Clinical outcomes of subtalar arthroereisis for the treatment of stage 1 flexible progressive collapsing foot deformity.

BACKGROUND: The use of subtalar arthroereisis as an adjunct to the surgical treatment of stage 1 flexible progressive collapsing foot deformity (PCFD) is controversial. The aim was to investigate the clinical outcomes and report the implant removal rate of subtalar arthroereisis as an adjunct for stage 1 PCFD. METHODS: A retrospective study of 212 consecutive feet undergoing operative management of stage 1 PCFD with adjunctive subtalar arthroereisis between October 2010 and April 2018. The primary outcome was the Foot and Ankle Outcome Score (FAOS). Secondary outcomes included Foot and Ankle Disability Index (FADI), Euroqol-5D-5L Index and implant removal rate. RESULTS: Post-operative clinical FAOS outcomes were collected for 153 feet (72.2%). At mean 2.5-year follow-up, the mean ± standard deviation FAOS for each domain was as follows; Pain: 81.5 ± 18.5, Symptoms: 79.5 ± 12.9, Activities of Daily Living: 82.5 ± 15.4 and Quality of Life: 64.2 ± 23.7. EQ-5D-5L Index was 0.884 ± 0.152. Pre-operative scores were available for 20 of these feet demonstrating a statistically significant improvement in all FAOS, FADI and EQ-5D-5L domains (p < 0.05). The implant removal rate for persistent sinus tarsi pain was 48.1% (n = 102). CONCLUSION: Use of a subtalar arthroereisis implant as an adjunct to conventional procedures in stage 1 flexible PCFD can result in significant improvement in pain and function. Patients should be counselled as to the relatively frequent rate of subsequent implant removal. LEVEL OF EVIDENCE: IV.

Opioid use and patient outcomes in an Australian hip and knee arthroplasty cohort.

BACKGROUND: To determine the prevalence of opioid use in Australian hip (THA) or knee (TKA) cohort, and its association with outcomes. METHODS: About 837 primary THA or TKA subjects prospectively completed Oxford Scores, and Knee or Hip Osteoarthritis Outcomes Score(KOOS/HOOS) and opioid use in the previous week before arthroplasty. Subjects repeated the baseline survey at 6 months, with additional questions regarding satisfaction. RESULTS: Opioid use was reported by 19% preoperatively and 7% at 6 months. Opioid use was 46% at 6 weeks and 10% at 6 months after TKR, and 16% at 6 weeks and 4% at 6 months after THR. Preoperative opioid use was associated with back pain(OR 2.2, P = 0.006), anxiety or depression(OR 1.8, P = 0.001) and Oxford knee scores <30(OR 5.6, P = 0.021) in TKA subjects, and females in THA subjects(OR 1.7, P = 0.04). There was no difference between preoperative opioid users and non-users for satisfaction, or KOOS or HOOS scores at 6 months. 77% of patients taking opioids before surgery had ceased by 6 months, and 3% of preoperative non users reported opioid use at 6 months. Opioid use at 6 months was associated with preoperative use (OR 6.6-14.7, P < 0.001), and lower 6 month oxford scores (OR 4.4-83.6, P < 0.01). CONCLUSION: One in five used opioids before arthroplasty. Pre-operative opioid use was the strongest risk factor for opioid use at 6 months, increasing odds 7-15 times. Prolonged opioid use was rarely observed in the opioid naïve (<5% TKA and 1% THA). Preoperative opioid use was not associated with inferior outcomes or satisfaction.

Foot Pain is Common, But Frequently Improves 1 Year After Total Knee Arthroplasty.

BACKGROUND: Osteoarthritis frequently affects multiple joints through the lower limbs. This study sought to examine the incidence of foot pain in subjects undergoing total knee arthroplasty (TKA) and determine if foot symptoms improved following surgery. METHODS: Six hundred ten subjects undergoing TKA completed patient-reported outcome measures preoperatively, and at 6 and/or 12 months after surgery including the incidence and severity of foot or ankle pain, Knee Injury and Osteoarthritis Outcome Scores (KOOS) Joint Replacement, Oxford Knee Scores (OKS), EQ5D, and satisfaction. RESULTS: Foot or ankle pain was reported in 45% before, 32% at 6 months, and 36% at 12 months after TKA. Of those with preoperative foot pain, 42% at 6 months and 50% at 12 months reported no foot pain after TKA, and the Visual Analog Scale severity reduced from a mean of 4.0 before to 1.7 after surgery. Those with preoperative foot pain had lower baseline KOOS (P = .001), OKS (P = .001), and more depression/anxiety (P = .010), but experienced equivalent postoperative KOOS, OKS, and satisfaction with surgery, compared to those without foot pain. CONCLUSION: Foot or ankle pain was reported by nearly half of TKA subjects, but resolved after surgery in 50%. Those with preoperative foot pain experienced at least equivalent improvement in knee-related symptoms and mobility compared to those without foot pain. The presence of foot pain should not be a deterrent to TKA.

Reprogramming human T cell function and specificity with non-viral genome targeting.

Decades of work have aimed to genetically reprogram T cells for therapeutic purposes1,2 using recombinant viral vectors, which do not target transgenes to specific genomic sites3,4. The need for viral vectors has slowed down research and clinical use as their manufacturing and testing is lengthy and expensive. Genome editing brought the promise of specific and efficient insertion of large transgenes into target cells using homology-directed repair5,6. Here we developed a CRISPR-Cas9 genome-targeting system that does not require viral vectors, allowing rapid and efficient insertion of large DNA sequences (greater than one kilobase) at specific sites in the genomes of primary human T cells, while preserving cell viability and function. This permits individual or multiplexed modification of endogenous genes. First, we applied this strategy to correct a pathogenic IL2RA mutation in cells from patients with monogenic autoimmune disease, and demonstrate improved signalling function. Second, we replaced the endogenous T cell receptor (TCR) locus with a new TCR that redirected T cells to a cancer antigen. The resulting TCR-engineered T cells specifically recognized tumour antigens and mounted productive anti-tumour cell responses in vitro and in vivo. Together, these studies provide preclinical evidence that non-viral genome targeting can enable rapid and flexible experimental manipulation and therapeutic engineering of primary human immune cells.

Pancreatic Histopathology of Human Monogenic Diabetes Due to Causal Variants in KCNJ11, HNF1A, GATA6, and LMNA.

Context: Monogenic diabetes is thought to account for 2% of all diabetes cases, but most patients receive misdiagnoses of type 1 or type 2 diabetes. To date, little is known about the histopathological features of pancreata from patients with monogenic diabetes. Objective: Retrospective study of the JDRF Network for Pancreatic Organ Donors with Diabetes biorepository to identify possible cases of monogenic diabetes and to compare effects of genetic variants on pancreas histology. Methods: We selected cases of diabetes for genetic testing on the basis of criteria that included young age at diagnosis, low body mass index, negative autoantibody status, and/or detectable C-peptide level. Samples underwent next-generation-targeted sequencing of 140 diabetes/diabetes-related genes. Pancreas weight and histopathology were reviewed. Results: Forty-one of 140 cases of diabetes met the clinical inclusion criteria, with 38 DNA samples available. Genetic variants of probable clinical significance were found in four cases: one each in KCNJ11, HNF1A, GATA6, and LMNA. The KCNJ11 and HNF1A samples had significantly decreased pancreas weight and insulin mass similar to that of type 1 diabetes but had no insulitis. The GATA6 sample had severe pancreatic atrophy but with abundant ß cells and severe amyloidosis similar to type 2 diabetes. The LMNA sample had preserved pancreas weight and insulin mass but abnormal islet architecture and exocrine fatty infiltrates. Conclusions: Four cases of diabetes had putative causal variants in monogenic diabetes genes. This study provides further insight into the heterogeneous nature of monogenic diabetes cases that exhibited clinical and pathophysiological features that overlap with type 1/type 2 diabetes.

Preservation of Reduced Numbers of Insulin-Positive Cells in Sulfonylurea-Unresponsive KCNJ11-Related Diabetes.

Context: The most common genetic cause of permanent neonatal diabetes mellitus is activating mutations in KCNJ11, which can usually be treated using oral sulfonylureas (SUs) instead of insulin injections, although some mutations are SU unresponsive. In this work, we provide a report of the pancreatic islet endocrine cell composition and area in a patient with an SU-unresponsive KCNJ11 mutation (p.G334D), in comparison with age-matched controls. Case Description: Pancreatic autopsy tissue sections from a 2-year-old female child diagnosed with KCNJ11-related diabetes at 4 days of age and 13 age-matched controls were stained with insulin, glucagon, somatostatin, pancreatic polypeptide, and Ki67 antibodies to determine islet endocrine cell composition and area. ß-cell ultrastructure was assessed by electron microscopic (EM) analysis. The patient's pancreas (sampling from head to tail) revealed insulin-positive cells in all regions. The pancreatic ß-cell (insulin) area was significantly reduced compared with controls: 0.50% ± 0.04% versus 1.67% ± 0.20%, respectively (P < 0.00001). There were no significant differences in α-cell (glucagon) or δ-cell (somatostatin) area. EM analysis revealed secretory granules with a dense core typical of mature ß-cells as well as granules with a lighter core characteristic of immature granules. Conclusions: Our results suggest that mechanisms exist that allow preservation of ß-cells in the absence of insulin secretion. It remains to be determined to what extent this reduction in ß-cells may be reversible.

Low-dose hydrocortisone replacement is associated with improved arterial stiffness index and blood pressure dynamics in severely adrenocorticotrophin-deficient hypopituitary male patients.

OBJECTIVE: Increased cardiovascular and cerebrovascular morbidity and mortality in hypopituitary subjects may be linked to inappropriate glucocorticoid exposure; however, the pathophysiology remains unclear. We aimed to examine the effect of three commonly prescribed hydrocortisone (HC) regimens on vascular risk factors. DESIGN: An open crossover study randomising ten hypopituitary men with severe adrenocorticotrophic hormone deficiency to three HC dose regimens: dose A (20mg mane and 10mg tarde), dose B (10mg mane and 10mg tarde) and dose C (10mg mane and 5mg tarde). METHODS: Following 6 weeks on each regimen, participants underwent 24-h serum cortisol sampling, 24-h ambulatory blood pressure (BP) measurements, calculation of the Ambulatory Arterial Stiffness Index (AASI), oral glucose tolerance testing and fasting serum osteoprotegerin (OPG) sampling. RESULTS: There were no differences in 24-h BP between dose regimens and controls; however, low-dose HC replacement (dose C) was associated with the lowest AASI, indicating a less stiff arterial tree (P<0.05) compared with the other dose regimens. Loss of the physiologic nocturnal BP dip was more common in higher HC replacement regimens, although only significant for dose B compared with dose C (P=0.03). Twenty per cent of patients had abnormal glucose tolerance, but this was unrelated to dose regimen. OPG correlated strongly with 24-h BP in those on dose A only (r=0.65, P=0.04). CONCLUSION: Currently prescribed HC replacement doses do not result in significant differences in absolute BP levels or improvements in insulin sensitivity. However, lower HC doses may result in lower arterial stiffness and a more physiological nocturnal BP dip. Long-term studies are required to confirm these findings and evaluate their impact on vascular morbidity in this patient group.