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Purpose The purpose of this study was to quantify changes in knee loading in the three clinical planes, compensatory gait adaptations and patient-reported outcome measures (PROMS) resulting from opening wedge high tibial osteotomy (HTO). Methods Gait analysis was performed on 18 participants (19 knees) with medial osteoarthritis (OA) and varus alignment pre- and post-HTO, along with 18 controls, to calculate temporal, kinematic and kinetic measures. Oxford Knee Score, Knee Outcome Survey and visual analogue pain scores were collected. Paired and independent sample tests identified changes following surgery and deviations from controls. Results HTO restored frontal and transverse plane knee joint loading to that of the control group, while reductions remained in the sagittal plane. Elevated frontal plane trunk sway ( p  = 0.031) and reduced gait speed ( p  = 0.042), adopted as compensatory gait changes pre-HTO, were corrected by the surgery. PROMs significantly improved ( p  ≤ 0.002). Centre of pressure (COP) was lateralised relative to the knee post-HTO ( p  < 0.001). Energy absorbed in the sagittal plane significantly increased post-HTO ( p  = 0.007), whilst work done in the transverse plane reduced ( p  ≤ 0.008). Pre-operative gait deviations from the control group that were retained post-HTO included smaller sagittal ( p  = 0.003) knee range of motion during gait, greater stance duration ( p  = 0.008) and altered COP location (anterior to the knee) in early stance ( p  = 0.025). Conclusions HTO surgery restored frontal and transverse plane knee loading to normal levels and improved PROMs. Gait adaptations known to reduce knee loading employed pre-HTO were not retained post-HTO. Some gait features were found to differ between post-HTO subjects and controls. Level of evidence II

High tibial osteotomy (HTO) is successful in treating symptomatic varus arthritis of the knee. We present a case where ankle pain and instability were attributed to varus ankle malalignment. This was found to be secondary to constitutional varus of the proximal tibia but the patient's knee was asymptomatic. The decision to operate on an asymptomatic knee in the hope of improving ankle symptoms took a period of careful consideration, planning and discussion. HTO was performed without immediate complication and the patient reported an excellent outcome with marked improvement in Mazur's foot and ankle score from 18 to 85. In well selected and planned cases, HTO may be considered as an instrument of deformity correction with improvement in symptoms from joints distant to the surgical site.

We present a case of distal radius fracture. Several sequential unfortunate events resulted in a poor outcome. The patient was poorly selected because the degree of early dementia was not fully appreciated, due to intermittent periods of lucidity. Having elected to treat this distal radius fracture with Kirschner wires, a wire snapped during the procedure and was deemed safe to leave within the medullary cavity. Subsequently, the patient was left in a cast for 4 weeks without regular pin site inspection. When the cast was removed a gross osteomyelitis had developed. This series of events, led to unnecessary morbidity and extended the immobilisation time with reduced wrist function. This case highlights the importance of careful patient selection, surgical tactics and continuity of care.

High tibial osteotomy (HTO) is successful in treating symptomatic varus arthritis of the knee. We present a case where ankle pain and instability were attributed to varus ankle malalignment. This was found to be secondary to constitutional varus of the proximal tibia but the patient's knee was asymptomatic. The decision to operate on an asymptomatic knee in the hope of improving ankle symptoms took a period of careful consideration, planning and discussion. HTO was performed without immediate complication and the patient reported an excellent outcome with marked improvement in Mazur's foot and ankle score from 18 to 85. In well selected and planned cases, HTO may be considered as an instrument of deformity correction with improvement in symptoms from joints distant to the surgical site.

We present a case of distal radius fracture. Several sequential unfortunate events resulted in a poor outcome. The patient was poorly selected because the degree of early dementia was not fully appreciated, due to intermittent periods of lucidity. Having elected to treat this distal radius fracture with Kirschner wires, a wire snapped during the procedure and was deemed safe to leave within the medullary cavity. Subsequently, the patient was left in a cast for 4 weeks without regular pin site inspection. When the cast was removed a gross osteomyelitis had developed. This series of events, led to unnecessary morbidity and extended the immobilisation time with reduced wrist function. This case highlights the importance of careful patient selection, surgical tactics and continuity of care.

Heterogeneous exposure to mosquitoes determines an individual’s contribution to vector-borne pathogen transmission. Particularly for dengue virus (DENV), there is a major difficulty in quantifying human-vector contacts due to the unknown coupled effect of key heterogeneities. To test the hypothesis that the reduction of human out-of-home mobility due to dengue illness will significantly influence population-level dynamics and the structure of DENV transmission chains, we extended an existing modeling framework to include social structure, disease-driven mobility reductions, and heterogeneous transmissibility from different infectious groups. Compared to a baseline model, naïve to human pre-symptomatic infectiousness and disease-driven mobility changes, a model including both parameters predicted an increase of 37% in the probability of a DENV outbreak occurring; a model including mobility change alone predicted a 15.5% increase compared to the baseline model. At the individual level, models including mobility change led to a reduction of the importance of out-of-home onward transmission ( R , the fraction of secondary cases predicted to be generated by an individual) by symptomatic individuals (up to -62%) at the expense of an increase in the relevance of their home (up to +40%). An individual’s positive contribution to R could be predicted by a GAM including a non-linear interaction between an individual’s biting suitability and the number of mosquitoes in their home (>10 mosquitoes and 0.6 individual attractiveness significantly increased R ). We conclude that the complex fabric of social relationships and differential behavioral response to dengue illness cause the fraction of symptomatic DENV infections to concentrate transmission in specific locations, whereas asymptomatic carriers (including individuals in their pre-symptomatic period) move the virus throughout the landscape. Our findings point to the difficulty of focusing vector control interventions reactively on the home of symptomatic individuals, as this approach will fail to contain virus propagation by visitors to their house and asymptomatic carriers.

Mouth ulcers are the most common ulcerative condition and encompass several clinical diagnoses, including recurrent aphthous stomatitis (RAS). Despite previous evidence for heritability, it is not clear which specific genetic loci are implicated in RAS. In this genome-wide association study ( n  = 461,106) heritability is estimated at 8.2% (95% CI: 6.4%, 9.9%). This study finds 97 variants which alter the odds of developing non-specific mouth ulcers and replicate these in an independent cohort ( n  = 355,744) (lead variant after meta-analysis: rs76830965, near IL12A , OR 0.72 (95% CI: 0.71, 0.73); P  = 4.4e−483). Additional effect estimates from three independent cohorts with more specific phenotyping and specific study characteristics support many of these findings. In silico functional analyses provide evidence for a role of T cell regulation in the aetiology of mouth ulcers. These results provide novel insight into the pathogenesis of a common, important condition. Oral ulcerations are sores of the mucous membrane of the mouth and highly prevalent in the population. Here, in a genome-wide association study, the authors identify 97 loci associated with mouth ulcers highlighting genes involved in T cell-mediated immunity and T H 1 responses.

Hyperemesis gravidarum (HG), severe nausea and vomiting of pregnancy, occurs in 0.3–2% of pregnancies and is associated with maternal and fetal morbidity. The cause of HG remains unknown, but familial aggregation and results of twin studies suggest that understanding the genetic contribution is essential for comprehending the disease etiology. Here, we conduct a genome-wide association study (GWAS) for binary (HG) and ordinal (severity of nausea and vomiting) phenotypes of pregnancy complications. Two loci, chr19p13.11 and chr4q12, are genome-wide significant ( p  < 5 × 10 −8 ) in both association scans and are replicated in an independent cohort. The genes implicated at these two loci are GDF15 and IGFBP7 respectively, both known to be involved in placentation, appetite, and cachexia. While proving the casual roles of GDF15 and IGFBP7 in nausea and vomiting of pregnancy requires further study, this GWAS provides insights into the genetic risk factors contributing to the disease. Hyperemesis gravidarum (HG) is a severe form of nausea and vomiting associated with unfavourable outcomes during pregnancy. Here, Fejzo et al. perform genome-wide scans for HG and pregnancy nausea and vomiting and identify genetic associations at two loci implicating the genes GDF15 and IGFBP7 .

Here we conducted a large-scale genetic association analysis of educational attainment in a sample of approximately 1.1 million individuals and identify 1,271 independent genome-wide-significant SNPs. For the SNPs taken together, we found evidence of heterogeneous effects across environments. The SNPs implicate genes involved in brain-development processes and neuron-to-neuron communication. In a separate analysis of the X chromosome, we identify 10 independent genome-wide-significant SNPs and estimate a SNP heritability of around 0.3% in both men and women, consistent with partial dosage compensation. A joint (multi-phenotype) analysis of educational attainment and three related cognitive phenotypes generates polygenic scores that explain 11–13% of the variance in educational attainment and 7–10% of the variance in cognitive performance. This prediction accuracy substantially increases the utility of polygenic scores as tools in research. Gene discovery and polygenic predictions from a genome-wide association study of educational attainment in 1.1 million individuals.

Ubiquitin proteasome system (UPS) impairment, excessive cellular oxidative stress, and iron dyshomeostasis are key to substantia nigra dopaminergic neuronal degeneration in Parkinson's disease (PD); however, a link between these features remains unconfirmed. Using the proteasome inhibitor lactacystin we confirm that nigral injury via UPS impairment disrupts iron homeostasis, in turn increasing oxidative stress and promoting protein aggregation. We demonstrate the neuroprotective potential of two novel 1-hydroxy-2(1H)-pyridinone (1,2-HOPO) iron chelators, compounds C6 and C9, against lactacystin-induced cell death. We demonstrate that this cellular preservation relates to the compounds’ iron chelating capabilities and subsequent reduced capacity of iron to form reactive oxygen species (ROS), where we also show that the ligands act as antioxidant agents. Our results also demonstrate the ability of C6 and C9 to reduce intracellular lactacystin-induced α-synuclein burden. Stability constant measurements confirmed a high affinity of C6 and C9 for Fe3+ and display a 3:1 HOPO:Fe3+ complex formation at physiological pH. Reducing iron reactivity could prevent the demise of nigral dopaminergic neurons. We provide evidence that the lactacystin model presents with several neuropathological hallmarks of PD related to iron dyshomeostasis and that the novel chelating compounds C6 and C9 can protect against lactacystin-related neurotoxicity.