bluuebunny/crossref_metadata_2025_split huggingface dataset:
The clinician impact and financial cost to the NHS of litigation over pregabalin: a cohort study in English primary care
Authors: Croker Richard , Smyth Darren , Walker Alex J , Goldacre Ben 
Published: June 2018

ObjectivesFollowing litigation over pregabalin’s second-use medical patent for neuropathic pain, National Health Service (NHS) England was required by the court to instruct general practitioners (GPs) to prescribe the branded form (Lyrica) for pain. Pfizer’s patent was found invalid in 2015, a ruling subject to ongoing appeals. If the Supreme Court appeal in February 2018, whose judgement is awaited, is unsuccessful, the NHS can seek to reclaim excess prescribing costs. We set out to describe the variation in prescribing of pregabalin as branded Lyrica, geographically and over time; to determine how clinicians responded to the NHS England instruction to GPs; and to model excess costs to the NHS attributable to the legal judgements.SettingEnglish primary care.ParticipantsEnglish general practices.Primary and secondary outcome measuresVariation in prescribing of branded Lyrica across the country before and after the NHS England instruction, by practice and by Clinical Commissioning Group; excess prescribing costs.ResultsThe proportion of pregabalin prescribed as Lyrica increased from 0.3% over 6 months before the NHS England instruction (September 2014 to February 2015) to 25.7% afterwards (April to September 2015). Although 70% of pregabalin is estimated to be for pain, including neuropathic pain, only 11.6% of practices prescribed Lyrica at this level; the median proportion prescribed as Lyrica was 8.8% (IQR 1.1%–41.9%). If pregabalin had come entirely off patent in September 2015, and Pfizer had not appealed, we estimate the NHS would have spent £502 million less on pregabalin to July 2017.ConclusionNHS England instructions to GPs regarding branded prescription of pregabalin were widely ignored and have created much debate around clinical independence in prescribing. Protecting revenue from ‘skinny labels’ will pose a challenge. If Pfizer’s final appeal on the patent is unsuccessful, the NHS can seek reimbursement of excess pregabalin prescribing costs, potentially £502 million.
Evaluation of the clinical and cost-effectiveness of the York Faecal Calprotectin Care Pathway
Authors: Turvill James , Turnock Daniel , Holmes Hayden , Jones Alison , Mclaughlan Eleanor , Hilton Victoria , Marriott Stacey 
Published: June 2018

ObjectiveTo evaluate the sensitivity and specificity of the York Faecal Calprotectin Care Pathway (YFCCP) and undertake a health economics analysis. The YFCCP has been introduced in support of the National Institute for Health and Care Excellence (NICE) guidance DG11. It is designed to improve the sensitivity and specificity of faecal calprotectin (FC) in discriminating the irritable bowel syndrome from inflammatory bowel disease in primary care.DesignTo prospectively evaluate the clinical outcomes at 6 months of the first 1005 patients entering the YFCCP. To develop a cost-consequence model using two comparators: one based on clinical assessment and the C reactive protein/erythrocyte sedimentation rate without using FC, and the second using single testing of the standard FC cut-off.SettingNorth Yorkshire primary care practices.PatientsPrimary care patients fulfilling NICE DG11.InterventionsThe YFCCP.Main outcome measuresClinical outcome measures from secondary care records.ResultsThe sensitivity and specificity of the YFCCP are 0.94 (0.85 to 0.98) and 0.92 (0.90 to 0.94), giving a negative and positive predictive value of 0.99 (0.98 to 1.0) and 0.51 (0.43 to 0.59), respectively.ConclusionsThe YFCCP overcomes the challenges experienced with FC use in primary care, its efficacy matching initial NICE projections. It is readily incorporated into clinical practice. It should represent the framework on which to increase NICE DG11 implementation nationally.
Prevalence of degenerative changes and overlap with spondyloarthritis-associated lesions in the spine of patients from the DESIR cohort
Authors: de Bruin Freek , Treyvaud Marco O , Feydy Antoine , de Hooge Manouk , Pialat Jean-Baptiste , Dougados Maxime , Gossec Laure , Bloem Johan L , van der Heijde Désirée , Reijnierse Monique 
Published: June 2018

ObjectivesTo describe the prevalence of degenerative changes on MRI and conventional radiographs of the spine in a young population with suspicion of axial spondyloarthritis (axSpA) and assess whether it is possible to discriminate between degenerative changes and lesions associated with axSpA.MethodsWhole spine MRI and cervical and lumbar radiographs of patients ≥18 years with chronic back pain (≥3 months, ≤3 years, onset <50 years) were assessed for degeneration by two readers, and for SpA lesions by two other readers, all blinded for clinical information and results of the other readers. Degenerative scores were adjudicated in case of disagreement (by a third reader). Patients fulfilling and not fulfilling the Assessment of SpondyloArthritis international Society axSpA criteria were compared for prevalence of degenerative lesions. Scores for degenerative and SpA lesions were compared, and overlap was defined as the presence of both types of lesions in a single vertebral unit (VU).ResultsIn 456/648 (70.4%) patients (46.8% men, mean age 33.6), degenerative lesions were found with similar percentages in patients with no axSpA and with axSpA (72.4% and 69.2%, p=0.45). Modic changes were found more often in patients with no axSpA (29/239, 12.1%) versus patients with axSpA (19/409, 4.6%, p=0.01). Other lesions were evenly distributed. Overlap was minimal in 19 patients (3.0%) and 32/14 674 (0.2%) VUs for SpA reader 1 and in 23 patients (3.6%) and 34/14 674 VUs (0.2%) for SpA reader 2.ConclusionThe prevalence of degeneration is high in an early inflammatory back pain cohort. Discrimination between degeneration and axSpA lesions is very well possible with little overlap between degenerative and axSpA readings.
Impact of the WHO FCTC over the first decade: a global evidence review prepared for the Impact Assessment Expert Group
Authors: Chung-Hall Janet , Craig Lorraine , Gravely Shannon , Sansone Natalie , Fong Geoffrey T 
Published: June 2018

ObjectiveTo present findings of a narrative review on the implementation and effectiveness of 17 Articles of the WHO Framework Convention on Tobacco Control (FCTC) during the Treaty’s first decade.Data sourcesPublished reports on global FCTC implementation; searches of four databases through June 2016; hand-search of publications/online resources; tobacco control experts.Study selectionWHO Convention Secretariat global progress reports (2010, 2012, 2014); 2015 WHO report on the global tobacco epidemic; studies of social, behavioural, health, economic and/or environmental impacts of FCTC policies.Data extractionProgress in the implementation of 17 FCTC Articles was categorised (higher/intermediate/lower) by consensus. 128 studies were independently selected by multiple authors in consultation with experts.Data synthesisImplementation was highest for smoke-free laws, health warnings and education campaigns, youth access laws, and reporting/information exchange, and lowest for measures to counter industry interference, regulate tobacco product contents, promote alternative livelihoods and protect health/environment. Price/tax increases, comprehensive smoking and marketing bans, health warnings, and cessation treatment are associated with decreased tobacco consumption/health risks and increased quitting. Mass media campaigns and youth access laws prevent smoking initiation, decrease prevalence and promote cessation. There were few studies on the effectiveness of policies in several domains, including measures to prevent industry interference and regulate tobacco product contents.ConclusionsThe FCTC has increased the implementation of measures across several policy domains, and these implementations have resulted in measurable impacts on tobacco consumption, prevalence and other outcomes. However, FCTC implementation must be accelerated, and Parties need to meet all their Treaty obligations and consider measures that exceed minimum requirements.
MACROD2 Haploinsufficiency Impairs Catalytic Activity of PARP1 and Promotes Chromosome Instability and Growth of Intestinal Tumors
Authors: Sakthianandeswaren Anuratha , Parsons Marie J. , Mouradov Dmitri , MacKinnon Ruth N. , Catimel Bruno , Liu Sheng , Palmieri Michelle , Love Christopher , Jorissen Robert N. , Li Shan , Whitehead Lachlan , Putoczki Tracy L. , Preaudet Adele , Tsui Cary , Nowell Cameron J. , Ward Robyn L. , Hawkins Nicholas J. , Desai Jayesh , Gibbs Peter , Ernst Matthias , Street Ian , Buchert Michael , Sieber Oliver M. 
Published: June 2018

Abstract
ADP-ribosylation is an important posttranslational protein modification that regulates diverse biological processes, controlled by dedicated transferases and hydrolases. Here, we show that frequent deletions (∼30%) of the MACROD2 mono-ADP-ribosylhydrolase locus in human colorectal cancer cause impaired PARP1 transferase activity in a gene dosage–dependent manner. MACROD2 haploinsufficiency alters DNA repair and sensitivity to DNA damage and results in chromosome instability. Heterozygous and homozygous depletion of Macrod2 enhances intestinal tumorigenesis in ApcMin/+ mice and the growth of human colorectal cancer xenografts. MACROD2 deletion in sporadic colorectal cancer is associated with the extent of chromosome instability, independent of clinical parameters and other known genetic drivers. We conclude that MACROD2 acts as a haploinsufficient tumor suppressor, with loss of function promoting chromosome instability, thereby driving cancer evolution.
Significance: Chromosome instability (CIN) is a hallmark of cancer. We identify MACROD2 deletion as a cause of CIN in human colorectal cancer. MACROD2 loss causes repression of PARP1 activity, impairing DNA repair. MACROD2 haploinsufficiency promotes CIN and intestinal tumor growth. Our results reveal MACROD2 as a major caretaker tumor suppressor gene. Cancer Discov; 8(8); 988–1005. ©2018 AACR.
See related commentary by Jin and Burkard, p. 921.
This article is highlighted in the In This Issue feature, p. 899
Clinical and Biological Correlates of Neurotoxicity Associated with CAR T-cell Therapy in Patients with B-cell Acute Lymphoblastic Leukemia
Authors: Santomasso Bianca D. , Park Jae H. , Salloum Darin , Riviere Isabelle , Flynn Jessica , Mead Elena , Halton Elizabeth , Wang Xiuyan , Senechal Brigitte , Purdon Terence , Cross Justin R. , Liu Hui , Vachha Behroze , Chen Xi , DeAngelis Lisa M. , Li Daniel , Bernal Yvette , Gonen Mithat , Wendel Hans-Guido , Sadelain Michel , Brentjens Renier J. 
Published: June 2018

AbstractCD19-specific chimeric antigen receptor (CAR) T-cell therapy is highly effective against relapsed or refractory acute lymphoblastic leukemia (ALL), but is hindered by neurotoxicity. In 53 adult patients with ALL, we found a significant association of severe neurotoxicity with high pretreatment disease burden, higher peak CAR T-cell expansion, and early and higher elevations of proinflammatory cytokines in blood. Patients with severe neurotoxicity had evidence of blood–cerebrospinal fluid (CSF) barrier disruption correlating with neurotoxicity grade without association with CSF white blood cell count or CAR T-cell quantity in CSF. Proinflammatory cytokines were enriched in CSF during severe neurotoxicity with disproportionately high levels of IL6, IL8, MCP1, and IP10, suggesting central nervous system–specific production. Seizures, seizure-like activity, myoclonus, and neuroimaging characteristics suggested excitatory neurotoxicity, and we found elevated levels of endogenous excitatory agonists in CSF during neurotoxicity.Significance: We detail the neurologic symptoms and blood, CSF, and neuroimaging correlates of neurotoxicity associated with CD19 CAR T cells and identify neurotoxicity risk factors. Our findings implicate cellular components other than T cells and suggest novel links between systemic inflammation and characteristic neurotoxicity symptoms. Cancer Discov; 8(8); 958–71. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 899
Tenacity of Collateral Perfusion in Proximal Cerebral Arterial Occlusions 6–12 h after Onset
Authors: Kim Beom Joon , Kim Hyeran , Jeong Han-Gil , Yang Mi Hwa , Jung Cheol Kyu , Han Moon-Ku , Kim Jae Hyoung  , Demchuk Andrew M. , Bae Hee-Joon 
Published: June 2018

<b><i>Background:</i></b> Clinical trials have shown that benefits of endovascular recanalization (EVT) for acute ischemic stroke patients with sizable penumbral tissues seems plausible even beyond 6 h after their last seen normal (LSN). Persistency of ischemic penumbra remains unclear in delayed periods. <b><i>Methods:</i></b> From a prospective stroke registry database, we identified 111 acute ischemic stroke patients who had internal carotid artery or middle cerebral artery occlusion with baseline National Institutes of Health Stroke Scale scores ≥6 points and arrived 6–12 h after LSN. Baseline information and functional outcomes were prospectively collected as a clinical registry. Attending physicians made treatment decisions for EVT based on the current guidelines and institutional protocols. MR image parameters, including the volume of diffusion-restricted lesions and mapping of the ­hypoperfused area, were quantified using automated commercial software. Binary logistic regression analysis models, with modified Rankin Scale (mRS) scores of 0–1 at 3 months after stroke included as a dependent variable, were constructed. <b><i>Results:</i></b> Between 6 and 12 h after onset, 58% had a mismatch ratio of ≥1.8 at baseline and 42% had favorable imaging profiles as determined by DEFUSE 2 study. After 9 h, there was a mismatch ratio of ≥1.8 in 47 and 38% favorable profiles. EVT was performed in 54% of cases. A 3-month mRS score of 0–1 was found in 19% (25% in EVT and 12% in medical treatment groups) of cases. EVT was associated with an increased OR of having a mRS score of 0–1 at 3 months after stroke (adjusted OR 7.59 [95% CI 1.28–61.60]). <b><i>Conclusions:</i></b> Penumbral tissues were persistent in a substantial proportion of anterior circulation occlusion cases 6–12 h after LSN. EVT at 6–12 h in a predominantly Asian cohort resulted in better outcomes.
Dialysate Potassium and Mortality in a Prospective Hemodialysis Cohort
Authors: Ferrey Antoney , You Amy S. , Kovesdy Csaba P. , Nakata Tracy , Veliz Mary , Nguyen Danh V. , Kalantar-Zadeh Kamyar , Rhee Connie M. 
Published: June 2018

<b><i>Background:</i></b> Studies examining the association of dialysate potassium concentration and mortality in hemodialysis patients show conflicting findings. We hypothesized that low dialysate potassium concentrations are associated with higher mortality, particularly in patients with high pre-dialysis serum potassium concentrations. <b><i>Methods:</i></b> We evaluated 624 hemodialysis patients from the prospective Malnutrition, Diet, and Racial Disparities in Kidney Disease study recruited from 16 outpatient dialysis facilities over 2011–2015 who underwent protocolized collection of dialysis treatment characteristics every 6 months. We examined the association of dialysate potassium concentration, categorized as 1, 2, and 3 mEq/L, with all-cause mortality risk in the ­overall cohort, and stratified by pre-dialysis serum potassium (&#x3c; 5 vs. ≥5 mEq/L) using case-mix adjusted Cox models. <b><i>Results:</i></b> In baseline analyses, dialysate potassium concentrations of 1 mEq/L were associated with higher mortality, whereas concentrations of 3 mEq/L were associated with similar mortality in the overall cohort (reference: 2 mEq/L): adjusted hazard ratios (aHRs; 95% CI) 1.70 (1.01–2.88) and 0.95 (0.64–1.39), respectively. In analyses stratified by serum potassium, baseline dialysate potassium concentrations of 1 mEq/L were associated with higher mortality in patients with serum potassium ≥5 mEq/L but not in those with serum potassium &#x3c; 5 mEq/L: aHRs (95% CI) 2.87 (1.51–5.46) and 0.74 (0.27–2.07), respectively (<i>p</i> interaction = 0.04). These findings were robust with incremental adjustment for serum potassium, potassium-binding resins, and potassium-modifying medications. <b><i>Conclusion:</i></b> Low (1 mEq/L) dialysate potassium ­concentrations were associated with higher mortality, particularly in hemodialysis patients with high pre-dialysis serum potassium. Further studies are needed to identify therapeutic strategies that mitigate inter-dialytic serum potassium accumulation and subsequent high dialysate serum potassium gradients in this population.
ВАРІАБЕЛЬНІСТЬ СЕРЦЕВОГО РИТМУ ПРИ ХРОНІЧНІЙ СЕРЦЕВІЙ НЕДОСТАТНОСТІ ЗІ ЗБЕРЕЖЕНОЮ ФРАКЦІЄЮ ВИКИДУ
Authors: Andreieva I. O. , Myrnyi D. P. 
Published: June 2018

Серцева недостатність залишається основною причиною передчасної смерті та низької якості життя у пацієнтів з різними кардіоваскулярних захворюваньМета дослідження: дослідити зміни варіабельності серцевого ритму у хворих з серцевою недостатністю зі збереженою фракцією викиду.Матеріали і методи: Обстежено 98 осіб з СНзЗФВ I-IIA стадії І-ІІ функціональних класів згідно класифікації NYHA (53 чоловіки та 45 жінок) віком від 19 до 66 років. Усім учасникам дослідження проведено загально клінічне обстеження з обов’язковим вимірюванням окружності талії та стегон, ваги та зросту, ехокардіографія, добове моніторування ЕКГ.Результати. В усіх пацієнтів з СНзЗФВ було зареєстровано зміни ВСР протягом доби і ригідний циркадний ритм ЧСС. Спостерігалось патологічне збільшення спектральних показників VLF, LF, LFN як у денний, так і у нічний час. Достатнього зниження спектральних показників VLF, LF, LFN у нічний час у основній групі не відбувалось. Не фіксувалось достатнього підйому HF та HFN у нічний час на відміну від контрольної групи. Співвідношення LF/HF відповідно було достовірно збільшене у хворих з СНзЗФВ. При кореляційному аналізі встановлено негативний кореляційний зв’язок віку з SDNN (r=−0,336, p<0,05), RMSSD (r=−0,312, p<0,05), рNN50 (r=−0,377, p<0,05), HF (r=−0,418, p<0,05) та позитивний кореляційний зв'язок зі співвідношенням LF/HF (r=0,384, p<0,05). SDNN корелював із час уповільнення кровотоку раннього діастолічного наповнення лівого шлуночка (r=−0,418, p<0,05) та час ізоволюметричного розслаблення (r=−0,436, p<0,05).Висновки. Розвиток хронічної серцевої недостатності зі збереженою фракцією викиду супроводжується зниженням загальною варіабельності серцевого ритму. У хворих з серцевою недостатністю зі збереженою фракцією викиду у порівнянні зі здоровими особами спостерігається зниження тонусу парасимпатичної ланки вегетативної нервової системи і збільшення тонусу симпатичної вегетативної ланки. За результатами однофакторного регресійного аналізу встановлено взаємозв’язок спектрального показника SDNN та часу ізоволюметричного розслаблення.
ОСОБЛИВОСТІ ПЕРЕБІГУ ПНЕВМОНІЙ ПРИ ОНКОЛОГІЧНИХ ЗАХВОРЮВАННЯХ КРОВІ
Authors: Bob A. O. , Khomitska A. I. , Chukur O. O. , Radetska L. V. , Bodnar L. P. , Kvasnitska O. S. , Horodetskyi V. Y. 
Published: June 2018

Найчастішими інфекційними ускладненнями при лейкозі є пневмонії, що досить часто є основною причиною смерті цих хворих.Метою роботи було визначення етіологічного чинника пневмоній у хворих з тяжкими порушеннями імунітету на фоні онкологічних захворювань крові.Матеріал та методи досліджень. Обстежено 124 хворих на пневмонію з онкологічними захворюванями крові. Проводилось мікробіологічне дослідження мокротиння та рідина бронхоальвеолярного лаважа шляхом вивчення нативних мазків із визначенням основних морфологічних типів збудників.Результати досліджень. За результатами мікробіологічних досліджень ймовірні бактеріальні збудники захворювання було визначено в 69,4% випадків. Серед 89 позитивних результатів мікробіологічних досліджень провідними були грамнегативні мікроорганізми, що становили 68,6%. Грампозитивні мікроорганізми були визначені в 26,7% досліджень. Асоціації патогенних мікроогранізмів визначені у 53,3% хворих групи дослідження: з грибковою флорою - 52,4%; асоціації бактерій – 26,7%.Висновки. Проблеми визначення етіологічного чинника пневмонії у хворих з онкологічними захворюваннями крові є актуальними та потребують подальших досліджень для оптимізації лікування та прогнозування перебігу пневмонії.
Basal Spontaneous Firing of Rabbit Sinoatrial Node Cells Is Regulated by Dual Activation of PDEs (Phosphodiesterases) 3 and 4
Authors: Vinogradova Tatiana M. , Sirenko Syevda , Lukyanenko Yevgeniya O. , Yang Dongmei , Tarasov Kirill V. , Lyashkov Alexey E. , Varghese Nevin J. , Li Yue , Chakir Khalid , Ziman Bruce , Lakatta Edward G. 
Published: June 2018

Background:

Spontaneous firing of sinoatrial node cells (SANCs) is regulated by cAMP-mediated, PKA (protein kinase A)-dependent (cAMP/PKA) local subsarcolemmal Ca
2+
releases (LCRs) from RyRs (ryanodine receptors). LCRs occur during diastolic depolarization and activate an inward Na
+
/Ca
2+
exchange current that accelerates diastolic depolarization rate prompting the next action potential. PDEs (phosphodiesterases) regulate cAMP-mediated signaling; PDE3/PDE4 represent major PDE activities in SANC, but how they modulate LCRs and basal spontaneous SANC firing remains unknown.

Methods:
Real-time polymerase chain reaction, Western blot, immunostaining, cellular perforated patch clamping, and confocal microscopy were used to elucidate mechanisms of PDE-dependent regulation of cardiac pacemaking.

RESULTS:

PDE3A, PDE4B, and PDE4D were the major PDE subtypes expressed in rabbit SANC, and PDE3A was colocalized with α-actinin, PDE4D, SERCA (sarcoplasmic reticulum Ca
2+
ATP-ase), and PLB (phospholamban) in Z-lines. Inhibition of PDE3 (cilostamide) or PDE4 (rolipram) alone increased spontaneous SANC firing by ≈20% (
P
<0.05) and ≈5% (
P
>0.05), respectively, but concurrent PDE3+PDE4 inhibition increased spontaneous firing by ≈45% (
P
<0.01), indicating synergistic effect. Inhibition of PDE3 or PDE4 alone increased L-type Ca
2+
current (I
Ca,L
) by ≈60% (
P
<0.01) or ≈5% (
P
>0.05), respectively, and PLB phosphorylation by ≈20% (
P
>0.05) each, but dual PDE3+PDE4 inhibition increased I
Ca,L
by ≈100% (
P
<0.01) and PLB phosphorylation by ≈110% (
P
<0.05). Dual PDE3+PDE4 inhibition increased the LCR number and size (
P
<0.01) and reduced the SR (sarcoplasmic reticulum) Ca
2+
refilling time (
P
<0.01) and the LCR period (time from action potential–induced Ca
2+
transient to subsequent LCR;
P
<0.01), leading to decrease in spontaneous SANC cycle length (
P
<0.01). When RyRs were disabled by ryanodine and LCRs ceased, dual PDE3+PDE4 inhibition failed to increase spontaneous SANC firing.

Conclusions:
Basal cardiac pacemaker function is regulated by concurrent PDE3+PDE4 activation which operates in a synergistic manner via decrease in cAMP/PKA phosphorylation, suppression of LCR parameters, and prolongation of the LCR period and spontaneous SANC cycle length.