Percent Decline Research Articles

Associations of awake and asleep blood pressure and blood pressure dipping with abnormalities of cardiac structure: the Coronary Artery Risk Development in Young Adults study.

To evaluate the associations of high awake blood pressure (BP), high asleep BP, and nondipping BP, determined by ambulatory BP monitoring (ABPM), with left ventricular hypertrophy (LVH) and geometry. Black and white participants (n = 687) in the Coronary Artery Risk Development in Young Adults study underwent 24-h ABPM and echocardiography at the Year 30 Exam in 2015-2016. The prevalence and prevalence ratios of LVH were calculated for high awake SBP (≥130 mmHg), high asleep SBP (≥110 mmHg), the cross-classification of high awake and asleep SBP, and nondipping SBP (percentage decline in awake-to-asleep SBP < 10%). Odds ratios for abnormal left ventricular geometry associated with these phenotypes were calculated. Overall, 46.0 and 49.1% of study participants had high awake and asleep SBP, respectively, and 31.1% had nondipping SBP. After adjustment for demographics and clinical characteristics, high awake SBP was associated with a prevalence ratio for LVH of 2.79 [95% confidence interval (95% CI) 1.63-4.79]. High asleep SBP was also associated with a prevalence ratio for LVH of 2.19 (95% CI 1.25-3.83). There was no evidence of an association between nondipping SBP and LVH (prevalence ratio 0.70, 95% CI 0.44-1.12). High awake SBP with or without high asleep SBP was associated with a higher odds ratio of concentric remodeling and hypertrophy. Awake and asleep SBP, but not the decline in awake-to-asleep SBP, were associated with increased prevalence of cardiac end-organ damage.

Global Confidence, Uncertainty, and Business Cycles

This paper investigates the role of global confidence cycles, measured as the common factor across a wide range of survey-based business or consumer confidence indicators on global macroeconomic fluctuations. I estimate a factor-augmented vector autoregression model, where global confidence shocks are identified through recursive restriction. I report three main results. First, the global confidence cycle, in particular that of consumer confidence, has played a key role in global business cycle fluctuations, explaining over a third and over a half, respectively, of total variation in global industrial production and employment over 1985-2019. Second, the results suggest that while global business confidence or uncertainty shocks are in nature demand-driven, global consumer confidence seems to reflect macroeconomic shocks in both demand and supply sides, in line with “animal spirit” and “news” views on the relation between confidence and economic activities. Third, the empirical results suggest that the plunges in economic confidence caused by the COVID-19 pandemic have led to around 25 percent decline in global industrial production by the end of 2020. The results are robust to the ordering of variables or alternative identifying schemes that include external instrument identification.

Broadband Internet and Household Welfare in Senegal

Senegal has experienced a rapid expansion in fixed and mobile broadband Internet infrastructure over the past decade. This paper examines the relationship between access to broadband internet and household welfare between 2011 and 2018 by integrating the latest two rounds of household budget surveys with data on the location of fiber-optic transmission nodes and coverage maps of third-generation (3G) mobile technology. Results show that 3G coverage is associated with a 14 percent increase in total consumption and a 10 percent decline in extreme poverty.These results are robust to controlling for spatial characteristics and access to complementary digital infrastructure, as well as to an instrumental variable approach that relies on distance to 3G coverage in neighboring areas. These effects are larger among households in urban areas and households headed by men or younger cohorts. Although in the same direction, welfare effects of proximity to fixed broadband infrastructure are not statistically significant.

A Carolina Bay in the Land of the Longleaf Pine

A Carolina Bay in the Land of the Longleaf Pine Evan E. Montpellier Unbeknownst to the majority of North Carolina beachgoers, just a few miles away lies a different kind of bay, a Pleistocene Era landform unique to the coastal southeastern United States. Carolina bays were once lakeshores. While their elevational relief is unassuming (~ 1 to 1.5 meters), they are home to a rich and unique anthropogenic, ecological, and climatological history that is worth exploring. Human presence on Carolina bays in North Carolina dates to the Paleoindian and Archaic periods (Brooks et al. 2015). Artifacts gathered at these sites reveal a history of hunting, ritual life, and temporary habitation (Gillam 2015). When Europeans forcibly settled North America, the longleaf pine trees depicted in this issue's cover photo occupied approximately 36.5 million hectares of the southeastern United States and were not exclusive to Carolina bays (Frost 2006). However, longleaf pine ecosystems became the site of the extractive turpentine industry. Raw sap was collected from longleaf pine trees by cutting notches at the base of the tree, removing its bark, and slashing the tree to force its resin to run. This raw resin was distilled to create turpentine. In the 19th century, turpentine was the South's third largest export with North Carolina accounting for approximately 97 percent of the national market (Outland 1996). Continued slashing, along with logging and modern fire suppression techniques have been responsible for a 97 percent decline in native longleaf pine ecosystems (Frost 2006). While many Carolina bay longleaf woodlands were affected by the turpentine and logging industries, others were spared due to inaccessibility. What remains at such sites are relic ecosystems teeming with biodiversity and mature longleaf pine trees. Redcockaded woodpeckers (RCW), a keystone species for longleaf pine ecosystems, are currently listed as an endangered species. RCW nest in hollowed cavities of mature longleaf pines that have historically been found on remote and minimally disturbed Carolina bays (Jose et al. 2007). Trees are marked with a white painted band (as seen on some trees in the cover photo) to indicate the presence of RCW cavities. Venus flytraps, the iconic carnivorous plant species, are endemic to Carolina bay ecosystems and are also currently threatened due to loss of habitat (Luken 2005). In addition, it is estimated that one third of rare flora species in the Southeast can be found in Carolina bays, longleaf pine savannas, and karst ponds (Sharitz 2003). The estimated 10,000 to 20,000 Carolina bays and surrounding pocosin wetlands are integral to the flora and fauna composition of the southeastern United States (Richardson and Gibbons 1993). [End Page 1] Carolina bays have been of interest for recent dendrochronology research that investigates tropical cyclone precipitation (TCP) recorded in the annual rings of longleaf pine trees (Knapp et al. 2016, Montpellier et al. 2019). Accessing Carolina bays with extant old-growth longleaf pines that were not logged or turpentined during the late 19th and early 20th centuries offers the opportunity to survey the 300-year old climatological record stored in their annual rings. Flat tops, flagging branches, gnarled trunks and RCW cavities, some of which can be seen in the issue's cover photo, are all visual indicators of mature longleaf (Harper et al. 1997). The leading hypothesis as to why longleaf pine are sensitive to TCP relates to root structure and water table height fluctuation. When TCP collects in the pocosin wetlands, the water table rises, and longleaf pine roots record this surplus water in their annual rings. This information can be used to assess how TCP has fluctuated over time (Knapp et al. 2016) and allows for the investigation of microelevational influences on tree growth and climate response (Montpellier et al. 2019). Carolina bays are not only a landscape that is unique to the southeastern United States, but they also serve as recorders of anthropogenic and climatological history and provide refuge for species on the brink of extinction. Their research and preservation are vital as historically significant, ecologically vital, and climatologically intriguing locations in the United States are becoming increasingly rare. Evan E. Montpellier University of Minnesota references cited Brooks, Mark J., Barbara E. Taylor, and Andrew H. Ivester. 2010...

Domestic Demand and Exports: Evidence from Turkish Firms

This study examines the relationship between real domestic sales and real exports for Turkish manufacturing firms. Dynamic panel data estimations based on firm-level data for the period 2004-2014 suggest that the two variables are substitutes. Other factors held constant, we estimate that a 10 percent decline in real domestic sales leads the real exports to increase by about 2.7 percent, on average. However, this relationship varies among manufacturing sub-sectors which are defined according to 2-digit NACE classification. Results indicate that substitutability between domestic and foreign sales is stronger for export-oriented, low-leveraged and younger firms, and for firms that operate in sectors whose exports are less import-dependent. Besides, the degree of substitution between the two variables significantly rises when domestic demand conditions are weak. This shows that exporter firms in the Turkish manufacturing industry can shift from domestic to international markets as a response to domestic demand shocks.

Strangling Angel: Diphtheria and Childhood Immunisation in Ireland by Michael Dwyer

Reviewed by: Strangling Angel: Diphtheria and Childhood Immunisation in Ireland by Michael Dwyer Mary Hatfield Strangling Angel: Diphtheria and Childhood Immunisation in Ireland By Michael Dwyer Liverpool: Liverpool University Press, 2018. x + 212 pp. Hardback £85.00. Michael Dwyer's debut monograph documents the history of diphtheria and the campaign to implement anti-diphtheria vaccination in the Irish Free State. Offering a new analysis of the Ring College disaster and the role of the British pharmaceutical company Burroughs Wellcome in Ireland's immunization initiatives, this book is an innovative and insightful study into the history of vaccination and public health policy. As the question of compulsory vaccination once again looms high on the public agenda, Dwyer's work casts a historical light on the challenges of pursuing innovation in public health policy while also ensuring protection of the vulnerable and individual rights. The volume is the first to focus on diphtheria in Ireland and the development of a vaccination. Given the extent of the disease and its fatality rate, this is a welcome addition to the literature on vaccination and childhood health in Ireland. The study utilizes Irish newspapers, government reports, and public health records to trace efforts taken to mitigate this childhood disease and the challenges and failures of early immunization campaigns. The book is not a social history of the disease, and therefore limited attention is paid to how parents and children experienced diphtheria or thought about the risks and rewards of vaccination. This study focuses on public health officials, on the medical community, and the scientific development of an antitoxin. [End Page 471] Dwyer makes a strong case for the prevalence of diphtheria as one of the deadliest childhood diseases, though it was often misclassified and underreported during the late nineteenth and early twentieth centuries. The book argues that Irish health policies were radically progressive, influenced by American and specifically New York's public health schemes. The Irish were one of the earliest European nations to adopt and implement childhood immunization. However, their progressive stance masks a darker history of vaccine experimentation carried out on children in Irish industrial schools, as well as the administration of experimental vaccines to children with limited parental consent. The vision of a diphtheria-free Ireland meant that some physicians took risks that were likely unacceptable to wider Irish society but were considered necessary among British and Irish medical communities. Dwyer focuses on the aggressive schemes launched in Cork and Dublin to bring about a bacteriological revolution. The vigor of such health policies was largely connected to the personality of the acting medical officer. Jack Saunders's energetic and extended appointment in Cork from 1929 to 1957 enabled a long-term commitment to childhood immunization schemes. The early successes of anti-diphtheria immunization were brought to a halt with the Ring College disaster in 1936–37. After a routine anti-diphtheria immunization by a local Waterford doctor, twenty-four children reportedly contracted tuberculosis and one 12-year-old girl died. The existing historiography relating to the Ring incident has insisted that Burroughs Wellcome mistakenly supplied a bottle of live tuberculosis in lieu of a bottle of the anti-diphtheria serum. Dwyer suggests that the local doctor and his advisors conspired to cover up initial negligence in administering the immunization and subsequently failed to provide medical treatment to the affected children in order to avoid blame. Perhaps the most striking element of the episode was the collusion of medical and school authorities to prevent parents from knowing that their children had been diagnosed as tubercular. Legal action against the prestigious Wellcome company produced an inconclusive verdict, and the real effect of the Ring College disaster was an 80 percent decline in children presented for immunization the following year. Dwyer's concluding chapter follows the development of vaccination schemes in Ireland until the 1960s, providing insight into the gradual acceptance of diphtheria immunization and the decline of the disease. There is a noticeable lack of tables and charts throughout the volume. These would have been very useful to contextualize and compare incidences of disease and immunization rates. There are several long sections in chapters [End Page 472] 3 and 4, drawn from yearly reports...

Advancing the Agency of Adolescent Girls

Abstract More than 98 million adolescent girls are not in school. Can girls inuence their schooling without changes in their family's economic environment? In Rajasthan, India, we examine the impact of a school-based life skills program that seeks to address low aspirations, narrow societal roles for girls and women, restricted networks of social support, and limited decision-making power. We find the intervention causes a 25 percent decline in school dropout that persists from seventh grade through the transition to high school. Improvements in socioemotional support among girls exposed to the intervention seem especially important in their decision to stay in school.

Addressing Behavioral Symptoms of Dementia Through STAR-VA Implementation: Do Outcomes Vary by Behavior Type?

The STAR-VA program in Veterans Health Administration Community Living Centers (CLCs, nursing home settings) trains teams to implement a psychosocial intervention with residents with behavioral symptoms of dementia (BSD). Across 71 CLCs, 302 residents selected as training cases had target behaviors categorized into one of 5 types: physically aggressive (PA), physically nonaggressive, verbally aggressive, verbally nonaggressive, and behavior deficit (BD). Across all groups, there were significant declines in team-rated behavior frequency (36%) and severity (44%), agitation (10%), distress behaviors (42%), depression (17%), and anxiety (20%). The magnitude of changes varied across behavior category. For example, those with a PA target behavior experienced a greater percentage decline in agitation and distress behavior scores, and those with a BD target behavior experienced a greater percentage decline in depressive and anxiety symptoms. STAR-VA, a multicomponent intervention, is generally effective across various types of behavioral symptoms associated with dementia.

Russian Ethnic Problem in Estonia

Due to historical conditions, the area of modern Estonia is multi-ethnic and multicultural. The influx of Russian people and extensive Sovietization led to the nationalization of part of the local community. This was accompanied by the marginalization of the Estonian language. Top-down Russian-Soviet ethnic policy has led to partial national degeneration and a percentage decline in the Estonian population, as well as a rapid increase in the number of Russians and the Russian-speaking population. A broad statistical approach to national transformations in the lands of modern Estonia, taken from a historical perspective, proves that ethnic changes were determined by geopolitical conditions. An important role from the point of view of national security policy is played by the Russian minority, which after the collapse of the Soviet Union lost its previous privileged social position. This population largely identifies with the tradition of the past system. After his fall, with the regaining of independence, the citizens of Estonia began to build a new political and socio-economic order. The collapse of the Soviet system saved Estonia from the coming ethnic and cultural disaster. Regaining independence prevented the loss of ethnic identity. It also gave the opportunity to build a new social and political order. The Estonian language has regained its original meaning and became a privileged state language. The Russian and Russian-speaking factors do not facilitate this process. Rather, it promotes the reintegration of the post-Soviet area. In counteracting the above, the Estonian authorities have introduced a relatively restrictive naturalization policy. Therefore, the situation of Slavic minorities can be a source of serious socio-political problems. Key words: Russia; Estonia; nationalities; conflict.

Vascular Rinsing and Chilling Carcasses: Effects on Quality Attributes and Metabolic Changes in Beef

ObjectivesRinse &amp; Chill® (RC) is a process applied early postmortem that provides the ability to manipulate muscle metabolism and can have a positive impact on meat quality traits. This study aimed to evaluate the effect of RC on pH decline, shear force, sarcomere length and cooking losses on different cull dairy cow carcass grades. Investigate the ability of different substrates to modulate contractile response as an indirect measure of metabolic activity on beef early postmortem.Materials and MethodsFor each carcass grade (lean, LE; light, LI), ten carcasses were conventionally chilled (CC) and twelve carcasses were chilled using RC technology (MPSC Inc.). The RC process involved infusion of a chilled isotonic solution (98.5% water; balance: glucose, phosphates, and maltose) through the vascular system, beginning in the arterial and exiting the venous side of the vasculature. Shear force and cooking losses were measured on Longissimus dorsi steaks aged (7 d). Sarcomere length (SL) was determined by a laser diffraction method. Animal served as the experimental unit and data were analyzed with a PROC MIXED procedure. For contraction measurements, a muscle-fiber bundle from the Sternomandibularis muscles (n = 14) was collected from cull dairy cows in a commercial packing plant, 15 min after bleeding. The muscle bundle was attached to a force transducer (FT-302, iWorx, Dover, NH). Stimulation electrodes were used to elicit a supramaximal electrical stimulus at a frequency of 50 V, 0.1 Hz (HCS-100 stimulator, iWorx). Muscle weight was standardized, and length was adjusted to obtain maximum twitch-tension output. After 3 min of rest in a test solution, 200 stimuli were given, and the contractile response was recorded. Four solutions were tested (A = RC, B = Fructose, C = Sodium phosphate, D = Dipotassium phosphate; substrates added at 1% except fructose 1.5%). Descriptive means for initial peak twitch force, final peak twitch force, percentage decline and percentage half-time decline were calculated to determine the response associated with each solution.ResultsRC reduced (P &lt; 0.05) shear force by 51.9% (6.79 kgf CC) and 55.8% (8.50 kgf CC) for LI and LE cows, respectively. LI cows were more tender than LE for CC (6.79 vs. 8.50 kgf; P &lt; 0.05). RC compared to CC had longer SLs (LE: 1.80 vs. 1.44µ; P &lt; 0.05) and LI (1.80 vs. 1.40µ; P &lt; 0.05). Purge and cooking losses were not affected by chilling method. The contractile responses of the muscle after the exposure to the solutions were slightly different. The average percentage decline of peak twitch force was higher for solution B, followed by solutions A, D, C (54.8%, 53.5%, 48.0%, 43.4%, respectively). Furthermore, the same pattern was observed for the average percentage decline at half time of the test (82.5%, 80.4%, 78.1% and 74.7%, respectively).ConclusionPacking plants that harvest cull dairy cows have the potential to dramatically improve tenderness and thereby merchandize a greater amount of whole muscle cuts as a result of the application of the Rinse &amp; Chill®. This improvement may be associated with accelerating postmortem glycolysis, thereby limiting cold shortening, although enhanced proteolysis may also be involved. Continuous electrical stimulation of isolated muscle-fiber bundles while being soaked in selected test solutions led to decreased and somewhat varied contractile force responses suggesting the potential to modify muscle metabolism.

Do dietary intakes influence the rate of decline in anti-Mullerian hormone among eumenorrheic women? A population-based prospective investigation

BackgroundDietary intakes are suggested to affect age at menopause but associations between dietary factors and ovarian reserve reduction have not yet been investigated. We aimed to examine dietary intakes in relation to the rate of decline in anti-Mullerian hormone (AMH), an indicator of ovarian reserve, in a generally healthy cohort of women.MethodsThis prospective investigation was conducted among 227 eumenorrheic women, aged 20–50 years, from the Tehran Lipid and Glucose study, who were followed over a mean of 16 years. AMH was measured twice, at baseline and the 5th follow-up examination cycle, and yearly rate of decline in AMH was calculated. Rapid decline in AMH was defined as the annual percent change AMH > 5.9%/year based on tertile 3 of the variable. Average usual dietary intakes were estimated using the food frequency questionnaires administered at the second, third, and the fourth follow-up examinations. After adjusting for potential covariates, the association between dietary factors and both risk of rapid decline in AMH and also annual percent decline of AMH (as a continuous variable) were examined using logistic regression and the Spearman correlation, respectively.ResultsThe baseline age of the participants and the median rate of decline in AMH were 37.2 years and was 5.7% yearly, respectively. The odds of rapid decline in AMH was reduced by 47% for dairy products (95% CIs = 0.36, 0.79; p = 0.002), 38% for milk (95% CIs = 0.41, 0.93; p = 0.020), and 36% for fermented dairy (95% CIs = 0.45, 0.93, p = 0.018) per one standard deviation (SD) increase in their dietary intakes. The odds of rapid decline in AMH was significantly reduced with higher intakes of fat, carbohydrate, protein, and calcium intakes from dairy sources, lactose and galactose. Annual rate of AMH decline was inversely correlated with dairy products, milk, fermented dairy, fruits, dairy carbohydrate, dairy fat, dairy protein, total calcium and dairy calcium, lactose and galactose, and positively correlated with organ meats.ConclusionDairy foods consumption may reduce the rate of AMH decline in regularly menstruating women. Life style modification in terms of dietary advice may be considered as a preventive strategy for reduction in the rate of ovarian reserve loss.

Воспроизводство населения Томска в 1918-1926 гг.

Целью исследования является характеристика динамики показателей воспроизводства населения Томска в 1918-1926 гг. В работе впервые представлены основные показатели воспроизводства населения, установлены тенденции динамики движения горожан. Задачи исследования: расчет демографических показателей, выявление основных демографических тенденций в зависимости от социально-экономических условий, определение влияния войн и революций на рост и снижение численности горожан. Использовались методы статистического анализа, статистическое наблюдение, сводка и группировка статистических материалов, абсолютные и относительные статистические величины, выборка, ряды динамики. Хронологические рамки охватывают 1918-1926 гг., выбор нижней границы объясняется началом Гражданской войны и изменением в динамике населения, выбор верхней границы определяется проведением Всесоюзной переписи населения в 1926 г. Делается вывод, что с 1918 г. начал проявляться демографический кризис, ставший в 1920-1922 гг. демографической катастрофой. Процент убыли городского населения в 1918-1922 гг. был наиболее высоким. Катастрофическое падение численности населения объяснялось гибелью молодых мужчин в Гражданской войне, тифозной и холерной эпидемиями. Сокращению населения способствовало закрытие большинства промышленных предприятий, что вызвало отток крестьян обратно в деревни.

Gestational Thrombocytopenia: Insights into Mechanism from 3730 Pregnancies

Introduction: Gestational thrombocytopenia (GT) is one of the most common hematologic disorders of young adults, observed in approximately 10% of pregnancies worldwide. Despite its prevalence, the cause of GT is not known. To gain insight into the potential mechanisms underlying GT, we analyzed clinical and laboratory features of the 3,730 pregnancies delivered at the Massachusetts General Hospital in 2017. Methods: Patients were identified and their clinical data were extracted from a standardized obstetric database. Results of 25,131 complete blood counts (CBCs) were obtained directly from the hospital laboratory record. CBCs obtained prior to pregnancy were removed from analysis. GT was defined as women with at least one recorded platelet count of &lt;150K at any time during day -100 to the day of the delivery (day 0). For CBCs obtained on day 0, the medical record was reviewed to ensure that only platelet counts prior to parturition were used to categorize the patient. Controls included all other patients with platelet counts &gt;150K during the final 100 days antepartum. For both GT and controls, women with an ICD-9 code for pre-eclampsia, antiphospholipid antibody syndrome, ITP, SLE, HIV, HCV, or HBV were excluded (n=29), as were women with a platelet count &lt;50K (n=6) at any time during the pregnancy. This method resulted in 3,695 deliveries available for analysis. Comparisons of GT versus controls used the chi-square test for categorical data, t-test for parametric data, and Wilcoxon test for non-parametric data. Results: Of 3,695 deliveries, we identified 453 (12%) as GT and 3,242 as controls. For each stage of pregnancy, the CBC closest to delivery was selected, yielding 13,792 total CBCs for analysis (Figure 1). Of particular importance, the average percent decline in platelet count between trimester 1 and day 0 was 25.7% in women with GT versus 16.9% in the controls (p&lt;0.0001). The decline in platelet count in both groups is much greater than the decline observed in hemoglobin (Hb) between trimester 1 and day 0: 1.1% decline in GT and 3.0% decline in controls. As shown in Table 1, the mean platelet volume (MPV) increased during pregnancy in both groups, with GT patients having a significantly higher MPV compared with controls in each trimester and at delivery (p&lt;0.0001). Among 51 GT women with &gt;1 CBC result post-partum, analysis revealed a greater than two-fold rise in platelet count within the first 7 days. The mean increases in platelet count compared with day 0 were: 100% on day 1, 117% on day 2, 142% on day 3, 159% on day 4, 187% on day 5, 214% on day 6, and 226% on day 7. Clinical and demographic data for the 2 groups are shown in Table 1. There was no significant difference between GT and controls in maternal age, gestational weeks at delivery, gravida, race, blood type, weight gain, mode of delivery, type of anesthesia, estimated blood loss, transfusions, rates of neonatal demise, APGAR scores, neonatal height or weight. A higher percentage of GT patients (9.1%, n=41) were given antenatal steroids versus controls (5.7%, n=186) (p=0.0059). There were more twin pregnancies among the GT group (5.1%, n=23) versus controls (2.9%, n=95) (p=0.015). Conclusions: Based on this retrospective analysis of 3695 pregnancies, GT is confirmed as a common hematologic disorder, occurring in 12% of pregnancies in this series. The significantly greater percent-decline in platelets during pregnancy in women with GT compared with controls suggests that GT is a distinct pathophysiology, and not that all pregnancies result in a similar degree of platelet decline with GT women simply starting at a lower platelet count. The data also argue against hemodilution as the etiology for GT given the relative stability in Hb compared with platelet decline throughout gestation in both groups and given the lack of significant difference in maternal weight gain between GTs and controls. The rapid doubling in platelet count within 7 days of delivery argues against an autoimmune mechanism, which would not likely demonstrate such spontaneous recovery kinetics. The progressive and statistically significant increase in MPV in women with GT compared with controls would be consistent with a high platelet turnover state in affected women, which may be exaggerated in pregnancy by increased blood flow sheer rates. Exploring causes for an increased rate of platelet turnover in GT as a component of the responsible mechanism merits further investigation. Disclosures No relevant conflicts of interest to declare.

Pre-Transplant Use of Tyrosine Kinase Inhibitors Increases Risk of Transplant Associated Thrombotic Microangiopathy - a Single Centre Analysis of Incidence, Risk Factors and Outcomes

Introduction Transplant associated thrombotic microangiopathy (TA-TMA) is a life-threatening complication post hematopoietic stem cell transplant (HSCT). Epidemiology, risk factors, prognosis and treatment of TA-TMA are not very clear. While type of transplant, and use of calcineurin inhibitors (CNIs) are established risk factors for TA-TMA, not much is known of other risk factors that affect TA-TMA and its outcome. We retrospectively analysed data of all patients who underwent allogeneic transplant for hematological malignancies at our centre to understand its incidence, possible risk factors and treatment outcomes. Methods All consecutive patients who underwent allogeneic HSCT for AML, ALL and CML from January 2008 to March 2019 were included. Conditioning regimens used were either myeloablative (CyTBI or BuCY) or reduced intensity (fludarabine with either melphalan, treosulfan or cyclophosphamide with or without 2 Gy TBI). Rabbit ATG was used at a dose of 2.5-5 mg/kg for patients who underwent matched unrelated donor (MUD) transplants. GVHD prophylaxis for matched sibling donor (MSD) and MUD transplants included CNIs with methotrexate or mycophenolate mofetil (MMF). Patients who underwent haploidentical (haplo) HSCT received post transplant cyclophosphamide (PTCy) on d+3 and d+4 and CNI with MMF from day+5 onwards. Definitive TA-TMA was defined using Blood and Marrow Transplant Clinical Trials Network (BMT-CTN) criteria ie schistocytes ≥2/HPF, elevated LDH, renal compromise (increase in creatinine 2 times baseline or 50 % decrease in creatinine clearance from baseline ) or unexplained neurological manifestations and negative coombs test. Probable TMA was defined as per criteria proposed by Cho et al ie schistocytes ≥2/HPF, elevated LDH, negative coombs test, no coagulopathy, drop in haemoglobin and thrombocytopenia (platelet &lt; 50 x 109/L or &gt; 50 percent decline in platelet count). Risk factors explored for development of TA-TMA were age, gender, diagnosis, type of transplant, acute and chronic GVHD, use of tyrosine kinase inhibitors (TKI) such as imatinib, dasatinib, nilotinib or sorafenib pre transplant and conditioning regimen used. Factors evaluated to affect the outcomes of TA- TMA were gender, baseline LDH, least platelet count, presence of acute GVHD, TA-TMA index (LDHx1000/platelet count per cumm), definitive vs probable TMA, and type of transplant. All categorical data was compared using Chi-square /Fisher exact test. OS probabilities were calculated using Kaplan -Meier method and were compared using log-rank test. Multivariate analysis to assess risk factors for TMA was carried out using logistic regression. Results Total 241 patients, 179 (74.2 %) male and 62 (25.7 %) female, with median age of 28.5 (3- 53) years were analysed. Donors were MSD (6/6 matched -174, and 9/10 matched-1), MUD (16) or haplo (50) donors. Diagnoses were 104(43 %) - AML, 85 (35%) - ALL (of which Ph+ patients --23) and 52 (22%) -CML patients. Conditioning regimens given were myeloablative (MAC; n= 64, 27 %) or reduced intensity (RIC; n=177, 73 %). Total 26 (10.7%) patients developed TA-TMA; 22 (85%) were males. Table 1 shows clinical features at diagnosis of TA-TMA. Median day of diagnosis of TA-TMA was d+102 (range 12- 722) post HSCT. Analysis of potential risk factors for TA-TMA is shown in table 2. Use of pre-HSCT TKI (OR 2.7, p=0.028), haplo HSCT (OR 3.16, p=0.018) and presence of acute GVHD within 30 days of diagnosis of TA-TMA (OR 4.17, p=0.003) were identified to be significant factors on multivariate analysis. CNIs were omitted as soon as TA-TMA was diagnosed. Low dose defibrotide (5mg/kg BD) was used in 4 patients. No patient received plasma exchange. Median follow up for whole cohort was 59.5 months. Median OS for whole cohort was 59.9 months (figure 1). The OS (figure 2) at 5 years was 51.1% in the patients who did not develop TA-TMA vs 29.6% in the group with TA-TMA (P=0.026).Ten (39%) patients with TA-TMA are alive at the time of analysis. No significant factors affecting outcomes of TA-TMA were identified. Conclusion Incidence of TA-TMA was 10% in our cohort. Pre-transplant TKI use, acute GVHD, and haplo HSCT are independent risk factor for TA-TMA. This is the first study in our knowledge to show pre-transplant TKI as a risk factor for development of TA-TMA. Higher index of suspicion of TA-TMA is thus warranted for those patients who receive pre transplant TKI. Disclosures No relevant conflicts of interest to declare.

Associations Between Chronic Exposure to Polycyclic Aromatic Hydrocarbons and Health Indices in Gulf of Mexico Tilefish (Lopholatilus chamaeleonticeps) Post Deepwater Horizon.

A time series of polycyclic aromatic hydrocarbon (PAH) data was collected for Gulf of Mexico demersal fishes in the years following the Deepwater Horizon oil spill (2012–2017). Tilefish (Lopholatilus chamaeleonticeps) were sampled via demersal longline at repeat stations in the northern Gulf of Mexico in 2012 to 2015 and 2017. Bile samples (n = 256) were analyzed via high‐performance liquid chromatography with fluorescence detection for PAH metabolites as a biomarker of exposure to PAHs. Liver tissues (n = 230) were analyzed for accumulation of PAHs and alkylated homologs via quick, easy, cheap, effective, rugged, and safe (QuEChERS) extractions and gas chromatography–tandem mass spectrometry quantification. Over the 6‐yr time series, exposure to petrogenic PAHs increased by an average of 178%, correlating with an average 22% decline in Fulton's condition factor. The decline in Fulton's condition factor was positively correlated with a 53% decline in percentage of liver lipid. There was no accumulation of PAHs in liver tissue over time. Together, these results suggest that increasing and chronic PAH exposure and metabolism may be taxing the energy budgets of tilefish, particularly adult females, with potentially negative impacts on fitness. Environ Toxicol Chem 2019;38:2659–2671. © 2019 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals, Inc. on behalf of SETAC.

The Impact of Reported Cybersecurity Breaches on Firm Innovation

ABSTRACTMany firms cite cyber risk as a primary risk factor due to the increase in cybersecurity breach (CSB) incidents. Existing research focuses on the negative, short-term impacts from CSBs, but the longer-term impact is still unknown. Our study investigates firms' levels of innovation following a CSB as an important determinant of firm growth and profitability. Examining reported breaches from 2005–2014, we find a 10 percent decline in research and development spending in the year following a CSB. Further investigation indicates that firms for which R&amp;D is not the primary business model drive the results. We also provide evidence of a decrease in patents two years after a breach, an increase in cash holdings in the year after the breach, and a decrease in investment efficiency four years following the breach. Our aggregate results suggest that CSBs are associated with future strategic decisions involving firm-level innovation and investment decisions.Data Availability: Data are available from the public sources cited in the text.

Longitudinal clinical outcomes in a real-world population of patients with idiopathic pulmonary fibrosis: the PROOF registry

BackgroundThe PROOF registry is an observational study initiated in October 2013 with the aim to monitor disease progression in a real-world population of patients with idiopathic pulmonary fibrosis (IPF). Here, we present longitudinal clinical outcomes from the PROOF registry.MethodsPatients with IPF were enrolled across eight centers in Belgium and Luxembourg. For all patients, clinical outcomes data were collected, including mortality, lung transplant, acute exacerbations, and pulmonary hypertension. For patients treated with pirfenidone at any time during follow-up (2013–2017), for any duration of treatment (the pirfenidone-treated population): pirfenidone treatment patterns were collected; changes in pulmonary function (forced vital capacity [FVC] and carbon monoxide diffusing capacity [DLco]) were reviewed up to 24 months post-inclusion; and time-to-event analyses from the time of registry inclusion were performed.ResultsThe PROOF registry enrolled a total of 277 patients. During follow-up, 23.1% of patients died, 5.1% received a lung transplant, 5.4% experienced an acute exacerbation, and 6.1% had comorbid pulmonary hypertension. In the pirfenidone-treated population (N = 233, 84.1%), 12.9% of patients had a temporary dose discontinuation and 31.8% had a temporary dose reduction; 4.3% of patients permanently discontinued pirfenidone due to an adverse drug reaction. Mean percent predicted FVC was 81.2% (standard deviation [SD] 19.0) at Month 0 and 78.3% (SD 25.0) at Month 24, and mean percent predicted DLco was 47.0% (SD 13.2) and 45.0% (SD 16.5), respectively. Rates of ≥ 10% absolute decline in percent predicted FVC and ≥ 15% absolute decline in percent predicted DLco over 24 months were 31.0% and 23.2%, respectively. Mean times from registry inclusion to categorical absolute decline in percent predicted FVC and percent predicted DLco were 20.1 (standard error [SE] 0.6) months and 23.4 (SE 0.5) months, respectively; mean time from registry inclusion to death was 31.0 (SE 0.9) months.ConclusionsThe PROOF registry is a source of European data characterizing longitudinal clinical outcomes of patients with IPF. Over 12 months of follow-up, pulmonary function remained largely stable in patients with IPF who received pirfenidone for any duration of treatment. Pulmonary function remained similar at 24 months of follow-up, although patient numbers were lower.Trial registrationPROOF is registered with the relevant authorities in Belgium and Luxembourg, with registration to Comité National d’Éthique et de Recherche (CNER) N201309/03–12 September 2013 and a notification to Comité National de Protection des Données (CNDP) for Luxembourg.

In-vitro studies of curcumin encapsulated mesoporous Fe-Phenanthroline nanocluster for reduction of amyloid β plaque

The etiology of Alzheimer's disease (AD) is attributed to the overproduction and accumulation of misfolded amyloid-β (Aβ) protein. Presently accessible drugs for AD only suppress the symptoms for a limited period of time, thereby limiting the efficacy of current therapies. Therefore, nanoformulation of potential therapeutics in AD, that can be more efficacious and that have limited off target effects and that are less toxic are warranted. In the current study, we engineered Curcumin (Cur) encapsulated NIP (within pores of average size 2.443 nm) which forms NCIP having size 48.86 ± 2.275 nm, spherical morphology and partially crystalline in nature. The novelty in this formulation is that for the first time we are reporting its nanoformulation and its use in the reduction of Aβ Plaque. Also it has the ability to cross the Blood Brain Barrier. We assessed the potentiality of a fluorescent NCIP in reducing Aβ plaques using an in-vitro AD model. We evaluated the anti-inflammatory effects of these Cur based nanoformulations by assessing the pro-inflammatory cytokines levels in the culture milieu. We noticed, NCIP is able to reduce Aβ plaque formation by 51.4% accompanied by significant percentage decline in Tumor Necrosis Factor- α (TNF-α; 93.4%), Apolipoprotein E (APOE; 90.4%) and Interleukin 8 (IL-8; 90.7%) expression respectively as compared to the untreated control. Our novel nanoformulation possesses significant anti-inflammatory properties and has potential therapeutic utility in AD. Additionally, the NCIP nanoformulation enables the utilization of the nutraceutical “Curcumin” as an effective therapeutic and circumvents the limitations of its utility due its poor solubility in water.

Minimal Detectable Change in Dual-Task Cost for Older Adults With and Without Cognitive Impairment.

Dual-task (DT) training has become a common intervention for older adults with balance and mobility limitations. Minimal detectable change (MDC) of an outcome measure is used to distinguish true change from measurement error. Few studies reporting on reliability of DT outcomes have reported MDCs. In addition, there has been limited methodological DT research on persons with cognitive impairment (CI), who have relatively more difficulty with DTs than persons without CI. The purpose of this study was to describe test-retest reliability and MDC for dual-task cost (DTC) in older adults with and without CI and for DTs of varying difficulty. Fifty participants 65 years and older attended 2 test sessions within 7 to 19 days. Participants were in a high cognitive group (n = 27) with a Montreal Cognitive Assessment (MoCA) score of 26 or more, or a low cognitive group (n = 23) with a MoCA score of less than 26. During both sessions, we used a pressure-sensing walkway to collect gait data from participants. We calculated motor DTC (the percent decline in motor performance under DT relative to single-task conditions) for 4 DTs: the Timed Up and Go (TUG) while counting forward by ones (TUG1) and counting backward by threes (TUG3); and self-selected walking speed (SSWS) with the same secondary tasks (SSWS1 and SSWS3). Intraclass correlation coefficients (ICCs) and MDCs were calculated for DTC for the time to complete the TUG and spatiotemporal gait variables during SSWS. A 3-way analysis of variance was used to compare differences in mean DTC between groups, tasks, and sessions. ICCs varied across groups and tasks, ranging from 0.02 to 0.76. MDCs were larger for individuals with low cognition and for DTs involving counting backward by threes. For example, the largest MDC was 503.1% for stride width during SSWS3 for individuals with low cognition, and the smallest MDC was 5.6% for cadence during SSWS1 for individuals with high cognition. Individuals with low cognition demonstrated greater DTC than individuals with high cognition. SSWS3 and TUG3 resulted in greater DTC than SSWS1 and TUG1. There were no differences in DTC between sessions for any variable. Our study provides MDCs for DTC that physical therapists may use to assess change in older adults who engage in DT training. Persons with low cognition who are receiving DT training must exhibit greater change in DTC before one can be confident the change is real. Also, greater change must be observed for more challenging DTs. Thus, cognitive level and task difficulty should be considered when measuring change with DT training.

Pirfenidone in patients with unclassifiable progressive fibrosing interstitial lung disease: a double-blind, randomised, placebo-controlled, phase 2 trial

At present, no approved pharmacotherapies are available for unclassifiable interstitial lung disease (ILD), which is characterised by progressive fibrosis of the lung. We aimed to assess the efficacy and safety of pirfenidone in patients with progressive fibrosing unclassifiable ILD. We did a multicentre, double-blind, randomised, placebo-controlled phase 2 trial at 70 centres in Australia, Belgium, Canada, Czech Republic, Denmark, Germany, Greece, Ireland, Israel, Italy, Poland, Portugal, Spain, and the UK. Eligible patients (aged ≥18-85 years) had progressive fibrosing unclassifiable ILD, a percent predicted forced vital capacity (FVC) of 45% or higher and percent predicted carbon monoxide diffusing capacity (DLco) of 30% or higher, more than 10% fibrosis on high-resolution CT, and a high-resolution CT from the previous 12 months. Patients were randomly assigned (1:1) to 2403 mg oral pirfenidone daily or placebo using a central validated interactive voice or web-based response system, stratified by concomitant mycophenolate mofetil use and presence or absence of interstitial pneumonia with autoimmune features. Investigators, site personnel, and patients were masked to treatment assignment. The primary endpoint was mean predicted change in FVC from baseline over 24 weeks, measured by daily home spirometry. Secondary endpoints were change in FVC measured by site spirometry, proportion of patients who had a more than 5% or more than 10% absolute or relative decline in percent predicted FVC measured by clinic-based spirometry, change in percent predicted DLco, change in 6-min walk distance (6MWD), change in University of California San Diego-Shortness of Breath Questionnaire (UCSD-SOBQ) score, change in Leicester Cough Questionnaire score, change in cough visual analogue scale, and changes in total and subscores of the St George's Respiratory Questionnaire (SGRQ), all of which were compared with baseline. Additional secondary endpoints included proportion of patients who had non-elective hospitalisation (respiratory and all-cause) and acute exacerbations, and progression-free survival. Efficacy was analysed in the intention-to-treat (ITT) population, which included all randomly assigned patients. Safety was assessed in the safety analysis set, which included all randomly assigned patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT03099187, and is no longer recruiting. Between May 15, 2017, and June 5, 2018, 253 patients were randomly assigned to receive 2403 mg pirfenidone (n=127) or placebo (n=126) and were included in the ITT analysis set. Analysis of the primary endpoint was affected by intraindividual variability in home spirometry values, which prevented application of the prespecified statistical model. Over 24 weeks, predicted median change in FVC measured by home spirometry was -87·7 mL (Q1-Q3 -338·1 to 148·6) in the pirfenidone group versus -157·1 mL (-370·9 to 70·1) in the placebo group. Over 24 weeks, predicted mean change in FVC measured by site spirometry was lower in patients given pirfenidone than placebo (treatment difference 95·3 mL [95% CI 35·9 to 154·6], p=0·002). Compared with the placebo group, patients in the pirfenidone group were less likely to have a decline in FVC of more than 5% (odds ratio [OR] 0·42 [95% CI 0·25 to 0·69], p=0·001) or more than 10% (OR 0·44 [0·23 to 0·84], p=0·011). At week 24, mean change in DLco from baseline was -0·7% (SD 7·1) for the pirfenidone group and -2·5% (8·8) for the placebo group, and mean change in 6MWD from baseline was -2·0 m (68·1) for the pirfenidone group and -26·7 m (79·3) for the placebo group. Changes from baseline in UCSD-SOBQ, Leicester Cough Questionnaire score, cough visual analogue scale, and SGRQ scores were similar between the pirfenidone and placebo groups at week 24. Analysis of acute exacerbations, hospital admissions, and time to death from respiratory causes during the study yielded no meaningful results due to a small number of events. No differences in progression-free survival were identified between the pirfenidone and placebo groups, irrespective of the definition of progression-free survival used. Treatment-emergent adverse events were reported in 120 (94%) of 127 patients in the pirfenidone group and 101 (81%) of 124 patients in the placebo group. Serious treatment-emergent adverse events were reported in 18 (14%) patients in the pirfenidone group and 20 (16%) patients in the placebo group. The most common treatment-related treatment-emergent adverse events were gastrointestinal disorders (60 [47%] in the pirfenidone group vs 32 [26%] in the placebo group), fatigue (16 [13%] vs 12 [10%]), and rash (13 [10%] vs nine [7%]). Although the planned statistical model could not be applied to the primary endpoint data, analysis of key secondary endpoints suggests that patients with progressive fibrosing unclassifiable ILD could benefit from pirfenidone treatment, which has an acceptable safety and tolerability profile. These findings support further investigation of pirfenidone as an effective treatment for patients with progressive fibrotic unclassifiable ILD. F Hoffmann-La Roche.