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Complex I is the first and the largest enzyme of respiratory chains in bacteria and mitochondria. The mechanism which couples spatially separated transfer of electrons to proton translocation in complex I is not known. Here we report five crystal structures of T. thermophilus enzyme in complex with NADH or quinone-like compounds. We also determined cryo-EM structures of major and minor native states of the complex, differing in the position of the peripheral arm. Crystal structures show that binding of quinone-like compounds (but not of NADH) leads to a related global conformational change, accompanied by local re-arrangements propagating from the quinone site to the nearest proton channel. Normal mode and molecular dynamics analyses indicate that these are likely to represent the first steps in the proton translocation mechanism. Our results suggest that quinone binding and chemistry play a key role in the coupling mechanism of complex I. Complex I (NADH:ubiquinone oxidoreductase) is the first enzyme of the respiratory chain in bacteria and mitochondria. Here, the authors present cryo-EM and crystal structures of T. thermophilus complex I in different conformational states and further analyse them by Normal Mode Analysis and molecular dynamics simulations and conclude that quinone redox reactions are important for the coupling mechanism of complex I.

Context: The treatment of colorectal cancer has improved considerably in recent years, but it remains the second commonest cause of cancer deaths in men and women in the United States. Better therapies have resulted in prolonged median survival for patients with metastatic disease and a select number of patients can now be cured. Evidence Acquisition: We conducted a computerized search using PubMed and Google Scholar for reports published between January 1993 and August 2009 using mesh headings and key words relating to the treatment of colorectal cancer. If reports identified by these criteria referred to other papers not in the initial search, then these were also reviewed if relevant to metastatic colorectal cancer (MCRC). Results: Seven new chemotherapy agents have been licensed for the treatment of advanced colorectal cancer, with associated improved median survival from 5 months to 2 years. Complete responses are rare with systemic chemotherapy alone, but higher overall response rates to systemic and intrahepatic chemotherapies have enabled initially unresectable patients to undergo potentially curative surgical resection of metastases. Improved surgical expertise together with the adjunctive use of radiofrequency ablation has further expanded the definition of resectability. Advances in the understanding of tumor biology have resulted in the development of clinically useful biomarkers and the emergence of active biological therapies. Conclusions: The multidisciplinary management of MCRC incorporating improved systemic and local therapies continues to improve median survival and enlarge the cohort of patients that can be approached with curative intent. Recent technological advances have facilitated a better understanding of tumor biology that promises continued advancements in patient care.

Disability in Parkinson’s disease (PD) is measured by standardised scales including the MDS-UPDRS, which are subject to high inter and intra-rater variability and fail to capture subtle motor impairment. The BRadykinesia Akinesia INcoordination (BRAIN) test is a validated keyboard tapping test, evaluating proximal upper-limb motor impairment. Here, a new Distal Finger Tapping (DFT) test was developed to assess distal upper-limb function. Kinetic parameters of the test include kinesia score (KS20, key taps over 20 s), akinesia time (AT20, mean dwell-time on each key) and incoordination score (IS20, variance of travelling time between key taps). To develop and evaluate a new keyboard-tapping test for objective and remote distal motor function in PD patients. The DFT and BRAIN tests were assessed in 55 PD patients and 65 controls. Test scores were compared between groups and correlated with the MDS-UPDRS-III finger tapping sub-scores. Nine additional PD patients were recruited for monitoring motor fluctuations. All three parameters discriminated effectively between PD patients and controls, with KS20 performing best, yielding 79% sensitivity for 85% specificity; area under the receiver operating characteristic curve (AUC) = 0.90. A combination of DFT and BRAIN tests improved discrimination (AUC = 0.95). Among three parameters, KS20 showed a moderate correlation with the MDS-UPDRS finger-tapping sub-score (Pearson’s r = − 0.40, p = 0.002). Further, the DFT test detected subtle changes in motor fluctuation states which were not reflected clearly by the MDS-UPDRS-III finger tapping sub-scores. The DFT test is an online tool for assessing distal movements in PD, with future scope for longitudinal monitoring of motor complications.

Rugby union is a field sport that is played at amateur and professional levels by male and female players globally. One of the most prevalent injury risks associated with the sport involves tackle collisions with opposition players. This suggests that a targeted injury reduction strategy could focus on the tackle area in the game. In amateur rugby union, injuries to the head, face and shoulder are the most common injury sites in youth rugby playing populations. A suboptimal tackle technique may contribute to an increased injury risk in these populations. One proposed mitigation strategy to reduce tackle-related injuries in youth populations may be to increase tackle proficiency by coaching an effective tackle technique. The present study aimed to demonstrate a proof of concept for a tackle technique coaching platform using inertial measurement units (IMUs) and a bespoke mobile application developed for a mobile device (i.e., a mobile phone). The test battery provided a proof of concept for the primary objective of modelling the motion of a player in a tackle event. The prototype (bespoke mobile application) modelled the IMU in a 3D space and demonstrated the orientation during a tackle event. The participants simulated ten tackle events that were ten degrees above and ten degrees below the zero degree of approach, and these (unsafe tackles) were indicated by a red light on the mobile display unit. The parameters of ten degrees above and below the zero angle of approach were measured using an inclinometer mobile application. These tackle event simulations provided a real-time stream of data that displayed the angle of tackles on a mobile device. The novel coaching platform could therefore constitute part of an injury reduction strategy for amateur or novice coaches to instruct safer tackle practice in youth rugby playing populations.

Abstract Within the last decade, the science of molecular testing has evolved from single gene and single protein analysis to broad molecular profiling as a standard of care, quickly transitioning from research to practice. Terms such as genomics, transcriptomics, proteomics, circulating omics, and artificial intelligence are now commonplace, and this rapid evolution has left us with a significant knowledge gap within the medical community. In this paper, we attempt to bridge that gap and prepare the physician in oncology for multiomics, a group of technologies that have gone from looming on the horizon to become a clinical reality. The era of multiomics is here, and we must prepare ourselves for this exciting new age of cancer medicine. Through multiomics, the combined use many available technologies, a more complete and dynamic vision of cancer can be obtained. This article bridges the gap between multiomics technology and oncology practice.

BackgroundMultiple studies have explored sex-differences in motor aspects of Parkinson’s disease (PD). However, many previous studies lack diversity and their results may not be generalisable.AimTo investigate sex-related differences in motor function in PD patients in East London.Methods184 PD patients enrolled in the East London Parkinson’s disease project were included in this study. In the present analysis, the primary assessment examined here was the Unified Parkinson’s Disease Rating Scale (UPDRS).Results38% of the participants were female. Overall motor burden was higher in male participants on the UPDRS II (mean total 5.4 vs 6.9, p=0.02), but not on the UPDRS III (mean total 37.4 in females vs 39.9 in males, p=0.47). Male participants showed increased speech difficulties (UPDRS 3.1 mean 0.84 vs 1.29, p=0.005) and rigidity (UPDRS 3.3 mean 6.74 vs 8.2, p=0.018). Total levodopa equivalent dose (mean 545.5mg females vs 673.7mg males, p= 0.148) and the prevalence of dyskinesia (females 23% vs males 19%, p=0.52) were comparable.ConclusionWhile our data reflected some previously reported sex-differences in motor symptoms, many differences were absent. Possible reasons include lack of statistical power or differences in the sex-specific manifestation of PD in this diverse population.

AimTo determine sex differences in cognitive function in patients with Parkinson’s disease (PD) in East London.BackgroundSex influences the development and progression of PD. Previous studies have identified higher rates, and faster progression, of cognitive impairment in men. Although this raises important consi- derations for clinical management, it has been understudied in diverse populations.MethodsWe included 184 PD patients enrolled in the East London Parkinson’s disease project (113 male and 71 female). The primary outcome for this analysis was the Montreal Cognitive Assessment (MoCA).ResultsMen were younger at assessment (mean 67.0 vs 70.4, p=0.042) and women left education earlier (mean 17.2 vs 19.5, p=0.009). Both sexes were below the UK average for deprivation index, but there was no difference between them (mean 4.2 male vs 3.6 female, p=0.23).Overall, there was no difference in cognitive impairment as assessed by MoCA (mean total men 21.7 vs women 20.8, p=0.539). Within ethnic groups, there were also no sex differences evident (White p=0.388, Black p=0.612, South Asian p=0.256).ConclusionsAlthough men are considered as having higher cognitive impairment burden, we propose that in diverse populations, other drivers such as education level and deprivation may be stronger deter- minants than sex.

BackgroundSex-related differences in non-motor Parkinson’s disease (PD) symptoms have been reported. However, many previous studies lack diversity and their results may not be generalisable.AimTo investigate sex-related non-motor symptom differences in PD patients in East London.Methods184 PD patients enrolled in the East London Parkinson’s disease project were included in this study. Assessments examined here were the Unified Parkinson’s disease rating scale (UPDRS), Non-Motor Symptoms Questionnaire, and REM Sleep Behaviour Disorder Screening Questionnaire.ResultsMale participants reported increased drooling (UPDRS 2.2 mean 1.0 vs 1.5, p=0.020), orthostatic hypotension (UPDRS 1.12 mean 1.1 vs 1.5, p=0.040), sexual problems (11% vs 43%, p<0.001), nocturia (65% vs 81%, p=0.024), daytime somnolence (14% vs 29%, p=0.029), and insomnia (48% vs 65%, p=0.034). Swollen legs were more common in female participants (53% vs 32%, p=0.007). No sex-differences in symptoms of RBD, pain, swallowing, or subjective hyposmia were observed.ConclusionWhile our data reflected some previously reported sex-differences in non-motor symptoms of PD, many differences were absent or, even sometimes, their sex-predominance was reversed. The dis- similarities seen in our patients demonstrate the importance of diverse recruitment to better understand sex-specific differences in PD.

A 52-year-old fit and well man presented with sudden band like sensation around his chest, eight hours after scuba diving. On movement, he developed abrupt left leg weakness the next day evolving over a few hours, with nadir bilateral leg power 0/5 and urinary retention. He received five hours of hyperbaric oxygen treatment (HBOT) and intravenous immunoglobulin for possible Guillain-Barre syndrome, with no improvement. Cerebrospinal fluid protein was 0.7g/L. Ten days later, on repatriation to the UK, first exam- ination revealed spastic paraparesis with power 2/5, pinprick sensory level at T4 and preserved dorsal column function. Brain imaging was normal but in the spinal cord there was an anterior non-enhancing lesion at T3-4, felt to be ischaemic. He received further prolonged HBOT and methylprednisolone. He suffered a pulmonary embolism, probably provoked by hospital acquired pneumonia, although bloods revealed one positive lupus anticoagulant. Repeat testing returned equivocal with negative anticardiolipin antibodies. Cerebrovascular and cardiovascular abnormalities were not identified on CT-angiogram and bubble echocardiogram. After HBOT there was significant improvement and at 6 months, he can walk with a stick. Neurological complications of scuba diving are rare. This case should alert neurologists to this possible phenomenon and to consider delayed hyperbaric oxygen treatment.

Background Lynch syndrome (LS) is an autosomal dominant hereditary cancer syndrome responsible for 2–4% of hereditary colorectal cancers (CRC). Mismatch repair protein deficiency (dMMR) is a characteristic feature of LS. It has been associated with a poor response to standard chemotherapy in metastatic colorectal cancer (mCRC). There is currently no LS database to monitor trends of disease in Ireland. We aim to centralise LS data in Ireland to assess the burden of LS in Ireland and guide improvements in prevention and treatment of LS-associated cancer. Methods A retrospective review was carried out including all medical records for LS patients from two of the three cancer genetics clinics in Ireland between 2000 and 2018 was carried out. Clinicopathological data of probands ( n  = 57) and affected family members including demographics, mutation status, cancer diagnosis and outcome was recorded. Statistical analysis was carried out using SPSS software. Results Fifty-seven families including three-hundred and forty-five individuals affected by cancer were identified. The most common cancers recorded were colorectal (53%), breast (12%) and endometrial (10%). One-hundred and thirty-eight confirmed carriers were identified: 65 path_MLH1 (47%), 43 path_MSH2 (31%), 11 path_MSH6 (8%), 17 path_PMS2 (12%) and two path_EPCAM (1%). Cancer type varied significantly by gene. Median age of first diagnosis was 44.5 years (range 23–81). Half of all deceased patients ( n  = 11) in this group died within 2.5 years of first diagnosis. These deaths were directly related to cancer in 59% of cases. Conclusions Under diagnosis of LS misses a powerful preventive and therapeutic opportunity. LS causes early onset dMMR cancer diagnoses with substantial societal impact. Implementation of ICBs into treatment policy for this small cohort of dMMR mCRC is an achievable therapeutic goal that may significantly improve survival. A prospective database for LS in Ireland is necessary to maximise prevention in this population.