Regulatory T-cell dysfunction and cutaneous exposure to Staphylococcus aureus underlie eczema in DOCK8 deficiency.

BACKGROUND: Dedicator of cytokinesis 8 (DOCK8)-deficient patients have severe eczema, elevated IgE, and eosinophilia, features of atopic dermatitis (AD). OBJECTIVE: We sought to understand the mechanisms of eczema in DOCK8 deficiency. METHODS: Skin biopsy samples were characterized by histology, immunofluorescence microscopy, and gene expression. Skin barrier function was measured by transepidermal water loss. Allergic skin inflammation was elicited in mice by epicutaneous sensitization with ovalbumin (OVA) or cutaneous application of Staphylococcus aureus. RESULTS: Skin lesions of DOCK8-deficient patients exhibited type 2 inflammation, and the patients' skin was colonized by Saureus, as in AD. Unlike in AD, DOCK8-deficient patients had a reduced FOXP3:CD4 ratio in their skin lesions, and their skin barrier function was intrinsically intact. Dock8-/- mice exhibited reduced numbers of cutaneous T regulatory (Treg) cells and a normal skin barrier. Dock8-/- and mice with an inducible Dock8 deletion in Treg cells exhibited increased allergic skin inflammation after epicutaneous sensitization with OVA. DOCK8 was shown to be important for Treg cell stability at sites of allergic inflammation and for the generation, survival, and suppressive activity of inducible Treg cells. Adoptive transfer of wild-type, but not DOCK8-deficient, OVA-specific, inducible Treg cells suppressed allergic inflammation in OVA-sensitized skin of Dock8-/- mice. These mice developed severe allergic skin inflammation and elevated serum IgE levels after topical exposure to Saureus. Both were attenuated after adoptive transfer of WT but not DOCK8-deficient Treg cells. CONCLUSION: Treg cell dysfunction increases susceptibility to allergic skin inflammation in DOCK8 deficiency and synergizes with cutaneous exposure to Saureus to drive eczema in DOCK8 deficiency.

Offset Acetabular Liners: Safer Than Previously Thought.

High offset liners help to restore soft tissue tension after primary total hip arthroplasty (THA). However, prior research has reported increased rates of aseptic loosening when using offset components. The purpose of this study was to examine the postoperative complication and revision rates of neutral vs offset acetabular liners at our institution. Two hundred eight primary THAs in 206 patients performed between 2016 and 2018 using neutral or offset liners were reviewed. All patients had a minimum 2-year clinical follow-up (mean, 3.3 years; range, 2.0-5.7 years). Postoperative complications and revision surgeries were reviewed. All offset liners were 4 mm in thickness. Twelve (10.0%) complications occurred in the neutral liner group, and 13 (14.8%) complications occurred in the offset liner group. Two cases of aseptic loosening occurred in the neutral liner group, with no cases reported in the offset liner group. Nine cases (7.5%) in the neutral group required revision surgery, whereas 3 cases in the offset group required revision surgery. Chi-square analysis found no difference between the groups in the rate of postoperative complications, χ2 (1, N=208)=1.09 (P>.05), or the rate of revision, χ2 (1, N=208)=1.56 (P>.05). We found no significant differences between the neutral and offset groups regarding the rates of postoperative complications, aseptic loosening, or revision surgery. Our findings suggest that contemporary high offset liners, up to 4 mm, are safe and effective when attempting to restore native hip mechanics after THA. [Orthopedics. 2023;46(5):e298-e302.].

Clinical, immunological, molecular and therapeutic findings in monogenic immune dysregulation diseases: Middle East and North Africa registry.

Monogenic immune dysregulation diseases (MIDD) are caused by defective immunotolerance. This study was designed to increase knowledge on the prevalence and spectrum of MIDDs, genetic patterns, and outcomes in Middle East and North Africa (MENA). MIDD patients from 11 MENA countries (Iran, Turkey, Kuwait, Oman, Algeria, Egypt, United Arab Emirates, Tunisia, Jordan, Qatar, and Azerbaijan) were retrospectively evaluated. 343 MIDD patients (58% males and 42% female) at a median (IQR) age of 101 (42-192) months were enrolled. The most common defective genes were LRBA (23.9%), LYST (8.2%), and RAB27A (7.9%). The most prevalent initial and overall manifestations were infections (32.2% and 75.1%), autoimmunity (18.6% and 41%), and organomegaly (13.3% and 53.8%), respectively. Treatments included immunoglobulin replacement therapy (53%), hematopoietic stem cell transplantation (HSCT) (14.3%), immunosuppressives (36.7%), and surgery (3.5%). Twenty-nine (59.2%) patients survived HSCT. Along with infectious complications, autoimmunity and organomegaly may be the initial or predominant manifestations of MIDD.

Outcome of autoimmune cytopenia after hematopoietic cell transplantation in primary immunodeficiency.

BACKGROUND: Post hematopoietic cell transplantation (HCT) autoimmune cytopenia (AIC) is a potentially life-threatening complication, but studies focusing on large cohorts of patients transplanted for primary immunodeficiency are lacking. OBJECTIVES: This study sought to determine the incidence, risk factors, and outcomes of post-HCT AIC and B-lymphocyte function following rituximab. METHODS: We retrospectively studied 502 children with primary immunodeficiency who were transplanted at our center between 1987 and 2018. RESULTS: Thirty-six patients (9%) developed post-HCT AIC, with a median onset of 6.5 months post-HCT. On univariate analysis, pre-HCT AIC, mismatched donor, alemtuzumab, anti-thymocyte antiglobulin, and acute and chronic graft versus host disease were significantly associated with post-HCT AIC. After multivariate analysis, alemtuzumab (subdistribution hazard ratio, 9.0; 95% CI, 1.50-54.0; P = .02) was independently associated with post-HCT AIC. Corticosteroid and high-dose intravenous immunoglobulin achieved remission in 50% (n = 18), additional rituximab led to remission in 25% (n = 9), and the remaining 25% were treated with a combination of various modalities including sirolimus (n = 5), bortezomib (n = 3), mycophenolate mofetil (n = 2), splenectomy (n = 2), and second HCT (n = 3). The mortality of post-HCT AIC reduced from 25% (4 of 16) prior to 2011 to 5% (1 of 20) after 2011. The median follow-up of 5.8 years (range, 0.4 to 29.1 years) showed that 26 of 30 survivors (87%) were in complete remission, and 4 were in remission with ongoing sirolimus and low-dose steroids. Of the 17 who received rituximab, 7 had B-lymphocyte recovery, 5 had persistent low B-lymphocyte count and remained on intravenous immunoglobulin replacement, 2 had second HCT, and 3 died. CONCLUSIONS: The frequency of post HCT AIC in our cohort was 9%, and the most significant risk factors for its occurrence were the presence of graft versus host disease and the use of alemtuzumab.

Genotype and functional correlates of disease phenotype in deficiency of adenosine deaminase 2 (DADA2).

BACKGROUND: Deficiency of adenosine deaminase 2 (DADA2) is a syndrome with pleiotropic manifestations including vasculitis and hematologic compromise. A systematic definition of the relationship between adenosine deaminase 2 (ADA2) mutations and clinical phenotype remains unavailable. OBJECTIVE: We sought to test whether the impact of ADA2 mutations on enzyme function correlates with clinical presentation. METHODS: Patients with DADA2 with severe hematologic manifestations were compared with vasculitis-predominant patients. Enzymatic activity was assessed using expression constructs reflecting all 53 missense, nonsense, insertion, and deletion genotypes from 152 patients across the DADA2 spectrum. RESULTS: We identified patients with DADA2 presenting with pure red cell aplasia (n = 5) or bone marrow failure (BMF, n = 10) syndrome. Most patients did not exhibit features of vasculitis. Recurrent infection, hepatosplenomegaly, and gingivitis were common in patients with BMF, of whom half died from infection. Unlike patients with DADA2 with vasculitis, patients with pure red cell aplasia and BMF proved largely refractory to TNF inhibitors. ADA2 variants associated with vasculitis predominantly reflected missense mutations with at least 3% residual enzymatic activity. In contrast, pure red cell aplasia and BMF were associated with missense mutations with minimal residual enzyme activity, nonsense variants, and insertions/deletions resulting in complete loss of function. CONCLUSIONS: Functional interrogation of ADA2 mutations reveals an association of subtotal function loss with vasculitis, typically responsive to TNF blockade, whereas more extensive loss is observed in hematologic disease, which may be refractory to treatment. These findings establish a genotype-phenotype spectrum in DADA2.

Order of Total Hip or Total Knee Arthroplasty Does Not Affect Length of Stay or Discharge Disposition in Patients With Coexisting Hip and Knee Arthritis.

Primary total joint arthroplasty (TJA) of the hip and knee are effective procedures for improving pain and function in patients with arthritis. This study examined whether order of surgery (TKA or THA first) affects length of stay (LOS) and discharge disposition among patients with coexisting knee and hip arthritis. A total joint arthroplasty database review was performed to collect all available data for arthroplasties performed at 2 campuses of a single institution between July 2013 and April 2017. Inclusion criteria were patients who underwent both primary THA and TKA within 18 months and were age 18 years or older. Patients were divided into 2 groups based on whether THA or TKA was performed first. For all procedures, the following data were collected: age, body mass index (BMI), time between cases, LOS, discharge disposition, and the number of 90-day adverse postoperative events. Adverse 90-day events included deep infection, fracture, hardware failure, urinary tract infection, other return to the operating room, emergency department visit, readmission, or death. A total of 211 patients underwent both THA and TKA within 18 months; 124 patients underwent THA first and 87 underwent TKA first. There was no difference in age or BMI between the 2 groups. There was a significantly longer time between the first and second arthroplasty in patients with TKA first by a mean of 2 months (P=.001). There was no difference in 90-day adverse postoperative events following THA whether done first or second (P=.371), and no difference in 90-day events following TKA whether done first or second (P=.524). There was no difference in discharge disposition (P=.833 and P=.395) or LOS (P=.695 and P=.473) between groups for the first or second procedure, respectively. In a patient with coexisting hip and knee arthritis, the current results do not support recommending THA or TKA first based on cost related to LOS and discharge disposition. [Orthopedics. 2019; 42(6):e528-e531.].

Does Taper Design Affect Taper Fretting Corrosion in Ceramic-on-Polyethylene Total Hip Arthroplasty? A Retrieval Analysis.

BACKGROUND: Ceramic-on-polyethylene (CoP) implants have exhibited lower fretting and corrosion scores than metal-on-polyethylene implants. This study aims at investigating the effect of taper design on taper corrosion and fretting in modular CoP total hip arthroplasty (THA) systems. METHODS: Under an institutional review board--approved protocol, a query of an implant retrieval library from 2002 to 2017 identified 120 retrieved CoP THA systems with zirconia toughened alumina femoral heads. Femoral stem trunnions were visually evaluated and graded for fretting, corrosion, and damage at the taper interface. Medical records were reviewed for patient demographics and implant characteristics. Data were statistically analyzed using Spearman correlation and rank-sum tests with a Dunn's post hoc test, with a significance level of α = 0.05. RESULTS: Four different taper designs were evaluated: 11/13 (n = 18), 12/14 (n = 53), 16/18 (n = 21), and V40 (n = 28). There were no statistically significant demographic differences between taper groups for duration of implantation, laterality, patient age, and patient sex, but patients with 16/18 tapers had a higher body mass index than V40 tapers (P = .012). Duration of implantation had a weak positive correlation with both trunnion fretting (ρ = 0.224, P = .016) and corrosion (ρ = 0.253, P = .006). Summed fretting and corrosion scores were significantly greater on the V40 and 16/18 tapers compared with the 12/14 tapers (all P ≤ .001). CONCLUSION: Taper fretting and corrosion were observed in CoP THA implants and were greatest with V40 and 16/18 tapers and lowest with 12/14 tapers. Differences in taper design characteristics may lead to greater micromotion at the taper-head interface, leading to increased fretting and corrosion.

Intramuscular hemangioma after total hip arthroplasty: an iatrogenic etiology.

Soft-tissue hemangioma is a common benign tumor that can develop cutaneously, subcutaneously, or intramuscularly. Hemangioma formation within a muscular compartment is most often developmental in etiology; however, some cases are known to occur after blunt trauma to the soft tissues. To our knowledge, no cases of hemangioma formation after joint arthroplasty have been reported. We present a case of intramuscular hemangioma development within the hip abductor musculature after total hip arthroplasty via an anterolateral approach. Aside from developing congenitally or posttraumatically, hemangiomas may form after surgical dissection and must be considered as a source of anomalous swelling after surgery.

Multidrug-Resistant Organisms in the Setting of Periprosthetic Joint Infection-Diagnosis, Prevention, and Treatment.

BACKGROUND: Periprosthetic joint infection (PJI) is a rare yet challenging problem in total hip and knee arthroplasties. The management of PJI remains difficult primarily due to the evolution of resistance by the infecting organisms. METHODS: This review profiles acquired mechanisms of bacterial resistance and summarizes established and emerging techniques in PJI diagnosis, prevention, and treatment. RESULTS: New techniques in PJI diagnosis and prevention continue to be explored. Antibiotics combined with 1 or 2-stage revision are associated with the higher success rates and remain the mainstay of treatment. CONCLUSION: With higher prevalence of antibiotic-resistant organisms, novel antibiotic implant and wound care materials, improved methods for organism identification, and well-defined organism-specific treatment algorithms are needed to optimize outcomes of PJI.

Four Weeks in a Single-Leg Weight-Bearing Hip Spica Cast is Sufficient Treatment for Isolated Femoral Shaft Fractures in Children Aged 1 to 3 Years.

BACKGROUND: Hip spica casting regimens for the treatment of femoral shaft fractures in a pediatric population aged 1 to 3 years vary. Patient charts were reviewed to determine if there are any clinical differences between 3 and 4 weeks in an ambulatory single-leg hip spica (SLHS) cast versus 6 to 8 weeks in a standard double-leg, non-weight-bearing hip spica cast. METHODS: The medical records of 109 patients with femoral shaft fractures treated with a hip spica casting from January 1, 2008 to December 31, 2011 were examined. After exclusions, 94 patients were eligible for inclusion in the study. Patient records were assessed, noting age, weight, type of cast, time in cast, and complications. All casts were applied by senior pediatric orthopaedic surgeons at a single institution. RESULTS: Two groups were evaluated: 59 patients in the SLHS group and 35 in the double-leg hip spica group. The 2 groups were demographically similar with an average age of 2 years, 70.2% of patients were male, 45.7% were black, and 35.1% were white. The average time to cast removal was 4.1 weeks for the single-leg group and 5.3 weeks for the double-leg group (P<0.001). Both groups had similar low rates of loss of reduction. The double-leg group had a significantly higher incidence of clinically significant limb-length discrepancy (7/35, 20%), compared with the single-leg group (1/59, 1.7%, P=0.004). In addition, the double-leg group also had more skin problems (11/35, 31.4%) compared with the single-leg group (6/59, 10.2%, P=0.013). Seventeen patients in the single-leg group were documented as walking in the cast as compared with no patients in the double-leg group (P<0.001). CONCLUSIONS: Patients treated with a single-leg spica cast for 4 weeks had fewer complications than patients treated in a traditional double-leg cast. Femoral shaft fractures in patients less than 4 years old can be treated in a weight-bearing SLHS casts for approximately 4 weeks with fewer alignment and skin complications. LEVEL OF EVIDENCE: Level III-clinical retrospective comparative study.