and behavioral outcomes in a group of 6 participants with DM1 with RI compared with a case-matched sample of 12 participants with DM1 with PR and a case-matched sample of 12 unaffected healthy comparison participants (UA). Results: In every measure, the RI participants were intermediate between UA and PR participants. For muscle strength, the RI group was significantly less impaired than the PR group. For measures of Full Scale IQ, depression, and sleepiness, all 3 groups were significantly different from each other with UA &gt; RI &gt; PR in order of impairment. The RI group was different from unaffected, but not significantly different from PR (UA &gt; RI = PR) in apathy and working memory. Finally, in finger tapping and processing speed, RI did not differ from UA comparisons, but PR had significantly lower scores than the UA comparisons (UA = RI &gt; PR). Conclusions: Our results support the notion that patients affected by DM1 with RI demonstrate a milder phenotype with the same pattern of deficits as those with PR indicating a similar disease process

Actual postoperative protein and calorie intake in patients undergoing major open abdominal cancer surgery:A prospective, observational cohort study

Background Adequate nutritional protein and energy intake are required for optimal postoperative recovery. There are limited studies reporting the actual postoperative protein and energy intake within the first week after major abdominal cancer surgery. The main objective of this study was to quantify the protein and energy intake after major abdominal cancer surgery. Methods We conducted a prospective cohort study. Nutrition intake was assessed with a nutrition diary. The amount of protein and energy consumed through oral, enteral, and parenteral nutrition was recorded and calculated separately. Based on the recommendations of the European Society for Clinical Nutrition and Metabolism (ESPEN), protein and energy intake were considered insufficient when patients received Fifty patients were enrolled in this study. Mean daily protein and energy intake was 0.61 +/- 0.44 g/kg/day and 9.58 +/- 3.33 kcal/kg/day within the first postoperative week, respectively. Protein and energy intake were insufficient in 45 [90%] and 41 [82%] of the 50 patients, respectively. Patients with Clavien-Dindo grade >= III complications consumed less daily protein compared with the group of patients without complications and patients with grade I or II complications. Conclusion During the first week after major abdominal cancer surgery, the majority of patients do not consume an adequate amount of protein and energy. Incorporating a registered dietitian into postoperative care and adequate nutrition support after major abdominal cancer surgery should be a standard therapeutic goal to improve nutrition intake

Campylobacter jejuni bacteremia and Helicobacter pylori in a patient with X-linked agammaglobulinemia

We describe a 15-year-old patient with X-linked agammaglobulinemia who developed malabsorption and bacteremia due to infection of Helicobacter pylori and Campylobacter jejuni. The Campylobacter bacteremia was only recognized after subculturing of blood culture bottles that failed to signal in the automated system. After 2 weeks of treatment with meropenem and erythromycin for 4 weeks, the patient developed a relapse of bacteremia 10 months later with a high level erythromycin resistant C. jejuni. Sequencing revealed an A2058C mutation in the 23 S rRNA gene associated with this resistance. Treatment with doxycycline for 4 weeks finally resulted in complete eradication. This case report illustrates the importance for physicians to use adapted culture methods and adequate prolonged therapy in patients with an immunodeficiency. A summary of published case reports and series of patients with hypogammaglobulinemia or agammaglobulinemia with Campylobacter or Helicobacter bacteremia is given

Effect of intraperitoneal chemotherapy concentration on morbidity and survival

Contains fulltext : 218098.pdf (publisher's version ) (Open Access)BACKGROUND: Selected patients with colorectal peritoneal metastases are treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). The concentration of intraperitoneal chemotherapy reflects the administered dose and perfusate volume. The aim of this study was to calculate intraperitoneal chemotherapy concentration during HIPEC and see whether this was related to clinical outcomes. METHODS: An observational multicentre study included consecutive patients with colorectal peritoneal metastases who were treated with CRS-HIPEC between 2010 and 2018 at three Dutch centres. Data were retrieved from prospectively developed databases. Chemotherapy dose and total circulating volumes of carrier solution were used to calculate chemotherapy concentrations. Postoperative complications, disease-free and overall survival were correlated with intraoperative chemotherapy concentrations. Univariable and multivariable logistic regression, Cox regression and survival analyses were performed. RESULTS: Of 320 patients, 220 received intraperitoneal mitomycin C (MMC) and 100 received oxaliplatin. Median perfusate volume for HIPEC was 5.0 (range 0.7-10.0) litres. Median intraperitoneal chemotherapy concentration was 13.3 (range 7.0-76.0) mg/l for MMC and 156.0 (91.9-377.6) mg/l in patients treated with oxaliplatin. Grade III or higher complications occurred in 75 patients (23.4 per cent). Median overall survival was 36.9 (i.q.r. 19.5-62.9) months. Intraperitoneal chemotherapy concentrations were not associated with postoperative complications or survival. CONCLUSION: CRS-HIPEC was performed with a wide variation in intraperitoneal chemotherapy concentrations that were not associated with complications or survival

Role of diagnostic laparoscopy in patients with suspicion of colorectal peritoneal metastases to evaluate suitability for cytoreductive surgery with hyperthermic intraperitoneal chemotherapy

Background: The aim of the present study was to determine the feasibility and safety of performing diagnostic laparoscopy (DLS) routinely in patients with suspicion of colorectal peritoneal metastases (PM) to evaluate suitability for cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS+ HIPEC). Methods: Data for consecutive patients who underwent DLS between 2012 and 2018 were extracted retrospectively from an institutional database. The primary outcome was the degree of visibility of the abdominal cavity during DLS. Good laparoscopic evaluation of the abdominal cavity was defined as visibility of at least the regions of the diaphragm, pelvis and small bowel. Secondary outcomes were reasons for perioperative exclusion for CRS+ HIPEC, major postoperative complications (Clavien-Dindo grade III or above) and difference in overall survival (OS) between patients deemed suitable or unsuitable for CRS+ HIPEC. Kaplan-Meier analyses were performed. Results: Some 184 patients were analysed. Good laparoscopic evaluation was possible in 138 patients (75.0 per cent), and 24 (13.0 per cent) had conversion to an open procedure. Ninety-three patients (50.5 per cent) were excluded for CRS+ HIPEC, most commonly because of absence of colorectal PM (34 patients, 37 per cent) or extensive disease (Peritoneal Cancer Index 20 or above) (33 patients, 35 per cent). Major complications occurred in five patients (2.7 per cent), with no postoperative deaths. Median OS was significantly decreased in patients who were excluded due to extensive disease (14 (95 per cent c.i. 10 to 18) months) compared with patients suitable for CRS+ HIPEC (36 (27 to 45) months) (P <0.001). Conclusion: Routinely performing DLS in patients with suspicion of colorectal PM to evaluate suitability for CRS+ HIPEC is feasible and safe, avoiding the morbidity of an unnecessary laparotomy in patients with extensive disease

Brain structural features of myotonic dystrophy type 1 and their relationship with CTG repeats

Background: Few adequately-powered studies have systematically evaluated brain morphology in adult-onset myotonic dystrophy type 1 (DM1). Objective: The goal of the present study was to determine structural brain differences between individuals with and without adult-onset DM1 in a multi-site, case-controlled cohort. We also explored correlations between brain structure and CTG repeat length. Methods: Neuroimaging data was acquired in 58 unaffected individuals (29 women) and 79 individuals with DM1 (50 women). CTG repeat length, expressed as estimated progenitor allele length (ePAL), was determined by small pool PCR. Statistical models were adjusted for age, sex, site, and intracranial volume (ICV). Results: ICV was reduced in DM1 subjects compared with controls. Accounting for the difference in ICV, the DM1 group exhibited smaller volume in frontal grey and white matter, parietal grey matter as well as smaller volume of the corpus callosum, thalamus, putamen, and accumbens. In contrast, volumes of the hippocampus and amygdala were significantly larger in DM1. Greater ePAL was associated with lower volumes of the putamen, occipital grey matter, and thalamus. A positive ePAL association was observed for amygdala volume and cerebellar white matter. Conclusions: Smaller ICV may be a marker of aberrant neurodevelopment in adult-onset DM1. Volumetric analysis revealed morphological differences, some associated with CTG repeat length, in structures with plausible links to key DM1 symptoms including cognitive deficits and excessive daytime somnolence. These data offer further insights into the basis of CNS disease in DM1, and highlight avenues for further work to identify therapeutic targets and imaging biomarkers