Childhood overweight and obesity and back pain risk : a cohort study of 466 997 children

To assess the association between age, sex, socioeconomic group, weight status and back pain risk in a large general population cohort of children. A dynamic cohort of children aged 4 years in the Information System for Research in Primary Care (SIDIAP) electronic primary care records data in Catalonia. Multivariable Cox models were fitted to explore the association between back pain and weight status categories according to the WHO 2007 growth reference groups (body mass index for age z-score). Models were adjusted for age, sex, socioeconomic status and nationality. Children seen at age 4 years at paediatric primary care clinics between 1 January 2006 and 31 December 2013 and followed up until 31 December 2016 or age 15 years. Incident back pain registered by paediatricians at primary care using the International Statistical Classification of Diseases and Health Related Problems, 10th Edition code M54. 466 997 children were followed for a median 5.0 years (IQR 5.1). In multivariable models, overweight and obesity increased back pain risk, with adjusted HRs of 1.18 (95% CI 1.09 to 1.27) and 1.34 (95%CI 1.19 to 1.51) for overweight and obesity, respectively. Females were at greater risk of back pain than males with adjusted HR 1.40 (95%CI 1.35 to 1.46). Adjusted HR was 1.43 (95%CI 1.33 to 1.55) for back pain in children from the most deprived socioeconomic groups compared with the least deprived socioeconomic groups. Maintaining a healthy weight from an early age may reduce the prevalence of back pain in both children and adults. Overweight female children from deprived socioeconomic groups are at greatest risk of back pain and represent a target population for intervention

Exploring ocean biogeochemistry using a lab-on-chip phosphate analyser on an underwater glider

The ability to make measurements of phosphate (PO43–) concentrations at temporal and spatial scales beyond those offered by shipboard observations offers new opportunities for investigations of the marine phosphorus cycle. We here report the first in situ PO43– dataset from an underwater glider (Kongsberg Seaglider) equipped with a PO43– Lab-on-Chip (LoC) analyser. Over 44 days, a 120 km transect was conducted in the northern North Sea during late summer (August and September). Surface depletion of PO43– (<0.2 μM) was observed above a seasonal thermocline, with elevated, but variable concentrations within the bottom layer (0.30–0.65 μM). Part of the variability in the bottom layer is attributed to the regional circulation and across shelf exchange, with the highest PO43– concentrations being associated with elevated salinities in northernmost regions, consistent with nutrient rich North Atlantic water intruding onto the shelf. Our study represents a significant step forward in autonomous underwater vehicle sensor capabilities and presents new capability to extend research into the marine phosphorous cycle and, when combined with other recent LoC developments, nutrient stoichiometry

Aggregatibacter actinomycetemcomitans-induced hypercitrullination links periodontal infection to autoimmunity in rheumatoid arthritis

A bacterial etiology of rheumatoid arthritis (RA) has been suspected since the beginnings of modern germ theory. Recent studies implicate mucosal surfaces as sites of disease initiation. The common occurrence of periodontal dysbiosis in RA suggests that oral pathogens may trigger the production of disease-specific autoantibodies and arthritis in susceptible individuals. We used mass spectrometry to define the microbial composition and antigenic repertoire of gingival crevicular fluid in patients with periodontal disease and healthy controls. Periodontitis was characterized by the presence of citrullinated autoantigens that are primary immune targets in RA. The citrullinome in periodontitis mirrored patterns of hypercitrullination observed in the rheumatoid joint, implicating this mucosal site in RA pathogenesis. Proteomic signatures of several microbial species were detected in hypercitrullinated periodontitis samples. Among these, Aggregatibacter actinomycetemcomitans (Aa), but not other candidate pathogens, induced hypercitrullination in host neutrophils. We identified the pore-forming toxin leukotoxin-A (LtxA) as the molecular mechanism by which Aa triggers dysregulated activation of citrullinating enzymes in neutrophils, mimicking membranolytic pathways that sustain autoantigen citrullination in the RA joint. Moreover, LtxA induced changes in neutrophil morphology mimicking extracellular trap formation, thereby releasing the hypercitrullinated cargo. Exposure to leukotoxic Aa strains was confirmed in patients with RA and was associated with both anti-citrullinated protein antibodies (ACPAs) and rheumatoid factor (RF). The effect of HLA-DRB1 shared epitope alleles on autoantibody positivity was limited to RA patients that were exposed to Aa. These studies identify the periodontal pathogen Aa as a candidate bacterial trigger of autoimmunity in RA

A preliminary modelling investigation into the safe correction zone for high tibial osteotomy

Purpose: High tibial osteotomy (HTO) re-aligns the weight-bearing axis (WBA) of the lower limb. The surgery reduces medial load (reducing pain and slowing progression of cartilage damage) while avoiding overloading the lateral compartment. The optimal correction has not been established. This study investigated how different WBA re-alignments affected load distribu- tion in the knee, to consider the optimal post-surgery re-alignment. Methods: We collected motion analysis and 7T MRI data from 3 healthy sub- jects, and combined this data to create sets of subject-specific finite element models (total=45 models). Each set of models simulated a range of potential post-HTO knee re-alignments. We shifted the WBA from its native align- ment to between 40% and 80% medial-lateral tibial width (corresponding to 2.8◦-3.1◦ varus and 8.5◦-9.3◦ valgus), in 3% increments. We then compared stress/pressure distributions in the models. Results/Discussion: Correcting the WBA to 50% tibial width (0◦ varus- valgus) approximately halved medial compartment stresses, with minimal changes to lateral stress levels, but provided little margin for error in under- correction. Correcting the WBA to a more commonly-used 62%-65% tibial width (3.4◦-4.6◦ valgus) further reduced medial stresses but introduced the danger of damaging lateral compartment tissues. To balance optimal loading environment with that of the historical risk of under-correction, we propose a new target: WBA correction to 55% tibial width (1.7◦-1.9◦ valgus), which anatomically represented the apex of the lateral tibial spine. Conclusions: Finite element models can successfully simulate a variety of HTO re-alignments. Correcting the WBA to 55% tibial width (1.7◦-1.9◦ valgus) optimally distributes medial and lateral stresses/pressures

Arthroscopic hip surgery compared with physiotherapy and activity modification for the treatment of symptomatic femoroacetabular impingement: multicentre randomised controlled trial.

OBJECTIVE: To compare arthroscopic hip surgery with physiotherapy and activity modification for improving patient reported outcome measures in patients with symptomatic femoroacetabular impingement (FAI). DESIGN: Two group parallel, assessor blinded, pragmatic randomised controlled trial. SETTING: Secondary and tertiary care centres across seven NHS England sites. PARTICIPANTS: 222 participants aged 18 to 60 years with symptomatic FAI confirmed clinically and with imaging (radiography or magnetic resonance imaging) were randomised (1:1) to receive arthroscopic hip surgery (n=112) or a programme of physiotherapy and activity modification (n=110). Exclusion criteria included previous surgery, completion of a physiotherapy programme targeting FAI within the preceding 12 months, established osteoarthritis (Kellgren-Lawrence grade ≥2), and hip dysplasia (centre-edge angle <20 degrees). INTERVENTIONS: Participants in the physiotherapy group received a goal based programme tailored to individual patient needs, with emphasis on improving core stability and movement control. A maximum of eight physiotherapy sessions were delivered over five months. Participants in the arthroscopic surgery group received surgery to excise the bone that impinged during hip movements, followed by routine postoperative care. MAIN OUTCOME MEASURES: The primary outcome measure was the hip outcome score activities of daily living subscale (HOS ADL) at eight months post-randomisation, with a minimum clinically important difference between groups of 9 points. Secondary outcome measures included additional patient reported outcome measures and clinical assessment. RESULTS: At eight months post-randomisation, data were available for 100 patients in the arthroscopic hip surgery group (89%) and 88 patients in the physiotherapy programme group (80%). Mean HOS ADL was 78.4 (95% confidence interval 74.4 to 82.3) for patients randomised to arthroscopic hip surgery and 69.2 (65.2 to 73.3) for patients randomised to the physiotherapy programme. After adjusting for baseline HOS ADL, age, sex, and study site, the mean HOS ADL was 10.0 points higher (6.4 to 13.6) in the arthroscopic hip surgery group compared with the physiotherapy programme group (P<0.001)). No serious adverse events were reported in either group. CONCLUSIONS: Patients with symptomatic FAI referred to secondary or tertiary care achieve superior outcomes with arthroscopic hip surgery than with physiotherapy and activity modification. TRIAL REGISTRATION: ClinicalTrials.gov NCT01893034.NIHR BRC oxfor

Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8(+) T cells

Depletion of immune elements before adoptive cell transfer (ACT) can dramatically improve the antitumor efficacy of transferred CD8(+) T cells, but the specific mechanisms that contribute to this enhanced immunity remain poorly defined. Elimination of CD4(+)CD25(+) regulatory T (T reg) cells has been proposed as a key mechanism by which lymphodepletion augments ACT-based immunotherapy. We found that even in the genetic absence of T reg cells, a nonmyeloablative regimen substantially augmented CD8(+) T cell reactivity to self-tissue and tumor. Surprisingly, enhanced antitumor efficacy and autoimmunity was caused by increased function rather than increased numbers of tumor-reactive T cells, as would be expected by homeostatic mechanisms. The γ (C) cytokines IL-7 and IL-15 were required for augmenting T cell functionality and antitumor activity. Removal of γ (C) cytokine–responsive endogenous cells using antibody or genetic means resulted in the enhanced antitumor responses similar to those seen after nonmyeloablative conditioning. These data indicate that lymphodepletion removes endogenous cellular elements that act as sinks for cytokines that are capable of augmenting the activity of self/tumor-reactive CD8(+) T cells. Thus, the restricted availability of homeostatic cytokines can be a contributing factor to peripheral tolerance, as well as a limiting resource for the effectiveness of tumor-specific T cells

Patient-Relevant Outcomes Following First Revision Total Knee Arthroplasty, by Diagnosis: An Analysis of Implant Survivorship, Mortality, Serious Medical Complications, and Patient-Reported Outcome Measures Utilizing the National Joint Registry Data Set.

BackgroundThe purpose of this study was to investigate patient-relevant outcomes following first revision total knee arthroplasties (rTKAs) performed for different indications.MethodsThis population-based cohort study utilized data from the United Kingdom National Joint Registry, Hospital Episode Statistics Admitted Patient Care, National Health Service Patient-Reported Outcome Measures, and the Civil Registrations of Death. Patients undergoing a first rTKA between January 1, 2009, and June 30, 2019, were included in our data set. Patient-relevant outcomes included implant survivorship (up to 11 years postoperatively), mortality and serious medical complications (up to 90 days postoperatively), and patient-reported outcome measures (at 6 months postoperatively).ResultsA total of 24,540 first rTKAs were analyzed. The patient population was 54% female and 62% White, with a mean age at the first rTKA of 69 years. At 2 years postoperatively, the cumulative incidence of re-revision surgery ranged from 2.7% (95% confidence interval [CI], 1.9% to 3.4%) following rTKA for progressive arthritis to 16.3% (95% CI, 15.2% to 17.4%) following rTKA for infection. The mortality rate at 90 days was highest following rTKA for fracture (3.6% [95% CI, 2.5% to 5.1%]) and for infection (1.8% [95% CI, 1.5% to 2.2%]) but was ConclusionsThis study found large differences in patient-relevant outcomes among different indications for first rTKA. The rate of complications was highest following rTKA for fracture or infection. Although rTKA resulted in large improvements in joint function for most patients, those who underwent surgery for stiffness and unexplained pain had worse outcomes.Level of evidenceTherapeutic Level III. See Instructions for Authors for a complete description of levels of evidence

The varied functions of aluminium-activated malate transporters–much more than aluminium resistance

The ALMT (aluminium-activated malate transporter) family comprises a functionally diverse but structurally similar group of ion channels. They are found ubiquitously in plant species, expressed throughout different tissues, and located in either the plasma membrane or tonoplast. The first family member identified was TaALMT1, discovered in wheat root tips, which was found to be involved in aluminium resistance by means of malate exudation into the soil. However, since this discovery other family members have been shown to have many other functions such as roles in stomatal opening, general anionic homoeostasis, and in economically valuable traits such as fruit flavour. Recent evidence has also shown that ALMT proteins can act as key molecular actors in GABA (γ-aminobutyric acid) signalling, the first evidence that GABA can act as a signal transducer in plants

Single-molecule multiparameter fluorescence spectroscopy reveals directional MutS binding to mismatched bases in DNA

Mismatch repair (MMR) corrects replication errors such as mismatched bases and loops in DNA. The evolutionarily conserved dimeric MMR protein MutS recognizes mismatches by stacking a phenylalanine of one subunit against one base of the mismatched pair. In all crystal structures of G:T mismatch-bound MutS, phenylalanine is stacked against thymine. To explore whether these structures reflect directional mismatch recognition by MutS, we monitored the orientation of Escherichia coli MutS binding to mismatches by FRET and anisotropy with steady state, pre-steady state and single-molecule multiparameter fluorescence measurements in a solution. The results confirm that specifically bound MutS bends DNA at the mismatch. We found additional MutS–mismatch complexes with distinct conformations that may have functional relevance in MMR. The analysis of individual binding events reveal significant bias in MutS orientation on asymmetric mismatches (G:T versus T:G, A:C versus C:A), but not on symmetric mismatches (G:G). When MutS is blocked from binding a mismatch in the preferred orientation by positioning asymmetric mismatches near the ends of linear DNA substrates, its ability to authorize subsequent steps of MMR, such as MutH endonuclease activation, is almost abolished. These findings shed light on prerequisites for MutS interactions with other MMR proteins for repairing the appropriate DNA strand