Anakinra in the treatment of polyarticular-course juvenile rheumatoid arthritis: safety and preliminary efficacy results of a randomized multicenter study

This study assessed the safety and preliminary efficacy of the interleukin-1 receptor antagonist anakinra in patients with polyarticular-course juvenile rheumatoid arthritis (JRA). Eighty-six patients entered a 12-week open-label run-in phase (1 mg/kg anakinra daily, ≤100 mg/day). Fifty responders were randomized to anakinra or placebo in a 16-week blinded phase, followed by a 12-month open-label extension (N = 44). Due to low enrollment, the primary endpoint was changed from efficacy to safety. The incidence and nature of adverse events were similar across all study phases, with the exception of injection site reactions, which were mild to moderate and decreased with time. Anakinra produced a nonsignificant (P = 0.11) reduction in disease flares compared with placebo. When normalized to 1 mg/kg dose, anakinra plasma concentrations were similar to values in adult patients with rheumatoid arthritis. These results indicate that anakinra 1 mg/kg once daily (≤100 mg/day) is safe and well tolerated in patients with JRA.     

Drug cross-resistance and therapy-induced resistance in chronic lymphocytic leukaemia by an enhanced method of individualised tumour response testing

Previous results with individualised tumour response testing (ITRT) in vitro in chronic lymphocytic leukaemia (CLL) have consistently shown good correlation with patient response and survival. We describe here an improved test and report its use with samples from the Leukaemia Research Fund CLL4 randomised clinical trial and previously treated patients. ITRT was performed by the tumour response to anti-neoplastic compounds (TRAC) assay, a modification of the differential staining cytotoxicity (DiSC) assay. Improvements included drying drugs into wells before assay and using the Octospot system to cytocentrifuge eight spots of cells onto one microscope slide. We successfully tested 765/782 (98%) cellular blood samples received within 48 h of phlebotomy. Cross-resistance (Pearson's r  > 0·7) in untreated CLL was found between similar drugs. Mitoxantrone ( r  = 0·31), cyclophosphamide ( r  = 0·35) and pentostatin ( r  = 0·29) had low cross-resistance with fludarabine. Treatment resulted in increased resistance to chlorambucil, cyclophosphamide, doxorubicin, mitoxantrone, corticosteroids, cladribine and fludarabine ( P  < 0·01) but not to pentostatin. These results provide further rationale for standard drug combinations such as fludarabine-mitoxantrone and fludarabine-mitoxantrone-cyclophosphamide and suggest possible pentostatin salvage in fludarabine-resistant patients. ITRT results could assist both in determining the best treatment for individual patients and in the design and rationale of future clinical trials.     

The impact of risk stratification by early bone-marrow response in childhood lymphoblastic leukaemia: results from the United Kingdom Medical Research Council trial ALL97 and ALL97/99

The 1997 acute lymphoblastic leukaemia (ALL) trial (ALL97) was a randomised comparison of prednisolone versus dexamethasone and of 6-mercaptopurine versus 6-thioguanine. During the first 2 years of the trial, review of survival data showed the preceding trial, UKALL XI, was no better than its predecessor and that survival for childhood ALL in the UK had not improved in the fashion witnessed by other cooperative treatment groups. The therapy template was therefore altered to an American Children's Cancer Group (CCG) style regimen, including stratification by age, white cell count and early response to therapy by assessment of the bone marrow. This phase of the trial was designated ALL97/99. Comparison of the two phases showed that the event-free survival (EFS) for both ALL97 and ALL97/99 was better than previous UKALL trials, as was overall survival (OS) for ALL97/99. Both EFS and OS were significantly better in ALL97/99 than in ALL97 (at five years, 80·0% vs. 74·0%, P  = 0·002; and 88·0% vs. 83·5%, P  = 0·005, respectively). Isolated central nervous system (CNS) relapse for patients in ALL97/99 was half that in ALL97 (3·0% vs. 4·9%), P  = 0·03) and the overall CNS relapse rate was halved in ALL97/99 (4·4% vs. 9·6%, P  < 0·00005). There were no significant differences for non-CNS relapse, induction deaths or deaths in remission between the two phases of the trial.     

Outcomes for older adults in an inpatient rehabilitation facility following hip fracture (HF) surgery

The purpose of the study was to evaluate patient and system outcomes regarding older community-residing adults who participated in a rehabilitation program following HF surgery. The health care professionals on the rehabilitation unit in this feasibility study had never cared for such patients who were so frail, with multiple co-morbidities including cognitive impairment (CI). After an innovative model of care was developed and the staff trained in the novel approach to care, the unit opened for all patients living within the community who had fractured their hip, regardless of their CI. Of the 31 elderly patients consecutively admitted post-HF in this retrospective study, 18 were found to have CI postoperatively as determined by a Mini-Mental State Examination (MMSE) score < or = 23. There were no differences in length of stay (LOS), rehabilitation efficiency, and motor FIM gain scores between the two groups of patients. This feasibility retrospective study suggests that staff can learn how to care for patients with CI in rehabilitation settings, and that such clients can achieve outcomes comparable to those without CI in a setting dedicated to caring for patients with a HF.     

Preventing falls in older multifocal glasses wearers by providing single-lens distance glasses: the protocol for the VISIBLE randomised controlled trial

Background

Recent research has shown that wearing multifocal glasses increases the risk of trips and falls in older people. The aim of this study is to determine whether the provision of single-lens distance glasses to older multifocal glasses wearers, with recommendations for wearing them for walking and outdoor activities, can prevent falls. We will also measure the effect of the intervention on health status, lifestyle activities and fear of falling, as well as the extent of adherence to the program.

Methods/Design

Approximately 580 older people who are regular wearers of multifocal glasses people will be recruited. Participants will be randomly allocated to either an intervention group (provision of single lens glasses, with counselling and advice about appropriate use) or a control group (usual care). The primary outcome measure will be falls (measured with 13 monthly calendars). Secondary measures will be quality of life, falls efficacy, physical activity levels and adverse events.

Discussions

The study will determine the impact of providing single-lens glasses, with advice about appropriate use, on preventing falls in older regular wearers of multifocal glasses. This pragmatic intervention, if found to be effective, will guide practitioners with regard to recommending appropriate glasses for minimising the risk of falls in older people.

Trial Registration

The protocol for this study was registered with the Clinical Trials.gov Protocol Registration System on June 7^th 2006 (#350855).     

Mechanism of protein remodeling by ClpA chaperone

ClpA, a newly discovered ATP-dependent molecular chaperone, remodels bacteriophage P1 RepA dimers into monomers, thereby activating the latent specific DNA binding activity of RepA. We investigated the mechanism of the chaperone activity of ClpA by dissociating the reaction into several steps and determining the role of nucleotide in each step. In the presence of ATP or a nonhydrolyzable ATP analog, the initial step is the self-assembly of ClpA and its association with inactive RepA dimers. ClpA-RepA complexes form rapidly and at 0°C but are relatively unstable. The next step is the conversion of unstable ClpA-RepA complexes into stable complexes in a time- and temperature-dependent reaction. The transition to stable ClpA-RepA complexes requires binding of ATP, but not ATP hydrolysis, because nonhydrolyzable ATP analogs satisfy the nucleotide requirement. The stable complexes contain approximately 1 mol of RepA dimer per mol of ClpA hexamer and are committed to activating RepA. In the last step of the reaction, active RepA is released upon exchange of ATP with the nonhydrolyzable ATP analog and ATP hydrolysis. Importantly, we discovered that one cycle of RepA binding to ClpA followed by ATP-dependent release is sufficient to convert inactive RepA to its active form.     

Endoscopic endonasal approach for growth hormone secreting pituitary adenomas: outcomes in 53 patients using 2010 consensus criteria for remission

We report the outcomes of the endoscopic endonasal approach (EEA) for resection of growth hormone secreting pituitary adenomas using 2010 consensus criteria. We also assess outcomes with additional medical therapy and radiosurgery (RS) for patients not achieving remission with EEA alone. A retrospective review of 53 patients who had follow up endocrinologic data at least 3 months post-surgery was performed among patients who were treated by EEA between 1998 and 2012. Data were analyzed for remission using GH and IGF-I levels based on 2010 consensus criteria. We also analyzed the outcomes using 2000 consensus criteria for ease in comparison to prior studies of outcomes of surgery for acromegaly. In this series of mostly large (88.2 % macroadenomas), invasive (46.9 % Hardy–Wilson C, D, E) adenomas, there were 27 patients (50.9 %) who achieved remission after EEA only. For patients who had no remission with EEA alone, RS and/or medical therapy were used and 37 patients (69.8 %) achieved remission overall. Statistical analysis showed larger tumor size, Hardy Stages C, D, E and Knosp Scores 3, 4 to be predictive against remission for EEA only and EEA with other modalities. The volume of residual tumor after EEA was not found to be predictive of remission with additional therapies. We used stringent consensus criteria from 2010 in a series which included a high proportion of invasive GH secreting adenomas to show that EEA alone or combined with other modalities results in comparable remission rates to earlier studies which used less strict criteria, while retaining low complication rates.     

Improved treatment completion for tuberculosis patients: The case for a dedicated social care team

ObjectivesThe increasing social needs of people with Tuberculosis (TB), and the poor adherence to anti-TB therapy (ATT) associated with homelessness, drug or alcohol abuse, and prison history, led us to introduce a social care team (SCT) to support patient engagement with care within this low TB incidence setting.MethodsUsing a risk assessment, patients with social risk factors (SRF) for non-adherence to ATT are identified and a referral made to the SCT, who then provide intensive casework support for areas including homelessness, housing, benefits, debt and immigration. Retrospective data analysis of the social care database from 2017 to 2019 was conducted. Patients who were (n = 170) and were not referred to the SCT (n = 734) were compared.ResultsPatients referred were significantly more likely to complete treatment for TB than those not (88.2% versus 77.7% respectively, p = 0.0025), irrespective of receipt of Directly/Video Observed Therapy and adjusting for confounders.ConclusionsThis paper demonstrates important evidence for the positive impact of a dedicated SCT within a TB service, and these improved treatment outcomes provide a strong argument for development of similar SCTs within UK TB services and similar healthcare settings.     

Society for Endocrinology UK guidance on the initial evaluation of an infant or an adolescent with a suspected disorder of sex development (Revised 2015)

It is paramount that any child or adolescent with a suspected disorder of sex development (DSD) is assessed by an experienced clinician with adequate knowledge about the range of conditions associated with DSD. If there is any doubt, the case should be discussed with the regional DSD team. In most cases, particularly in the case of the newborn, the paediatric endocrinologist within the regional team acts commonly as the first point of contact. This clinician should be part of a multidisciplinary team experienced in management of DSD and should ensure that the affected person and parents have access to specialist psychological support and that their information needs are comprehensively addressed. The underlying pathophysiology of DSD and the strengths and weaknesses of the tests that can be performed should be discussed with the parents and affected young person and tests undertaken in a timely fashion. Finally, in the field of rare conditions, it is imperative that the clinician shares the experience with others through national and international clinical and research collaboration.