Gene Edited T Cell Therapies for Inborn Errors of Immunity.

Inborn errors of immunity (IEIs) are a heterogeneous group of inherited disorders of the immune system. Many IEIs have a severe clinical phenotype that results in progressive morbidity and premature mortality. Over 450 IEIs have been described and the incidence of all IEIs is 1/1,000-10,000 people. Current treatment options are unsatisfactory for many IEIs. Allogeneic haematopoietic stem cell transplantation (alloHSCT) is curative but requires the availability of a suitable donor and carries a risk of graft failure, graft rejection and graft-versus-host disease (GvHD). Autologous gene therapy (GT) offers a cure whilst abrogating the immunological complications of alloHSCT. Gene editing (GE) technologies allow the precise modification of an organisms' DNA at a base-pair level. In the context of genetic disease, this enables correction of genetic defects whilst preserving the endogenous gene control machinery. Gene editing technologies have the potential to transform the treatment landscape of IEIs. In contrast to gene addition techniques, gene editing using the CRISPR system repairs or replaces the mutation in the DNA. Many IEIs are limited to the lymphoid compartment and may be amenable to T cell correction alone (rather than haematopoietic stem cells). T cell Gene editing has the advantages of higher editing efficiencies, reduced risk of deleterious off-target edits in terminally differentiated cells and less toxic conditioning required for engraftment of lymphocytes. Although most T cells lack the self-renewing property of HSCs, a population of T cells, the T stem cell memory compartment has long-term multipotent and self-renewal capacity. Gene edited T cell therapies for IEIs are currently in development and may offer a less-toxic curative therapy to patients affected by certain IEIs. In this review, we discuss the history of T cell gene therapy, developments in T cell gene editing cellular therapies before detailing exciting pre-clinical studies that demonstrate gene editing T cell therapies as a proof-of-concept for several IEIs.

Developing Irelands first National Student Mental Health and Suicide Prevention Framework for Higher Education.

This article focuses on the development of Ireland's first National Student Mental Health and Suicide Prevention Framework for Higher Education. There is growing concern for student mental health in higher education nationally and globally. The majority of students are aged between 18 and 24, which is identified as a high-risk group for mental health difficulties. Recent surveys of student mental illness, mental distress, and low well-being have been recognized by the World Health Organization, the Union of Students in Ireland National Report on Student Mental Health in Third Level Education, the My World survey and the My World 2 study. The Higher Education Authority in Ireland made a commitment to the Department of Health Connecting for Life (Ireland's National Strategy to Reduce Suicide 2015-2020) to form national guidelines for suicide prevention in higher education. In order to deliver on this commitment, The National Student Mental Health and Suicide Prevention Framework was developed. The Framework is informed by international evidence and was the product of a collaborative cross sector and cross disciplinary team including health professionals, government representatives, educators, students, policy makers, community organizations, researchers and clinicians.

Spinal radiographic progression over 2 years in ankylosing spondylitis patients treated with secukinumab: a historical cohort comparison.

OBJECTIVE: The aim of this study was to compare radiographic progression in patients with ankylosing spondylitis (AS) treated for up to 2 years with secukinumab (MEASURE 1) with a historical cohort of biologic-naïve patients treated with NSAIDs (ENRADAS). METHODS: Baseline and 2-year lateral cervical and lumbar spine radiographs were independently evaluated using mSASSS by two readers, who were blinded to the chronology and cohort of the radiographs. The primary endpoint was the proportion of patients with no radiographic progression (mSASSS change ≤ 0 from baseline to year 2). The Primary Analysis Set included patients with baseline (≤ day 30) and post-baseline day 31-743 radiographs. Sensitivity analyses were performed to assess the robustness of the comparison between the two cohorts, as follows: Sensitivity Analysis Set 1 included all patients with baseline (≤ day 30) and year 2 (days 640-819) radiographs; Sensitivity Analysis Set 2 included all patients with baseline and post-baseline (> day 30) radiographs. RESULTS: A total of 168 patients (84%) from the MEASURE 1 cohort and 69 (57%) from the ENRADAS cohort qualified for the Primary Analysis Set. Over 2 years, the LS (SE) mean change from baseline in mSASSS for the primary analysis was 0.55 (0.139) for MEASURE 1 vs 0.89 (0.216) for ENRADAS (p = 0.1852). Mean changes from baseline in mSASSS were lower in MEASURE 1 vs ENRADAS for the primary and sensitivity analyses. The proportion of patients with no radiographic progression was consistently higher in the MEASURE 1 vs ENRADAS cohort across all cutoffs for no radiographic progression (change in mSASSS from baseline to year 2 of ≤ 0, ≤ 0.5, ≤ 1, and ≤ 2), but the differences were not statistically significant. CONCLUSION: Secukinumab-treated patients demonstrated a numerical, but statistically non-significant, higher proportion of non-progressors and lower change in mSASSS over 2 years versus a cohort of biologic-naïve patients treated with NSAIDs.

Long-term safety of secukinumab in patients with moderate-to-severe plaque psoriasis, psoriatic arthritis, and ankylosing spondylitis: integrated pooled clinical trial and post-marketing surveillance data.

BACKGROUND: Secukinumab, a fully human immunoglobulin G1-kappa monoclonal antibody that directly inhibits interleukin (IL)-17A, has been shown to have robust efficacy in the treatment of moderate-to-severe psoriasis (PsO), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) demonstrating a rapid onset of action and sustained long-term clinical responses with a consistently favorable safety profile in multiple Phase 2 and 3 trials. Here, we report longer-term pooled safety and tolerability data for secukinumab across three indications (up to 5 years of treatment in PsO and PsA; up to 4 years in AS). METHODS: The integrated clinical trial safety dataset included data pooled from 21 randomized controlled clinical trials of secukinumab 300 or 150 or 75 mg in PsO (14 Phase 3 trials and 1 Phase 4 trial), PsA (3 Phase 3 trials), and AS (3 Phase 3 trials), along with post-marketing safety surveillance data with a cut-off date of June 25, 2017. Adverse events (AEs) were reported as exposure-adjusted incident rates (EAIRs) per 100 patient-years. Analyses included all patients who received ≥ 1 dose of secukinumab. RESULTS: A total of 5181, 1380, and 794 patients from PsO, PsA, and AS clinical trials representing secukinumab exposures of 10,416.9, 3866.9, and 1943.1 patient-years, respectively, and post-marketing data from patients with a cumulative exposure to secukinumab of ~ 96,054 patient-years were included in the analysis. The most frequent AE was upper respiratory tract infection. EAIRs across PsO, PsA, and AS indications were generally low for serious infections (1.4, 1.9, and 1.2, respectively), Candida infections (2.2, 1.5, and 0.7, respectively), inflammatory bowel disease (0.01, 0.05, and 0.1, respectively), and major adverse cardiac events (0.3, 0.4, and 0.6, respectively). No cases of tuberculosis reactivation were reported. The incidence of treatment-emergent anti-drug antibodies was low with secukinumab across all studies, with no discernible loss of efficacy, unexpected alterations in pharmacokinetics, or association with immunogenicity-related AEs. CONCLUSIONS: Secukinumab demonstrated a favorable safety profile over long-term treatment in patients with PsO, PsA, and AS. This comprehensive assessment demonstrated that the safety profile of secukinumab was consistent with previous reports in patients with PsO, PsA, and AS, supporting its long-term use in these chronic conditions.

Patient perceptions of clear/almost clear skin in moderate-to-severe plaque psoriasis: results of the Clear About Psoriasis worldwide survey.

BACKGROUND: Therapeutic advances have made the achievement of clear/almost clear skin possible for many patients with moderate-to-severe plaque psoriasis. OBJECTIVE: To determine patient perceptions of the impact of psoriasis and of attaining clear/almost clear skin. METHODS: Global survey of patients with moderate-to-severe psoriasis. RESULTS: A total of 8338 patients from 31 countries participated. The majority (57%) had not achieved self-assessed clear/almost clear skin with their current therapy, and 56% of those who had not met this goal believed it would be impossible to do so. Among the patients who had clear/almost clear skin, 73% had not initiated their current treatment until >1 year after psoriasis diagnosis, and 28% had to wait >5 years. Eighty-four percent of all respondents experienced discrimination and/or humiliation due to psoriasis, and many reported negative effects on work, intimate relationships, sleep and mental health. Patients without clear/almost clear skin reported that such achievement would open new possibilities, such as swimming (58%), a wider choice of clothing (40%), and meeting new people (26%). A limitation of this study, as with any survey-based research, is that selection and recall bias may have been present. Additionally, respondent definitions of clear/almost clear skin were subjective and may have varied. CONCLUSION: Despite the importance of clear/almost clear skin to psoriasis patients, most are still not achieving it, and many are unaware it is possible.

Enough is not enough: Medical students' knowledge of early warning signs of childhood cancer.

BACKGROUND: The reported incidence of childhood cancer in upper-middle-income South Africa (SA) is much lower than in high-income countries, partly due to under-diagnosis and under-reporting. Documented survival rates are disturbingly low, prompting an analysis of potential factors that may be responsible. OBJECTIVES: To determine final-year medical students' level of knowledge of early warning signs of childhood cancer and whether a correlation existed between test scores and participants' age, gender and previous exposure to a person with cancer. METHODS: A two-part questionnaire based on the Saint Siluan mnemonic, testing both recall and recognition of early warning signs of childhood cancer, was administered. The Mann-Whitney-Wilcoxon test was used to assess differences in continuous and count variables between demographic data, experience and responses, and Fisher's exact test and Spearman's rank correlation coefficient were used to determine correlations between demographic data, previous contact with persons with cancer and test scores. A novel equality ratio was calculated to compare the recall and recognition sections and allowed analysis of recall v. recognition. RESULTS: The 84 participants recalled a median of six signs each (interquartile range 4 - 7) and correctly recognised a median of 70% in the recognition section, considered a pass mark. There was no correlation between participants' age, gender, previous contact with a person with cancer and recognition scores. Students with previous exposure to a person with cancer had higher scores in the recall section, but this did not achieve statistical significance. Students were able to recognise more signs of haematological malignancies than central nervous system (CNS) malignancies. CONCLUSION: The study demonstrated a marked inconsistency between recall and recognition of signs of childhood cancer, with signs of CNS malignancies being least recognised. However, the majority of students could recognise enough early warning signs to meet the university pass standard. Although this study demonstrated acceptable recognition of early warning signs of childhood cancer at one university, we suggest that long-term recall in medical practitioners is poor, as reflected in the low age-standardised ratios of childhood cancer in SA. We recommend increased ongoing exposure to paediatric oncology in medical school and improved awareness programmes to increase early referrals.

Secukinumab sustains good efficacy and favourable safety in moderate-to-severe psoriasis after up to 3 years of treatment: results from a double-blind extension study.

BACKGROUND: Secukinumab has demonstrated significant efficacy with a good safety profile through 1 year in plaque psoriasis. Given the chronic nature of this disease, long-term follow-up is needed to evaluate psoriasis therapies fully. OBJECTIVES: To determine the long-term (3-year) efficacy and safety of secukinumab in moderate-to-severe psoriasis. METHODS: Patients completing 52 weeks of secukinumab treatment in the SCULPTURE core study entered an extension in which they continued the same double-blind regimens. Dosing regimens included a fixed-interval schedule (FI; every 4 weeks) and retreatment as needed (RAN), in which patients were withdrawn from secukinumab and received placebo until the start of relapse, at which time secukinumab every 4 weeks was reinitiated. The study was registered with number NCT01640951. RESULTS: In total 168 patients receiving secukinumab 300 mg FI and 172 receiving secukinumab 300 mg RAN entered the extension. Secukinumab 300 mg FI sustained high efficacy: at the end of year 3, the proportion of responders achieving ≥ 90% improvement in Psoriasis Area and Severity Index (PASI 90) was 63·8%, and of PASI 100 responders it was 42·6%. The mean absolute PASI remained low (2-4) from week 52 to week 152 with 300 mg FI, with approximately two-thirds of patients reporting no impact of skin disease on their lives (Dermatology Life Quality Index of 0 or 1). Improvements in overall and subscale scores on all quality-of-life instruments were well sustained. As in the core study, FI dosing was consistently more efficacious than RAN. No new safety signals were identified to year 3. CONCLUSIONS: Secukinumab 300 mg FI sustained high responses and improved quality of life with no new safety concerns through 3 years.

Intuitive Density Functional Theory-Based Energy Decomposition Analysis for Protein-Ligand Interactions.

First-principles quantum mechanical calculations with methods such as density functional theory (DFT) allow the accurate calculation of interaction energies between molecules. These interaction energies can be dissected into chemically relevant components such as electrostatics, polarization, and charge transfer using energy decomposition analysis (EDA) approaches. Typically EDA has been used to study interactions between small molecules; however, it has great potential to be applied to large biomolecular assemblies such as protein-protein and protein-ligand interactions. We present an application of EDA calculations to the study of ligands that bind to the thrombin protein, using the ONETEP program for linear-scaling DFT calculations. Our approach goes beyond simply providing the components of the interaction energy; we are also able to provide visual representations of the changes in density that happen as a result of polarization and charge transfer, thus pinpointing the functional groups between the ligand and protein that participate in each kind of interaction. We also demonstrate with this approach that we can focus on studying parts (fragments) of ligands. The method is relatively insensitive to the protocol that is used to prepare the structures, and the results obtained are therefore robust. This is an application to a real protein drug target of a whole new capability where accurate DFT calculations can produce both energetic and visual descriptors of interactions. These descriptors can be used to provide insights for tailoring interactions, as needed for example in drug design.

The risk of depression, suicidal ideation and suicide attempt in patients with psoriasis, psoriatic arthritis or ankylosing spondylitis.

BACKGROUND: Sparse information is available concerning mental health issues in psoriasis, psoriatic arthritis (PsA) and ankylosing spondylitis (AS) patients. OBJECTIVE: To estimate risk of depression, suicidal ideation and suicide attempt in patients with psoriasis, PsA and AS, respectively, compared with the general population. METHODS: This population-based cohort study analysed 36 214 psoriasis patients, 5138 PsA patients and 1878 AS patients who were frequency-matched with a general population cohort. Annual incidence rate of depression, suicidal ideation and suicide attempt was calculated separately for psoriasis, PsA and AS. RESULTS: There was an increased risk of depression in the three cohorts; adjusted IRR: psoriasis, 1.14 (95% CI, 1.11, 1.17); PsA, 1.22 (95% CI, 1.16, 1.29); AS, 1.34 (95% CI, 1.23, 1.47). There was no significantly increased risk for suicidal ideations or suicide attempt among psoriasis, PsA or AS patients. LIMITATIONS: Patients were not excluded if previously diagnosed with depression, suicidal ideation or suicide attempt. Suicide attempt and completed suicide analyses were not adjusted for presence of depression. Use of systemic psoriasis treatment to measure severe psoriasis could lead to psoriasis severity misclassification. CONCLUSION: The risk of depression, but not suicidal ideation or suicide attempt, was significantly increased in patients with psoriasis, PsA and AS.

Secukinumab administration by autoinjector maintains reduction of plaque psoriasis severity over 52 weeks: results of the randomized controlled JUNCTURE trial.

BACKGROUND: User satisfaction is an important factor associated with treatment adherence in chronic diseases including moderate-to-severe psoriasis. OBJECTIVE: To evaluate the efficacy, safety and patient acceptability of 300 and 150 mg secukinumab - a fully human anti-interleukin-17A monoclonal antibody that has demonstrated efficacy in the treatment of patients with moderate-to-severe plaque psoriasis - self-administered by autoinjection. METHODS: Patients with moderate-to-severe plaque psoriasis were randomized to secukinumab 300 mg, secukinumab 150 mg or placebo self-administered by autoinjection at baseline, Weeks 1, 2 and 3 and then every 4 weeks from Week 4 to Week 48. Efficacy responses [≥75/90/100% improvement in Psoriasis Area and Severity Index (PASI 75/90/100) and clear/almost clear skin by Investigator's Global Assessment 2011 modified version (IGA mod 2011 0/1)] were measured at Week 52. Patient-reported usability of the autoinjector was evaluated by the self-injection assessment questionnaire to Week 48. RESULTS: At Week 52 with secukinumab 300 mg, PASI 75/90/100 and IGA mod 2011 0/1 responses were achieved by 81.4/64.1/38.8% and 69.6% of patients, respectively, by multiple imputation. At Week 52 with secukinumab 150 mg, PASI 75/90/100 and IGA mod 2011 0/1 responses were achieved by 75.2/57.4/33.1% and 60.2% of patients, respectively, by multiple imputation. Patient-assessed acceptability of the autoinjector remained high to Week 48. The proportion of patients experiencing adverse events was greater with secukinumab 300 mg (88.6%) than with secukinumab 150 mg (78.7%). CONCLUSION: Self-administration of secukinumab using an autoinjector was associated with robust and sustained efficacy, a good safety profile and high acceptability.

Secukinumab, a fully human anti-interleukin-17A monoclonal antibody, exhibits minimal immunogenicity in patients with moderate-to-severe plaque psoriasis.

BACKGROUND: The proinflammatory cytokine interleukin (IL)-17A plays a pivotal role in psoriasis pathogenesis. Secukinumab, a fully human monoclonal antibody (mAb) that selectively targets IL-17A, has been demonstrated to be highly efficacious for the treatment of moderate-to-severe psoriasis, starting at early time points, with a sustained effect and a favourable safety profile. mAb therapies may be associated with production of antidrug antibodies (ADAs) that can affect drug pharmacokinetics, diminish response or cause hypersensitivity reactions. OBJECTIVES: To investigate the immunogenicity of secukinumab across six phase III clinical trials in which patients with plaque psoriasis were treated with secukinumab for up to 52 weeks and additionally followed up at week 60. METHODS: Immunogenicity in patients with plaque psoriasis exposed to secukinumab was evaluated at baseline and at weeks 12, 24, 52 and 60. Treatment-emergent (TE)-ADAs were defined as a positive ADA signal detected in post-treatment samples from patients with a negative baseline signal. Confirmed positive samples were further analysed for their drug-neutralizing potential. RESULTS: Among 2842 patients receiving secukinumab and evaluated for ADAs, 11 (0·4%) developed TE-ADAs. Associations between TE-ADAs and secukinumab dose, frequency or mode of administration were not observed. Neutralizing antibodies were detected in three of nine evaluable patients with TE-ADAs. CONCLUSIONS: Secukinumab immunogenicity was low, as shown by TE-ADA detection in only 11 of 2842 (0·4%) patients with moderate-to-severe plaque psoriasis treated with secukinumab. All but one of the patients with TE-ADAs were biologic naive. Neither TE-ADAs nor neutralizing antibodies were associated with loss of secukinumab efficacy or issues of clinical concern.

Energy Decomposition Analysis Based on Absolutely Localized Molecular Orbitals for Large-Scale Density Functional Theory Calculations in Drug Design.

We report the development and implementation of an energy decomposition analysis (EDA) scheme in the ONETEP linear-scaling electronic structure package. Our approach is hybrid as it combines the localized molecular orbital EDA (Su, P.; Li, H. J. Chem. Phys., 2009, 131, 014102) and the absolutely localized molecular orbital EDA (Khaliullin, R. Z.; et al. J. Phys. Chem. A, 2007, 111, 8753-8765) to partition the intermolecular interaction energy into chemically distinct components (electrostatic, exchange, correlation, Pauli repulsion, polarization, and charge transfer). Limitations shared in EDA approaches such as the issue of basis set dependence in polarization and charge transfer are discussed, and a remedy to this problem is proposed that exploits the strictly localized property of the ONETEP orbitals. Our method is validated on a range of complexes with interactions relevant to drug design. We demonstrate the capabilities for large-scale calculations with our approach on complexes of thrombin with an inhibitor comprised of up to 4975 atoms. Given the capability of ONETEP for large-scale calculations, such as on entire proteins, we expect that our EDA scheme can be applied in a large range of biomolecular problems, especially in the context of drug design.

Towards (99m)Tc-based imaging agents with effective doxorubicin mimetics: a molecular and cellular study.

Doxorubicin is a clinical benchmark drug, which is applied in the treatment of numerous cancers. Known for its accumulation in the nucleus and ability to intercalate into DNA, it targets quickly dividing i.e. hypermitotic cells. Through this mechanism, it could be an ideal structural motif for a new class of imaging agents, given that the new entity approximates the in vitro profile of the parent drug. Here we describe design, synthesis and biological activity of a small array of Doxorubicin-metalloconjugates (M = (99m)Tc, Re). We demonstrate that the conjugates preferably accumulate in the nuclear compartment, tightly bind to DNA and retain an appreciable cytotoxicity. Moreover, the Re conjugates effectively act as inhibitors of the human Topoisomerase II enzyme, which is the widely accepted mechanism of action of the parent drug. Since the conjugates effectively mimic the in vitro behavior of native Doxorubicin, the (99m)Tc compounds are prospective imaging agents.

Photocatalytic proton reduction with ruthenium and cobalt complexes immobilized on fumed reversed-phase silica.

Heterogeneous photocatalytic hydrogen production with a non-covalently immobilized molecular ruthenium based photosensitizer (PS) and a cobalt polypyridyl based water reducing catalyst (WRC) is reported. PS and WRC were derivatized with C18-alkyl chains and immobilized by adsorption on hydrophobic fumed silica. The resulting loaded support was suspended in water with anionic or cationic surfactants and subjected to heterogeneous photocatalytic H2 production with ascorbate as sacrificial electron donor (SED). No leaching was observed under catalytic conditions, thus catalysis was truly heterogeneous. The catalytic performance of immobilized PS and WRC clearly exceeded that of homogeneous catalysis at low concentrations. At high concentration, diffusion and light limitation lead to lower reaction rates, but the same stability as for homogeneous reactions was still achieved. WRC concentration variations indicated a relatively high stability (up to 1300 H2/Co) and mobility of amphiphilic catalysts on the hydrophobic silica surface. Comparison of fumed silica with porous and non-porous silica showed, that a high BET surface area along with a good accessibility from the reaction media are crucial for catalytic performance. Mechanistic investigations by transient absorption spectroscopy displayed reductive quenching of excited PS by ascorbate followed by on particle electron transfer to WRC as reaction pathway. Particles with additional cationic surfactants exhibited a significantly higher catalytic performance as compared to anionic surfactants. Non-covalent anchoring of correspondingly derivatized WRCs or PSs to reversed-phase silica offers a rapid and versatile transition from homogeneous to heterogeneous molecular proton reduction.

Improvement of dyskinesias with L-dopa infusion in advanced Parkinson's disease.

OBJECTIVES: We wanted to investigate whether continuous intrajejunal levodopa-carbidopa intestinal gel (LCIG) therapy has an antidyskinetic effect in patients with Parkinson's disease (PD) and troublesome dyskinesias. We also sought to examine the effect of LCIG therapy on motor function and health-related quality of life (HRQoL). MATERIALS AND METHODS: This open-label pilot study used a single group pre-post design with follow-up at 6 months. Nine patients with PD who reported to spend at least 3 h per day in on with troublesome dyskinesia were included. The patients were examined at baseline using clinical and self-assessment measures and then switched from peroral/transdermal pharmacotherapy to LCIG therapy. Data collection was repeated 6 months after the pharmaceutical intervention. Nonparametric statistical methods were used for data analyses. RESULTS: The mean time spent in on with troublesome dyskinesia per day after 6 months of LCIG therapy decreased by 47% (P < 0.05). This observation was paralleled by a 112% increase in mean time spent in on without troublesome dyskinesia (P < 0.01). Patient self-assessment of dyskinesia intensity on the visual analog scale displayed a 90% reduction of mean dyskinesia intensity (P < 0.01) and patients also exhibited less dyskinesia during standardized levodopa tests. Furthermore, we noted improvements in motor function and HRQoL. CONCLUSIONS: In this pilot study, we found indications that LCIG therapy has a substantial antidyskinetic effect and could be an alternative also for PD patients with dyskinesias as a major symptom. However, further studies with blinded evaluation and larger numbers of patients are warranted to confirm the findings.

Outcome of one-stage correction of deformities of the ankle and hindfoot and fusion in Charcot neuroarthropathy using a retrograde intramedullary hindfoot arthrodesis nail.

We report the outcomes of 20 patients (12 men, 8 women, 21 feet) with Charcot neuro-arthropathy who underwent correction of deformities of the ankle and hindfoot using retrograde intramedullary nail arthrodesis. The mean age of the patients was 62.6 years (46 to 83); their mean BMI was 32.7 (15 to 47) and their median American Society of Anaesthetists score was 3 (2 to 4). All presented with severe deformities and 15 had chronic ulceration. All were treated with reconstructive surgery and seven underwent simultaneous midfoot fusion using a bolt, locking plate or a combination of both. At a mean follow-up of 26 months (8 to 54), limb salvage was achieved in all patients and 12 patients (80%) with ulceration achieved healing and all but one patient regained independent mobilisation. There was failure of fixation with a broken nail requiring revision surgery in one patient. Migration of distal locking screws occurred only when standard screws had been used but not with hydroxyapatite-coated screws. The mean American Academy of Orthopaedic Surgeons Foot and Ankle (AAOS-FAO) score improved from 50.7 (17 to 88) to 65.2 (22 to 88), (p = 0.015). The mean Short Form (SF)-36 Health Survey Physical Component Score improved from 25.2 (16.4 to 42.8) to 29.8 (17.7 to 44.2), (p = 0.003) and the mean Euroqol EQ­5D­5L score improved from 0.63 (0.51 to 0.78) to 0.67 (0.57 to 0.84), (p = 0.012). Single-stage correction of deformity using an intramedullary hindfoot arthrodesis nail is a good form of treatment for patients with severe Charcot hindfoot deformity, ulceration and instability provided a multidisciplinary care plan is delivered.

Linked distal radioulnar joint arthroplasty: an analysis of the APTIS prosthesis.

Painful radioulnar convergence following resection of the distal ulna can produce substantial disability and prove a challenging surgical problem, particularly in the revision setting. The purpose of this study was to evaluate the outcome of a series of patients with chronic distal radioulnar joint instability or multiple prior procedures treated with linked distal radioulnar joint arthroplasty with the APTIS prosthesis. A series of ten patients were identified with a mean follow up of 4.0 years. At final follow-up nine of ten implants survived free from revision or removal, with patients experiencing good pain relief and functional outcomes, with reasonable overall satisfaction in all seven patients who returned the questionnaires. Despite the medium-term follow-up and small number of patients, our results suggest the linked distal radioulnar joint arthroplasty may be a viable option for treating painful radioulnar convergence following multiple failed procedures at the distal radioulnar joint.

Zinc absorption in Brazilian subjects fed a healthy meal.

BACKGROUND: The high amounts of phytic acid present in diets from developing countries are considered as important inhibitors of zinc (Zn) absorption. The present study aimed to assess the fractional absorption of Zn from a meal containing common Brazilian foods using the stable isotope technique. METHODS: Twelve men, aged 19-42 years, were fed a healthy experimental diet comprising lettuce, tomato, French fries, steak with onions, rice, beans, papaya, orange, pineapple, and passion fruit juice. Each subject received one intravenous dose of enriched (70) Zn, and the lunch was extrinsically labelled with enriched (67) Zn. Urinary (67) Zn and (70) Zn enrichments were assessed by inductively coupled plasma mass spectrometry. RESULTS: The labelled meal phytate : Zn molar ratio was very divergent with respect to chemically determined and calculated data. Subjects presented a normal Zn nutritional status before and after the study. The mean Zn absorption from the labelled meal was 30% (range 11-47%). CONCLUSIONS: According to the World Health Organization parameters, the results denote a moderate/high Zn bioavailability in the evaluated meal, with a variability in the absorption percentage that is similar to other studies. The data show that a typical Brazilian meal, with an adequate energy amount and a balanced macronutrient distribution, presents a Zn bioavailability in accordance with the worldwide recommended standard.