The First Genome-Wide Association Study for Type 2 Diabetes in Youth: The Progress in Diabetes Genetics in Youth (ProDiGY) Consortium

The prevalence of type 2 diabetes in youth has increased substantially, yet the genetic underpinnings remain largely unexplored. To identify genetic variants predisposing to youth-onset type 2 diabetes, we formed ProDiGY, a multiethnic collaboration of three studies (TODAY, SEARCH, and T2D-GENES) with 3,006 youth case subjects with type 2 diabetes (mean age 15.1 ± 2.9 years) and 6,061 diabetes-free adult control subjects (mean age 54.2 ± 12.4 years). After stratifying by principal component–clustered ethnicity, we performed association analyses on ∼10 million imputed variants using a generalized linear mixed model incorporating a genetic relationship matrix to account for population structure and adjusting for sex. We identified seven genome-wide significant loci, including the novel locus rs10992863 in PHF2 (P = 3.2 × 10⁻⁸; odds ratio [OR] = 1.23). Known loci identified in our analysis include rs7903146 in TCF7L2 (P = 8.0 × 10⁻²⁰; OR 1.58), rs72982988 near MC4R (P = 4.4 × 10⁻¹⁴; OR 1.53), rs200893788 in CDC123 (P = 1.1 × 10⁻¹²; OR 1.32), rs2237892 in KCNQ1 (P = 4.8 × 10⁻¹¹; OR 1.59), rs937589119 in IGF2BP2 (P = 3.1 × 10⁻⁹; OR 1.34), and rs113748381 in SLC16A11 (P = 4.1 × 10⁻⁸; OR 1.04). Secondary analysis with 856 diabetes-free youth control subjects uncovered an additional locus in CPEB2 (P = 3.2 × 10⁻⁸; OR 2.1) and consistent direction of effect for diabetes risk. In conclusion, we identified both known and novel loci in the first genome-wide association study of youth-onset type 2 diabetes.     

Compliant Compression Reconstruction of the Proximal Femur Is Durable Despite Minimal Bone Formation in the Compression Segment

BackgroundCompliant compression fixation was developed to promote permanent bone-prosthesis osteointegration while preserving bone stock in patients needing endoprosthetic reconstructions. This has demonstrated durability in the distal femur, with reliable cortical hypertrophy adjacent to the implant. However, the extent of bone formation and prosthetic survivorship of proximal femoral replacements with compliant compression fixation has not been established.Questions/purposes(1) How much bone formation occurs across the compression segment in patients treated with a proximal femoral replacement implant using compliant compression fixation? (2) What were the Musculoskeletal Tumor Society (MSTS) scores at minimum 24-month follow-up of patients who received this reconstruction? (3) What is the implant survivorship free from implant removal or revision for any reason at final follow-up?MethodsFrom 2006 to 2018, we performed 213 proximal femoral replacements in patients with oncologic conditions of the proximal femur where the trochanters could not be preserved. Of these, 6% (12 of 213) were performed with an implant that used compliant compression fixation. We used this device in primary oncologic reconstructions in patients younger than 65 years of age without metastases who had nonirradiated bone with the requisite ≥ 2.5 mm of cortical thickness in the hope that it would provide more durable fixation and bone stock preservation than conventional reconstructions. All patients were followed for longer than 2 years except one who died in that interval. Median (range) follow-up was 6 years (2 to 10 years). Seven patients received diagnosis-specific chemotherapy in a consistent manner based on Children’s Oncology Group chemotherapy protocols. Using the NIH-developed ImageJ open-access software, we measured the area of bone under compression on 3-, 6-, 9-, 12-, 18-, and 24-month radiographs and the length of the traction bar potential-compression distance, reconciling independent measures from two investigators using the identical method as published for the distal femur with compression fixation. The duration of prosthesis retention was evaluated using a competing risk analysis for the 11 surviving patients.ResultsBone hypertrophy in the compression segment was scant. At the final analysis, cortical bone formation was a median (range) of 4 (-7 to 14) above baseline. The median (range) MSTS score was 27 (19 to 30). One implant failed after trauma, and the patient underwent revision of the implant.ConclusionDespite scant bone formation across the compression segment and drastically less formation than reported for distal femoral replacements, compliant compression fixation of the proximal femur demonstrated good survivorship in patients 65 years or younger with localized sarcoma and nonirradiated, adequate bone stock in this small, retrospective series. Patients achieved good functional outcomes at final follow-up. The potential benefit of this reconstruction method should be weighed against the initial period of limited weightbearing and the life expectancy of the patient.Level of EvidenceLevel IV, cohort study.     

Gain-of-Function Lrp5 Mutation Improves Bone Mass and Strength and Delays Hyperglycemia in a Mouse Model of Insulin-Deficient Diabetes

High fracture rate and high circulating levels of the Wnt inhibitor, sclerostin, have been reported in diabetic patients. We studied the effects of Wnt signaling activation on bone health in a mouse model of insulin-deficient diabetes. We introduced the sclerostin-resistant Lrp5^A214V mutation, associated with high bone mass, in mice carrying the Ins2^Akita mutation (Akita), which results in loss of beta cells, insulin deficiency, and diabetes in males. Akita mice accrue less trabecular bone mass with age relative to wild type (WT). Double heterozygous Lrp5^A214V/Akita mutants have high trabecular bone mass and cortical thickness relative to WT animals, as do Lrp5^A214V single mutants. Likewise, the Lrp5^A214V mutation prevents deterioration of biomechanical properties occurring in Akita mice. Notably, Lrp5^A214V/Akita mice develop fasting hyperglycemia and glucose intolerance with a delay relative to Akita mice (7 to 8 vs. 5 to 6 weeks, respectively), despite lack of insulin production in both groups by 6 weeks of age. Although insulin sensitivity is partially preserved in double heterozygous Lrp5^A214V/Akita relative to Akita mutants up to 30 weeks of age, insulin-dependent phosphorylated protein kinase B (pAKT) activation in vitro is not altered by the Lrp5^A214V mutation. Although white adipose tissue depots are equally reduced in both compound and Akita mice, the Lrp5^A214V mutation prevents brown adipose tissue whitening that occurs in Akita mice. Thus, hyperactivation of Lrp5-dependent signaling fully protects bone mass and strength in prolonged hyperglycemia and improves peripheral glucose metabolism in an insulin independent manner. Wnt signaling activation represents an ideal therapeutic approach for diabetic patients at high risk of fracture. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).     

Pretreatment Primary Tumor Stage is a Risk Factor for Recurrence in Patients with Esophageal Squamous Cell Carcinoma Who Achieve Pathological Complete Response After Neoadjuvant Chemoradiotherapy

Annals of Surgical Oncology - Although pathological complete response (pCR) after multimodal treatment for esophageal cancer is associated to the best prognosis, recurrence may occur in...     

Developmental dysplasia of the hip screening during the lockdown for COVID-19: experience from Northern Italy

PurposeDevelopmental dysplasia of the hip (DDH) ultrasound screening (USS), which is usually performed in Italy as an outpatient, was halted for an indefinite period in most centres during lockdown. The aim of this study was to analyze the effect of COVID-19 on DDH-USS, in two paediatric orthopaedic centres in one of the most critical areas of the western World.MethodsAn academic teaching hospital and paediatric trauma centre (T) and a University hospital and DDH referral centre (H), classified as national COVID-19 hubs, were involved. Graf’s method was applied in both centres. In T, paediatricians directly referred only patients with delayed DDH-USS or suspicious unstable hips; in H, paediatricians or parents could directly refer to the screening service.ResultsThe mean age of the 95 patients (190 hips) who were referred for DDH-USS in T, was 3.85 months (0.1 to 7.4); 175 were type I, nine were type IIa (+ and -), five type D and one type IV. In H, the screened patients in 2020 were only 78% of the same period in 2019. A total of 28 patients with 32 hips (8 IIb, 5 IIc, 8 D, 11 III) had late diagnosis at a mean age of 114 days (96 to 146). In the same period in 2019 only eight patients with 11 hips (8 IIb, 1 D, 1 III, 1 IV) at a mean age of 142 days (92 to 305) had late diagnosis.ConclusionDDH-USS was the only screening in newborns which halted during lockdown. Few centres, which still performed diagnosis and treatment, were overloaded causing a delay in DDH management.Level of evidenceIV.     

New anatomical reference systems for the bones of the foot and ankle complex: definitions and exploitation on clinical conditions

Medial tibial stress syndrome (MTSS) is one of the most common lower leg injuries in sporting populations. It accounts for between 6 and 16% of all running injuries, and up to 53% of lower leg injuries in military recruits. Various treatment modalities are available with varying degrees of success. In recalcitrant cases, surgery is often the only option. To evaluate whether ultrasound-guided injection of 15% dextrose for treatment of recalcitrant MTSS decreases pain and facilitates a return to desired activity levels for those who may otherwise be considering surgery or giving up the sport. The study design was a prospective consecutive case series involving eighteen patients: fifteen male and three female; (mean age = 31.2 years) with recalcitrant MTSS. They were referred from sports injury clinics across the UK, having failed all available conservative treatment. An ultrasound-guided sub-periosteal injection of 15% dextrose was administered by the same clinician (NP) along the length of the symptomatic area. Typically, 1 mL of solution was injected per cm of the symptomatic area. Pain was assessed using a 10-cm visual analog scale (VAS) at baseline, short-term, medium-term (mean 18 weeks), and long-term (mean 52 weeks) follow-up. Symptom resolution and return to activity were measured using a Likert scale at medium and long-term follow-up. Statistical analyses were performed using SPSS for Mac version 19.0.0 (IBM, New York, NY, US). The Shapiro-Wilk test was used to evaluate the normality of the distribution of data. Friedman’s non-parametric test was used to compare the within-patient treatment response over time. Post-hoc Wilcoxon signed-rank tests with Bonferroni corrections were performed to determine VAS average pain response to treatment over five paired periods. Patients reported a significant (p < 0.01) reduction in median VAS pain score at medium and long-term follow-up compared to baseline. Median improvement per patient was 4.5/10. Patients rated their condition as ‘much improved’ at medium-term follow-up and the median return to sports score was ‘returned to desired but not pre-injury level’ at medium-term and long-term follow-up. No adverse events were reported. Ultrasound-guided 15% dextrose prolotherapy injection has a significant medium-term effect on pain in MTSS. This benefit may be maintained long-term; however, more robust trials are required to validate these findings in the absence of controls. Clinicians should consider the use of ultrasound-guided injection of 15% dextrose as a viable treatment option to reduce pain and aid return to activity for patients with recalcitrant MTSS.     

Robotic transanal total mesorectal excision: Is the future now?

Total mesorectal excision (TME) is the standard surgical treatment for the curative radical resection of rectal cancers. Minimally invasive TME has been gaining ground favored by the continuous technological advancements. New procedures, such as transanal TME (TaTME), have been introduced to overcome some technical limitations, especially in low rectal tumors, obese patients, and/or narrow pelvis. The earliest TaTME reports showed promising results when compared with the conventional laparoscopic TME. However, recent publications raised concerns regarding the high rates of anastomotic leaks or local recurrences observed in national series. Robotic TaTME (R-TaTME) has been proposed as a novel technique incorporating the potential benefits of a perineal dissection together with precise control of the distal margins, and also offers all those advantages provided by the robotic technology in terms of improved precision and dexterity. Encouraging short-term results have been reported for R-TaTME, but further studies are needed to assess the real role of the new technique in the long-term oncological or functional outcomes. The present review aims to provide a general overview of R-TaTME by analyzing the body of the available literature, with a special focus on the potential benefits, harms, and future perspectives for this novel approach.     

Healthy by Association: The relationship between social participation and self-rated physical and psychological health

This paper investigates the relationship between social participation and subjective health. Using individual-level data from the British Household Panel Survey, we show that being an active member of a social or sport organisation increases self-rated physical and psychological health. For men, the benefits of social interaction work primarily via physical pathways, while women report a more psychosocial channel. We separate the main results by occupation and document some heterogeneity. Manual workers find more physical and psychological relief via social involvement, whereas non-manual workers are more likely to take relief from sport participation. Interestingly, as the number of associations in which the individual is active increases, the incremental increase in social benefits diminishes. Our findings point to the importance of promoting social and sport activities in health communication and policy making.