Kidney transplant outcomes in patients with antibodies to human neutrophil antigen 3a.

BACKGROUND: Antibody mediated rejection (ABMR) of kidney transplants has been shown to occur in the absence of a known donor specific antibody to human leucocyte antigen (HLA). Antibodies to the human neutrophil antigen (HNA) system have been detected in kidney transplant recipients and linked to ABMR in the absence of an HLA donor specific antibody (DSA), but there remains limited literature regarding this. METHODS: Case series analysis was carried out examining three cases of HNA-3a antibody positive flow cytometry cross match (FC-XM) from two transplant centres in Scotland. RESULTS: All patients included were female and had been sensitised as a result of pregnancy. One live donor recipient with HNA-3a antibodies identified prior to transplant received ATG induction and has had a good outcome. The remaining two patients received deceased donor transplants. HNA-3a antibodies were indicated following a retrospective flow cytometry crossmatch. Both patients received Basiliximab induction and both have experienced ABMR requiring supplementary immunosuppression. CONCLUSIONS: The predicted rate of HNA-3a antibodies amongst patients awaiting kidney transplant in the UK is <1%. However, with increasing evidence to support a role for HNA-3a antibodies in the development of ABMR there may be value in screening at risk groups to allow for augmented immunosuppression to be considered at the time of kidney transplant.

Defining postoperative C5 palsy and recovery: a systematic review.

OBJECTIVE: Postoperative C5 palsy (C5P) is a well-recognized and often-delayed complication of cervical spine surgery. Most patients recover within 6 months of onset, but the prognosis of severe cases is poor. The clinical significance and natural history of mild versus severe C5P appear to differ substantially, but palsy severity and recovery have been poorly characterized in the literature. METHODS: Owing to the varying prognoses and expanding treatment options such as nerve transfer surgery to reconstruct the C5 myotome, this systematic review attempted to describe how C5P severity is classified and how C5P and its recovery are defined, with the aim of proposing a postoperative C5P scale to support clinical decision-making. PubMed was searched for articles in English published since 2000 that offer a clear definition of postoperative C5P or its recovery. Only articles reporting exclusively on C5 palsy for patients undergoing surgery for degenerative disease were included. A single reviewer screened titles and abstracts and reviewed the full text of relevant articles, with consultation as needed from a second reviewer. Data collected included postoperative C5P definitions, classification of C5P severity, and definition and/or classification of C5P recovery. Qualitative analysis was performed. RESULTS: Full-text reviews were conducted of 98 of 272 articles identified and screened, and 43 met the inclusion criteria. Postoperative C5P was most commonly defined as a reduction in deltoid muscle strength by ≥ 1 grade using manual muscle testing (MMT), with potential biceps involvement also noted by some studies. The few studies that stratified C5P on the basis of severity unanimously characterized severe C5P as MMT grade ≤ 2. Nine studies reported on C5P recovery. Deltoid muscle strength improvement of MMT grade 5 commonly defined complete recovery, with no MMT improvement considered partial recovery. CONCLUSIONS: This review identified clear discrepancies in the definitions of C5P and its recovery, leading to heterogeneity in its evaluation and management. With the emergence of therapeutic procedures for severe C5P, standardization of the definitions of C5P and its recovery is critical. The authors propose MMT grades of 4, 3, and ≤ 2 to classify C5P as mild, moderate, and severe, respectively, and grades of 5, 4, and 3 to classify recovery as complete, sufficient, and useful, respectively.

Comparison of kidney transplant outcomes in HLA compatible and incompatible transplantation: A national cohort study.

BACKGROUND: Reports of HLA incompatible (HLAi) kidney transplant outcomes are inconclusive, especially in the context of lower level Donor Specific Antibodies (DSA). METHODS: Multi-centre national cohort study of HLAi kidney transplant recipients matched in 1:2 ratio with HLA compatible (HLAc) kidney transplant recipients. HLAi defined as DSA identified by Luminex. Antibody mediated rejection (AMR) and transplant-survival were analysed using Kaplan-Meier plots. Propensity score (PS) matching was used to compare recipient and transplant survival between groups. RESULTS: We included 61 HLAi and 122 HLAc recipients; mean age 46 years; 60% female. MFIT0 : 3327 (IQR 1352-6458), 23 (38%) were Flow cytometry crossmatch positive (FC-XMPOS ). DSAPOS /FC-XMPOS transplantation carried an increased risk of AMR at 1 year (52%) compared to DSAPOS /FC-XMNEG (27%) and HLAc (0%). Unadjusted death censored graft loss at 3 years was 13% (HLAi) and 8% (HLAc). Three-year patient survival was 95% in HLAc, 84% in DSAPOS /FC-XMNEG and 69% in DSAPOS /FC-XMPOS recipients; 58% of HLAi deaths were infection-related. HLA incompatibility was associated with a decreased 3-year survival in our PS-matched cohort. CONCLUSION: In kidney transplantation, DSA and positive FC-XM carries an increased risk of AMR. Despite inferior transplant and survival outcomes compared to HLAc transplantation, it remains a realistic option for highly sensitized patients facing prolonged waiting times and reduced survival on dialysis.

Key Drivers and Facilitators of the Choice to Use mHealth Technology in People With Neurological Conditions: Observational Study.

BACKGROUND: There is increasing interest in the potential uses of mobile health (mHealth) technologies, such as wearable biosensors, as supplements for the care of people with neurological conditions. However, adherence is low, especially over long periods. If people are to benefit from these resources, we need a better long-term understanding of what influences patient engagement. Previous research suggests that engagement is moderated by several barriers and facilitators, but their relative importance is unknown. OBJECTIVE: To determine preferences and the relative importance of user-generated factors influencing engagement with mHealth technologies for 2 common neurological conditions with a relapsing-remitting course: multiple sclerosis (MS) and epilepsy. METHODS: In a discrete choice experiment, people with a diagnosis of MS (n=141) or epilepsy (n=175) were asked to select their preferred technology from a series of 8 vignettes with 4 characteristics: privacy, clinical support, established benefit, and device accuracy; each of these characteristics was greater or lower in each vignette. These characteristics had previously been emphasized by people with MS and or epilepsy as influencing engagement with technology. Mixed multinomial logistic regression models were used to establish which characteristics were most likely to affect engagement. Subgroup analyses explored the effects of demographic factors (such as age, gender, and education), acceptance of and familiarity with mobile technology, neurological diagnosis (MS or epilepsy), and symptoms that could influence motivation (such as depression). RESULTS: Analysis of the responses to the discrete choice experiment validated previous qualitative findings that a higher level of privacy, greater clinical support, increased perceived benefit, and better device accuracy are important to people with a neurological condition. Accuracy was perceived as the most important factor, followed by privacy. Clinical support was the least valued of the attributes. People were prepared to trade a modest amount of accuracy to achieve an improvement in privacy, but less likely to make this compromise for other factors. The type of neurological condition (epilepsy or MS) did not influence these preferences, nor did the age, gender, or mental health status of the participants. Those who were less accepting of technology were the most concerned about privacy and those with a lower level of education were prepared to trade accuracy for more clinical support. CONCLUSIONS: For people with neurological conditions such as epilepsy and MS, accuracy (ie, the ability to detect symptoms) is of the greatest interest. However, there are individual differences, and people who are less accepting of technology may need far greater reassurance about data privacy. People with lower levels of education value greater clinician involvement. These patient preferences should be considered when designing mHealth technologies.

BSHI guideline: HLA matching and donor selection for haematopoietic progenitor cell transplantation.

A review of the British Society for Histocompatibility and Immunogenetics (BSHI) Guideline 'HLA matching and donor selection for haematopoietic progenitor cell transplantation' published in 2016 was undertaken by a BSHI appointed writing committee. Literature searches were performed and the data extracted were presented as recommendations according to the GRADE nomenclature.

Remote Assessment of Disease and Relapse in Epilepsy: Protocol for a Multicenter Prospective Cohort Study.

BACKGROUND: In recent years, a growing body of literature has highlighted the role of wearable and mobile remote measurement technology (RMT) applied to seizure detection in hospital settings, whereas more limited evidence has been produced in the community setting. In clinical practice, seizure assessment typically relies on self-report, which is known to be highly unreliable. Moreover, most people with epilepsy self-identify factors that lead to increased seizure likelihood, including mood, behavior, sleep pattern, and cognitive alterations, all of which are amenable to measurement via multiparametric RMT. OBJECTIVE: The primary aim of this multicenter prospective cohort study is to assess the usability, feasibility, and acceptability of RMT in the community setting. In addition, this study aims to determine whether multiparametric RMT collected in populations with epilepsy can prospectively estimate variations in seizure occurrence and other outcomes, including seizure frequency, quality of life, and comorbidities. METHODS: People with a diagnosis of pharmacoresistant epilepsy will be recruited in London, United Kingdom, and Freiburg, Germany. Participants will be asked to wear a wrist-worn device and download ad hoc apps developed on their smartphones. The apps will be used to collect data related to sleep, physical activity, stress, mood, social interaction, speech patterns, and cognitive function, both passively from existing smartphone sensors (passive remote measurement technology [pRMT]) and actively via questionnaires, tasks, and assessments (active remote measurement technology [aRMT]). Data will be collected continuously for 6 months and streamed to the Remote Assessment of Disease and Relapse-base (RADAR-base) server. RESULTS: The RADAR Central Nervous System project received funding in 2015 from the Innovative Medicines Initiative 2 Joint Undertaking under Grant Agreement No. 115902. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation program and European Federation of Pharmaceutical Industries and Associations. Ethical approval was obtained in London from the Bromley Research Ethics Committee (research ethics committee reference: 19/LO/1884) in January 2020. The first participant was enrolled on September 30, 2020. Data will be collected until September 30, 2021. The results are expected to be published at the beginning of 2022. CONCLUSIONS: RADAR Epilepsy aims at developing a framework of continuous data collection intended to identify ictal and preictal states through the use of aRMT and pRMT in the real-life environment. The study was specifically designed to evaluate the clinical usefulness of the data collected via new technologies and compliance, technology acceptability, and usability for patients. These are key aspects to successful adoption and implementation of RMT as a new way to measure and manage long-term disorders. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/21840.

UNUSUAL PRESENTATIONS OF LMNA-ASSOCIATED LIPODYSTROPHY WITH COMPLEX PHENOTYPES AND GENERALIZED FAT LOSS: WHEN THE GENETIC DIAGNOSIS UNCOVERS NOVEL FEATURES.

OBJECTIVE: Lipodystrophy represents a group of rare diseases characterized by loss of body fat. While patients with generalized lipodystrophy exhibit near-total lack of fat, partial lipodystrophy is associated with selective fat loss affecting certain parts of the body. Although classical familial partial lipodystrophy (FPLD) is a well-described entity, recent reports indicate phenotypic heterogeneity among carriers of LMNA pathogenic variants. METHODS: We have encountered 2 unique cases with complex phenotypes, generalized fat loss, and very low leptin levels that made the distinction between generalized versus partial lipodystrophy quite challenging. RESULTS: We present a 61-year-old female with generalized fat loss, harboring the heterozygous pathogenic variant p.R541P (c.1622G>C) on the LMNA gene. The discovery of the pathogenic variant led to correct clinical diagnosis of her muscle disease, identification of significant heart disease, and a recommendation for the implantation of a defibrillator. She was able to start metreleptin based on her generalized fat loss pattern and demonstration of the genetic variant. Secondly, we report a 40-year-old Turkish female with generalized fat loss associated with a novel heterozygous LMNA pathogenic variant p.K486E (c.1456A>G), who developed systemic B cell follicular lymphoma. CONCLUSION: Clinicians need to recognize that the presence of an LMNA variant does not universally lead to FPLD type 2, but may lead to a phenotype that is more complex and may resemble more closely generalized lipo-dystrophy. Additionally, providers should recognize the multisystem features of laminopathies and should screen for these features in affected patients, especially if the variant is not at the known hotspot for FPLD type 2.

Electrophysiological Changes After Human Muscle Tear: A Potential Confounder.

The goal of this prospective electrophysiologic study is to describe the chronological electromyographic findings observed in a human gastrocnemius muscle after a traumatic tear. A 30-yr-old man sustained a tear of the medial gastrocnemius. Needle electromyography was performed serially at 5, 15, and 26 wks after injury, with the contralateral gastrocnemius muscle serving as a control. Audiovisual recordings of the studies were analyzed in a blinded manner. Five weeks after injury, the affected gastrocnemius displayed increased insertional activity on electromyography. By 15-wk postinjury, insertional activity had diminished. However, motor unit action potentials showed chronic neurogenic morphological changes not previously observed. These changes persisted 26 wks after injury. The study findings reveal a chronological trajectory of increased insertional activity followed by reinnervation changes in a human muscle after local trauma, paralleling a course previously observed in a rat model. Electrodiagnosticians unaware of this phenomenon are at risk for making erroneous interpretations when examining patients with a history of muscle trauma.

HLA antibodies in haematopoietic stem cell transplantation.

The negative impact of donor specific HLA alloantibodies in solid organ transplantation is well known and understood within the histocompatibility and immunogenetics community. However the influence of donor-specific antibodies in the outcome of haematopoietic stem cell transplantation is less well regarded. As donor choices have evolved from HLA matched siblings and extremely well matched unrelated donors to mismatched cord blood and haplo-identical-related donors, we are now identifying more patients with antibodies reactive against their donor mismatches. The clinical significance of the antibodies that can be detected has not yet been fully elucidated.

The omission of the "wet" pre-transplant crossmatch in renal transplant centres in Scotland.

The methods used for assessment of immunological risk for a patient receiving a kidney from a deceased donor have undergone significant change in the last few years. Many centres now proceed to transplant without any additional laboratory-based HLA testing for patients who are well defined as HLA antibody negative. Using rapid HLA antibody tests at the time of donor offer, such as Luminex, it is also possible to omit wet crossmatches in many sensitised patients. This virtual crossmatch (vXM) approach provides benefits in reducing cold ischaemia time (CIT), but also carries risks such as missing clinically relevant non-HLA reactivity or allelic HLA antibody reactivity. A number of factors need to be in place in a laboratory to enable a vXM policy to be extended to both sensitised and non-sensitised patients including access to complete donor HLA typing, ability to undertake Luminex-based HLA antibody testing out of working hours, and access to senior H&I Scientist expertise to assess and interpret results. Other approaches, such as using peripheral blood lymphocytes for crossmatching, may also enable a reduction in CIT and transplant units need to assess the risks of extending vXM processes for their patients against potential benefits.

Effect of fascicle composition on ulnar to musculocutaneous nerve transfer (Oberlin transfer) in neonatal brachial plexus palsy.

OBJECTIVE Neonatal brachial plexus palsy (NBPP) continues to be a problematic occurrence impacting approximately 1.5 per 1000 live births in the United States, with 10%-40% of these infants experiencing permanent disability. These children lose elbow flexion, and one surgical option for recovering it is the Oberlin transfer. Published data support the use of the ulnar nerve fascicle that innervates the flexor carpi ulnaris as the donor nerve in adults, but no analogous published data exist for infants. This study investigated the association of ulnar nerve fascicle choice with functional elbow flexion outcome in NBPP. METHODS The authors conducted a retrospective study of 13 cases in which infants underwent ulnar to musculocutaneous nerve transfer for NBPP at a single institution. They collected data on patient demographics, clinical characteristics, active range of motion (AROM), and intraoperative neuromonitoring (IONM) (using 4 ulnar nerve index muscles). Standard statistical analysis compared pre- and postoperative motor function improvement between specific fascicle transfer (1-2 muscles for either wrist flexion or hand intrinsics) and nonspecific fascicle transfer (> 2 muscles for wrist flexion and hand intrinsics) groups. RESULTS The patients' average age at initial clinic visit was 2.9 months, and their average age at surgical intervention was 7.4 months. All NBPPs were unilateral; the majority of patients were female (61%), were Caucasian (69%), had right-sided NBPP (61%), and had Narakas grade I or II injuries (54%). IONM recordings for the fascicular dissection revealed a donor fascicle with nonspecific innervation in 6 (46%) infants and specific innervation in the remaining 7 (54%) patients. At 6-month follow-up, the AROM improvement in elbow flexion in adduction was 38° in the specific fascicle transfer group versus 36° in the nonspecific fascicle transfer group, with no statistically significant difference (p = 0.93). CONCLUSIONS Both specific and nonspecific fascicle transfers led to functional recovery, but that the composition of the donor fascicle had no impact on early outcomes. In young infants, ulnar nerve fascicular dissection places the ulnar nerve at risk for iatrogenic damage. The data from this study suggest that the use of any motor fascicle, specific or nonspecific, produces similar results and that the Oberlin transfer can be performed with less intrafascicular dissection, less time of surgical exposure, and less potential for donor site morbidity.

HLA Immunogenotype Determines Persistent Human Papillomavirus Virus Infection in HIV-Infected Patients Receiving Antiretroviral Treatment.

A proportion of human immunodeficiency virus (HIV)-infected patients develop persistent, stigmatizing human papillomavirus (HPV)-related cutaneous and genital warts and anogenital (pre)cancer. This is the first study to investigate immunogenetic variations that might account for HPV susceptibility and the largest to date to categorize the HPV types associated with cutaneous warts in HIV-positive patients. The HLA class I and II allele distribution was analyzed in 49 antiretroviral (ART)-treated HIV-positive patients with persistent warts, 42 noninfected controls, and 46 HIV-positive controls. The allele HLA-B*44 was more frequently identified in HIV-positive patients with warts (P = .004); a susceptible haplotype (HLA-B*44, HLA-C*05; P = .001) and protective genes (HLA-DQB1*06; P = .03) may also contribute. Cutaneous wart biopsy specimens from HIV-positive patients harbored common wart types HPV27/57, the unusual wart type HPV7, and an excess of Betapapillomavirus types (P = .002), compared with wart specimens from noninfected controls. These findings suggest that HLA testing might assist in stratifying those patients in whom vaccination should be recommended.

Identification of Molecular Markers of Delayed Graft Function Based on the Regulation of Biological Ageing.

INTRODUCTION: Delayed graft function is a prevalent clinical problem in renal transplantation for which there is no objective system to predict occurrence in advance. It can result in a significant increase in the necessity for hospitalisation post-transplant and is a significant risk factor for other post-transplant complications. METHODOLOGY: The importance of microRNAs (miRNAs), a specific subclass of small RNA, have been clearly demonstrated to influence many pathways in health and disease. To investigate the influence of miRNAs on renal allograft performance post-transplant, the expression of a panel of miRNAs in pre-transplant renal biopsies was measured using qPCR. Expression was then related to clinical parameters and outcomes in two independent renal transplant cohorts. RESULTS: Here we demonstrate, in two independent cohorts of pre-implantation human renal allograft biopsies, that a novel pre-transplant renal performance scoring system (GRPSS), can determine the occurrence of DGF with a high sensitivity (>90%) and specificity (>60%) for donor allografts pre-transplant, using just three senescence associated microRNAs combined with donor age and type of organ donation. CONCLUSION: These results demonstrate a relationship between pre-transplant microRNA expression levels, cellular biological ageing pathways and clinical outcomes for renal transplantation. They provide for a simple, rapid quantitative molecular pre-transplant assay to determine post-transplant allograft function and scope for future intervention. Furthermore, these results demonstrate the involvement of senescence pathways in ischaemic injury during the organ transplantation process and an indication of accelerated bio-ageing as a consequence of both warm and cold ischaemia.

Clinical description of toxic neuropathies.

Toxic neuropathy, although rare, is an important consideration in the setting of a known or suspected toxic exposure in the workplace or other environment. This chapter discusses the clinical and electrodiagnostic evaluation of peripheral neuropathies, highlighting findings that direct further workup and may point to specific toxins as etiology. The difficulty of establishing causality of a toxin in relation to peripheral neuropathy is discussed; guidelines for establishing causality are presented. Examples of common industrial toxins are listed, including their typical industrial uses and their mechanisms of action in producing neuropathy. Characteristic clinical presentations of specific toxic neuropathies are highlighted with selected case studies.