During protein crystallization and purification, proteins are commonly found in concentrated salt solutions. The exact interplay of the hydration shell, the salt ions, and protein-protein ...interactions under these conditions is far from being understood on a fundamental level, despite the obvious practical relevance. We have studied a model globular protein (bovine serum albumin, BSA) in concentrated salt solutions by small-angle neutron scattering (SANS). The data are also compared to previous studies using SAXS. The SANS results for dilute protein solutions give an averaged volume of BSA of 91,700 Å(3), which is about 37% smaller than that determined by SAXS. The difference in volume corresponds to the contribution of a hydration shell with a hydration level of 0.30 g g(-1) protein. The forward intensity I(0) determined from Guinier analysis is used to determine the second virial coefficient, A(2), which describes the overall protein interactions in solution. It is found that A(2) follows the reverse order of the Hofmeister series, i.e. (NH(4))(2)SO(4) < Na(2)SO(4) < NaOAc < NaCl < NaNO(3) < NaSCN. The dimensionless second virial coefficient B(2), corrected for the particle volume and molecular weight, has been calculated using different approaches, and shows that B(2) with corrections for hydration and the non-spherical shape of the protein describes the interactions better than those determined from the bare protein. SANS data are further analyzed in the full q-range using liquid theoretical approaches, which gives results consistent with the A(2) analysis and the experimental structure factor.
Data routinely captured in clinical registries may be leveraged to enhance efficiency of prospective research. The quality of registry data for this purpose has not been studied, however. We ...evaluated the completeness and accuracy of perioperative data within congenital heart centers' local surgical registries.
Within 12 Pediatric Heart Network (PHN) sites, we evaluated 31 perioperative variables (and their subcategories, totaling 113 unique fields) collected via sites' local clinical registries for submission to The Society of Thoracic Surgeons Database, compared with chart review by PHN research coordinators. Both used standard STS definitions. Data were collected on 10 subjects for 2 to 5 procedures/site and adjudicated by the study team. Completeness and accuracy (agreement of registry data with medical record review by PHN coordinator, adjudicated by the study team) were evaluated.
A total of 56,500 data elements were collected on 500 subjects. With regard to data completeness, 3.1% of data elements were missing from the registry, 0.6% from coordinator-collected data, and 0.4% from both. Overall, registry data accuracy was 98%. In total, 94.7% of data elements were both complete/non-missing and accurate within the registry, although there was variation across data fields and sites. Mean total time for coordinator chart review per site was 49.1 hours versus 7.0 hours for registry query.
This study suggests that existing surgical registry data constitute a complete, accurate, and efficient information source for prospective research. Variability across data fields and sites also suggest areas for improvement in some areas of data quality.
Summary Background For patients with newly diagnosed rheumatoid arthritis, treatment aim is early, rapid, and sustained remission. We compared the efficacy and safety of strategies initiating the ...interleukin-6 receptor-blocking monoclonal antibody tocilizumab with or without methotrexate (a conventional synthetic disease-modifying antirheumatic drug DMARD), versus initiation of methotrexate monotherapy in line with international guidelines. Methods We did a 2-year, multicentre, randomised, double-blind, double-dummy, strategy study at 21 rheumatology outpatient departments in the Netherlands. We included patients who had been diagnosed with rheumatoid arthritis within 1 year before inclusion, were DMARD-naive, aged 18 years or older, met current rheumatoid arthritis classification criteria, and had a disease activity score assessing 28 joints (DAS28) of at least 2·6. We randomly assigned patients (1:1:1) to start tocilizumab plus methotrexate (the tocilizumab plus methotrexate arm), or tocilizumab plus placebo-methotrexate (the tocilizumab arm), or methotrexate plus placebo-tocilizumab (the methotrexate arm). Tocilizumab was given at 8 mg/kg intravenously every 4 weeks with a maximum of 800 mg per dose. Methotrexate was started at 10 mg per week orally and increased stepwise every 4 weeks by 5 mg to a maximum of 30 mg per week, until remission or dose-limiting toxicity. We did the randomisation using an interactive web response system. Masking was achieved with placebos that were similar in appearance to the active drug; the study physicians, pharmacists, monitors, and patients remained masked during the study, and all assessments were done by masked assessors. Patients not achieving remission on their initial regimen switched from placebo to active treatments; patients in the tocilizumab plus methotrexate arm switched to standard of care therapy (typically methotrexate combined with a tumour necrosis factor inhibitor). When sustained remission was achieved, methotrexate (and placebo-methotrexate) was tapered and stopped, then tocilizumab (and placebo-tocilizumab) was also tapered and stopped. The primary endpoint was the proportion of patients achieving sustained remission (defined as DAS28 <2·6 with a swollen joint count ≤four, persisting for at least 24 weeks) on the initial regimen and during the entire study duration, compared between groups with a two-sided Cochran-Mantel-Haenszel test. Analysis was based on an intention-to-treat method. This trial was registered at ClinicalTrials.gov , number NCT01034137. Findings Between Jan 13, 2010, and July 30, 2012, we recruited and assigned 317 eligible patients to treatment (106 to the tocilizumab plus methotrexate arm, 103 to the tocilizumab arm, and 108 to the methotrexate arm). The study was completed by a similar proportion of patients in the three groups (range 72–78%). The most frequent reasons for dropout were adverse events or intercurrent illness: 27 (34%) of dropouts, and insufficient response: 26 (33%) of dropouts. 91 (86%) of 106 patients in the tocilizumab plus methotrexate arm achieved sustained remission on the initial regimen, compared with 86 (84%) of 103 in the tocilizumab arm, and 48 (44%) of 108 in the methotrexate arm (relative risk RR 2·00, 95% CI 1·59–2·51 for tocilizumab plus methotrexate vs methotrexate, and 1·86, 1·48–2·32 for tocilizumab vs methotrexate, p<0·0001 for both comparisons). For the entire study, 91 (86%) of 106 patients in the tocilizumab plus methotrexate arm, 91 (88%) of 103 in the tocilizumab arm, and 83 (77%) of 108 in the methotrexate arm achieved sustained remission (RR 1·13, 95% CI 1·00–1·29, p=0·06 for tocilizumab plus methotrexate vs methotrexate, 1·14, 1·01–1·29, p=0·0356 for tocilizumab vs methotrexate, and p=0·59 for tocilizumab plus methotrexate vs tocilizumab). Nasopharyngitis was the most common adverse event in all three treatment groups, occurring in 38 (36%) of 106 patients in the tocilizumab plus methotrexate arm, 40 (39%) of 103 in the tocilizumab arm, and 37 (34%) of 108 in the methotrexate arm. The occurrence of serious adverse events did not differ between the treatment groups (17 16% of 106 patients in the tocilizumab plus methotrexate arm vs 19 18% of 103 in the tocilizumab arm and 13 12% of 108 in the methotrexate arm), and no deaths occurred during the study. Interpretation For patients with newly diagnosed rheumatoid arthritis, strategies aimed at sustained remission by immediate initiation of tocilizumab with or without methotrexate are more effective, and with a similar safety profile, compared with initiation of methotrexate in line with current standards. Funding Roche Nederland BV.
Low cardiorespiratory fitness is an established risk factor for cardiovascular and total mortality; however, mechanisms responsible for these associations are uncertain.
To test whether low fitness, ...estimated by short duration on a maximal treadmill test, predicted the development of cardiovascular disease risk factors and whether improving fitness (increase in treadmill test duration between examinations) was associated with risk reduction.
Population-based longitudinal cohort study of men and women 18 to 30 years of age in the Coronary Artery Risk Development in Young Adults (CARDIA) study. Participants who completed the treadmill examination according to the Balke protocol at baseline were followed up from 1985-1986 to 2000-2001. A subset of participants (n = 2478) repeated the exercise test in 1992-1993.
Incident type 2 diabetes, hypertension, the metabolic syndrome (defined according to National Cholesterol Education Program Adult Treatment Panel III), and hypercholesterolemia (low-density lipoprotein cholesterol > or =160 mg/dL 4.14 mmol/L).
During the 15-year study period, the rates of incident diabetes, hypertension, the metabolic syndrome, and hypercholesterolemia were 2.8, 13.0, 10.2, and 11.7 per 1000 person-years, respectively. After adjustment for age, race, sex, smoking, and family history of diabetes, hypertension, or premature myocardial infarction, participants with low fitness (<20th percentile) were 3- to 6-fold more likely to develop diabetes, hypertension, and the metabolic syndrome than participants with high fitness (> or =60th percentile), all P<.001. Adjusting for baseline body mass index diminished the strength of these associations to 2-fold (all P<.001). In contrast, the association between low fitness and hypercholesterolemia was modest (hazard ratio HR, 1.4; 95% confidence interval CI, 1.1-1.7; P =.02) and attenuated to marginal significance after body mass index adjustment (P =.13). Improved fitness over 7 years was associated with a reduced risk of developing diabetes (HR, 0.4; 95% CI, 0.2-1.0; P =.04) and the metabolic syndrome (HR, 0.5; 95% CI, 0.3-0.7; P<.001), but the strength and significance of these associations was reduced after accounting for changes in weight.
Poor fitness in young adults is associated with the development of cardiovascular disease risk factors. These associations involve obesity and may be modified by improving fitness.
To understand the relationship between drug dose and efficacy, pharmacokinetic (PK) and pharmacodynamic (PD) characteristics need to be integrated. Patterns of antimicrobial activity fall into one of ...two major patterns: time-dependent killing and concentration-dependent killing. Time-dependent killing is characteristic of many antibiotic classes, such as β-lactams and macrolides, and seeks to optimise the duration of exposure of a pathogen to an antimicrobial. The major PK/PD parameter correlating with efficacy of time-dependent antimicrobials is the serum concentration present for 40–50% of the dosing interval, and this concentration is the susceptibility limit or breakpoint for the dosing regimen used. The second pattern, concentration-dependent killing, seeks to maximise antimicrobial concentration and is seen with aminoglycosides, quinolones and azalides. The major PK/PD parameter correlating with efficacy of these agents is the 24-h area under the curve to MIC ratio, which should be ≥25 for less severe infections or in immunocompetent hosts, and ≥100 in more severe infections or in immunocompromised hosts. PK/PD breakpoints for concentration-dependent agents can therefore be calculated from the formula AUC ÷ 25. This enables development of PK/PD breakpoints based on the above parameters for time- and concentration-dependent agents for defined dosing regimens. For an antimicrobial to be useful empirically, the MIC90s of the agent against the common pathogens responsible for the disease being treated should be below the PK/PD breakpoint. This is particularly important for oral dosing regimens for treating emerging resistant respiratory tract pathogens, where efficacy against the predominant pathogens, Streptococcus pneumoniae and Haemophilus influenzae, is required.
Summary Background Infants of women with diabetes in pregnancy are at increased risk of hypoglycaemia, admission to a neonatal intensive care unit (NICU), and not being exclusively breastfed. Many ...clinicians encourage women with diabetes in pregnancy to express and store breastmilk in late pregnancy, yet no evidence exists for this practice. We aimed to determine the safety and efficacy of antenatal expressing in women with diabetes in pregnancy. Methods We did a multicentre, two-group, unblinded, randomised controlled trial in six hospitals in Victoria, Australia. We recruited women with pre-existing or gestational diabetes in a singleton pregnancy from 34 to 37 weeks' gestation and randomly assigned them (1:1) to either expressing breastmilk twice per day from 36 weeks' gestation (antenatal expressing) or standard care (usual midwifery and obstetric care, supplemented by support from a diabetes educator). Randomisation was done with a computerised random number generator in blocks of size two and four, and was stratified by site, parity, and diabetes type. Investigators were masked to block size but masking of caregivers was not possible. The primary outcome was the proportion of infants admitted to the NICU. We did the analyses by intention to treat; the data were obtained and analysed masked to group allocation. This trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12611000217909. Findings Between June 6, 2011, and Oct 29, 2015, we recruited and randomly assigned 635 women: 319 to antenatal expressing and 316 to standard care. Three were not included in the primary analysis (one withdrawal from the standard care group, and one post-randomisation exclusion and one withdrawal from the antenatal expressing group). The proportion of infants admitted to the NICU did not differ between groups (46 15% of 317 assigned to antenatal expressing vs 44 14% of 315 assigned to standard care; adjusted relative risk 1·06, 95% CI 0·66 to 1·46). In the antenatal expressing group, the most common serious adverse event for infants was admission to the NICU for respiratory support (for three <1% of 317. In the standard care group, the most common serious adverse event for infants was moderate to severe encephalopathy with or without seizures (for three <1% of 315). Interpretation There is no harm in advising women with diabetes in pregnancy at low risk of complications to express breastmilk from 36 weeks' gestation. Funding Australian National Health and Medical Research Council.
Chronic nonbacterial osteomyelitis (CNO) is a rare autoinflammatory bone disorder primarily affecting children and adolescents. It can lead to chronic pain, bony deformities and fractures. The ...pathophysiology of CNO is incompletely understood. Scientific evidence suggests dysregulated expression of pro- and anti-inflammatory cytokines to be centrally involved. Currently, treatment is largely based on retrospective observational studies and expert opinion. Treatment usually includes nonsteroidal anti-inflammatory drugs and/or glucocorticoids, followed by a range of drugs in unresponsive cases. While randomised clinical trials are lacking, retrospective and prospective non-controlled studies suggest effectiveness of TNF inhibitors and bisphosphonates. The objective of the Bayesian consensus meeting was to quantify prior expert opinion.
Twelve international CNO experts were randomly chosen to be invited to a Bayesian prior elicitation meeting.
Results showed that a typical new patient treated with pamidronate would have an 84% chance of improvement in their pain score relative to baseline at 26 weeks and an 83% chance on adalimumab. Experts thought there was a 50% chance that a new typical patient would record a pain score of 28mm (pamidronate) to 30mm (adalimumab) or better at 26 weeks. There was a modest trend in prior opinion to indicate an advantage of pamidronate vs adalimumab, with a 68% prior chance that pamidronate is superior to adalimumab by some margin. However, it is clear that there is considerable uncertainty about the precise relative merits of the two treatments.
The rarity of CNO leads to challenges in conducting randomised controlled trials with sufficient power to provide a definitive outcome. We address this using a Bayesian design, and here describe the process and outcome of the elicitation exercise to establish expert prior opinion. This opinion will be tested in the planned prospective CNO study. The process for establishing expert consensus opinion in CNO will be helpful for developing studies in other rare paediatric diseases.
Physical exercise is an important component in the management of type 1 diabetes across the lifespan. Yet, acute exercise increases the risk of dysglycaemia, and the direction of glycaemic excursions ...depends, to some extent, on the intensity and duration of the type of exercise. Understandably, fear of hypoglycaemia is one of the strongest barriers to incorporating exercise into daily life. Risk of hypoglycaemia during and after exercise can be lowered when insulin-dose adjustments are made and/or additional carbohydrates are consumed. Glycaemic management during exercise has been made easier with continuous glucose monitoring (CGM) and intermittently scanned continuous glucose monitoring (isCGM) systems; however, because of the complexity of CGM and isCGM systems, both individuals with type 1 diabetes and their healthcare professionals may struggle with the interpretation of given information to maximise the technological potential for effective use around exercise (i.e. before, during and after). This position statement highlights the recent advancements in CGM and isCGM technology, with a focus on the evidence base for their efficacy to sense glucose around exercise and adaptations in the use of these emerging tools, and updates the guidance for exercise in adults, children and adolescents with type 1 diabetes.
Graphical abstract
Purpose
Anterior cutaneous nerve entrapment (ACNES) is characterized by neuropathic pain in a predictable, circumscript abdominal area. The diagnostic delay is long, with half of ACNES-affected ...individuals reporting nausea, bloating, or loss of appetite mimicking visceral disease. The aim of this study was to describe these phenomena and to determine whether treatment could successfully reverse the visceral symptoms.
Methods
This prospective observational study was conducted between July 2017 and December 2020 at SolviMáx, Center of Excellence for Chronic Abdominal Wall and Groin Pain, Máxima Medical Center, Eindhoven. Adult patients who fulfilled published criteria for ACNES and reported at least one visceral symptom at intake were eligible for the study. A self-developed Visceral Complaints ACNES Score (VICAS) questionnaire that scores several visceral symptoms (minimum 1 point, maximum 9 points) was completed before and after therapy. The success of treatment was defined as at least 50% reduction in pain.
Results
Data from 100 selected patients (86 females) aged 39 ± 5 years were available for analysis. Frequently reported symptoms were abdominal bloating (78%), nausea (66%) and altered defecation (50%). Successful treatment significantly reduced the number of visceral symptoms, with a VICAS before of 3 (range 1–8) and after of 1 (range 0–6) (
p
< 0.001). A low baseline VICAS was associated with successful treatment outcome (OR 0.738, 95% CI 0.546–0.999).
Conclusion
Patients with ACNES may report a variety of visceral symptoms. Successful treatment substantially reduces these visceral symptoms in selected patients.
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