The evolution of lung cancer and impact of subclonal selection in TRACERx.

Lung cancer is the leading cause of cancer-associated mortality worldwide1. Here we analysed 1,644 tumour regions sampled at surgery or during follow-up from the first 421 patients with non-small cell lung cancer prospectively enrolled into the TRACERx study. This project aims to decipher lung cancer evolution and address the primary study endpoint: determining the relationship between intratumour heterogeneity and clinical outcome. In lung adenocarcinoma, mutations in 22 out of 40 common cancer genes were under significant subclonal selection, including classical tumour initiators such as TP53 and KRAS. We defined evolutionary dependencies between drivers, mutational processes and whole genome doubling (WGD) events. Despite patients having a history of smoking, 8% of lung adenocarcinomas lacked evidence of tobacco-induced mutagenesis. These tumours also had similar detection rates for EGFR mutations and for RET, ROS1, ALK and MET oncogenic isoforms compared with tumours in never-smokers, which suggests that they have a similar aetiology and pathogenesis. Large subclonal expansions were associated with positive subclonal selection. Patients with tumours harbouring recent subclonal expansions, on the terminus of a phylogenetic branch, had significantly shorter disease-free survival. Subclonal WGD was detected in 19% of tumours, and 10% of tumours harboured multiple subclonal WGDs in parallel. Subclonal, but not truncal, WGD was associated with shorter disease-free survival. Copy number heterogeneity was associated with extrathoracic relapse within 1 year after surgery. These data demonstrate the importance of clonal expansion, WGD and copy number instability in determining the timing and patterns of relapse in non-small cell lung cancer and provide a comprehensive clinical cancer evolutionary data resource.

Safety and immunogenicity of SARS-CoV-2 recombinant protein vaccine formulations in healthy adults: interim results of a randomised, placebo-controlled, phase 1-2, dose-ranging study.

BACKGROUND: CoV2 preS dTM is a stabilised pre-fusion spike protein vaccine produced in a baculovirus expression system being developed against SARS-CoV-2. We present interim safety and immunogenicity results of the first-in-human study of the CoV2 preS dTM vaccine with two different adjuvant formulations. METHODS: This phase 1-2, randomised, double-blind study is being done in healthy, SARS-CoV-2-seronegative adults in ten clinical research centres in the USA. Participants were stratified by age (18-49 years and ≥50 years) and randomly assigned using an interactive response technology system with block randomisation (blocks of varying size) to receive one dose (on day 1) or two doses (on days 1 and 22) of placebo or candidate vaccine, containing low-dose (effective dose 1·3 µg) or high-dose (2·6 µg) antigen with adjuvant AF03 (Sanofi Pasteur) or AS03 (GlaxoSmithKline) or unadjuvanted high-dose antigen (18-49 years only). Primary endpoints were safety, assessed up to day 43, and immunogenicity, measured as SARS-C0V-2 neutralising antibodies (geometric mean titres), assessed on days 1, 22, and 36 serum samples. Safety was assessed according to treatment received in the safety analysis set, which included all randomly assigned participants who received at least one dose. Neutralising antibody titres were assessed in the per-protocol analysis set for immunogenicity, which included participants who received at least one dose, met all inclusion and exclusion criteria, had no protocol deviation, had negative results in the neutralisation test at baseline, and had at least one valid post-dose serology sample. This planned interim analysis reports data up to 43 days after the first vaccination; participants in the trial will be followed up for 12 months after the last study injection. This trial is registered with ClinicalTrials.gov, NCT04537208, and is ongoing. FINDINGS: Between Sept 3 and Sept 29, 2020, 441 individuals (299 aged 18-49 years and 142 aged ≥50 years) were randomly assigned to one of the 11 treatment groups. The interim safety analyses included 439 (>99%) of 441 randomly assigned participants (299 aged 18-49 years and 140 aged ≥50 years). Neutralising antibody titres were analysed in 326 (74%) of 441 participants (235 [79%] of 299 aged 18-49 years and 91 [64%] of 142 aged ≥50 years). There were no vaccine-related unsolicited immediate adverse events, serious adverse events, medically attended adverse events classified as severe, or adverse events of special interest. Among all study participants, solicited local and systemic reactions of any grade after two vaccine doses were reported in 81% (95% CI 61-93; 21 of 26) of participants in the low-dose plus AF03 group, 93% (84-97; 74 of 80) in the low-dose plus AS03 group, 89% (70-98; 23 of 26) in the high-dose plus AF03 group, 95% (88-99; 81 of 85) in the high-dose plus AS03 group, 29% (10-56; five of 17) in the unadjuvanted high-dose group, and 21% (8-40; six of 29) in the placebo group. A single vaccine dose did not generate neutralising antibody titres above placebo levels in any group at days 22 or 36. Among participants aged 18-49 years, neutralising antibody titres after two vaccine doses were 13·1 (95% CI 6·40-26·9) in the low-dose plus AF03 group, 20·5 (13·1-32·1) in the low-dose plus AS03 group, 43·2 (20·6-90·4) in the high-dose plus AF03 group, 75·1 (50·5-112·0) in the high-dose plus AS03 group, 5·00 (not calculated) in the unadjuvanted high-dose group, and 5·00 (not calculated) in the placebo group. Among participants aged 50 years or older, neutralising antibody titres after two vaccine doses were 8·62 (1·90-39·0) in the low-dose plus AF03 group, 12·9 (7·09-23·4) in the low-dose plus AS03 group, 12·3 (4·35-35·0) in the high-dose plus AF03 group, 52·3 (25·3-108·0) in the high-dose plus AS03 group, and 5·00 (not calculated) in the placebo group. INTERPRETATION: The lower than expected immune responses, especially in the older age groups, and the high reactogenicity after dose two were probably due to higher than anticipated host-cell protein content and lower than planned antigen doses in the formulations tested, which was discovered during characterisation studies on the final bulk drug substance. Further development of the AS03-adjuvanted candidate vaccine will focus on identifying the optimal antigen formulation and dose. FUNDING: Sanofi Pasteur and Biomedical Advanced Research and Development Authority.

A replication-competent adenovirus-vectored influenza vaccine induces durable systemic and mucosal immunity.

BACKGROUNDTo understand the features of a replicating vaccine that might drive potent and durable immune responses to transgene-encoded antigens, we tested a replication-competent adenovirus type 4 encoding influenza virus H5 HA (Ad4-H5-Vtn) administered as an oral capsule or via tonsillar swab or nasal spray.METHODSViral shedding from the nose, mouth, and rectum was measured by PCR and culturing. H5-specific IgG and IgA antibodies were measured by bead array binding assays. Serum antibodies were measured by a pseudovirus entry inhibition, microneutralization, and HA inhibition assays.RESULTSAd4-H5-Vtn DNA was shed from most upper respiratory tract-immunized (URT-immunized) volunteers for 2 to 4 weeks, but cultured from only 60% of participants, with a median duration of 1 day. Ad4-H5-Vtn vaccination induced increases in H5-specific CD4+ and CD8+ T cells in the peripheral blood as well as increases in IgG and IgA in nasal, cervical, and rectal secretions. URT immunizations induced high levels of serum neutralizing antibodies (NAbs) against H5 that remained stable out to week 26. The duration of viral shedding correlated with the magnitude of the NAb response at week 26. Adverse events (AEs) were mild, and peak NAb titers were associated with overall AE frequency and duration. Serum NAb titers could be boosted to very high levels 2 to 5 years after Ad4-H5-Vtn vaccination with recombinant H5 or inactivated split H5N1 vaccine.CONCLUSIONReplicating Ad4 delivered to the URT caused prolonged exposure to antigen, drove durable systemic and mucosal immunity, and proved to be a promising platform for the induction of immunity against viral surface glycoprotein targets.TRIAL REGISTRATIONClinicalTrials.gov NCT01443936 and NCT01806909.FUNDINGIntramural and Extramural Research Programs of the NIAID, NIH (U19 AI109946) and the Centers of Excellence for Influenza Research and Surveillance (CEIRS), NIAID, NIH (contract HHSN272201400008C).

Prolonged evolution of the memory B cell response induced by a replicating adenovirus-influenza H5 vaccine.

Induction of an antibody response capable of recognizing highly diverse strains is a major obstacle to the development of vaccines for viruses such as HIV and influenza. Here, we report the dynamics of B cell expansion and evolution at the single-cell level after vaccination with a replication-competent adenovirus type 4 recombinant virus expressing influenza H5 hemagglutinin. Fluorescent H1 or H5 probes were used to quantitate and isolate peripheral blood B cells and their antigen receptors. We observed increases in H5-specific antibody somatic hypermutation and potency for several months beyond the period of active viral replication that was not detectable at the serum level. Individual broad and potent antibodies could be isolated, including one stem-specific antibody that is part of a new multidonor class. These results demonstrate prolonged evolution of the B cell response for months after vaccination and should be considered in efforts to evaluate or boost vaccine-induced immunity.

First U-Pb zircon ages for late Miocene Ashfall Konservat-Lagerstätte and Grove Lake ashes from eastern Great Plains, USA.

This paper documents the first U-Pb zircon ages for Ashfall Fossil Beds (Nebraska, USA), a terrestrial Konservat-Lagerstätte mass-death assemblage that is arguably the most diverse of its type and age. The Ashfall tephra was correlated with ignimbrites from the Bruneau-Jarbidge volcanic field (12.7-10.5 Ma) in southwest Idaho based on geochemical analysis. The methods and geochemical data supporting the original age assessment of the ash bed, however, were never published, and there has been a persistent misconception that dateable heavy minerals (e.g., zircon) are absent. Notwithstanding, we recovered abundant zircons from Ashfall Fossil Beds, and from an ash bed ~6 km to the southeast at Grove Lake, Nebraska, and analyzed them through LA-ICP-MS. Our new zircon U-Pb age of 11.86 ± 0.13 Ma substantiates correlation of the Ashfall Fossil Beds deposit to tuffs originating from the Bruneau-Jarbidge caldera (~12.7-10.5 Ma). Our U-Pb zircon age of 6.42 ± 0.06 Ma for the Grove Lake ash bed coincides with supervolcanic activity in the Heise volcanic field (6.6-4.3 Ma) in eastern Idaho. These new dates improve age constraints of strata comprising the Ogallala Group and the important paleontological site. Moreover, we find that detrital and airfall zircons are unevenly distributed in the stratified ash beds we describe herein and presumably in similar deposits worldwide. Therefore, a higher-resolution sampling scheme is necessary in such cases.

Passive Transfer of Immune Sera Induced by a Zika Virus-Like Particle Vaccine Protects AG129 Mice Against Lethal Zika Virus Challenge.

Zika virus (ZIKV) poses a serious public health threat due to its association with birth defects in developing fetuses and Guillain-Barré Syndrome in adults. We are developing a ZIKV vaccine based on virus-like particles (VLPs) generated in transiently transfected HEK293 cells. The genetic construct consists of the prM and envelope structural protein genes of ZIKV placed downstream from a heterologous signal sequence. To better understand the humoral responses and correlates of protection (CoP) induced by the VLP vaccine, we evaluated VLP immunogenicity with and without alum in immune-competent mice (C57Bl/6 x Balb/c) and observed efficient induction of neutralizing antibody as well as a dose-sparing effect of alum. To assess the efficacy of the immune sera, we performed passive transfer experiments in AG129 mice. Mice that received the immune sera prior to ZIKV infection demonstrated significantly reduced viral replication as measured by viral RNA levels in the blood and remained healthy, whereas control mice succumbed to infection. The results underscore the protective effect of the antibody responses elicited by this ZIKV VLP vaccine candidate. These studies will help define optimal vaccine formulations, contribute to translational efforts in developing a vaccine for clinical development, and assist in the definition of immunologic CoP.

Comparison of paracorporeal and continuous flow ventricular assist devices in children: preliminary results.

Objectives: With the scarcity of organs, a durable, reliable ventricular assist device (VAD) is required. The Berlin Heart EXCOR ® (BH) remains the most established VAD in the paediatric population. Implantable continuous flow (CF) VADs have been introduced to the paediatric field with encouraging early results. In this study, we compared the results of a newly introduced CF VAD (HeartWare VAD [HVAD] ® ) to results in a matched group of BH recipients. Methods: The study included patients aged <16 years who received mechanical left VAD (LVAD) support between December 2005 and January 2016. The preimplant characteristics and postimplant outcomes of patients who received the HVAD were compared with those of a matched group who received the BH. Patients with congenital heart disease were excluded. Results: Thirty patients were included in the study: 13 had received the HVAD and were matched with 17 patients who had received the BH LVAD. The only difference in preimplant characteristics was the need for higher inotropic support in the BH group. There was no difference in the need for right ventricular (RV) support (58.8% for BH vs 53.8% for HVAD, P = 1.00) or in the incidence of cerebrovascular accidents (12.5% vs 7.7%, respectively, P = 1.00), though the BH group showed prolonged mechanical ventilation (31.3% vs 0%, P = 0.047). There were no deaths while on VAD support in either group. Patients with the HVAD showed a bimodal distribution for the primary end point (transplant/explant): All HVAD recipients who also required early RV support reached this end point within 30 days of receiving the implant. Conclusions: Our early experience with the CF intracorporeal LVAD system (HVAD) indicates outcomes comparable to those with the well-established pulsatile flow paracorporeal LVAD (BH). The theoretical durability of the CF device, which might also allow for the possibility of hospital discharge and better quality of life, is yet to be proven.

The use of history to identify anterior cruciate ligament injuries in the acute trauma setting: the 'LIMP index'.

OBJECTIVE: To identify the injury history features reported by patients with anterior cruciate ligament (ACL) injuries and determine whether history may be used to identify patients requiring follow-up appointments from acute trauma services. METHODS: Multisite cross-sectional service evaluation using a survey questionnaire design conducted in the UK. The four injury history features investigated were 'leg giving way at the time of injury', 'inability to continue activity immediately following injury', 'marked effusion' and 'pop (heard or felt) at the time of injury'(LIMP). RESULTS: 194 patients with ACL injury were identified, of which 165 (85.5%) attended an acute trauma service. Data on delay was available for 163 (98.8%) of these patients of which 120 (73.6%) had a follow-up appointment arranged. Patients who had a follow-up appointment arranged waited significantly less time for a correct diagnosis (geometric mean 29 vs 198 days; p<0.001) and to see a specialist consultant (geometric mean 61 vs 328 days; p<0.001). Using a referral threshold of any two of the four LIMP injury history features investigated, 95.8% of patients would have had a follow-up appointment arranged. CONCLUSIONS: Findings support the value of questioning patients on specific injury history features in identifying patients who may have suffered ACL injury. Using a threshold of two or more of the four LIMP history features investigated would have reduced the percentage of patients inappropriately discharged by 22.2%. Evidence presented suggests that this would significantly reduce the time to diagnosis and specialist consultation minimising the chance of secondary complications.

Case report: imaging the clinical course of FOPE-a cause of adolescent knee pain.

Focal periphyseal oedema (FOPE) is a rare MRI finding associated with pain in adolescent patients with very few reported cases. We present a case of FOPE in a 13-year-old girl and the only follow-up imaging available for an isolated presentation of this condition.This article describes a clinical course that correlates well with the imaging obtained. This article describes a clinical course that correlates well with the imaging obtained.

Outcome of mechanical cardiac support in children using more than one modality as a bridge to heart transplantation.

OBJECTIVES: Mechanical cardiac support (MCS) can successfully be applied as a bridging strategy for heart transplantation (OHTx) in children with life-threatening heart failure. Emergent use of MCS is often required before establishing the likelihood of OHTx. This can require bridge-to-bridge strategies to increase survival on the waiting list. We compared the outcome of children with heart failure who underwent single MCS with those who required multiple MCS as a bridge to OHTx. METHODS: A retrospective study of patients aged less than 16 years was conducted. From March 1998 to October 2005, we used either a veno-arterial extracorporeal membrane oxygenator (VA-ECMO), or the Medos® para-corporeal ventricular assist device (VAD). From November 2005 onwards, the Berlin Heart EXCOR® (BHE) device was implanted in the majority of cases. Several combinations of bridge-to-bridge strategies have been used: VA-ECMO and then conversion to BHE; BHE and then conversion to VA-ECMO; left VAD and then upgraded to biventricular support (BIVAD); conversion from pulsatile to continuous-flow pumps. RESULTS: A total of 92 patients received MCS with the intent to bridge to OHTx, including 21 (23%) supported with more than one modality. The mean age and weight at support was similar in both groups, but multimodality MCS was used more often in infancy (P = 0.008) and in children less than 10 kg in weight (P = 0.02). The mean duration of support was longer in the multiple MCS group: 40 ± 48 vs 84 ± 43 days (P = 0.0003). Usage of multimodality MCS in dilated cardiomyopathy (19%) and in other diagnoses (29%) was comparable. Incidence of major morbidity (haematological sequelae, cerebrovascular events and sepsis) was similar in both groups. Survival to OHTx/explantation of the device (recovery) and survival to discharge did not differ between single MCS and multiple MCS groups (78 vs 81% and 72 vs 76%, respectively). CONCLUSION: Bridge to OHTx with multiple MCS does not seem to influence the outcome in our population. Infancy and body weight less than 10 kg do not tend to produce higher mortality in the multiple MCS group. However, children receiving more than one modality are supported for longer durations.

Oral priming with replicating adenovirus serotype 4 followed by subunit H5N1 vaccine boost promotes antibody affinity maturation and expands H5N1 cross-clade neutralization.

A Phase I trial conducted in 2009-2010 demonstrated that oral vaccination with a replication competent Ad4-H5 (A/Vietnam) vector with dosages ranging from 107-1011 viral particles was well tolerated. HA-specific T-cell responses were efficiently induced, but very limited hemagglutination-inhibiting (HI) humoral responses were measured. However, a single boost of Ad4-H5-Vtn vaccinated individuals with a unadjuvanted licensed H5N1 (A/Vietnam) subunit vaccine resulted in superior HI titers compared with unprimed subjects. In the current study, the impact of Ad4-H5 priming on the quality of the polyclonal humoral immune response was evaluated using a real-time kinetics assay by surface plasmon resonance (SPR). Total binding of serum polyclonal antibodies from the Ad4-H5-Vtn primed groups against both homologous H5N1-A/Vietnam/1194/2004 (clade 1) and heterologous A/Indonesia-5/2005 (clade 2.1) HA1 head domain was significantly higher compared with sera from individuals that received subunit H5N1 vaccination alone. SPR measurements also demonstrated that the antigen-antibody complex dissociation rates (a surrogate for antibody affinity) of serum antibodies against the HA1 of H5N1-A/Vietnam were significantly higher in the Ad4-H5 primed groups compared with those from the unprimed group. Furthermore, strong correlations were observed between the antibody affinities for HA1 (but not HA2) and the virus neutralization titers against the homologous strain and a panel of heterologous clade 2 H5N1 strains. These findings support the concept of oral prime-boost vaccine approaches against pandemic influenza to elicit long-term memory B cells with high affinity capable of rapid response to variant pandemic viruses likely to emerge and adapt to human transmissions.

Haemodialysing babies weighing <8 kg with the Newcastle infant dialysis and ultrafiltration system (Nidus): comparison with peritoneal and conventional haemodialysis.

BACKGROUND: To compare the efficacy of the Newcastle infant dialysis and ultrafiltration system (Nidus) with peritoneal dialysis (PD) and conventional haemodialysis (HD) in infants weighing <8 kg. METHODS: We compared the urea, creatinine and phosphate clearances, the ultrafiltration precision, and the safety of the Nidus machine with PD in 7 piglets weighing 1-8 kg, in a planned randomised cross-over trial in babies, and in babies for whom no other therapy existed, some of whom later graduated to conventional HD. RESULTS: Two babies entered the randomised trial; 1 recovered rapidly on PD, the other remained on the Nidus as PD failed. Additionally, 9 babies were treated on the Nidus on humanitarian grounds: 3 because of failed PD, and 3 with permanent kidney failure later converted to conventional HD. We haemodialysed 10 babies weighing between 1.8 and 5.9 kg for 2,475 h during 354 Nidus sessions without any clinically important incidents, and without detectable haemolysis. Single-lumen vascular access was used with no blood priming of circuits. The urea, creatinine and phosphate clearances using the Nidus were around 1.5 to 2.0 ml/min in piglets and babies, and were consistently higher than PD clearances, which ranged from about 0.2 to 0.8 ml/min (p ≤ 0.0002 for each chemical). Ultrafiltration was achieved to microlitre precision by the Nidus, but varied widely with PD. Fluid removal using conventional HD was imprecise and resulted in some hypovolaemic episodes requiring correction. CONCLUSION: The Nidus can provide HD in the Pediatric Intensive Care Unit (PICU) and outpatient intermittent HD without blood priming for babies weighing <8 kg, It generates higher dialysis clearances than PD, and delivers more precise ultrafiltration control than either PD or conventional HD.

Thoratec CentriMag for temporary treatment of refractory cardiogenic shock or severe cardiopulmonary insufficiency: a systematic literature review and meta-analysis of observational studies.

The aim of the study was to systematically evaluate effect of CentriMag heart pump (Thoratec Corporation) as temporary ventricular assist device (VAD) and part of extracorporeal membrane oxygenation (ECMO) system on outcomes in patients with cardiac or cardiac-respiratory failure. A systematic search was conducted in five databases for the period 2003 to 2012. Fifty-three publications with data for 999 patients, supported with CentriMag, were included. In 72% studies, CentriMag was used as a VAD and in 25% as part of ECMO circuit. Mean duration of VAD support was 25.0 days in precardiotomy group, 10.9 days in postcardiac surgery cardiogenic shock group, 8.8 days in post-transplant graft failure and rejection group, and 16.0 days in post-LVAD placement right ventricular failure group. Survival on support was 82% (95% CI 70-92) for VAD support in precardiotomy cardiogenic shock indication, 63% (95% CI 46-78) in VAD support in postcardiac surgery cardiogenic shock indication, 62% (95% CI 46-76) in VAD support in post-transplant graft rejection or failure indication, and 83% (95% CI 73-92) in VAD support in post-LVAD placement right ventricular failure indication. CentriMag is an effective technology for temporary support of patients with cardiac and cardiorespiratory failure.

The cost impact of short-term ventricular assist devices and extracorporeal life support systems therapies on the National Health Service in the UK.

OBJECTIVES: The objective of the study was to assess the cost of using different blood pumps for short-term ventricular assist device (VAD) and extracorporeal life support (ECLS) systems for cardiac and cardiorespiratory failure in the UK. METHODS: The cost analysis presented was based on evaluation of the time required to provide circulatory support for the following indications: post-cardiac surgery cardiogenic shock, postacute myocardial infarction cardiogenic shock, deteriorating end-stage heart failure (ESHF) and the ability of different blood pumps to provide support for the necessary duration. The maximum length of support for each device was based on the manufacturers' recommendations. Direct medical cost of each treatment was evaluated only for the period of mechanical circulatory support in adults and children. Only the cost of device, placement and replacement procedures were considered. List prices were used for devices; resource use was based on expert opinion; unit costs were obtained from official UK sources and Wythenshawe hospital, Manchester, UK. Hospital perspective was utilized for analysis. Three VADs were selected for comparison in adults and two in children. Four centrifugal ECLS systems were selected for comparison in adults and two in children. RESULTS: In both VAD and ECLS indications, the CentriMag® was the least expensive when used for support of patients with end-stage heart failure. Compared with Cardiohelp® for ECLS (which has the same maximum claim duration of support of 30 days), CentriMag® lead to cost savings of £4294 per patient in all three clinical conditions considered. In post-cardiac surgery cardiogenic shock, CentriMag® VAD lead to savings of £5014 per patient compared with BPX-80. Results were robust in one-way sensitivity analysis in comparison with Cardiohelp®. CONCLUSIONS: CentriMag® and PediVAS® blood pumps can lead to significant cost savings to the National Health Service, when used instead of other pumps for short-term VAD or ECLS treatment.

A longer waiting game: bridging children to heart transplant with the Berlin Heart EXCOR device--the United Kingdom experience.

BACKGROUND: Mechanical circulatory support (MCS) is used to support children with end-stage heart failure to heart transplant. METHODS: This was a retrospective cohort study of 7 years' experience with the Berlin Heart (BH) EXCOR (Berlin Heart AG, Berlin Germany) paracorporeal ventricular assist device (VAD) in 2 United Kingdom (UK) pediatric heart transplant centers and the effect of this program on the UK pediatric heart transplant service. RESULTS: Of 102 children who received BH support, 84% survived to transplant or BH explant and 81% survived to discharge. Neither age nor duration of support influenced outcome. Stroke, ongoing requirement for ventilation while on BH, and diagnosis other than dilated cardiomyopathy were the only independent mortality risk factors. Children who weighed < 20 kg had significantly (p = 0.03) longer support times than bigger children. The number of children treated with a BH increased over time (p = 0.01). Currently > 50% of pediatric heart transplants are bridged with a BH; however, pediatric transplants per year have not increased significantly (p = 0.07) CONCLUSIONS: BH use in the UK has allowed significant increases in the number of children with end-stage heart failure who can be successfully bridged to transplant and the length of time they can be supported. The total number of transplants has not increased.

Examination of the relative importance of hospital employment in non-metropolitan counties using location quotients.

INTRODUCTION: The US Health Care and Social Services sector (North American Industrial Classification System 'sector 62') has become an extremely important component of the nation's economy, employing approximately 18 million workers and generating almost $753 billion in annual payrolls. At the county level, the health care and social services sector is typically the largest or second largest employer. Hospital employment is often the largest component of the sector's total employment. Hospital employment is particularly important to non-metropolitan or rural communities. A high quality healthcare sector serves to promote economic development and attract new businesses and to provide stability in economic downturns. The purpose of this study was to examine the intensity of hospital employment in rural counties relative to the nation as a whole using location quotients and to draw conclusions regarding how potential changes in Medicare and Medicaid might affect rural populations. METHODS: Estimates for county-level hospital employment are not commonly available. Estimates of county-level hospital employment were therefore generated for all counties in the USA the Census Bureau's County Business Pattern Data for 2010. These estimates were used to generate location quotients for each county which were combined with demographic data to generate a profile of factors that are related to the magnitude of location quotients. The results were then used to draw inferences regarding the possible impact of the Patient Protection and Affordable Care Act 2010 (ACA) and the possible imposition of aspects of the Budget Control Act 2011 (BCA). RESULTS: Although a very high percentage of rural counties contain medically underserved areas, an examination of location quotients indicates that the percentage of the county workforce employed by hospitals in the most rural counties tends to be higher than for the nation as a whole, a counterintuitive finding. Further, when location quotients are regressed upon data related to poverty, county demographics, and the percentage of the population insured, a relationship between the proportion of the population over 65 years, the percentage of the population living in poverty, the percentage of the population without insurance and county density was found. CONCLUSION: The results of the analysis suggest that hospital employment in rural communities is higher than would be expected in the absence of programs that provide external funding to support hospital hiring. The most important public programs providing this support are Medicare and Medicaid. Social Security is another source of federal funding important for rural populations. Sequestration and other cuts in funding could impact rural communities significantly. This can be even worse in states that fail to expand Medicaid and in states that fail to increase Medicaid reimbursements for services important in rural communities.

Midterm Outcomes and Predictors of Clinical Success With the KineSpring Knee Implant System.

The purpose of this study was to (1) evaluate joint pain and function in knee osteoarthritis (OA) patients treated with a joint-sparing, extracapsular implant and (2) identify patient characteristics that influenced clinical outcomes. This study included 99 patients with symptomatic medial knee OA refractory to conservative care who were treated with the KineSpring Knee Implant System and followed for a mean of 17 months (range, 1.5 to 48 months). All devices were successfully implanted and activated with no intraoperative complications. Statistically significant mean improvements of 56%, 50%, and 38% were observed for Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain, Function, and Stiffness scales, respectively (all P < 0.001). Regardless of gender, age group, body mass index classification, or disease severity, all WOMAC domain scores significantly improved during the postoperative follow-up period. WOMAC clinical success rates were 77.8% for Pain, 77.8% for Function, and 68.7% for Stiffness. Neither gender, age group, body mass index classification, nor disease severity predicted clinical success in any WOMAC domain. In conclusion, the KineSpring System yields clinically meaningful improvements in joint pain and function in patients with medial knee OA. Additionally, unlike joint-altering procedures such as knee arthroplasty or high tibial osteotomy, patient characteristics had little association with postoperative clinical outcomes.