Similarities and differences in interactions of thyroid stimulating and blocking autoantibodies with the TSH receptor

Binding of a new thyroid-stimulating human monoclonal autoantibody (MAb) K1-18 to the TSH receptor (TSHR) leucine-rich domain (LRD) was predicted using charge-charge interaction mapping based on unique complementarities between the TSHR in interactions with the thyroid-stimulating human MAb M22 or the thyroid-blocking human MAb K1-70. The interactions of K1-18 with the TSHR LRD were compared with the interactions in the crystal structures of the M22-TSHR LRD and K1-70-TSHR LRD complexes. Furthermore, the predicted position of K1-18 on the TSHR was validated by the effects of TSHR mutations on the stimulating activity of K1-18. A similar approach was adopted for predicting binding of a mouse thyroid-blocking MAb RSR-B2 to the TSHR. K1-18 is predicted to bind to the TSHR LRD in a similar way as TSH and M22. The binding analysis suggests that K1-18 light chain (LC) mimics binding of the TSH-α chain and the heavy chain (HC) mimics binding of the TSH-β chain. By contrast, M22 HC mimics the interactions of TSH-α while M22 LC mimics TSH-β in interactions with the TSHR. The observed interactions in the M22-TSHR LRD and K1-70-TSHR LRD complexes (crystal structures) with TSH-TSHR LRD (comparative model) and K1-18-TSHR LRD (predictive binding) suggest that K1-18 and M22 interactions with the receptor may reflect interaction of thyroid-stimulating autoantibodies in general. Furthermore, K1-70 and RSR-B2 interactions with the TSHR LRD may reflect binding of TSHR-blocking autoantibodies in general. Interactions involving the C-terminal part of the TSHR LRD may be important for receptor activation by autoantibodies.     

Hybrid closed-loop therapy: Where are we in 2021?

Hybrid closed-loop systems are characterized by the coexistence of algorithm-driven automated insulin delivery combined with manual mealtime boluses. Used correctly, these insulin delivery systems offer better glucose control and reduced risk of hypoglycaemia and represent the most advanced form of insulin delivery available for people with type 1 diabetes. The aim of this paper was to compare the currently available commercial hybrid closed-loop systems in the UK: the Medtronic 670G/780G, Tandem t:slim X2 Control IQ and CamAPS FX systems. The Medtronic 670G/780G systems use Guardian 3 sensor (7-day use, two to four calibrations per day), while Tandem and CamAPS systems use the calibration-free Dexcom G6 sensor (10 days). The CamAPS system is available as an android app, whereas the other two systems have the algorithm embedded in the insulin pump. During pivotal studies, depending on the study population and baseline glycated haemoglobin level, these systems achieve a time spent in the target range 3.9 to 10 mmol/L (70 to 180 mg/dL) of 65% to 76% with low burden of hypoglycaemia. All three systems allow a higher glucose target for announced exercise, while the Tandem system offers an additional night-time tighter target. The CamAPS system offers fully customizable glucose targets and is the only system licensed for use during pregnancy. Additional education is required for both users and healthcare professionals to harness the best performance from these systems as well as to troubleshoot when “automode exits” occur. We provide consensus recommendations to develop pragmatic pathways to guide patients, clinicians and commissioners in making informed decisions on the appropriate use of the diabetes technology.     

Improved Hand Function,Self‐Rated Health,and Decreased Activity Limitations: Results After a Two‐Month Hand Osteoarthritis Group Intervention

Objective

To evaluate the effects on hand function, activity limitations, and self‐rated health of a primary care hand osteoarthritis (OA) group intervention. Hand OA causes pain, impaired mobility, and reduced grip force, which cause activity limitations. OA group interventions in primary care settings are sparsely reported.

Methods

Sixty‐four individuals with hand OA agreed to participate; 15 were excluded due to not fulfilling the inclusion criteria. The 49 remaining (90% female) participated in an OA group intervention at a primary care unit with education, paraffin wax bath, and hand exercise over a 6‐week period. Data were collected at baseline, end of intervention, and after 1 year. Instruments used were the Grip Ability Test (GAT), the Signals of Functional Impairment (SOFI), dynamometry (grip force), hand pain at rest using a visual analog scale (VAS), the Patient‐Specific Functional Scale (PSFS), the Quick Disabilities of the Arm, Shoulder, and Hand (Quick‐DASH), and the EuroQol VAS (EQ VAS). Data were analyzed using nonparametric statistics.

Results

Hand function, activity limitation, and self‐rated health significantly improved from baseline to end of intervention, grip force (right hand: P < 0.001; left hand: P = 0.008), SOFI (P = 0.011), GAT (P < 0.001), hand pain at rest (P < 0.001), PSFS (1: P = 0.008, 2: P < 0.001, and 3: P = 0.004), Quick‐DASH (P = 0.001), and EQ VAS (P = 0.039), and the effects were sustained after 1 year.

Conclusion

The hand OA group intervention in primary care improves hand function, activity limitation, and self‐rated health. The benefits are sustained 1 year after completion of the intervention.

     

Analysis of rearranged immunoglobulin genes indicating a process of clonal evolution in chronic lymphocytic leukaemia

Summary. Chronic lymphocytic leukaemia (CLL) is known to be a stable monoclonal neoplasm. In contrast to early studies demonstrating no more than two hybridizing immunoglobulin heavy chain bands corresponding to the two expected alleles, we have demonstrated an unexpected multiband pattern when the HindIII-digested DNA samples from 38 CLL patients were analysed by Southern blot hybridization using J_H and Cμ gene probes. In order to characterize the genetic basis for the multiband pattern, we molecularly cloned the immunoglobulin heavy chain genes of one of the patients whose leukaemic DNA sample demonstrated three hybridizing J_H bands and a loss of the germline band. The cloned rearranged immunoglobulin genes could be divided, based on the restriction mapping and the hybridization with the various probes, into two basic patterns representing two alleles. In one of the cloned rearranged immunoglobulin genes a secondary rearrangement occurred that resulted in the addition of 300 base-pair long sequence into the switch region, and the creation of a HindIII restriction site.
The results of the study suggest that clonal evolution occurs in some CLL, and that many of these neoplasms are indeed oligoclonal due to the accumulation of secondary genetic changes.     

Caregiver education and support: results of a multi-site pilot in an HMO

Caregiver workshops were offered to members by a group practice HMO as part of a larger demonstration of adding community care to HMO services. Of 1,200 members indicating interest at four sites, 532 participated in workshops and 320 completed pre- and post-questionnaires on effectiveness. Analyses showed improvements in caregiving preparedness and reductions in sadness and depression. Engagement in the workshops (completing 3 or more sessions) and improvements were more likely for individuals with more independent lives and social capital. Alternative helping strategies are recommended for caregivers who are less likely to engage in classes due to burden or lack of respite or transportation.     

Obstetrics during Civil War: six months on a maternity ward in Mallavi,northern Sri Lanka

A long-term, large-scale ethnic armed conflict continues in Sri Lanka, where militant separatists control a northern section of the island. The conflict has resulted in a large population of internally displaced persons and a shortage of medical staff. Drug and equipment shortages compound the difficulty in access to medical care. This article reports the experiences from 1 November 2000 to 30 April 2001 recorded by review of medical records and by interviews, in the peripheral unit, in a separatist controlled area of the Mallavi maternity ward. There were 704 births. Most of the mothers had been displaced by the war (69.5 per cent) and had experienced food shortage (67.5 per cent). Referred patients (18.1 per cent) had a high rate of caesarean section (44.3 per cent) and had travelled a mean of 57.6 km to reach Mallavi. There had been substantial antenatal care (94.0 per cent), tetanus toxoid vaccination (95.1 per cent) and malaria prophylaxis (86.4 per cent). Risk factors for low birth weight included a maternal body mass index less than 19 (RR 1.55, CI 1.11-2.16, P = .011), primiparity (RR 1.44, CI 1.05-1.97, P = .024) and self-reported malarial infection during pregnancy (RR 1.42, CI 1.03-1.97, P = .036). Rates of low birth weight, stillbirths, neonatal deaths and maternal mortality in the Mallavi units were higher than the Sri Lankan national averages. Improvements in quality of care and access to health care are unlikely while the war continues.