Specific human leucocyte antigen-DQ risk epitope mismatches are associated with chronic lung allograft dysfunction after lung transplantation.

A high-risk epitope mismatch (REM) (found in DQA1∗05 + DQB1∗02/DQB1∗03:01) is associated with de novo donor specific antibodies after lung transplantation (LTx). Chronic lung allograft dysfunction (CLAD) remains a barrier to LTx survival. This study aimed to measure the association between DQ REM and the risk of CLAD and death after LTx. A retrospective analysis of LTx recipients at a single center was conducted between January 2014 and April 2019. Molecular typing at human leucocyte antigen-DQA/DQB identified DQ REM. Multivariable competing risk and Cox regression models were used to measure the association between DQ REM, time-to-CLAD, and time-to-death. DQ REM was detected in 96/268 (35.8%), and DQ REM de novo donor specific antibodies were detected in 34/96 (35.4%). CLAD occurred in 78 (29.1%), and 98 (36.6%) recipients died during follow-up. When analyzed as a baseline predictor, DQ REM status was associated with CLAD (subdistribution hazard ratio (SHR), 2.19; 95% confidence interval [CI], 1.40-3.43; P = .001). After adjustment for time-dependent variables, DQ REM dn-DSA (SHR, 2.43; 95% CI, 1.10-5.38; P = .029) and A-grade rejection score (SHR, 1.22; 95% CI, 1.11-1.35; P = <.001), DQ REM status was not independently associated with CLAD. DQ REM was not associated with death (hazard ratio, 1.18; 95% CI, 0.72-1.93; P = .51). Classification of DQ REM may identify patients at risk of poor outcomes and should be incorporated into clinical decision-making.

The Introduction of cPRA and Its Impact on Access to Deceased Donor Kidney Transplantation for Highly Sensitized Patients in Australia.

BACKGROUND: In March 2016, Australia's deceased donor kidney allocation program introduced calculated panel reactive antibody (cPRA) based on antibody exclusions using multiplex assays to define sensitization for waitlisted candidates. We aimed to assess the impact of this change and review access to transplantation for highly sensitized patients under the current allocation rules. METHODS: Registry data were used to reconstruct changes in panel reactive antibody (PRA)/cPRA for all patients active on the waiting list between 2013 and 2018. A multilevel, mixed-effects negative binomial regression model was used to determine the association between sensitization and transplantation rate in the cPRA era. RESULTS: Following the introduction of cPRA, there was an increase in the percentage of the waiting list classified as highly sensitized (PRA/cPRA ≥80%) from 7.2% to 27.8% and very highly sensitized (PRA/cPRA ≥99%) from 2.7% to 15.3%. Any degree of sensitization was associated with a decreased rate of transplantation with a marked reduction for those with cPRA 95%-98% (adjusted incidence rate ratio, 0.36 [95% confidence interval, 0.28-0.47], P < 0.001) and cPRA ≥99% (adjusted incidence rate ratio, 0.09 [95% confidence interval, 0.07-0.12], P < 0.001). CONCLUSIONS: The proportion of the waiting list classified as highly sensitized increased substantially following the introduction of cPRA, and despite current prioritization, very highly sensitized patients have markedly reduced access to deceased donor transplantation.

Exploring Physical Therapist Adherence to Clinical Guidelines When Treating Patients With Knee Osteoarthritis in Australia: A Mixed Methods Study.

OBJECTIVE: The authors aimed to understand how physical therapists used practice guidelines to manage patients with knee osteoarthritis (OA) in Australia. METHODS: This study used a concurrent triangulation mixed-method approach to explore how physical therapists applied clinical guidelines when managing patients with knee OA in an outpatient setting via completion of a semi-structured interview. Interviews were thematically analyzed by 2 investigators using an inductive approach. Themes were then triangulated to the results of an audit that evaluated the level of adherence to respective areas in the clinical guidelines among physical therapists at the participating site. RESULTS: One main theme and 3 subthemes were identified from 18 participants: (1) physical therapists were most confident in applying guidelines to improving range of movement and strength; (2) lack of knowledge in prescription of aerobic exercise, weight, and pain management; (3) pain is a bigger barrier in areas where knowledge is lacking; and (4) lack of clarity around the scope of practice. Themes converged with the reported level of adherence to guidelines. CONCLUSIONS: Physical therapists commonly include range of movement and muscle strength exercises when managing people with knee OA. However, they were less confident in prescribing aerobic exercise and recommending weight and pain management strategies. IMPACT: Apart from the need to upskill physical therapists in the aforementioned areas of clinical practice, the role of a physical therapist in the management of people with knee OA requires further clarification.

Rapid reduction of high-level pre-formed donor-specific antibodies after simultaneous liver-kidney transplantation: a report of two cases.

BACKGROUND: Kidney transplantation performed in the presence of high-titre donor-specific antibodies (DSA) may result in hyper-acute or accelerated antibody-mediated rejection and rapid allograft loss. Previous studies have shown that this risk may be mitigated with simultaneous liver-kidney transplantation (SLKT); however, the mechanisms are not well defined. Here we report the evolution of pre-formed, high-level DSAs in two highly sensitised SLKT recipients peri-operatively and describe a profound sustained depletion of all DSAs from the time of liver anastomosis with no extra desensitisation therapy required. CASE PRESENTATION: Two patients underwent SLKT and received our centre's standard renal transplant immunosuppression with basiliximab and methylprednisolone for induction therapy and prednisolone, mycophenolate and tacrolimus for maintenance therapy. HLA antibody samples were collected pre-operatively, and immediately post-liver and post-kidney revascularisation, and then regularly in the post-transplant period. Complement Dependant Cytotoxicity (CDC) crossmatches were also performed. Both patients were highly sensitised with a PRA over 97%. One patient had a positive B- and T-cell crossmatch pre-transplant. These positive CDC crossmatches became negative and the level of pre-formed DSAs reduced profoundly and rapidly, within 3 h post-liver revascularisation. The reduction in pre-formed DSAs, regardless of subclass, was seen immediately post-liver revascularisation, before implantation of the renal allografts. No significant reduction in non-donor specific HLA-antibodies was observed. Both patients maintained good graft function with no rejection on kidney allograft protocol biopsies performed at 10-weeks post-transplant. CONCLUSIONS: These cases support the protective immunoregulatory role of the liver in the setting of SLKT, with no extra desensitisation treatment given pre-operatively for these highly sensitised patients.

Development and outcomes of de novo donor-specific antibodies in low, moderate, and high immunological risk kidney transplant recipients.

De novo donor-specific antibodies (dnDSA) play an important role in antibody-mediated rejection (ABMR) and graft failure, yet their development in kidney transplant recipients (KTx) of higher immunological risk has not been characterized. We prospectively determined the incidence of dnDSA at 3 and 12 months posttransplant and assessed their associations with outcomes in recipients stratified by low, moderate, and high immunological risk. Adult KTx were screened for DSA pretransplant, months 3 and 12 posttransplant, and when clinically indicated. Outcomes included incidence of dnDSA, death-censored graft survival (DCGS), and ABMR. Of 371 recipients, 154 (42%) were transplanted across a pretransplant DSA that became undetectable by 12 months posttransplant in 78% of cases. dnDSA were detected in 16% (95% confidence interval [CI]: 12-20%) by 3 months and 23% (95% CI: 18-29%) by 12 months posttransplant. Incidence at 12 months was higher in the moderate (30%) and high-risk groups (29%) compared to the low-risk group (16%). dnDSA were associated with an increased risk of ABMR (hazard ratio [HR] 2.2; 95% CI: 1.1-4.4; P = .04) but were not an independent risk factor for DCGS. In conclusion, dnDSA were more frequent in transplant recipients of higher immune risk and associated with an increased risk of ABMR.

A Comparison of the Effect of One, Three, or Six Weeks of Immobilization on Function and Pain After Open Reduction and Internal Fixation of Distal Radial Fractures in Adults: A Randomized Controlled Trial.

BACKGROUND: The optimum period of immobilization following open reduction and internal fixation (ORIF) of distal radial fractures has not been established. METHODS: One hundred and thirty-three adults with a distal radial fracture treated with ORIF (using a volar locked plate) were randomly allocated, with stratification according to age, to 1, 3, or 6 weeks of postoperative immobilization in a parallel-design, assessor-blinded, randomized controlled trial (RCT). After cast removal, a standardized education and exercise program was followed for 6 weeks. Primary outcomes were function (according to the Patient-Rated Wrist Evaluation [PRWE]), worst (visual analog scale [VAS]-W) and usual (VAS-U) pain in the past week, and active wrist extension and forearm supination range of motion. All measures were recorded at 6, 12, and 26 weeks following surgery. Secondary outcomes were wrist flexion, radial deviation, ulnar deviation, and forearm pronation active range of motion; function (Disabilities of the Arm, Shoulder and Hand [DASH]); grip strength; postoperative adverse events; return to work and/or usual daily activities; and compliance with the home exercise program. RESULTS: More than 90% of the participants received treatment as allocated, and 87% completed the 6-month follow-up. At 6 weeks, both the 1-week and 3-week groups had significantly better PRWE scores, wrist extension, and flexion active range of motion than the 6-week group. However, no treatment group was superior to another with respect to primary or secondary outcomes at 12 weeks or 6 months following surgery. Analyses considering only the main effect of the intervention group indicated a preference for the 3-week group, which performed significantly better than the 6-week group with respect to the PRWE, pain (VAS-W and VAS-U), wrist flexion, ulnar deviation, forearm pronation active range of motion, and DASH score. CONCLUSIONS: For patient function, range of motion, and pain, this investigation demonstrated that immobilization periods of 1 and 3 weeks produced superior short-term outcomes compared with those after 6 weeks of immobilization. These differences were not evident at 3 and 6 months following surgery, with the immobilization period having no significant effect on long-term function, range of motion, or pain. There were no significant differences in adverse events associated with shorter immobilization periods. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

The impact of wrist fracture, surgical repair and immobilization on patients: a qualitative study.

OBJECTIVE: To investigate patients' experience following wrist fracture, surgical repair and immobilization. DESIGN: A qualitative investigation involving individual participant interviews. SETTING: A metropolitan trauma service. SUBJECTS: In all, 31 participants were consecutively recruited from three groups within a randomized controlled trial comparing immobilization for one ( n = 11), three ( n = 10) or six weeks ( n = 10) following surgical treatment for wrist fracture. INTERVENTION: Individual interviews were conducted within three months of cast removal. Questions prompted discussion of the experience of fracture, surgery and immobilization. Interviews were audio-recorded, transcribed verbatim. At least two independent researchers performed coding and theming following principles of thematic analysis. RESULTS: Two themes were identified: (1) impact of the injury varies widely and (2) health care consumers want trustworthy dialogue. Participant reports indicated that recovery from wrist fracture, surgery and immobilization is challenging with significant changes to social role and increased dependence. For many, lack of empathy from health professionals and limited acknowledgement of the personal impact of injury led to dissatisfaction. Health professionals did not consistently tailor communication or adopt strategies to address specific needs for pain management, education and support requirements. There was no evidence that processes were implemented to enhance participant recall and comprehension. Most participants experienced their cast as a barrier to function. However, within the group of participants immobilized for one week, a number felt the cast was removed too soon. CONCLUSION: Participant reports indicate that recovery from surgically repaired wrist fracture is challenging. Opportunities exist to refine care in pain management, education and active engagement of patients in their care.

The Association Between Broad Antigen HLA Mismatches, Eplet HLA Mismatches and Acute Rejection After Kidney Transplantation.

BACKGROUND: Epitope matching, which evaluates mismatched amino acids within antigen-antibody interaction sites (eplets), may better predict acute rejection than broad antigen matching alone. We aimed to determine the association between eplet mismatches and acute rejection in kidney transplant recipients. METHODS: The association between eplet mismatches, broad antigen mismatches and acute rejection was assessed using adjusted Cox proportional hazard regression. Model discrimination for acute rejection was evaluated using the area under receiver operating characteristic curves. RESULTS: Of the 3,499 kidney transplant recipients from 2006 to 2011, the average (SD) number of broad antigen and eplet mismatches were 3.4 (1.7) and 22.8 (12.2), respectively. Compared with 0 to 2 eplet mismatches, the adjusted hazard ratio (HR) for acute rejection among those with 20 or greater eplet mismatches was 2.16 (95% confidence interval [CI], 1.33-3.52; P = 0.001). The adjusted area under the curve for broad antigen mismatches was 0.58 (95% CI, 0.56-0.61), similar to that for eplet mismatches (HR, 0.59; 95% CI, 0.56-0.61; P = 0.365). In recipients who were considered as low immunological risk (0-2 broad antigen HLA-ABDR mismatch), those with 20 or greater eplet mismatches experienced an increased risk of rejection compared to those with less than 20 mismatches (adjusted HR, 1.85; 95% CI, 1.11-3.08; P = 0.019). CONCLUSIONS: Increasing number of eplet mismatches is associated with acute rejection in kidney transplant recipients. Consideration of eplet HLA mismatches may improve risk stratification for acute rejection in a selected group of kidney transplant candidates.

Reliability of radiographic measurements for acute distal radius fractures.

BACKGROUND: The management of distal radial fractures is guided by the interpretation of radiographic findings. The aim of this investigation was to determine the intra- and inter-observer reliability of eight traditionally reported anatomic radiographic parameters in adults with an acute distal radius fracture. METHODS: Five observers participated. All were routinely involved in making treatment decisions based on distal radius fracture radiographs. Observers performed independent repeated measurements on 30 radiographs for eight anatomical parameters: dorsal shift (mm), intra-articular gap (mm), intra-articular step (mm), palmar tilt (degrees), radial angle (degrees), radial height (mm), radial shift (mm), ulnar variance (mm). Intraclass correlation coefficients (ICCs) and the magnitude of retest errors were calculated. RESULTS: Measurement reliability was summarised as high (ICC > 0.80), moderate (0.60-0.80) or low (<0.60). Intra-observer reliability was high for dorsal shift and palmar tilt; moderate for radial angle, radial height, ulnar variance and radial shift; and low for intra-articular gap and step. Inter-observer reliability was high for palmar tilt; moderate for dorsal shift, ulnar variance, radial angle and radial height; and low for radial shift, intra-articular gap and step. Error magnitude (95 % confidence interval) was within 1-2 mm for intra-articular gap and step, 2-4 mm for ulnar variance, 4-6 mm for radial shift, dorsal shift and radial height, and 6-8° for radial angle and palmar tilt. CONCLUSIONS: Based on previous reports of critical values for palmar tilt, ulnar variance and radial angle, error margins appear small enough for measurements to be useful in guiding treatment decisions. Our findings indicate that clinicians cannot reliably measure values ≤1 mm for intra-articular gap and step when interpreting radiographic parameters using the standardised methods investigated in this study. As a guide for treatment selection, palmar tilt, ulnar variance and radial angle measurements may be useful, but intra-articular gap and step appear unreliable.

HLA-DQ Mismatches and Rejection in Kidney Transplant Recipients.

BACKGROUND AND OBJECTIVES: The current allocation algorithm for deceased donor kidney transplantation takes into consideration HLA mismatches at the ABDR loci but not HLA mismatches at other loci, including HLA-DQ. However, the independent effects of incompatibilities for the closely linked HLA-DQ antigens in the context of HLA-DR antigen matched and mismatched allografts are uncertain. We aimed to determine the effect of HLA-DQ mismatches on renal allograft outcomes. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Using data from the Australia and New Zealand Dialysis and Transplant Registry, we examined the association between HLA-DQ mismatches and acute rejections in primary live and deceased donor kidney transplant recipients between 2004 and 2012 using adjusted Cox regression models. RESULTS: Of the 788 recipients followed for a median of 2.8 years (resulting in 2891 person-years), 321 (40.7%) and 467 (59.3%) received zero and one or two HLA-DQ mismatched kidneys, respectively. Compared with recipients who have received zero HLA-DQ mismatched kidneys, those who have received one or two HLA-DQ mismatched kidneys experienced greater numbers of any rejection (50 of 321 versus 117 of 467; P<0.01), late rejections (occurring >6 months post-transplant; 8 of 321 versus 27 of 467; P=0.03), and antibody-mediated rejections (AMRs; 12 of 321 versus 38 of 467; P=0.01). Compared with recipients of zero HLA-DQ mismatched kidneys, the adjusted hazard ratios for any and late rejections in recipients who had received one or two HLA-DQ mismatched kidneys were 1.54 (95% confidence interval [95% CI], 1.08 to 2.19) and 2.85 (95% CI, 1.05 to 7.75), respectively. HLA-DR was an effect modifier between HLA-DQ mismatches and AMR (P value for interaction =0.02), such that the association between HLA-DQ mismatches and AMR was statistically significant in those who have received one or two HLA-DR mismatched kidneys, with adjusted hazard ratio of 2.50 (95% CI, 1.05 to 5.94). CONCLUSIONS: HLA-DQ mismatches are associated with acute rejection, independent of HLA-ABDR mismatches and initial immunosuppression. Clinicians should be aware of the potential importance of HLA-DQ matching in the assessment of immunologic risk in kidney transplant recipients.

High transplant rates of highly sensitized recipients with virtual crossmatching in kidney paired donation.

BACKGROUND: In kidney paired donation (KPD), flexibility in the allocation of incompatible pairs is required if a critical mass of pairs to efficiently find matches cannot be reached. METHODS: In the Australian KPD program, virtual crossmatch is used for the allocation of suitable donors to registered recipients. Matching is based on acceptable mismatches, and donors are excluded from matching to recipients with donor-specific antibodies (DSAs) greater than 2000 mean fluorescence intensity (MFI). Match and transplant rates in the first year of the program were reviewed with respect to recipient and donor characteristics, including blood group distribution, level of recipient's sensitization, and postallocation crossmatches. RESULTS: Four quarterly match runs were performed, which included 53 pairs and 2 altruistic donors. Human leukocyte antigen incompatibility accounted for 90% of the listed pairs. In the second run, the DSA threshold was increased to greater than 8000 MFI, because no matches were found with standard allocation. Optional ABO-incompatible matching was introduced from run 3. Matches were identified in 37 (70%) patients, of whom 92% had a negative crossmatch with their matched donor. Crossmatch positive results were found only in recipients with DSAs greater than 2000 MFI in the second run. In 4 cases immunological reasons and in 4 cases other reasons resulted in breakdown of chains and 17 patients not progressing to transplantation. Eventually, 20 (38%) patients received a KPD transplant, and 35% of these had a calculated panel-reactive antibody greater than 90%. CONCLUSIONS: KPD using virtual crossmatch is a valid and effective solution for patients with immunologically incompatible donors even in the context of highly sensitized recipients.

Association of Fc gamma receptor IIA polymorphisms with acute renal-allograft rejection.

Acute rejection is a leading cause of early renal-allograft failure. The human Fc gamma receptor IIA (FcgammaRIIA) forms an essential link between the humoral branch and the effector cells of the immune system. In this study, we examined FcgammaRIIA genotypes in renal-allograft recipients (rejectors) with acute graft rejection and in a number of control groups to investigate a possible association between FcgammaRIIA polymorphism and acute renal-allograft rejection. The distribution of the genotypes in the study patient group differed from the control groups. The frequency of homozygosity for FcagammaRIIA-R/R131 in the rejectors was significantly higher than that in the recipients (nonrejectors) with well-functioning renal allografts and in blood donors (P< 0.05). In comparison with the control groups, the rejectors displayed a higher R131 allele frequency (P< 0.05) and a lower H131 allele frequency (P< 0.05). These results reveal a significant association between FcgammaRIIA-R/R131 and acute renal-graft rejection, and it is likely that FcgammaRIIA polymorphisms could be useful markers for potential risk of rejection.