tbuckley/cabot-search huggingface dataset:
Network Analysis of Protein Adaptation: Modeling the Functional Impact of Multiple Mutations
Authors: Violeta Beleva Guthrie, David L Masica, Andrew Fraser, Joseph Federico, Yunfan Fan, Manel Camps, Rachel Karchin
Journal: Molecular Biology and Evolution (2018)

The evolution of new biochemical activities frequently involves complex dependencies between mutations and rapid evolutionary radiation. Mutation co-occurrence and covariation have previously been used to identify compensating mutations that are the result of physical contacts and preserve protein function and fold. Here, we model pairwise functional dependencies and higher order interactions that enable evolution of new protein functions. We use a network model to find complex dependencies between mutations resulting from evolutionary trade-offs and pleiotropic effects. We present a method to construct these networks and to identify functionally interacting mutations in both extant and reconstructed ancestral sequences (Network Analysis of Protein Adaptation). The time ordering of mutations can be incorporated into the networks through phylogenetic reconstruction. We apply NAPA to three distantly homologous β-lactamase protein clusters (TEM, CTX-M-3, and OXA-51), each of which has experienced recent evolutionary radiation under substantially different selective pressures. By analyzing the network properties of each protein cluster, we identify key adaptive mutations, positive pairwise interactions, different adaptive solutions to the same selective pressure, and complex evolutionary trajectories likely to increase protein fitness. We also present evidence that incorporating information from phylogenetic reconstruction and ancestral sequence inference can reduce the number of spurious links in the network, whereas preserving overall network community structure. The analysis does not require structural or biochemical data. In contrast to function-preserving mutation dependencies, which are frequently from structural contacts, gain-of-function mutation dependencies are most commonly between residues distal in protein structure.
Theoretical course for the diploma of the Faculty of Sexual and Reproductive Health (DFSRH)
Authors: Chirag Mehta, Mark Williams, Milan Mehta
Journal: BMJ (2009)

Any medically qualified person who is fully registered with the General Medical Council. It is for doctors who are interested in sexual and reproductive health, especially general practitioners, trainees in general practice, and trainees in obstetrics and gynaecology.

We are all completing general practice specialty training; two of us are first year specialist trainees and one of us is a general practice registrar. We completed the midweek, four day course (28 to 31 October 2008) during our placement in general practice.

About one in every 10 sexually active females (<24 years old) and males (20-24 years old) are currently infected with chlamydia, so sexual and reproductive health is a hot topic in primary and secondary care.1 We wanted to improve our knowledge and skills in these important …
Remodelling consultant roles will be difficult in current financial climate, says King’s Fund
Authors: Matthew Limb
Journal: BMJ (2014)

Extending consultants’ roles outside of hospital will be challenging within current health budgets, the King’s Fund has said.

A recent King’s Fund report said that consultants could lead clinical change by improving the delivery of specialist services in primary and community care settings.1 It said that giving consultants extra responsibilities would improve management of chronic conditions and reduce waiting times.

Ruth Robertson, fellow at the King’s Fund and coauthor of the report, said that the health service would find it difficult to introduce such changes. Speaking at a King’s Fund conference on the NHS workforce, she said, “Implementing this new way of working is a …
Sir James Paget—Contributions of a Surgeon and Pathologist
Authors: Manthan Patel, Varun Ayyaswami, Arpan V. Prabhu
Journal: JAMA Dermatology (2018)

Sir James Paget is remembered as one of the greatest English surgeons and fathers of pathology. After passing the College of Surgeon's Examination in 1836, he struggled to find a job practicing medicine and spent 7 years doing various odd jobs for minimal compensation.1
Ventilatory response to exercise in cardiopulmonary disease: the role of chemosensitivity and dead space
Authors: Jason Weatherald, Caroline Sattler, Gilles Garcia, Pierantonio Laveneziana
Journal: European Respiratory Journal (2018)

The lungs and heart are irrevocably linked in their oxygen (O 2 ) and carbon dioxide (CO 2 ) transport functions. Functional impairment of the lungs often affects heart function and vice versa . The steepness with which ventilation ( V ′ E ) rises with respect to CO 2 production ( V ′ CO 2 ) ( i.e. the V ′ E / V ′ CO 2 slope) is a measure of ventilatory efficiency and can be used to identify an abnormal ventilatory response to exercise. The V ′ E / V ′ CO 2 slope is a prognostic marker in several chronic cardiopulmonary diseases independent of other exercise-related variables such as peak O 2 uptake ( V ′ O 2 ). The V ′ E / V ′ CO 2 slope is determined by two factors: 1) the arterial CO 2 partial pressure ( P aCO 2 ) during exercise and 2) the fraction of the tidal volume ( V T ) that goes to dead space ( V D ) ( i.e. the physiological dead space ratio ( V D / V T )). An altered P aCO 2 set-point and chemosensitivity are present in many cardiopulmonary diseases, which influence V ′ E / V ′ CO 2 by affecting P aCO 2 . Increased ventilation–perfusion heterogeneity, causing inefficient gas exchange, also contributes to the abnormal V ′ E / V ′ CO 2 observed in cardiopulmonary diseases by increasing V D / V T . During cardiopulmonary exercise testing, the P aCO 2 during exercise is often not measured and V D / V T is only estimated by taking into account the end-tidal CO 2 partial pressure ( P ETCO 2 ); however, P aCO 2 is not accurately estimated from P ETCO 2 in patients with cardiopulmonary disease. Measuring arterial gases ( P aO 2 and P aCO 2 ) before and during exercise provides information on the real (and not “estimated”) V D / V T coupled with a true measure of gas exchange efficiency such as the difference between alveolar and arterial O 2 partial pressure and the difference between arterial and end-tidal CO 2 partial pressure during exercise.
DIFFUSE MYOCARDIAL FIBROSIS MEASURED BY EXTRACELLULAR VOLUME ASSOCIATES WITH INCIDENT VENTRICULAR ARRHYTHMIA IN IMPLANTABLE CARDIOVERTER DEFIBRILLATOR RECIPIENTS MORE THAN FOCAL FIBROSIS
Authors: Eric Olausson, Fredrika Fröjdh, Maren Maanja, Louise Niklasson, Yaron Fridman, Patrick Bering, Jonathan Wertz, Timothy Wong, Peter Kellman, Chris Miller, Samir Saba, Martin Ugander, Erik Schelbert
Journal: Journal of the American College of Cardiology (2018)
Duodenum Cryptococcosis Mimicking Primary Duodenum Cancer on PET/CT Imaging
Authors: Yan Xiu, Jie Zhang, Hongcheng Shi
Journal: Clinical Nuclear Medicine (2018)

Abstract A 73-year-old man presented with fatigue and anorexia and underwent FDG PET/CT scan to evaluate a right lung nodule revealed by a chest CT. The FDG PET/CT not only showed that the lung nodule was hypermetabolic but also revealed that there was significantly increased activity in the region of the duodenum. The findings were suspected as primary duodenal malignancy with metastases. However, an upper gastrointestinal tract endoscopic examination with further culture led to a diagnosis of duodenal cryptococcosis.
Distinction between serological responses following tick-borne encephalitis virus (TBEV) infection vs vaccination, Sweden 2017
Authors: Bo Albinsson, Sirkka Vene, Lars Rombo, Jonas Blomberg, Åke Lundkvist, Bengt Rönnberg
Journal: Eurosurveillance (2018)

Tick-borne encephalitis virus (TBEV) is an important European vaccine-preventable pathogen. Discrimination of vaccine-induced antibodies from those elicited by infection is important. We studied anti-TBEV IgM/IgG responses, including avidity and neutralisation, by multiplex serology in 50 TBEV patients and 50 TBEV vaccinees. Infection induced antibodies reactive to both whole virus (WV) and non-structural protein 1 (NS1) in 48 clinical cases, whereas 47 TBEV vaccinees had WV, but not NS1 antibodies, enabling efficient discrimination of infection/vaccination.
HABITUAL PHYSICAL ACTIVITY AND SURVIVAL IN OLDER ADULTS UNDERGOING TRANS CATHETER AORTIC VALVE REPLACEMENT: INSIGHTS FROM THE FRAILTY-AVR STUDY
Authors: Janarthanan Sathananthan, Nicolo Piazza, Giuseppe Martucci, Dae Hyun Kim, Jeffrey Popma, Anita Asgar, Louis Perrault, Thierry Lefèvre, Marino Labinaz, Andre Lamy, Mark Peterson, Rakesh C. Arora, Nicolas Noiseux, Philippe Genereux, John Webb, Sandra Lauck, Jonathan Afilalo
Journal: Journal of the American College of Cardiology (2018)
Clinical outcome of patients (Pts) with metastatic renal cell carcinoma (mRCC) progressing on front-line immune-oncology based combination (IO-COMBO) regimens.
Authors: Pedro C. Barata, Alfonso Gomez de Liano, Prateek Mendiratta, Valerie Crolley, Bernadett Szabados, Laura S. Wood, Beth Zanick, Kimberly D Allman, Allison Janine Tyler, Allison Martin, Timothy D. Gilligan, Petros Grivas, Moshe Chaim Ornstein, Jorge A. Garcia, Thomas Powles, Brian I. Rini
Journal: Journal of Clinical Oncology (2018)

613 Background: Several IO-COMBO regimens are under investigation in front-line mRCC. The clinical outcome of pts who progress on an IO-COMBO regimen and receive subsequent systemic therapy is unknown. Methods: A retrospective analysis of all pts with clear-cell mRCC enrolled in one of seven clinical trials investigating an IO-COMBO at Cleveland Clinic Taussig Cancer Institute and Barts Cancer Institute was conducted. Clinical outcome of subsequent therapy including best objective response according to RECIST v1.1, progression-free survival (PFS) and adverse events (AEs) using CTCAE v4.0, were collected. Results: From a total of 89 pts enrolled on an IO-COMBO trial, final analysis included 32 pts with PD who received ≥1 line of subsequent therapy, median age 57 (41-77), 83% male, 72% ECOG 0, 78% IMDC fav-/intm- risk. Prior IO-COMBO included atezolizumab/bevacizumab (n = 20), ipilimumab/nivolumab (n = 10) and axitinib/avelumab (n = 2). All except 1 pt received IO-COMBO in the front-line setting. All pts received 1 subsequent therapy (axitinib n = 15; pazopanib n = 9; sunitinib n = 4; cabozantinib n = 3; nivolumab n = 1) after progression on IO-COMBO, 12 pts were treated with a second subsequent therapy and 5 pts were treated with ≥3 subsequent lines of treatment. For pts with available response (n = 26), the overall best response to first subsequent therapy was 27% PR, 50% SD and 15% PD. Median PFS for the first subsequent therapy was 7.9 months (95% CI, 4.5-11.3) with 8 pts remaining on treatment. The median PFS for pts previously treated with a combination of IO plus anti-VEGF was 7.9 months (95% CI, 3.1-12.7) and was 9.3 months (95% CI, 3.5-15.0) for pts treated with a prior IO plus IO combination (p = 0.732). The most frequent G3/G4 treatment-related AEs observed with first subsequent therapy were LFT elevation (9%) and diarrhea (7%); 2 pts discontinued subsequent treatment due to toxicity. Conclusions: VEGF-TKIs have clinical activity in mRCC refractory to IO-COMBO therapy, possibly impacted by the inclusion of an anti-VEGF agent in prior IO-COMBO therapy. Subsequent therapy was in general well tolerated.
Preventing Delirium in the Intensive Care Unit
Authors: Anthony Delaney, Naomi Hammond, Edward Litton
Journal: JAMA (2018)

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ARTERIAL STIFFNESS AND VASCULAR CALCIFICATION PREDICTS ADVERSE CARDIOVASCULAR EVENTS IN SUBJECTS WITH CORONARY ARTERY DISEASE AFTER PERCUTANEOUS CORONARY INTERVENTION
Authors: Evangelos Oikonomou, Gerasimos Siasos, Georgios Georgiopoulos, Emmanouil Vavuranakis, Georgia Vogiatzi, Konstantinos Maniatis, Alexios Antonopoulos, Sotirios Tsalamandris, Vasiliki Tsigkou, George-Angelo Papamikroulis, Athina Goliopoulou, Dimitris Tousoulis
Journal: Journal of the American College of Cardiology (2018)
Abstract P5-07-10: Circulating microRNAs as early predictors of relapse in operable breast cancer
Authors: S Agelaki, C Papadaki, M Stratigos, M Spiliotaki, G Markakis, G Mastrostamatis, D Mavroudis, S Ioannis
Journal: Cancer Research (2018)

Abstract Background: Metastasis remains a major threat for patients (pts) with operable breast cancer (BC). Recurrence could arise from a state of tumour dormancy during which there is growth restriction of undetectable micrometastases. The expression of dormancy and metastasis related miRNAs was evaluated in the plasma of pts with operable BC obtained before adjuvant therapy in order to discover novel biomarkers for the prediction of relapse. Methods: Plasma miR-21, miR-23b, miR-190, miR-200b and miR-200c expression was assessed by qRT-PCR in 133 pts with early BC (non-relapsed, n=84; relapsed, n=49). Expression was classified as high or low according to the median values and was associated with pts' clinicopathological characteristics and clinical outcome. Results: No correlation was observed between the expression of miRNAs and the clinicopathological characteristics of pts. After a median f-up of 90.5 mo, median Disease Free Interval (DFI) was significantly lower in pts with high compared to low miR-21 [105 mo vs not reached (NR); p=0.001], miR-200c (105.2 mo vs NR; p=0.007), or both miR-21 and miR-200c expression (81.37 mo vs NR; p=0.001). miR-21-high was also associated with decreased median Overall Survival (OS; p=0.041). In multivariate analysis the number of infiltrated axillary lymph nodes (N3 vs N0-N2, HR: 2.86; p= 0.004) and miR-21 expression (high vs low, HR: 2.824; p=0.001) were independent negative prognostic factors for DFI, whereas negative hormone receptor status (HR: 3.062; p=0.024) and miR-21 high (HR: 3.545; p=0.029) independently predicted for worse OS. Moreover, miR-21 expression was higher in pts presenting early relapse (defined as relapse at ≤ 3 yrs) compared to those without relapse at 5 yrs (p=0.032). Furthermore, higher miR-21 (p=0.038), miR-23b (p=0.039), miR-200b (p=0.027) and miR-200c (p&amp;lt;0.001) levels were observed in pts with late relapse (at ≥ 5 yrs) compared to those without relapse. Conclusions: Differential expression levels of metastasis and/or dormancy related circulating miRNAs are encountered before adjuvant therapy in pts with operable BC presenting subsequent relapse compared to non-relapsed pts. In addition, circulating miRNAs could predict for early or late recurrence years before clinical detection of metastases. These results merit prospective validation in an independent pt cohort. Citation Format: Agelaki S, Papadaki C, Stratigos M, Spiliotaki M, Markakis G, Mastrostamatis G, Mavroudis D, Ioannis S. Circulating microRNAs as early predictors of relapse in operable breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-07-10.
CAN WE USE THE INTRINSIC LEFT VENTRICULAR DELAY (QLV) TO OPTIMIZE THE PACING CONFIGURATION FOR CARDIAC RESYNCHRONIZATION THERAPY WITH A QUADRIPOLAR LEFT VENTRICULAR LEAD?
Authors: Wouter van Everdingen, Alwin Zweerink, Maarten Jan Cramer, Pieter Doevendans, Uyen Chau Nguyen, Albert van Rossum, Frits Prinzen, Kevin Vernooy, Cornelis Allaart, Mathias Meine
Journal: Journal of the American College of Cardiology (2018)
Medical education bodies to cut training after last minute change to funding allocation
Authors: Helen Jaques
Journal: BMJ (2013)

Medical education organisations are planning to make cuts to their training and workforce plans for 2013-14, after a last minute change to the funding allocation formula left many boards millions of pounds short.

Continuing professional development, workforce planning, and expansion of general practitioner posts could all be hit in the regions where education boards had the biggest unplanned drops in funding.

The organisations that took control of medical education and training in England this April—previously known as local education and training boards (LETBs) but now simply known as committees of Health Education England—were given draft funding allocations in January 2013. However, a decision in March by Health Education England to change the funding allocation formula has meant that five boards are receiving millions of pounds less for 2013-14 than …
Harnessing the Power of Patient-Reported Outcomes in Oncology
Authors: Ryan D. Nipp, Jennifer S. Temel
Journal: Clinical Cancer Research (2018)

Patient-reported outcomes (PRO) represent an increasingly important mechanism for incorporating patients' experiences and perspectives into their care to enhance cancer care delivery and outcomes. In this article, we discuss the importance of integrating PROs into both the clinical and research settings in oncology and highlight potential challenges. Clin Cancer Res; 24(8); 1777-9. ©2018 AACRSee related article by Kim et al., p. 1780.
Long-term effects of discontinuation from antipsychotic maintenance following first-episode schizophrenia and related disorders: a 10 year follow-up of a randomised, double-blind trial
Authors: Christy L M Hui, William G Honer, Edwin H M Lee, Wing Chung Chang, Sherry K W Chan, Emily S M Chen, Edwin P F Pang, Simon S Y Lui, Dicky W S Chung, Wai Song Yeung, Roger M K Ng, William T L Lo, Peter B Jones, Pak Sham, Eric Y H Chen
Journal: The Lancet Psychiatry (2018)
Cell-based molecularly targeted therapy: targeting oncoproteins with T cell receptor gene therapy
Authors: Christian S. Hinrichs
Journal: Journal of Clinical Investigation (2018)

As oncogenes drive carcinogenesis and promote cancer cell survival, they are highly attractive therapeutic targets, and oncogene-targeting small molecules have achieved some clinical success. While many oncogenes are presently considered to be "druggable," tumors often acquire treatment resistance, and patients are rarely cured in response to oncogene-specific treatment. In this issue of the JCI, Veatch and colleagues describe a patient with metastatic acral melanoma who experienced a complete tumor response following infusion of tumor-infiltrating T cells that targeted multiple tumor antigens, including a BRAFV600E driver mutation. T cells genetically engineered to express an anti-BRAFV600E T cell receptor (TCR) from the patient demonstrated recognition of an epitope that spanned the BRAFV600E mutation. These findings suggest that BRAFV600E might be targeted therapeutically with adoptive transfer of anti-BRAFV600E T cells. This research supports the emerging therapeutic paradigm of targeting oncogenic drivers with T cell immunotherapy.
Impact of sleep alterations on weaning duration in mechanically ventilated patients: a prospective study
Authors: Arnaud W. Thille, Faustine Reynaud, Damien Marie, Stéphanie Barrau, Ludivine Rousseau, Christophe Rault, Véronique Diaz, Jean-Claude Meurice, Rémi Coudroy, Jean-Pierre Frat, René Robert, Xavier Drouot
Journal: European Respiratory Journal (2018)

Sleep is markedly altered in intensive care unit (ICU) patients and may alter respiratory performance. Our objective was to assess the impact of sleep alterations on weaning duration. We conducted a prospective physiological study at a French teaching hospital. ICU patients intubated for at least 24 h and difficult to wean were included. Complete polysomnography (PSG) was performed after the first spontaneous breathing trial failure. Presence of atypical sleep, duration of sleep stages, particularly rapid eye movement (REM) sleep, and electroencephalogram (EEG) reactivity at eyes opening were assessed by a neurologist. 20 out of 45 patients studied (44%) had atypical sleep that could not be classified according to the standard criteria. Duration of weaning between PSG and extubation was significantly longer in patients with atypical sleep (median (interquartile range) 5 (2–8) versus 2 (1–2) days; p=0.001) and in those with no REM sleep compared with the others. Using multivariate logistic regression analysis, atypical sleep remained independently associated with prolonged weaning (&gt;48 h after PSG). Altered EEG reactivity at eyes opening was a good predictor of atypical sleep. Our results suggest for the first time that brain dysfunction may have an influence on the ability to breathe spontaneously.
Bradyarrhythmias and pacemakers
Authors: S Honarbakhsh, L Hunter, A Chow, Ross J Hunter
Journal: BMJ (2018)

### What you need to know

Bradyarrhythmias are heart rhythms with a rate of <60 beats/min, commonly due to conduction abnormalities in the heart such as sinus node disease or atrioventricular block.1 There is increased risk of sudden cardiac death due to slowing or stopping of the heart, and of falls, especially in older people, due to fainting.

Worldwide over one million pacemakers are implanted annually for bradyarrhythmias.23 With an ageing population this is expected to increase.4 New technologies such as leadless pacemakers are being introduced, which general physicians will increasingly encounter. This update will help physicians identify and manage bradyarrhythmias appropriately and will familiarise them with an increasingly complex array of pacemakers.



Fig 1 
Position of sinus and atrioventricular nodes in the heart, with ECG features and causes of sinus node disease, first degree heart block, and atrioventricular node disease are described.



### Sources and selection criteria

We used the 2016 European Society of Cardiology (ESC) heart failure guidelines,29 the 2013 ESC13 and 2012 American College of Cardiology Foundation (ACCF)/American Heart Association (AHA)/Heart Rhythm Society (HRS) pacing guidelines16 and the 2014 National Institute …