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Background Transvenous lead extraction (TLE) is rising in parallel to cardiac implantable electronic device implantations. Persistent left side superior vena cava (PLSVC) is a relatively common anatomical variant in the healthy population; TLE in patients with a PLSVC is rare. Method Data were collated from 6 European TLE institutes of 10 patients who had undergone lead extraction with a PLSVC. Patient demographics, procedural challenges and outcomes were reported. Results Ten patients aged 73.4 ± 7.8 years (60% male) underwent TLE of 20 leads (3 left ventricle, 10 right ventricle, 7 right atrium) with dwell time of 82.95 ± 39.1 months. Of the 10 cases, 4 had an infection indication and 5 were biventricular system extractions; 25% of the extracted leads were defibrillator leads. The majority of the procedures were completed in the cardiac catheterization suite (80%) under general anaesthesia (60%) by cardiologists (80%) using a rotational powered sheath (65%). The Tandem approach was used successfully in 3 cases. Complete procedural success was obtained in 100% of cases in the absence of complications within 127.4 ± 74.7 min. There was no 30-day mortality. Conclusion TLE in PLSVC is feasible albeit rare. Standard extraction techniques in experienced hands are associated with favorable outcomes; the Tandem procedure may be an additional technique to improve the safety and efficacy of TLE in PLSVC.

Background High adherence to remote monitoring (RM) in pacemaker (PM) patients improves outcomes; however, adherence remains suboptimal. Bluetooth low-energy (BLE) technology in newer-generation PMs enables communication directly with patient-owned smart devices using an app without a bedside console. Objective To evaluate the success rate of scheduled RM transmissions using the app compared to other RM methods. Methods The BlueSync Field Evaluation was a prospective, international cohort evaluation, measuring the success rate of scheduled RM transmissions using a BLE PM or cardiac resynchronization therapy PM coupled with the MyCareLink Heart app. App transmission success was compared to 3 historical “control” groups from the Medtronic de-identified CareLink database: (1) PM patients with manual communication using a wand with a bedside console (PM manual transmission), (2) PM patients with wireless automatic communication with the bedside console (PM wireless); (3) defibrillator patients with similar automatic communication (defibrillator wireless). Results Among 245 patients enrolled (age 64.8±15.6 years, 58.4% men), 953 transmissions were scheduled through 12 months, of which 902 (94.6%) were successfully completed. In comparison, transmission success rates were 56.3% for PM manual transmission patients, 77.0% for PM wireless patients, and 87.1% for defibrillator wireless patients. Transmission success with the app was superior across matched cohorts based on age, sex, and device type (single vs dual vs triple chamber). Conclusion The success rate of scheduled RM transmissions was higher among patients using the smart device app compared to patients using traditional RM using bedside consoles. This novel technology may improve patient engagement and adherence to RM., Graphical abstract

Aims Remote monitoring of patients with physiological data derived from cardiac implanted electronic devices (CIEDs) offers potential to reconfigure clinical services. The ‘Heart Failure Risk Score' (HFRS) uses input from integrated device physiological monitoring to risk‐stratify patients as low‐risk, medium‐risk, or high‐risk of a heart failure event in the next 30 days. This study aimed to evaluate a novel clinical pathway utilizing a combination of CIED risk‐stratification and telephone triage to identify patients with worsening heart failure (WHF). Methods and results A prospective, single‐centre, real‐world evaluation of the ‘Triage‐HF Plus' clinical pathway (HFRS in combination with telephone triage) over a 27 month period. One hundred and fifty‐seven high‐risk HFRS transmissions were referred for telephone triage assessment. Interventions were at the discretion of the clinical assessor acting in accordance with clinical guidelines. An additional 3month consecutive sample of low and medium HFRS transmissions (control group) were also contacted for telephone triage assessment (n = 98). Successful telephone contact was made in 127 (81%) of referred high‐risk HFRS cases: 71 (55.9%) were confirmed to have WHF requiring intervention; 19 (14.9%) had an alternative acute medical problem; one patient had been recently discharged from hospital with WHF; and 36 (28.0%) had no apparent cause for the high score. In the control group, only one patient had symptoms of WHF. The sensitivity and specificity of CIED‐based remote monitoring to identify WHF 98.6% (92.5–100.0%) and 63.4% (55.2–71.0%), respectively. Conclusions The Triage‐HF Plus clinical pathway is a potentially useful remote monitoring tool for patients with heart failure and in situ CIEDs.

Aims The CardioMEMS HF System Post‐Market Study (COAST) was designed to evaluate the safety, effectiveness, and feasibility of haemodynamic‐guided heart failure (HF) management using a small sensor implanted in the pulmonary artery of New York Heart Association (NYHA) Class III HF patients in the UK, Europe, and Australia. Methods and results COAST is a prospective, international, multicentre, open‐label clinical study (NCT02954341). The primary clinical endpoint compares annualized HF hospitalization rates after 1 year of haemodynamic‐guided management vs. the year prior to sensor implantation in patients with NYHA Class III symptoms and a previous HF hospitalization. The primary safety endpoints assess freedom from device/system‐related complications and pressure sensor failure after 2 years. Results from the first 100 patients implanted at 14 out of the 15 participating centres in the UK are reported here. At baseline, all patients were in NYHA Class III, 70% were male, mean age was 69 ± 12 years, and 39% had an aetiology of ischaemic cardiomyopathy. The annualized HF hospitalization rate after 12 months was 82% lower [95% confidence interval 72–88%] than the previous 12 months (0.27 vs. 1.52 events/patient‐year, respectively, P

Background Previous results from global Micra Transcatheter Pacemaker clinical trials have demonstrated leadless pacing as a safe and attractive option for patients with prior cardiac implantable electronic device (CIED) infection and extraction. Whether outcomes differ based upon the timing of prior device extraction has not been studied. Purpose To describe characteristics and outcomes of patients undergoing CIED extraction during or prior to Micra implantation. Methods Patients who underwent CIED explant and Micra implantation were identified from the Micra Post-Approval Registry and Micra Acute Performance studies. Baseline characteristics were summarized. A Fine-Gray competing risk model was used to compare risk for major complication through 24 months. Results Of the 2739 patients included in the studies, 99 (3.6%) patients had CIED extraction the day of Micra implantation (same day) and 127 (4.6%) patients had CIED extraction within 30 days prior to Micra implantation (prior). Although infection was the primary reason for CIED extraction in both groups, a larger proportion of prior patients underwent extraction for this reason (87.4% vs. 42.4%). In contrast, more same day patients underwent CIED extraction for physician/elective reasons (16.2% vs. 3.1%). Same day patients prior device history included pacemaker (42 dual chamber and 30 single chamber), ICD (1 single chamber and 4 dual chamber), CRT (7 CRT-ICD and 13 CRT-P) while prior patients device history included pacemaker (29 single chamber, 80 dual chamber), ICD (3 dual chamber), CRT (5 CRT-ICD and 7 CRT-P). Overall, patients with extraction were aged 72.8±14.3 years, predominantly male (65.9%), and medical history was similar between groups, with the exception to CHF, which was higher for the same day group (18.2% vs 6.3%, P=0.021). The implant success rate was 98.0% for same day patients and 100% for prior patients. Median procedure duration was not significantly different between the groups (26.0 minutes and 25.0 minutes for same day and prior, respectively). Average follow-up duration was 16.5±13.8 months (range 0–53.4) for same day patients and 18.2±15.2 months (range 0–58.3) for subsequent patients. The rate of acute major complications ( Conclusion The Micra leadless pacemaker was implanted with a high success rate following CIED extraction. Outcomes following CIED extraction appear similar, whether the extraction is performed during or prior to Micra implant. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Medtronic, Inc. Risk of major complications

Aims This study aims to establish the feasibility, safety, and efficacy of outpatient intravenous (IV) diuretic treatment for the management of decompensated heart failure (HF) for patients enrolled in the HeartFailure@Home service. Methods and results We retrospectively analysed the clinical episodes of decompensated HF for patients enrolled in the HeartFailure@Home service, managed by ambulatory IV diuretic treatment either at home or on a day‐case unit. A control group consisting of HF patients admitted to hospital for IV diuretics (standard‐of‐care) was also evaluated. In total, 203 episodes of decompensated HF (n = 154 patients) were evaluated. One hundred and fourteen episodes in 79 patients were managed exclusively by the ambulatory IV diuretic service—78 (68.4%) on a day‐case unit and 36 (31.6%) domiciliary; 84.1% of patient episodes under the HF@Home service were successfully managed entirely in an out‐patient setting without hospitalization. Eleven patients required admission in order to administer higher doses of IV diuretics than could be provided in the ambulatory setting. During follow‐up, there were 20 (17.5%) 30 day re‐admissions with HF or death in the ambulatory IV group and 29 (32.6%) in the standard‐of‐care arm (P = 0.02). There was no difference in 30 day HF readmissions between the two groups (14.9% ambulatory vs. 13.5% inpatients, P = 0.8), but 30 day mortality was significantly lower in the ambulatory group (3.5% vs. 21.3% inpatients, P

Background The use of transvenous pacing leads is associated with the risk of developing tricuspid valve (TV) dysfunction. This develops through several mechanisms including the failure of leaflet coaptation or direct damage to the TV or to its sub-valvular apparatus and can result in significant tricuspid regurgitation (TR). Multiple approaches to pacemaker implantation after transvenous lead extraction (TLE) or surgical TV repair have been described. Placement of pacing leads across the TV is generally avoided in such circumstances. Case summary A 66-year-old woman presented with a year-long history of exertional dyspnoea, peripheral oedema, and postural neck pulsations. Her medical history included a dual-chamber pacemaker implantation for sinus node dysfunction 14 years ago. Echocardiography revealed severe lead-related TR. Her case was discussed in our multi-disciplinary team meeting. A decision was made to perform a TLE and implant a leadless pacemaker in an attempt to avoid open-heart surgery if possible. This was reserved as an option in the event of persistent severe TR. Transvenous extraction of the right ventricular lead was performed. The atrial lead was preserved and connected to and AAI device. A Micra AV was implanted allowing for atrioventricular (AV) synchronous pacing. Discussion We present the first case of successful implementation of AV sequential pacing using a dual-pacemaker approach involving the use of an AAI pacemaker and a Micra AV device. This was performed after TLE for severe lead-related TR.

We present Pingball, an audio-based mobile game that makes the classic experience of a physical pinball machine accessible to everyone, including those with visual impairments or complete blindness. Pingball keeps the essential game mechanics of traditional pinball, but both the game design and the level design were totally overhauled, to be playable without any visuals. This was accomplished by building every feature from the ground up using only sonification techniques, such as shifting pitches and varying volumes, and spatialization techniques, such as moving audio sources through three-dimensional space. The level design makes use of a broad stereo-field by having a widened playing area featuring gameplay objectives spread over different locations. Evaluation has shown the game was considered quite playable and enjoyable by players both with and without a visual impairment.

Lead displacement is a common complication of pacemaker device implantation, often resulting in prolonged hospital stays and increased costs. The frequency of long-term lead displacement ranges between 1.8% and 8.0%. In our case, the patient did not present any symptoms and the lead displacement was seen at a relatively late stage. During a routine pacemaker follow up, it was noted that the right ventricular (RV) threshold had increased and deteriorated over time. The pacemaker box had rotated anticlockwise and the RV lead had developed a loop that eventually led to its retraction from the RV implantation position into the pulmonary artery. The patient was asymptomatic; however, he underwent RV lead revision. Patient education, opening an appropriate pocket for the size of the generator, fixing the sleeves to an appropriate tightness and securing the battery with a strong suture all can be used to avoid lead displacement.

Background/introduction Previous studies examining the utility of cardiac implantable electronic devices (CIEDs) to remotely monitor heart failure patients for decompensation have not demonstrated an impact on hard end-points. However, a key limitation of these prior studies (REM-HF and MORE-CARE) has been the failure to stratify patients according to their risk of worsening heart failure (WHF) prior to randomization (usual care vs active monitoring). We examined a different approach, using a single manufacturer’s remote monitoring platform, whereby only patients with CIED-derived data indicating the highest risk of WHF are contacted for assessment. The validated ‘Triage Heart Failure Risk Score’ (Triage-HFRS) is a medical algorithm within Medtronic CIEDs that can risk-stratify patients as low-, medium- or high-risk of WHF in the next 30 days based on integrated monitoring of physiological parameters. Purpose This study is the largest prospective evaluation of the Triage-HFRS, and examines the additional role of contacting those patients with a ‘High-Risk’ Triage-HFRS alert by telephone (Triage-HF Plus pathway). Methods Prospective, real-world evaluation of the Triage-HF Plus pathway undertaken between June 2016 and September 2019. 326 high-risk Triage-HFRS transmissions were contacted for telephone triage assessment. Screening questions were designed to identify episodes of WHF and non-heart failure events. Interventions were at the discretion of the clinical practitioner and in line with guideline-directed practice. An additional 3-month consecutive sample of low and medium Triage-HFRS transmissions (control group) were also contacted for telephone triage assessment (n= 98). Results Successful telephone contact was made following 245 high-risk Triage-HFRS alerts. Following contact, 194 (79.1%) patients reported an acute medical issue: 137 (70.6%) reported symptoms consistent with worsening heart failure (WHF) requiring intervention; and 57 (29.4%) had an alternative acute medical problem. 51 (26.2%) had no apparent reason for the high score. The sensitivity and specificity of CIED-based remote monitoring to identify any HF and non-HF events requiring intervention was 99.5% (97.2-99.9%) and 65.5% (57.3-73.2%) respectively; positive predictive value was 79.2%. The negative predictive value of a non-high risk score to rule out an acute event was 98.9%. Overall accuracy of the pathway to identify an acute issue (HF or non-HF related) was 84.8%. Conclusion The Triage-HF Plus clinical pathway is a potentially useful remote monitoring tool for patients with heart failure. The pathway has high diagnostic accuracy to identify patients with WHF and a wide range of non-HF issues which are just as relevant in a population who often have multiple complex co-morbidities and are known for their high health care utilisation.

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Aim Surgical site infection (SSI) and wound dehiscence are dreaded complications following laparotomy in general surgical patients, and can potentially occur more often in various comorbid states. Negative-pressure wound therapy (NPWT) has a positive effect of on open and complicated wounds and so has been used for at-risk surgical incisions with the aim of redistributing lateral tension and holding incision edges together. The aim of the present study was to compare the rate of wound complications following laparotomy in high-risk general surgical patients with a clean incision treated with closed-incision negative-pressure therapy (ciNPT) with those receiving conventional care. Method A retrospective review was performed of the hospital medical records of patients who underwent laparotomy between 1 October 2010 and 31 March 2012. Records of 69 patients who received ciNPT and 112 who were managed by adherent gauze dressings were included in the final analysis. Results Two (2.9%) patients in the ciNPT group and 23 (20.5%) in the non-NPWT group developed a wound complication following laparotomy (P

Parasites of genus Leishmania are the causative agents of complex neglected diseases called leishmaniasis and continue to be a significant health concern globally. Iron is a vital nutritional requirement for virtually all organisms, including pathogenic trypanosomatid parasites, and plays a crucial role in many facets of cellular metabolism as a cofactor of several enzymes. Iron acquisition is essential for the survival of parasites. Yet parasites are also vulnerable to the toxicity of iron and reactive oxygen species. The aim of this review is to provide an update on the current knowledge about iron acquisition and usage by Leishmania species. We have also discussed about host strategy to modulate iron availability and the strategies deployed by Leishmania parasites to overcome iron withholding defences and thus favour parasite growth within host macrophages. Since iron plays central roles in the host's response and parasite metabolism, a comprehensive understanding of the iron metabolism is beneficial to identify potential viable therapeutic opportunities against leishmaniasis.

Introduction: Leadless pacemakers may provide a safe and attractive pacing option to patients with cardiac implantable electronic device (CIED) infection. We describe the characteristics and outcomes of patients with a recent CIED infection undergoing Micra implant attempt. Methods and Results: Patients with prior CIED infection and device explant with Micra implant within 30 days, were identified from the Micra post approval registry. Procedure characteristics and outcomes were summarized. A total of 105 patients with prior CIED infection underwent Micra implant attempt ≤30 days from prior system explant (84 [80%] pacemakers and 13 [12%] ICD/CRT-D). All system components were explanted in 93% of patients and explant occurred a median of 6 days before Micra implant, with 37% occurring on the day of Micra implant. Micra was successfully implanted in 99% patients, mean follow-up duration was 8.5 ± 7.1 months (range 0-28.5). The majority of patients (91%) received IV antibiotics preimplant, while 42% of patients received IV antibiotics postprocedure. The median length of hospitalization following Micra implant was 2 days (IQR, 1-7). During follow-up, two patients died from sepsis and four patients required system upgrade, of which two patients received Micra to provide temporary pacing support. There were no Micra devices explanted due to infection. Conclusion: Implantation of the Micra transcatheter pacemaker is safe and feasible in patients with a recent CIED infection. No recurrent infections that required Micra device removal were seen. Leadless pacemakers appear to be a safe pacing alternative for patients with CIED infection who undergo extraction.

Background\ud There are limited reports outlining the financial cost of treating cardiac implantable electronic device (CIED) infection outside the United States. This study aimed to determine the average treatment cost of CIED infection in a large UK tertiary referral centre and compared costs of different treatment pathways that are recognised in the management of CIED infection (early versus delayed re-implantation).\ud \ud Methods\ud We retrospectively analysed cost and length of stay (LOS) data for consecutive patients undergoing infected CIED extraction with cardiac resynchronization therapy (CRT-D [with defibrillator], CRT-P [with pacemaker]), implantable cardioverter-defibrillators (ICDs) and permanent pacemakers (PPMs).\ud \ud Results\ud Between January 2013 and March 2015, complete data was available for 84 patients (18 [21.4%] CRT-D, 24 [28.6%] ICDs and 42 [50.0%] PPMs). When all cases were considered the cost of infection ranged from £5,139 (PPM) to £24,318 (CRT-D). Considering different treatment strategies; 41 (48.8%) underwent CIED extraction and re-implantation during the same admission (early re-implant strategy (ER). 43 (51.2%) underwent extraction, but were then discharged home to be re-admitted for day-case re-implantation (delayed re-implant strategy (DR)). Median LOS was significantly shorter in DR compared to ER (5.0 vs. 18.0 days, p

Leishmania is a unicellular protozoan parasite which causes leishmaniasis, a neglected tropical disease. It possess a unique thiol metabolism comprising of several proteins among which, tryparedoxin (cTXN) and tryparedoxin peroxidase (cTXNPx), function in concert as oxidoreductases, utilizing trypanothione as a source of electrons to reduce the hydroperoxides produced by macrophages during infection. This detoxification pathway is unique and essential for the survival of Leishmania. Herein, we report the functional characterization of Leishmania donovani cTXN and its interaction with cTXNPx. The full length recombinant cTXN and cTXNPx proteins were purified in the native state and biochemical analysis showed that the cTXN-cTXNPx coupled system efficiently degraded hydrogen peroxide and tert-butyl hydroperoxide by transferring reducing equivalents from trypanothione. In silico investigation of the potential interaction between cTXN and cTXNPx proteins showed strong interaction of model structures with amino acids Ile109, Thr132, Glu107, Trp70, Trp39, Cys40 and His129 of Ld-cTXN and Thr54, Lys93, Arg128 and Asn152 of Ld-cTXNPx predicted to be involved in interaction. Moreover, co-purification, pull down assay and immunoprecipitation studies confirmed the interaction between Ld-cTXN and Ld-cTXNPx proteins. In addition, for the first time, we demonstrated at the translational level that Ld-cTXN protein is upregulated in Amp B resistant isolates accompanied by enhanced peroxidase activity, as compared to sensitive strains. Thus, our results show that Ld-cTXN and Ld-cTXNPx proteins acts in concert by physical interaction to form a strong peroxide stress detoxification system in Leishmania and their upregulation in Amp B resistant isolates imparts better stress tolerance, and hence fitter pathogens, as compared to sensitive strains.

Background Advances in clinical management have improved life expectancy in the ACHD population; as a result, implantable cardiac devices remain in situ for longer periods than ever before. These patients pose unique challenges, including; young age at implant, multiple device procedures during their lifetime, complex venous and cardiac anatomy, and co-morbidities which may predispose to infection. In the non-ACHD population, there is useful long-term research which helps to guide clinical decision-making; however, small numbers and incomplete outcome data has lead to limited comparability against ACHD patients. Aims This study aimed to examine 20 years of pacing experience in a large ACHD centre, using novel data-mining techniques to generate comprehensive lead survival data. Methodology A retrospective analysis was performed of pacing and defibrillator leads implanted between June 1996 and December 2016 in a 173 patient ACHD cohort. Automated text searching algorithms with manual review of over 1 00 000 pieces of clinical correspondence was used to maximise identification of outcomes. Lead-specific complications, non-elective removal and overall lead survival were compared for surgical and transvenous leads in patients with complex and non-complex ACHD anatomy. Results 340 leads with complete implant and follow-up data were identified of which 53% were in patients with complex ACHD anatomy and 15% were in patients with tricuspid valve abnormalities. Median lead survival time was 13.6 years in transvenous leads and 15.9 years in surgical leads (p=n .s.) Transvenous leads were associated with a higher risk of major infection than were surgically-implanted leads (11.5% vs 0% p Conclusion In this large cohort of patients with ACHD, lead survival appears to be reasonable regardless of whether a transvenous or surgical approach is used. A higher incidence of infection in transvenous leads is offset by a higher electrical failure rate in surgical leads. Further work examining large cohorts is required to determine optimal pacing strategies tailored to patient-specific anatomical challenges.

Purpose The NHS Bowel cancer screening programme (NHSBCSP) aims to reduce colorectal cancer (CRC) cumulative mortality by up to 23 per cent; long-term outcomes at national level are not yet known. The purpose of this paper is to examine a local population of CRC patients of screening age for their characteristics and long-term survival in relation to their presentation, including through the NHSBCSP. Design/methodology/approach Retrospective analysis of a prospectively maintained CRC database for the years 2009-2014 in a single district hospital providing bowel cancer screening and tertiary rectal cancer services. Findings Of 528 CRC patients diagnosed in the screening age range, 144(27.3 per cent) presented through NHSBCSP, 308(58.3 per cent) electively with symptoms and 76(14.4 per cent) as emergency. NHSBCSP-diagnosed patients were younger (median 66 vs 68 and 69 years, respectively, p=0.001), had more often left-sided cancers (59(41.0 per cent) vs 82(26.6 per cent) and 24(31.6 per cent), respectively, p=0.001), more UICC-stage I (42(29.2 per cent) vs 49(15.9 per cent) and 2(2.6 per cent)), stage III (59(41.0 per cent) vs 106(34.4 per cent) and 20(26.3 per cent)) and less stage IV disease (8(5.6 per cent) vs 61(19.8 per cent) and 34 (44.7 per cent), respectively, pp Originality/value Patients diagnosed within the NHSBCSP have improved outcome compared to both symptomatic elective and emergency presentations. A reduction in overall cumulative mortality in order of 25 per cent may well be achieved, but continuing high levels of emergency presentations and undetected right-sided disease emphasise need for further improvement in public participation in the NHSBCSP and research into more sensitive and acceptable alternative screening methods.

The pathogenicity of protozoan parasites is frequently attributed to their ability to circumvent the deleterious effects of ROS and Fe-S clusters are among their susceptible targets with paramount importance for parasite survival. The biogenesis of Fe-S clusters is orchestrated by ISC system; the sulfur donor IscS and scaffold protein IscU being its core components. However, among protozoan parasites including Leishmania, no information is available regarding biochemical aspect of IscU, its interaction partners and regulation. Here, we show that Leishmania donovani IscU homolog, LdIscU, readily assembles [2Fe-2S] clusters and, interestingly, follows Michaelis-Menten enzyme kinetics. It is localized in the mitochondria of the parasite and interacts with LdIscS to form a stable complex. Additionally, LdIscU and Fe-S proteins activity is significantly upregulated in resistant isolates and during stationary growth stage indicating an association between them. The differential expression of LdIscU modulated by Fe-S proteins demand suggests its potential role in parasite survival and drug resistance. Thus, our study provides novel insight into the Fe-S scaffold protein of a protozoan parasite.

Leishmania donovani is a unicellular protozoon parasite that causes visceral leishmaniasis (VL), which is a fatal disease if left untreated. Certain Fe-S proteins of the TCA cycle and respiratory chain have been found in the Leishmania parasite but the precise mechanisms for their biogenesis and the maturation of Fe-S clusters remains unknown. Fe-S clusters are ubiquitous cofactors of proteins that perform critical cellular functions. The clusters are biosynthesized by the mitochondrial Iron-Sulphur Cluster (ISC) machinery with core protein components that include the catalytic cysteine desulphurase IscS, the scaffold proteins IscU and IscA, and frataxin as an iron carrier/donor. However, no information regarding frataxin, its regulation, or its role in drug resistance is available for the Leishmania parasite. In this study, we characterized Ld-frataxin to investigate its role in the ISC machinery of L. donovani. We expressed and purified the recombinant Ld-frataxin protein and observed its interaction with Ld-IscU by co-purification and pull-down assay. Furthermore, we observed that the cysteine desulphurase activity of the purified Ld-IscS protein was stimulated in the presence of Ld-frataxin and Ld-IscU, particularly in the presence of iron; neither Ld-frataxin nor Ld-IscU alone had significant effects on Ld-IscS activity. Interestingly, RT-PCR and western blotting showed that Ld-frataxin is upregulated in AmpB-resistant isolates compared to sensitive strains, which may support higher Fe-S protein activity in AmpB-resistant L. donovani. Additionally, Ld-frataxin was localized in the mitochondria, as revealed by digitonin fractionation and indirect immunofluorescence. Thus, our results suggest the role of Ld-frataxin as an iron binding/carrier protein for Fe-S cluster biogenesis that physically interacts with other core components of the ISC machinery within the mitochondria.

Objectives Recently published clinical guidelines recommend cardiac resynchronisation therapy (CRT) for patients with heart failure (HF) with reduced LVEF and non-left bundle branch block (non-LBBB) QRS morphology. We sought to define the potential benefit of CRT in these patients through meta-analysis of randomised controlled trials (RCTs) that have reported outcomes in patients with non-LBBB QRS morphology. Methods We searched MEDLINE and EMBASE for RCTs of CRT that reported outcomes according to QRS morphology. We performed meta-analysis of these RCTs to assess the effect of CRT on the end points of death, HF hospitalisation, and the composite of death and HF hospitalisation. Results Five RCTs were analysed, including 6523 participants (1766 with non-LBBB QRS morphology). CRT was not associated with a reduction in death and/or HF hospitalisation in subjects with non-LBBB QRS morphology (HR 0.99 95% CI 0.82 to 1.20). Conclusions CRT is not associated with a reduction in death or HF hospitalisation in patients with non-LBBB QRS morphology. Wide QRS with non-LBBB morphology remains an area of uncertainty for CRT, which is included in the recent European Society of Cardiology guidelines with a weaker strength of recommendation, but is not supported by a dedicated RCT.

AIMS: To examine the utility of (18)F-fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) in the early diagnosis of cardiac implantable electronic device (CIED) generator pocket infection. METHODS AND RESULTS: A total of 86 patients with CIEDs were evaluated with (18)F-FDG PET/CT imaging: 46 with suspected generator pocket infection and 40 without any history of infection. (18)F-FDG activity in the region of the generator pocket was expressed as a semi-quantitative ratio (SQR)-defined as the maximum count rate around the CIED divided by the mean count rate between normal right and left lung parenchyma. All patients underwent standard clinical management, independent of the PET/CT result. Patients with suspected generator pocket infection that required CIED extraction (n = 32) had significantly higher (18)F-FDG activity compared with those that did not (n = 14), and compared with controls (n = 40) [SQR: 4.80 (3.18-7.05) vs. 1.40 (0.88-1.73) vs. 1.10 (0.98-1.40), respectively; P < 0.001]. On receiver operator characteristic analysis, SQR had a high diagnostic accuracy (area under curve = 0.98) for the early identification of patients with confirmed infection (i.e. those ultimately needing extraction)-with an optimal SQR cut-off value of >2.0 (sensitivity = 97%; specificity = 98%). CONCLUSION: This study highlights the potential benefits of evaluating patients with suspected CIED generator pocket infection using (18)F-FDG PET/CT. In this study, (18)F-FDG PET/CT had a high diagnostic accuracy in the early diagnosis of CIED generator pocket infection, even where initial clinical signs were underwhelming.

We report here a Leishmania donovani ornithine decarboxylase (Ld-ODC) gene used as a DNA vaccine against visceral leishmaniasis in a murine Balb/c mouse model. This study also evaluated the possible mechanism of action directed by this candidate. We found a Th1 immune response after immunization using an Ld-ODC DNA vaccine, with results based on the rearrangement of TCR-V-α-2, proliferation of Carboxy fluorescein Succinimidyle ester positive T cells, which were able to produce cytokines such as TNF-α, IFN-γ, IL-12 and IL-2, but not IL-4, IL-5, IL-6 and IL-10, and modulations of the STAT-1 and p38 MAP kinase signaling pathways. The results were corroborated with the reduction in the amastigote proliferation and parasite killing in spleens after infection in vitro. We conclude this study suggesting that the Ld-ODC DNA construct could be a new vaccine candidate against visceral leishmaniasis.

Purpose Higher caseloads are associated with better outcomes for many conditions treated in secondary and tertiary care settings, including colorectal cancer (CRC). There is little known whether such volume-outcome relationship exist in primary care settings. The purpose of this paper is to examine general practitioner (GP) CRC-specific caseload for possible associations with referral pathways, disease stage and CRC patients’ overall survival. Design/methodology/approach The paper retrospectively analyses a prospectively maintained CRC database for 2009-2014 in a single district hospital providing bowel cancer screening and tertiary rectal cancer services. Findings Of 1,145 CRC patients, 937 (81.8 per cent) were diagnosed as symptomatic cancers. In total, 210 GPs from 44 practices were stratified according to their CRC caseload over the study period into low volume (LV, 1-4); medium volume (MV, 5-7); and high volume (HV, 8-21 cases). Emergency presentation (LV: 49/287 (17.1 per cent); MV: 75/264 (28.4 per cent); HV: 105/386 (27.2 per cent); p=0.007) and advanced disease at presentation (LV: 84/287 (29.3 per cent); MV: 94/264 (35.6 per cent); HV: 144/386 (37.3 per cent); p=0.034) was more common amongst HV GPs. Three-year mortality risk was significantly higher for HV GPs (MV: (hazard ratio) HR 1.185 (confidence interval=0.897-1.566), p=0.231, and HV: HR 1.366 (CI=1.061-1.759), p=0.016), but adjustment for emergency presentation and advanced disease largely accounted for this difference. There was some evidence that HV GPs used elective cancer pathways less frequently (LV: 166/287 (57.8 per cent); MV: 130/264 (49.2 per cent); HV: 182/386 (47.2 per cent); p=0.007) and more selectively (CRC/referrals: LV: 166/2,743 (6.1 per cent); MV: 130/2,321 (5.6 per cent); HV: 182/2,508 (7.3 per cent); p=0.048). Originality/value Higher GP CRC caseload in primary care may be associated with advanced disease and poorer survival; more work is required to determine the reasons and to develop targeted intervention at local level to improve elective referral rates.

Background:\ud Subcutaneous implantable cardioverter defibrillators (S-ICD) are an alternative to conventional transvenous implantable cardioverter defibrillators (TV-ICD) in patients not requiring pacing. We sought to define the efficacy and safety of S-ICD through literature review.\ud \ud Methods:\ud We searched MEDLINE and EMBASE for studies evaluating efficacy and safety outcomes among patients undergoing S-ICD implantation. We performed narrative synthesis and pooled efficacy and safety outcomes across studies.\ud \ud Results:\ud 16 studies were included with 5,380 participants (mean age range 33–56 years). Short-term follow-up data were available for 1670 subjects. The commonest complication was pocket infection, affecting 2.7% (range 0–19%). Other complications included delayed wound healing (0.6%), wound discomfort (0.8%), haematoma (0.4%) and lead migration (0.3%). A total of 3.8% (range 0–12%) of S-ICDs were explanted. The commonest reason for explant was pocket infection. Mortality rates in hospital (0.4%) and during follow-up (3.4% from 12 studies reporting, 2.1% per person-years) were low. The number of patients experiencing ventricular arrhythmia varied across studies from 0 to 12%. Overall shock efficacy for treatment of ventricular arrhythmias exceeded 96%. Inappropriate shocks affected 4.3% (range 0–15%) of patients and was most commonly caused by T-wave oversensing.\ud \ud Conclusions:\ud Although long-term randomised data are lacking, observational data suggest shock efficacy, peri-procedural and short-term complication rates of the S-ICD are similar to TV-ICD, making the S-ICD a suitable alternative in patients without an indication for pacing.

BACKGROUNDPredicting which individuals will have a decline in left ventricular (LV) function after pacemaker implantation remains an important challenge. We investigated whether LV global longitudinal strain (GLS), measured by 2D speckle tracking strain echocardiography, can identify patients at risk of pacing-induced left ventricular dysfunction (PIVD) or pacing-induced cardiomyopathy (PICMP).METHODSFifty-five patients with atrioventricular block and preserved LV function underwent dual-chamber pacemaker implantation and were followed with serial transthoracic echocardiography for 12 months for the development of PIVD (defined as a reduction in LV ejection fraction (LVEF) ≥5 percentage points at 12 months) or PICMP (reduction in LVEF to RESULTSAt 12 months, 15 (27%) patients developed PIVD; of these, 4 patients developed PICMP. At one month, GLS was significantly lower in the 15 patients who subsequently developed PIVD, compared to those who did not (n = 40) (GLS -12.6 vs. -16.4 respectively; p = 0.022). When patients with PICMP were excluded, one month GLS was significantly reduced compared to baseline whereas LVEF was not. One-month GLS had high predictive accuracy for determining subsequent development of PIVD or PICMP (AUC = 0.80, optimal GLS threshold: CONCLUSIONSGLS is a novel predictor of decline in LV systolic function following pacemaker implantation, with the potential to identify patients at risk of PIVD before measurable changes in LVEF are apparent. GLS measured one month after implantation has high predictive accuracy for identifying patients who later develop PIVD or PICMP.

OBJECTIVE Implantation of biventricular devices (BiV) with a transvenous left ventricular lead is complex requiring a significant fluoroscopy time and radiation dose. In the United Kingdom, the Health Protection Agency (HPA) collects data regarding radiographic procedures and sets national diagnostic reference levels (DRL) at the 75th percentile of the distribution of doses for a wide range of procedures. Insufficient data were returned to the HPA to allow them to set DRL for BiV devices at the last publication in 2010. Due to the large variation in data available and small datasets for BiV procedures we aimed to collect a large dataset to guide standards for implantation. METHODS We collected retrospective data (fluoroscopy time and radiation dose [DAP]) for new BiV devices for the three years 2009-2011 from three high volume tertiary centres in the North West of England. Databases were scrutinised to ensure the quality of the data. RESULTS From a total of 1374 implants we identified data for 1319 patients for fluoroscopy time and 1316 for DAP. The mean fluoroscopy time for all three centres combined was 18.7±0.3 min. The 75th percentile fluoroscopy time for the combined data was 24.2 min. The mean DAP for the three centres combined was 25.1±1.3 Gy cm2. The 75th percentile DAP for the combined data was 27.7 Gy cm2. CONCLUSIONS We present a large dataset of new biventricular device implants, based on the 75th percentile data we suggest a DRL of 24.2 min and 27.7 Gy cm2.

The cysteine desulfurase, IscS, is a highly conserved and essential component of the mitochondrial iron-sulfur cluster (ISC) system that serves as a sulfur donor for Fe-S clusters biogenesis. Fe-S clusters are versatile and labile cofactors of proteins that orchestrate a wide array of essential metabolic processes, such as energy generation and ribosome biogenesis. However, no information regarding the role of IscS or its regulation is available in Leishmania, an evolving pathogen model with rapidly developing drug resistance. In this study, we characterized LdIscS to investigate the ISC system in AmpB-sensitive vs resistant isolates of L. donovani and to understand its regulation. We observed an upregulated Fe-S protein activity in AmpB-resistant isolates but, in contrast to our expectations, LdIscS expression was upregulated in the sensitive strain. However, further investigations showed that LdIscS expression is positively correlated with ROS level and negatively correlated with Fe-S protein activity, independent of strain sensitivity. Thus, our results suggested that LdIscS expression is regulated by ROS level with Fe-S clusters/proteins acting as ROS sensors. Moreover, the direct evidence of a mechanism, in support of our results, is provided by dose-dependent induction of LdIscS-GFP as well as endogenous LdIscS in L. donovani promastigotes by three different ROS inducers: H2O2, menadione, and Amphotericin B. We postulate that LdIscS is upregulated for de novo synthesis or repair of ROS damaged Fe-S clusters. Our results reveal a novel mechanism for regulation of IscS expression that may help parasite survival under oxidative stress conditions encountered during infection of macrophages and suggest a cross talk between two seemingly unrelated metabolic pathways, the ISC system and redox metabolism in L. donovani.

A 58-year-old woman noticed right-hand jerky tremor exclusively while curling her hair. Her tremor-generating posture was reminiscent of the Asturian pourer of cider, or “escanciador,” who holds the bottle above the head when vertically pouring to aerate the liquid (figure). On examination, we asked her to hold a water bottle as if it were a hair curler. This elicited an action-induced, position-dependent, task-specific, weight-sensitive tremor, which attenuated when touching her affected hand with the unaffected one (closed-loop sensory feedback or sensory trick) (video 1). The rest of the examination was normal. These 5 clinical features distinguish dystonic tremor from all other tremor syndromes.1,2

Background: The use of pacemakers in the treatment of cardioinhibitory vasovagal syncope is controversial with a mixed message from the limited evidence base. Single chamber leadless pacemakers have been shown to be an effective alternative option to conventional pacemakers. Objective: This study examines the use of leadless pacemakers in a cardioinhibitory vasovagal population in the United Kingdom. Methods: Observational data on 32 patients implanted with the Micra Transcatheter Pacemaker System for vasovagal syncope are presented. Data was collected on implant indications, implant procedure and follow up data from 12 centres across the United Kingdom that had elected to use a Micra leadless pacemaker in this patient population. Results: 32 patients aged 37 ± 14 years (range 18 to 64 years) with 62% of the patients being female were recruited to the study. Vasovagal syncope was diagnosed clinically and with the support of Holter monitoring, tilt table testing and implantable loop recorders. The duration of symptoms was 8 ± 8 yrs. with an average frequency of syncope being 4 ± 6 times/year. The Micra pacemaker was successfully implanted in all patients with a major complication rate of 3.1%. Patients were followed up for 404 ± 237 days (range 63–928 days). At follow up 28 (87%) patients were free from symptoms. Conclusions: This observational study suggests that the use of a single chamber leadless pacemaker in the treatment of cardioinhibitory vasovagal syncope might be a reasonable clinical option. Keywords: Vasovagal, Cardioinhibitory, Syncope, Pacemaker, Leadless pacemaker, Micra

Due to expanding clinical indications and an aging society there has been an increase in the use of implantable pacemakers. At the same time, due to increased diagnostic yield over other imaging modalities and the absence of ionizing radiation, there has been a surge in demand for magnetic resonance imaging (MRI) assessment, of both cardiac and noncardiac conditions. Patients with an implantable device have a 50-75% chance of having a clinical indication for MRI during the lifetime of their device. The presence of an implantable cardiac device has been seen as a relative contraindication to MRI assessment, limiting the prognostic and diagnostic utility of MRI in many patients with these devices. The introduction of MRI conditional pacemakers will enable more patients to undergo routine MRI assessment without risk of morbidity or device malfunction. This review gives a general overview of the principles and current evidence for the use of MRI conditional implantable cardiac devices. Furthermore, we appraise the differences between those pacemakers currently released to market.

Pacing-induced ventricular dysfunction and pacing-induced cardiomyopathy (PiCMP) are recognized complications of chronic right ventricular pacing. Alterations in myocardial perfusion and sympathetic innervation contribute to the development of pacing-induced heart disease. However, it is unlikely that these are the only processes involved. Matrix metalloproteinases (MMPs) are proteolytic enzymes that degrade the collagenous extracellular matrix and play a central role in left ventricular remodelling during the development of heart failure. While the pathophysiological mechanisms and altered MMP expression that occur in chronic pressure overload, ischaemic and non-ischaemic dilated cardiomyopathy have been defined, those that occur in the clinical setting of pacing-induced ventricular dysfunction and PiCMP have not been reported. Here we review the clinical epidemiology of pacing-induced ventricular dysfunction and discuss how data derived from animal models provide insight into how changes in MMP expression and function contribute to the development of PiCMP. The review concludes by exploring pacing strategies that may be used to prevent pacing-induced ventricular dysfunction.

Leishmania possess a unique trypanothione redox metabolism with undebated roles in protection from oxidative damage and drug resistance. The biosynthesis of trypanothione depends on l-cysteine bioavailability which is regulated by cysteine biosynthesis pathway. The de novo cysteine biosynthesis pathway is comprised of serine O-acetyltransferase (SAT) and cysteine synthase (CS) enzymes which sequentially mediate two consecutive steps of cysteine biosynthesis, and is absent in mammalian host. However, despite the apparent dependency of redox metabolism on cysteine biosynthesis pathway, the role of SAT and CS in redox homeostasis has been unexplored in Leishmania parasites. Herein, we have characterized CS and SAT to investigate their interaction and relative abundance of these proteins in promastigote vs. amastigote growth stages of L. donovani. CS and SAT genes of L. donovani (LdCS and LdSAT) were cloned, expressed, and fusion proteins purified to homogeneity with affinity column chromatography. Purified LdCS contains PLP as cofactor and showed optimum enzymatic activity at pH 7.5. Enzyme kinetics showed that LdCS catalyses the synthesis of cysteine using O-acetylserine and sulfide with a Km of 15.86 mM and 0.17 mM, respectively. Digitonin fractionation and indirect immunofluorescence microscopy showed that LdCS and LdSAT are localized in the cytoplasm of promastigotes. Size exclusion chromatography, co-purification, pull down and immuno-precipitation assays demonstrated a stable complex formation between LdCS and LdSAT proteins. Furthermore, LdCS and LdSAT proteins expression/activity was upregulated in amastigote growth stage of the parasite. Thus, the stage specific differential expression of LdCS and LdSAT suggests that it may have a role in the redox homeostasis of Leishmania.

Primary headache disorders affect large number of people worldwide. Migraine and tension type headaches constitute 95% of all headaches. Both tension type headaches and migraine impose huge socioeconomic impact on society. The role of non-pharmacological interventions in management of primary headaches is not entirely clear. Acupuncture is one of the most historical non pharmacological ways of treating migraine and tension type headaches. The evidence in support of its effectiveness however is conflicting. This review evaluates the available evidence regarding effectiveness of acupuncture for migraine and tension type headaches.

Introduction:There are several options to achieve a sufficient safety margin in a patient with a high defibrillation threshold (DFT), with varying and typically modest success. Programming fixed (millisecond) durations of both phases of a biphasic waveform in an implantable cardioverter defibrillator (ICD) has demonstrated utility. Methods:We established an informal multisite registry of ICD implanting facilities. Each facility agreed to attempt the use of fixed duration waveforms whenever there was an inadequate safety margin with tilt-based waveforms. A 3.5-ms-based fixed duration shock was tried first. If that failed to achieve a 10-J safety margin then a 2-ms-based shock was used. We also tabulated an HEDFT (high estimate DFT) as precise DFTs were not determined. Results:Sixteen patients (15 M, 1 F) were entered into the registry (age 58.2 ± 17.9 years) with ejection fractions of .30 ±.11. Superior vena cava coils were used in 7 patients according to physician preference. The tilt-based HEDFTs were 35.4 ± 3.2 J delivered and 35.8 ± 3.3 J stored energy. The 3.5-ms based shocks were evaluated on 14 patients and the HEDFT fell to 23.4 ± 6.3 J delivered (P < 0.0001) and 26.2 ± 6.9 J stored energy (P < 0.0001). The 2-ms-based fixed duration shocks were then evaluated on 6 patients and the delivered energy HEDFT was 22.2 ± 5.8 J (P = 0.001 vs. tilt-based shocks) while the stored energy HEDFT was 27.9 ± 6.4 J (P = 0.01 vs. tilt-based shocks). Using the better of the two fixed duration waveforms, the mean safety margin was improved from −1.2 ± 1.9 J to 9.5 ± 5.9 J (P < 0.00001). Multivariate predictors of the safety margin improvement were the absence of the Superior Vena Cava (SVC) coil and absence of Ventricular fibrillation (VF) presentation. Four patients still required lead repositioning after the use of the fixed duration waveforms. No additional leads were implanted. Conclusion:The use of a selection of directly programmed fixed duration biphasic shocks had a striking impact on the HEDFT for these difficult patients. Adequate safety margins were obtained for 12 of 16 patients with no lead manipulation or other approaches.