Interrelationships between Cellular Density,Mosaic Patterning,and Dendritic Coverage of VGluT3 Amacrine Cells

Amacrine cells of the retina are conspicuously variable in their morphologies, their population demographics, and their ensuing functions. Vesicular glutamate transporter 3 (VGluT3) amacrine cells are a recently characterized type of amacrine cell exhibiting local dendritic autonomy. The present analysis has examined three features of this VGluT3 population, including their density, local distribution, and dendritic spread, to discern the extent to which these are interrelated, using male and female mice. We first demonstrate that Bax-mediated cell death transforms the mosaic of VGluT3 cells from a random distribution into a regular mosaic. We subsequently examine the relationship between cell density and mosaic regularity across recombinant inbred strains of mice, finding that, although both traits vary across the strains, they exhibit minimal covariation. Other genetic determinants must therefore contribute independently to final cell number and to mosaic order. Using a conditional KO approach, we further demonstrate that Bax acts via the bipolar cell population, rather than cell-intrinsically, to control VGluT3 cell number. Finally, we consider the relationship between the dendritic arbors of single VGluT3 cells and the distribution of their homotypic neighbors. Dendritic field area was found to be independent of Voronoi domain area, while dendritic coverage of single cells was not conserved, simply increasing with the size of the dendritic field. Bax-KO retinas exhibited a threefold increase in dendritic coverage. Each cell, however, contributed less dendrites at each depth within the plexus, intermingling their processes with those of neighboring cells to approximate a constant volumetric density, yielding a uniformity in process coverage across the population.SIGNIFICANCE STATEMENT Different types of retinal neuron spread their processes across the surface of the retina to achieve a degree of dendritic coverage that is characteristic of each type. Many of these types achieve a constant coverage by varying their dendritic field area inversely with the local density of like-type neighbors. Here we report a population of retinal amacrine cells that do not develop dendritic arbors in relation to the spatial positioning of such homotypic neighbors; rather, this cell type modulates the extent of its dendritic branching when faced with a variable number of overlapping dendritic fields to approximate a uniformity in dendritic density across the retina.     

Effectiveness,Patient Satisfaction,and Cost Reduction of Virtual Joint Replacement Clinic Follow-Up of Hip and Knee Arthroplasty

BackgroundTotal hip and knee arthroplasties are increasingly performed operations, and routine follow-up places huge demands on orthopedic services. This study investigates the effectiveness, patients’ satisfaction, and cost reduction of Virtual Joint Replacement Clinic (VJRC) follow-up of total hip arthroplasty and total knee arthroplasty patients in a university hospital. VJRC is especially valuable when in-person appointments are not advised or feasible such as during the COVID-19 pandemic.MethodsA total of 1749 patients who were invited for VJRC follow-up for knee or hip arthroplasty from January 2017 to December 2018 were included in this retrospective study. Patients were referred to VJRC after their 6-week postoperative review. Routine VJRC postoperative review was undertaken at 1 and 7 years and then 3-yearly thereafter. We evaluated the VJRC patient response rate, acceptability, and outcome. Patient satisfaction was measured in a subgroup of patients using a satisfaction survey. VJRC costs were calculated compared to face-to-face follow-up.ResultsThe VJRC had a 92.05% overall response rate. Only 7.22% required further in-person appointments with only 3% being reviewed by an orthopedic consultant. VJRC resulted in an estimated saving of £42,644 per year at our institution. The patients’ satisfaction survey showed that 89.29% of the patients were either satisfied or very satisfied with VJRC follow-up.ConclusionVJRC follow-up for hip and knee arthroplasty patients is an effective alternative to in-person clinic assessment which is accepted by patients, has high patient satisfaction, and can reduce the cost to both health services and patients.     

Hip Displacement in Cerebral Palsy: The Role of Surveillance

IntroductionHip displacement is common in cerebral palsy (CP) and is related to the severity of neurological and functional impairment. It is a silent, but progressive disease, and can result in significant morbidity and decreased quality of life, if left untreated. The pathophysiology of hip displacement in CP is a combination of hip flexor-adductor muscle spasticity, abductor muscle weakness, and delayed weight-bearing, resulting in proximal femoral deformities and progressive acetabular dysplasia. Due to a lack of symptoms in the early stages of hip displacement, the diagnosis is easily missed. Awareness of this condition and regular surveillance by clinical examination and serial radiographs of the hips are the key to early diagnosis and treatment.Hip surveillance programmesSeveral population-based studies from around the world have demonstrated that universal hip surveillance in children with CP allows early detection of hip displacement and appropriate early intervention, with a resultant decrease in painful dislocations. Global hip surveillance models are based upon the patients’ age, functional level determined by the Gross Motor Function Classification system (GMFCS), gait classification, standardized clinical exam, and radiographic indices such as the migration percentage (MP), as critical indicators of progressive hip displacement.ConclusionDespite 25 years of evidence showing the efficacy of established hip surveillance programmes, there is poor awareness among healthcare professionals in India about the importance of regular hip surveillance in children with CP. There is a need for professional organizations to develop evidence-based guidelines for hip surveillance which are relevant to the Indian context.     

A Phase I Dose Escalation Study of the Safety,Tolerability, and Pharmacokinetics of Ipilimumab in Chinese Patients with Select Advanced Solid Tumors

Lessons Learned

• The overall safety profiles of ipilimumab 3 mg/kg and 10 mg/kg administered every 3 weeks, were consistent between Chinese patients with solid tumors in the current study and patients from previous U.S. ipilimumab monotherapy studies. No new safety signals were identified.
• The mean systemic exposures to ipilimumab (assessed by first dose area under the curve during the dosing interval and maximum serum concentration) were numerically lower in the Chinese patient population than in U.S. patients for both 3 mg/kg and 10 mg/kg doses; however, the range of serum concentrations in the Chinese and U.S. populations overlapped (3 mg/kg and 10 mg/kg), suggesting that ipilimumab pharmacokinetics was ethnically insensitive in this study.

BackgroundThis phase I, open‐label study assessed ipilimumab safety, tolerability, pharmacokinetics (PK), immunogenicity, and antitumor activity in Chinese patients with unresectable, metastatic, recurrent malignant melanoma (MM) or nasopharyngeal carcinoma (NPC).MethodsOf 39 patients enrolled, 25 received ipilimumab (11 patients received 3 mg/kg, and 14 patients received 10 mg/kg). Reasons for not receiving treatment were withdrawal of consent (3 patients), no longer meeting the criteria (10 patients), and one recorded as “other.” During the induction phase, patients received ipilimumab (3 mg/kg, i.v.), on day 1 of a 3‐week cycle, to a maximum of four doses or progressive disease (PD). During the maintenance phase at week 24, patients received ipilimumab (3 mg/kg, i.v.) on day 1 of a 12‐week cycle, to a maximum of 3 years or PD. Considering the co‐primary safety and PK endpoints, the successive dosing required nine patients with two or fewer dose‐limiting toxicities during the 42‐day observation period to proceed with a new cohort of nine patients at 10 mg/kg.ResultsIpilimumab safety and PK profiles were similar in Chinese and predominantly White populations. Ipilimumab was well tolerated. Most adverse events (AEs) were grades 1–2 and experienced by 11 patients treated with 3 mg/kg and 14 patients treated with 10 mg/kg. There were no new safety concerns. Incidence of anti‐ipilimumab antibodies was low (1 of 10 in the 3 mg/kg patients and 2 of 13 in the 10 mg/kg patients) and without safety implications. In the 3 mg/kg group, 8 of 11 patients had PD. In the 10 mg/kg group (all NPC, 0 MM patients), 11 of 14 patients had PD. Three patients had stable disease (one at 3 mg/kg and two at 10 mg/kg).ConclusionIpilimumab was well tolerated in Chinese patients, showing similar safety and PK to previous studies in predominantly White populations.