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1.
mBio ; 11(3)2020 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-32605989

RESUMO

Alphaviruses are enveloped positive-sense RNA viruses that can cause serious human illnesses such as polyarthritis and encephalitis. Despite their widespread distribution and medical importance, there are no licensed vaccines or antivirals to combat alphavirus infections. Berberine chloride (BBC) is a pan-alphavirus inhibitor that was previously identified in a replicon-based small-molecule screen. This work showed that BBC inhibits alphavirus replication but also suggested that BBC might have additional effects later in the viral life cycle. Here, we show that BBC has late effects that target the virus nucleocapsid (NC) core. Infected cells treated with BBC late in infection were unable to form stable cytoplasmic NCs or assembly intermediates, as assayed by gradient sedimentation. In vitro studies with recombinant capsid protein (Cp) and purified genomic RNA (gRNA) showed that BBC perturbs core-like particle formation and potentially traps the assembly process in intermediate states. Particles produced from BBC-treated cells were less infectious, despite efficient particle production and only minor decreases in genome packaging. In addition, BBC treatment of free virus particles strongly decreased alphavirus infectivity. In contrast, the infectivity of the negative-sense RNA virus vesicular stomatitis virus was resistant to BBC treatment of infected cells or free virus. Together, our data indicate that BBC alters alphavirus Cp-gRNA interactions and oligomerization and suggest that this may cause defects in NC assembly and in disassembly during subsequent virus entry. Thus, BBC may be considered a novel alphavirus NC assembly inhibitor.IMPORTANCE The alphavirus chikungunya virus (CHIKV) is an example of an emerging human pathogen with increased and rapid global spread. Although an acute CHIKV infection is rarely fatal, many patients suffer from debilitating chronic arthralgia for years. Antivirals against chikungunya and other alphaviruses have been identified in vitro, but to date none have been shown to be efficacious and have been licensed for human use. Here, we investigated a small molecule, berberine chloride (BBC), and showed that it inhibited infectious virus production by several alphaviruses including CHIKV. BBC acted on a late step in the alphavirus exit pathway, namely the formation of the nucleocapsid containing the infectious viral RNA. Better understanding of nucleocapsid formation and its inhibition by BBC will provide important information on the mechanisms of infectious alphavirus production and may enable their future targeting in antiviral strategies.

2.
JCI Insight ; 2020 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-32573497

RESUMO

De novo lipogenesis (DNL) plays a role in the development of hepatic steatosis. In humans with lipodystrophy, reduced adipose tissue causes lower plasma leptin, insulin resistance, dyslipidemia and ectopic triglyceride (TG) accumulation. We hypothesized that recombinant leptin (metreleptin) for 6 months in 11 patients with lipodystrophy would reduce DNL by decreasing insulin resistance and glycemia, thus reducing circulating and hepatic-TG. The percentage of TG-rich lipoprotein particle (TRLP)-TG derived from DNL (%DNL) was measured by deuterium incorporation from body water into palmitate. At baseline, DNL was elevated with levels similar to levels previously shown in obesity-associated nonalcoholic fatty liver disease (NAFLD). After metreleptin, DNL decreased into the normal range. Similarly, absolute DNL (TRLP-TG x % DNL) decreased by 88% to near-normal levels. Metreleptin improved peripheral insulin sensitivity (hyperinsulinemic-euglycemic clamp) and lowered HbA1c and hepatic-TG. Both before and after metreleptin, DNL positively correlated with insulin resistance, insulin doses, and hepatic-TG, supporting the hypothesis that hyperinsulinemia stimulates DNL and that elevated DNL is integral to the pathogenesis of lipodystrophy-associated NAFLD.These data suggest that leptin-mediated improvement in insulin sensitivity increases clearance of blood glucose by peripheral tissues, reduces hepatic carbohydrate flux, and lowers insulinemia, resulting in DNL reductions, and improvements in hepatic steatosis and dyslipidemia.

4.
Inquiry ; 57: 46958020931311, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32525421

RESUMO

Women Veterans are a growing population with complex care needs. While previous research has examined the experiences of women Veterans, little attention has been paid to the specific experiences of older women Veterans. These case studies present the experiences of 2 older women Veterans who have been enrolled in Veterans Affairs (VA) health care for several decades. Results suggest that these older women Veterans have faced gender-specific challenges and barriers throughout their time accessing VA care. The experiences of these participants suggest that they have gender-sensitive needs that are not always addressed by VA primary care and that women's groups are important mechanisms by which they have gained psychological support in a gender-sensitive environment. These cases suggest that access to gender-sensitive services and women-centered spaces are important for these 2 older women Veterans and should be explored in future research.

5.
Gastroenterology ; 2020 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-32445858

RESUMO

BACKGROUND AND AIMS: Calcineurin is a ubiquitously expressed central Ca2+-responsive signaling molecule that mediates acute pancreatitis, but little is known about its effects. We compared the effects of calcineurin expression by hematopoietic cells vs pancreas in mouse models of pancreatitis and pancreatitis-associated lung inflammation. METHODS: We performed studies with mice with hematopoietic-specific or pancreas-specific deletion of protein phosphatase 3, regulatory subunit B, alpha isoform (PPP3R1, also called CNB1), in mice with deletion of CNB1 (Cnb1UBC△/△), and in the corresponding controls for each deletion of CNB1. Acute pancreatitis was induced in mice by administration of caerulein or high-pressure infusion of radiocontrast into biliopancreatic ducts; some mice were also given intraductal infusions of an adeno-associated virus vector that expressed NFAT-luciferase into pancreas. Pancreas, bone marrow, liver, kidney, heart, and lung were collected and analyzed by histopathology, immunohistochemistry, and immunoblots; levels of cytokines were measured in serum. Mouse and human primary pancreatic acinar cells were transfected with a vector that expressed NFAT-luciferase and incubated with an agent that blocks interaction of NFAT with calcineurin; cells were analyzed by immunofluorescence. Calcineurin-mediated neutrophil chemotaxis and reactive oxygen species (ROS) production were measured in neutrophils from mice. RESULTS: Mice with hematopoietic-specific deletion of CNB1 developed the same level of local pancreatic inflammation as control mice after administration of caerulein or infusion of radiocontrast into biliopancreatic ducts. Cnb1UBC△/△ mice or mice with pancreas-specific deletion of CNB1 developed less severe pancreatitis and reduced pancreatic inflammation after administration of caerulein or infusion of radiocontrast into biliopancreatic ducts compared with control mice. NFAT was activated in pancreas of Swiss Webster mice given caerulein or infusions of radiocontrast into biliopancreatic ducts. Blocking the interaction between calcineurin and NFAT did not reduce pancreatic acinar cell necrosis in response to caerulein or infusions of radiocontrast. Mice with hematopoietic-specific deletion of CNB1 (but not mice with pancreas-specific deletion of CNB1) had reduced infiltration of lung tissues by neutrophils. Neutrophil chemotaxis and production of ROS were decreased following incubation with a calcineurin inhibitor. CONCLUSION: Hematopoietic and neutrophil expression of calcineurin promotes pancreatitis-associated lung inflammation, whereas pancreatic calcineurin promotes local pancreatic inflammation. The findings indicate that the protective effects of blocking or deleting calcineurin on pancreatitis are mediated by the source of its expression. This information should be used in development of strategies to inhibit calcineurin for prevention of pancreatitis and pancreatitis-associated lung inflammation.

6.
Lancet Child Adolesc Health ; 4(6): 444-454, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32407710

RESUMO

BACKGROUND: Very low birthweight or preterm infants are at increased risk of adverse outcomes including sepsis, necrotising enterocolitis, and death. We assessed whether supplementing the enteral diet of very low-birthweight infants with lactoferrin, an antimicrobial protein, reduces all-cause mortality or major morbidity. METHODS: We did a multicentre, double-blind, pragmatic, randomised superiority trial in 14 Australian and two New Zealand neonatal intensive care units. Infants born weighing less than 1500 g and aged less than 8 days, were eligible and randomly assigned (1:1) using minimising web-based randomisation to receive once daily 200 mg/kg pasteurised bovine lactoferrin supplements or no lactoferrin supplement added to breast or formula milk until 34 weeks' post-menstrual age (or for 2 weeks, if longer), or until discharge from the study hospital if that occurred first. Designated nurses preparing the daily feeds were not masked to group assignment, but other nurses, doctors, parents, caregivers, and investigators were unaware. The primary outcome was survival to hospital discharge or major morbidity (defined as brain injury, necrotising enterocolitis, late-onset sepsis at 36 weeks' post-menstrual age, or retinopathy treated before discharge) assessed in the intention-to-treat population. Safety analyses were by treatment received. We also did a prespecified, PRISMA-compliant meta-analysis, which included this study and other relevant randomised controlled trials, to estimate more precisely the effects of lactoferrin supplementation on late-onset sepsis, necrotising enterocolitis, and survival. This trial is registered with the Australian and New Zealand Clinical Trials Registry, ACTRN12611000247976. FINDINGS: Between June 27, 2014, and Sept 1, 2017, we recruited 1542 infants; 771 were assigned to the intervention group and 771 to the control group. One infant who had consent withdrawn before beginning lactoferrin treatment was excluded from analysis. In-hospital death or major morbidity occurred in 162 (21%) of 770 infants in the intervention group and in 170 (22%) of 771 infants in the control group (relative risk [RR] 0·95, 95% CI 0·79-1·14; p=0·60). Three suspected unexpected serious adverse reactions occurred; two in the lactoferrin group, namely unexplained late jaundice and inspissated milk syndrome, but were not attributed to the intervention and one in the control group had fatal inspissated milk syndrome. Our meta-analysis identified 13 trials completed before Feb 18, 2020, including this Article, in 5609 preterm infants. Lactoferrin supplements significantly reduced late-onset sepsis (RR 0·79, 95% CI 0·71-0·88; p<0·0001; I2=58%), but not necrotising enterocolitis or all-cause mortality. INTERPRETATION: Lactoferrin supplementation did not improve death or major morbidity in this trial, but might reduce late-onset sepsis, as found in our meta-analysis of over 5000 infants. Future collaborative studies should use products with demonstrated biological activity, be large enough to detect moderate and clinically important effects reliably, and assess greater doses of lactoferrin in infants at increased risk, such as those not exclusively receiving breastmilk or infants of extremely low birthweight. FUNDING: Australian National Health and Medical Research Council.

7.
Artigo em Inglês | MEDLINE | ID: mdl-32279144

RESUMO

An altered processing of negative salient stimuli has been suggested to play a central role in the pathophysiology of major depression (MD). Besides negative affective and social stimuli, physical pain as a subtype of negative sensory stimulation has been investigated in this context. However, the few neuroimaging studies on unpleasant sensory stimulation or pain processing in MD report heterogeneous findings. Here, we investigated 47 young females, 22 with MD and 25 healthy controls (HC) using fMRI (3.0 T). Four levels of increasingly unpleasant electrical stimulation were applied. Ratings of stimulus intensity were assessed by a visual analogue scale. fMRI-data were analyzed using a 2 × 4 ANOVA. Behavioral results revealed no group differences regarding accuracy of unpleasant stimulation level ratings and sensitivity to stimulation. Regarding neural activation related to increasing levels of unpleasant stimulation, we observed increasing activation of brain regions related to the pain and salient stimulus processing corresponding to increasingly unpleasant stimulation in controls. This modulation was significantly smaller in MD compared to controls, particularly in the dorsal anterior cingulate cortex, the somatosensory cortex, and the posterior insula. Overall, brain regions associated with the processing of unpleasant sensory stimulation, but also associated with the salience network, were highly reactive but less modulated in female patients with MD. These results support and extent findings on altered processing of salience and of negative sensory stimuli even of a non-painful quality in female patients with MD.

8.
BMC Public Health ; 20(1): 497, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32295561

RESUMO

BACKGROUND: Recovery Education Centres (RECs) are increasingly implemented to support the process of recovery for individuals experiencing mental health challenges. However, the evidence on key REC mechanisms and outcomes, particularly for diverse subpopulations or service delivery contexts is scant. This study identified mechanisms and outcomes of an REC focused on adults with mental health challenges transitioning from homelessness. METHODS: Qualitative methods were used to explore in-depth the experiences of homeless and unstably housed participants experiencing mental health challenges in Toronto, Canada. Twenty service users participated in semi-structured interviews between July 2017 and June 2018, six to 14 months following REC enrollment. A realist informed interview guide explored participants' perspectives on key REC mechanisms and outcomes. Interviews were audio-recorded, transcribed verbatim and analyzed using inductive thematic analysis. Investigator triangulation and member checking processes enhanced analytical rigour. RESULTS: Participants perceived that program participation supported the process of recovery through several mechanisms: a judgment-free environment; supportive relationships, mutuality and role modelling; deconstruction of self-stigma; and reclaiming of one's power. Participants described several outcomes at the personal, interpersonal and social levels, including improvements in health and well-being; self-esteem, confidence and identity; sense of empowerment, control and personal responsibility; as well as improvements in interpersonal skills, pro-social behaviours and ability to self-advocate; and increased goal development and future orientation. CONCLUSIONS: Findings suggest RECs can support the process of recovery among people transitioning from homelessness and can successfully support subpopulations experiencing mental health challenges and social disadvantage.

9.
J Clin Invest ; 130(7): 3592-3602, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32191645

RESUMO

BACKGROUNDPostreceptor insulin resistance (IR) is associated with hyperglycemia and hepatic steatosis. However, receptor-level IR (e.g., insulin receptor pathogenic variants, INSR) causes hyperglycemia without steatosis. We examined 4 pathologic conditions of IR in humans to examine pathways controlling lipid metabolism and gluconeogenesis.METHODSCross-sectional study of severe receptor IR (INSR, n = 7) versus postreceptor IR that was severe (lipodystrophy, n = 14), moderate (type 2 diabetes, n = 9), or mild (obesity, n = 8). Lipolysis (glycerol turnover), hepatic glucose production (HGP), gluconeogenesis (deuterium incorporation from body water into glucose), hepatic triglyceride (magnetic resonance spectroscopy), and hepatic fat oxidation (plasma ß-hydroxybutyrate) were measured.RESULTSLipolysis was 2- to 3-fold higher in INSR versus all other groups, and HGP was 2-fold higher in INSR and lipodystrophy versus type 2 diabetes and obesity (P < 0.001), suggesting severe adipose and hepatic IR. INSR subjects had a higher contribution of gluconeogenesis to HGP, approximately 77%, versus 52% to 59% in other groups (P = 0.0001). Despite high lipolysis, INSR subjects had low hepatic triglycerides (0.5% [interquartile range 0.1%-0.5%]), in contrast to lipodystrophy (10.6% [interquartile range 2.8%-17.1%], P < 0.0001). ß-hydroxybutyrate was 2- to 7-fold higher in INSR versus all other groups (P < 0.0001), consistent with higher hepatic fat oxidation.CONCLUSIONThese data support a key pathogenic role of adipose tissue IR to increase glycerol and FFA availability to the liver in both receptor and postreceptor IR. However, the fate of FFA diverges in these populations. In receptor-level IR, FFA oxidation drives gluconeogenesis rather than being reesterified to triglyceride. In contrast, in postreceptor IR, FFA contributes to both gluconeogenesis and hepatic steatosis.TRIAL REGISTRATIONClinicalTrials.gov NCT01778556, NCT00001987, and NCT02457897.FUNDINGNational Institute of Diabetes and Digestive and Kidney Diseases, US Department of Agriculture/Agricultural Research Service 58-3092-5-001.

10.
J Clin Endocrinol Metab ; 105(7)2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32193531

RESUMO

CONTEXT: Familial partial lipodystrophy, Dunnigan variety (FPLD2) is a rare autosomal dominant disorder resulting from LMNA causal variants, which is characterized by loss of subcutaneous fat from the extremities and predisposition to metabolic complications. The diagnostic value of various anthropometric measurements for FPLD2 remains unknown. OBJECTIVE: To determine specificity and sensitivity of anthropometric measurements for the diagnosis of FPLD2. METHODS: We measured skinfold thickness and regional body fat by dual energy X-ray absorptiometry (DXA) in 50 adult females and 6 males with FPLD2 at UT Southwestern and compared their data with the sex- and age-matched controls from the National Health and Nutrition Examination Survey (NHANES) 1999-2010. We further compared data from 1652 unaffected females from the Dallas Heart Study and 23 females with FPLD2 from the National Institutes of Health with the NHANES data. RESULTS: The DXA-derived lower limb fat (%) had the best specificity (0.995) and sensitivity (1.0) compared with the upper limb fat, truncal fat, the ratio of lower limb to truncal fat, and triceps skinfold thickness for adult females with FPLD2. The lower limb fat below 1st percentile of NHANES females had a false-positive rate of 0.0054 and a false negative rate of 0. The diagnostic value of anthropometric parameters could not be determined for males with FPLD2 due to small sample size. CONCLUSIONS: The lower limb fat (%) is the best objective anthropometric measure for diagnosing FPLD2 in females. Women with below the 1st percentile lower limb fat should undergo genetic testing for FPLD2, especially if they have metabolic complications.

12.
J Gen Intern Med ; 35(6): 1813-1820, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31965522

RESUMO

BACKGROUND: More than half of homeless adults are of age ≥ 50 years. Falls are a common cause of morbidity in older adults in the general population. Risk factors for falls in the general population include poor health, alcohol use, and exposure to unsafe environments. Homeless adults aged ≥ 50 have a high prevalence of known risk factors and face additional potential risks. OBJECTIVES: To examine the prevalence of and risk of falling in a cohort of older homeless adults. DESIGN: Longitudinal cohort study with participant interviews every 6 months for 3 years; data were analyzed using generalized estimating equations (GEEs). PARTICIPANTS: Three hundred fifty adults aged ≥ 50, homeless at study entry, recruited via population-based sampling. MEASURES: The dependent variable is any falls in prior 6 months; independent variables include individual (i.e., illness, behaviors) and social/environmental (i.e., social support, experiencing violence, living unsheltered) factors. RESULTS: Over three quarters of participants were men (77.1%) and Black (79.7%). The median age was 58 (IQR 54, 61). At baseline, one third (33.7%) reported a fall in the prior 6 months. At follow-up visits, 23.1% to 31.2% of participants reported having fallen. In GEE models, individual risk factors (non-Black race, being a women, older age, functional impairment, urinary incontinence, history of stroke, and use of assistive devices, opioid, and marijuana) were associated with increased odds of falls. Environmental and social factors (spending any nights unsheltered (adjusted odds ratio (AOR) = 1.42, CI = 1.10-1.83) and experiencing physical assault (AOR = 1.67, CI = 1.18-2.37) were also associated. CONCLUSIONS: Older homeless adults fall frequently. Likely contributors include having a high prevalence of conditions that increase the risk of falls, compounded by heightened exposure to unsafe environments. Fall prevention in this population should target those at highest risk and address modifiable environmental conditions. Providing shelter or housing and addressing substance use could reduce morbidity from falls in homeless older adults.

13.
J Clin Endocrinol Metab ; 105(3)2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31588494

RESUMO

CONTEXT: Patients with mutations of the insulin receptor gene (INSR) have extreme insulin resistance and are at risk for early morbidity and mortality from diabetes complications. A case report suggested that thyroid hormone could improve glycemia in INSR mutation in part by increasing brown adipose tissue (BAT) activity and volume. OBJECTIVE: To determine if thyroid hormone increases tissue glucose uptake and improves hyperglycemia in INSR mutation. DESIGN: Single-arm, open-label study of liothyronine. SETTING: National Institutes of Health. PARTICIPANTS: Patients with homozygous (n = 5) or heterozygous (n = 2) INSR mutation. INTERVENTION: Liothyronine every 8 hours for 2 weeks (n = 7); additional 6 months' treatment in those with hemoglobin A1c (HbA1c) > 7% (n = 4). OUTCOMES: Whole-body glucose uptake by isotopic tracers; tissue glucose uptake in muscle, white adipose tissue (WAT) and BAT by dynamic [18F] fluorodeoxyglucose positron emission tomography/computed tomography; HbA1c. RESULTS: There was no change in whole-body, muscle, or WAT glucose uptake from baseline to 2 weeks of liothyronine. After 6 months, there was no change in HbA1c (8.3 ± 1.2 vs 9.1 ± 3.0%, P = 0.27), but there was increased whole-body glucose disposal (22.8 ± 4.9 vs 30.1 ± 10.0 µmol/kg lean body mass/min, P = 0.02), and muscle (0.7 ± 0.1 vs 2.0 ± 0.2 µmol/min/100 mL, P < 0.0001) and WAT glucose uptake (1.2 ± 0.2 vs 2.2 ± 0.3 µmol/min/100 mL, P < 0.0001). BAT glucose uptake could not be quantified because of small volume. There were no signs or symptoms of hyperthyroidism. CONCLUSION: Liothyronine administered at well-tolerated doses did not improve HbA1c. However, the observed increases in muscle and WAT glucose uptake support the proposed mechanism that liothyronine increases tissue glucose uptake. More selective agents may be effective at increasing tissue glucose uptake without thyroid hormone-related systemic toxicity.Clinical Trial Registration Number: NCT02457897; https://clinicaltrials.gov/ct2/show/NCT02457897.

14.
Health Soc Care Community ; 28(3): 842-849, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31815341

RESUMO

Although permanent supportive housing (PSH) has been credited with a decline in the number of chronically homeless adults in the United States since 2007, the extent to which PSH can accommodate the needs of a prematurely aging population, including reducing the likelihood of falls, is unclear. The objective of this study is to examine the prevalence and correlates of falls with a sample of 237 tenants (45- to 80-year olds) from two PSH programmes in Los Angeles from 1 January 2017 to 10 August 2017. We also explore the location and severity of fall-related injury using a subsample of 66 tenants. Standard surveys queried demographics, health status, history of homelessness and falls. Multivariable logistic regression assessed the correlates of falling in the past year. More than half of the sample had fallen and more than 40% had multiple falls in the past year. Functional impairment, frailty and persistent pain were all associated with increased fall risk. For the 66 tenants who provided more detailed fall information, more than 40% fell at home and of those nearly half fell in their bathroom. Fall-related injuries were common, with more than one-third of the subsample experiencing serious injury. These findings suggest that fall prevention is needed in PSH but that more research is needed to understand the degree to which individual and environmental risk factors are contributing to falls.

15.
J Gastrointest Surg ; 24(5): 1173-1182, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31845141

RESUMO

BACKGROUND: Potential advantages of laparoscopic sigmoidectomy for perforated diverticulitis are still under consideration. This study is designed to determine if emergent laparoscopic sigmoidectomy for perforated diverticulitis is associated with outcomes comparable to the traditional open approach. METHODS: The American College of Surgeons-National-Surgical-Quality-Improvement-Program (ACS-NSQIP) database was queried for laparoscopic and open emergent sigmoidectomy cases for perforated diverticulitis from 2012 through 2017. Using propensity score weights, 30-day outcomes between laparoscopic and open approaches were compared in two ways: one with converted cases as a separate group and another with converted cases combined with the laparoscopic-completed group (intention-to-treat). RESULTS: A total of 3756 cases met inclusion criteria-282 laparoscopic-completed, 175 laparoscopic-converted-to-open, and 3299 open. The laparoscopic-completed approach had significantly better outcomes than open and laparoscopic-converted cases. When combining laparoscopic-completed and laparoscopic-converted cases (intention-to-treat), the laparoscopic approach still had significantly fewer complications per patient, less unplanned intubation (p = 0.01), and acute renal failure (p = 0.005) than the open group. Laparoscopic groups had longer operating times and shorter hospital length of stay than the open group. Subgroup analysis comparing laparoscopic and open Hartmann's procedure and primary anastomosis with and without diverting stoma also showed favorable outcomes for the laparoscopic group. CONCLUSIONS: Laparoscopic emergent sigmoid resection for perforated diverticulitis is associated with favorable outcomes compared to the open approach. Hartmann's procedure is still common and conversion rate is high. Training efforts that increase adoption of minimally invasive surgery and decrease conversion rates are justified. Randomized trials comparing laparoscopic and open approaches may allow further critical assessment of these findings.

18.
Trials ; 20(1): 624, 2019 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-31706324

RESUMO

BACKGROUND: Recruitment and retention of participants are both critical for the success of trials, yet both remain significant problems. The use of incentives to target participants and trial staff has been proposed as one solution. The effects of incentives are complex and depend upon how they are designed, but these complexities are often overlooked. In this paper, we used a scoping review to 'map' the literature, with two aims: to develop a checklist on the design and use of incentives to support recruitment and retention in trials; and to identify key research topics for the future. METHODS: The scoping review drew on the existing economic theory of incentives and a structured review of the literature on the use of incentives in three healthcare settings: trials, pay for performance, and health behaviour change. We identified the design issues that need to be considered when introducing an incentive scheme to improve recruitment and retention in trials. We then reviewed both the theoretical and empirical evidence relating to each of these design issues. We synthesised the findings into a checklist to guide the design of interventions using incentives. RESULTS: The issues to consider when designing an incentive system were summarised into an eight-question checklist. The checklist covers: the current incentives and barriers operating in the system; who the incentive should be directed towards; what the incentive should be linked to; the form of incentive; the incentive size; the structure of the incentive system; the timing and frequency of incentive payouts; and the potential unintended consequences. We concluded the section on each design aspect by highlighting the gaps in the current evidence base. CONCLUSIONS: Our findings highlight how complex the design of incentive systems can be, and how crucial each design choice is to overall effectiveness. The most appropriate design choice will differ according to context, and we have aimed to provide context-specific advice. Whilst all design issues warrant further research, evidence is most needed on incentives directed at recruiters, optimal incentive size, and testing of different incentive structures, particularly exploring repeat arrangements with recruiters.


Assuntos
Lista de Checagem , Ensaios Clínicos como Assunto , Motivação , Seleção de Pacientes , Projetos de Pesquisa , Humanos
19.
Artigo em Inglês | MEDLINE | ID: mdl-31732689

RESUMO

A drug delivery system is designed to administer a therapeutic dose according to its label claim. Upon delivery of a parenteral drug product, the volume remaining inside the container which cannot be extracted at the end of drug administration is called the hold-up volume (HUV) and is primarily considered product wastage. In order to meet the label claim every drug product container is filled with a slight excess volume to meet the label claim. For early stage products in clinical phase, where material availability is often a limitation, excess volume in drug product containers has to be determined experimentally using several grams of product. In such scenarios, established models which can predict HUV in primary drug product containers would be valuable for product development. The objective of this study was to determine HUV with 95% confidence intervals across various container closures and drug delivery systems by using aqueous PEG400 solution mimicking the viscosity of biologic drug products. ISO 2R, 6R and 10R vials and single-use hypodermic syringe attached to luer lock needle (25G, 1½â€³) were used to mimic parenteral drug product container and delivery systems for determination of HUV. Glass PFS in 1mL and 2.25 mL configurations were also used to determine HUV with 95% confidence intervals. A linear regression model was developed for determination of HUV as a function of viscosity and as a function of container closure and needle based delivery system. This model predicting HUV was confirmed by using mAbs of varying formulations and viscosities for container closure and delivery systems tested in this study. The model provided here can be used to determine HUV for a particular container closure for a drug solution with known viscosity which can subsequently be used to evaluate fill volume specifications and label claim for a dosage form.

20.
PLoS Pathog ; 15(11): e1008061, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31697791

RESUMO

Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that causes persistent arthritis in a subset of human patients. We report the isolation and functional characterization of monoclonal antibodies (mAbs) from two patients infected with CHIKV in the Dominican Republic. Single B cell sorting yielded a panel of 46 human mAbs of diverse germline lineages that targeted epitopes within the E1 or E2 glycoproteins. MAbs that recognized either E1 or E2 proteins exhibited neutralizing activity. Viral escape mutations localized the binding epitopes for two E1 mAbs to sites within domain I or the linker between domains I and III; and for two E2 mAbs between the ß-connector region and the B-domain. Two of the E2-specific mAbs conferred protection in vivo in a stringent lethal challenge mouse model of CHIKV infection, whereas the E1 mAbs did not. These results provide insight into human antibody response to CHIKV and identify candidate mAbs for therapeutic intervention.


Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Antivirais/imunologia , Febre de Chikungunya/imunologia , Vírus Chikungunya/imunologia , Epitopos/imunologia , Glicoproteínas/imunologia , Proteínas do Envelope Viral/imunologia , Adulto , Animais , Anticorpos Neutralizantes/imunologia , Febre de Chikungunya/virologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR
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