bluuebunny/crossref_metadata_2025 huggingface dataset:
Intracellular Tenofovir-Diphosphate and Emtricitabine-Triphosphate in Dried Blood Spots following Directly Observed Therapy
Authors: Anderson Peter L. , Liu Albert Y. , Castillo-Mancilla Jose R. , Gardner Edward M. , Seifert Sharon M. , McHugh Cricket , Wagner Theresa , Campbell Kayla , Morrow Mary , Ibrahim Mustafa , Buchbinder Susan , Bushman Lane R. , Kiser Jennifer J. , MaWhinney Samantha
Published: October 2017

Studies of daily emtricitabine-tenofovir disoproxil fumarate (FTC-TDF) for HIV preexposure prophylaxis (PrEP) in men who have sex with men (MSM) modeled intracellular tenofovir-diphosphate (TFV-DP) in dried blood spots (DBS) to assess adherence and corresponding PrEP outcomes. We conducted a prospective, randomized, crossover pharmacokinetic study of TFV-DP in DBS during 33%, 67%, or 100% of daily dosing under directly observed therapy (DOT). Participants were assigned to two 12-week dosing regimens, separated by a 12-week washout. Forty-eight adults (25 women) from Denver and San Francisco were included. TFV-DP exhibited a median half-life of 17 days, reaching steady state in 8 weeks. TFV-DP was dose proportional with mean (SD) steady-state concentrations of 530 (159), 997 (267), and 1,605 (405) fmol/punch for the 33%, 67%, and 100% arms, respectively. Prior work in MSM demonstrated clinically meaningful TFV-DP thresholds of 350, 700, and 1,250 fmol/punch, which were estimated 25th percentiles for 2, 4, and 7 doses/week. In the present study, corresponding TFV-DP was within 3% of the prior estimates, and subgroups by site, race, and sex were within 14% of prior estimates, although males had 17.6% (95% confidence intervals [CIs], 6.5, 27.4%) lower TFV-DP than females. The thresholds of 350, 700, and 1,250 fmol/punch were achieved by 75% of men taking ≥1.2, 3.2, and 6 doses/week and 75% of women taking ≥0.6, 2.0, and 5.3 doses/week, indicating that lower dosing reached these thresholds for both sexes. In conclusion, TFV-DP arising from DOT was similar to previous estimates and is useful for interpreting PrEP adherence and study outcomes. (This study has been registered at ClinicalTrials.gov under identifier NCT02022657.)
Targeting Human-Cytomegalovirus-Infected Cells by Redirecting T Cells Using an Anti-CD3/Anti-Glycoprotein B Bispecific Antibody
Authors: Meng Weixu , Tang Aimin , Ye Xiaohua , Gui Xun , Li Leike , Fan Xuejun , Schultz Robbie D. , Freed Daniel C. , Ha Sha , Wang Dai , Zhang Ningyan , Fu Tong-Ming , An Zhiqiang
Published: October 2017

The host immune response to human cytomegalovirus (HCMV) is effective against HCMV reactivation from latency, though not sufficient to clear the virus. T cells are primarily responsible for the control of viral reactivation. When the host immune system is compromised, as in transplant recipients with immunosuppression, HCMV reactivation and progressive infection can cause serious morbidity and mortality. Adoptive T cell therapy is effective for the control of HCMV infection in transplant recipients. However, it is a highly personalized therapeutic regimen and is difficult to implement in routine clinical practice. In this study, we explored a bispecific-antibody strategy to direct non-HCMV-specific T cells to recognize and exert effector functions against HCMV-infected cells. Using a knobs-into-holes strategy, we constructed a bispecific antibody in which one arm is specific for CD3 and can trigger T cell activation, while the other arm, specific for HCMV glycoprotein B (gB), recognizes and marks HCMV-infected cells based on the expression of viral gB on their surfaces. We showed that this bispecific antibody was able to redirect T cells with specificity for HCMV-infected cells
in vitro
. In the presence of HCMV infection, the engineered antibody was able to activate T cells with no HCMV specificity for cytokine production, proliferation, and the expression of phenotype markers unique to T cell activation. These results suggested the potential of engineered bispecific antibodies, such as the construct described here, as prophylactic or therapeutic agents against HCMV reactivation and infection.
Clinical Evolution of New Delhi Metallo-β-Lactamase (NDM) Optimizes Resistance under Zn(II) Deprivation
Authors: Bahr Guillermo , Vitor-Horen Luisina , Bethel Christopher R. , Bonomo Robert A. , González Lisandro J. , Vila Alejandro J.
Published: October 2017

Carbapenem-resistant
Enterobacteriaceae
(CRE) are rapidly spreading and taking a staggering toll on all health care systems, largely due to the dissemination of genes coding for potent carbapenemases. An important family of carbapenemases are the Zn(II)-dependent β-lactamases, known as metallo-β-lactamases (MBLs). Among them, the New Delhi metallo-β-lactamase (NDM) has experienced the fastest and widest geographical spread. While other clinically important MBLs are soluble periplasmic enzymes, NDMs are lipoproteins anchored to the outer membrane in Gram-negative bacteria. This unique cellular localization endows NDMs with enhanced stability upon the Zn(II) starvation elicited by the immune system response at the sites of infection. Since the first report of NDM-1, new allelic variants (16 in total) have been identified in clinical isolates differing by a limited number of substitutions. Here, we show that these variants have evolved by accumulating mutations that enhance their stability or the Zn(II) binding affinity
in vivo
, overriding the most common evolutionary pressure acting on catalytic efficiency. We identified the ubiquitous substitution M154L as responsible for improving the Zn(II) binding capabilities of the NDM variants. These results also reveal that Zn(II) deprivation imposes a strict constraint on the evolution of this MBL, overriding the most common pressures acting on catalytic performance, and shed light on possible inhibitory strategies.
CTX-M-15-Producing Shewanella Species Clinical Isolate Expressing OXA-535, a Chromosome-Encoded OXA-48 Variant, Putative Progenitor of the Plasmid-Encoded OXA-436
Authors: Jousset Agnès B. , Dabos Laura , Bonnin Rémy A. , Girlich Delphine , Potron Anaïs , Cabanel Nicolas , Dortet Laurent , Glaser Philippe , Naas Thierry
Published: October 2017

Shewanella
spp. constitute a reservoir of antibiotic resistance determinants. In a bile sample, we identified three extended-spectrum-β-lactamase (ESBL)-producing bacteria (
Escherichia coli
,
Klebsiella pneumoniae
, and
Shewanella
sp. strain JAB-1) isolated from a child suffering from cholangitis. Our objectives were to characterize the genome and the resistome of the first ESBL-producing isolate of the genus
Shewanella
and determine whether plasmidic exchange occurred between the three bacterial species. Bacterial isolates were characterized using matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS), standard biochemical tools, and antimicrobial susceptibility testing.
Shewanella
sp. JAB-1 and ESBL gene-encoding plasmids were characterized using PacBio and Illumina whole-genome sequencing, respectively. The
Shewanella
sp. JAB-1 chromosome-encoded OXA-48 variant was cloned and functionally characterized. Whole-genome sequencing (WGS) of the
Shewanella
sp. clinical isolate JAB-1 revealed the presence of a 193-kb plasmid belonging to the IncA/C incompatibility group and harboring two ESBL genes,
bla
CTX-M-15
and
bla
SHV-2a
.
bla
CTX-M-15
gene-carrying plasmids belonging to the IncY and IncR incompatibility groups were also found in the
E. coli
and
K. pneumoniae
isolates from the same patient, respectively. A comparison of the
bla
CTX-M-15
genetic environment indicated the independent origin of these plasmids and dismissed
in vivo
transfers. Furthermore, characterization of the resistome of
Shewanella
sp. JAB-1 revealed the presence of a chromosome-carried
bla
OXA-535
gene, likely the progenitor of the plasmid-carried
bla
OXA-436
gene, a novel
bla
OXA-48
-like gene. The expression of
bla
OXA-535
in
E. coli
showed the carbapenem-hydrolyzing activity of OXA-535. The production of OXA-535 in
Shewanella
sp. JAB-1 could be evidenced using molecular and immunoenzymatic tests, but not with biochemical tests that monitor carbapenem hydrolysis. In this study, we have identified a CTX-M-15-producing
Shewanella
species that was responsible for a hepatobiliary infection and that is likely the progenitor of OXA-436, a novel plasmid-encoded OXA-48-like class D carbapenemase.
Modulators of Enterococcus faecalis Cell Envelope Integrity and Antimicrobial Resistance Influence Stable Colonization of the Mammalian Gastrointestinal Tract
Authors: Banla Ismael L. , Kommineni Sushma , Hayward Michael , Rodrigues Marinelle , Palmer Kelli L. , Salzman Nita H. , Kristich Christopher J.
Published: October 2017

The Gram-positive bacterium
Enterococcus faecalis
is both a colonizer of the gastrointestinal tract (GIT) and an agent of serious nosocomial infections. Although it is typically required for pathogenesis, GIT colonization by
E. faecalis
is poorly understood.
E. faecalis
tolerates high concentrations of GIT antimicrobials, like cholate and lysozyme, leading us to hypothesize that resistance to intestinal antimicrobials is essential for long-term GIT colonization. Analyses of
E. faecalis
mutants exhibiting defects in antimicrobial resistance revealed that IreK, a determinant of envelope integrity and antimicrobial resistance, is required for long-term GIT colonization. IreK is a member of the PASTA kinase protein family, bacterial transmembrane signaling proteins implicated in the regulation of cell wall homeostasis. Among several determinants of cholate and lysozyme resistance in
E. faecalis
, IreK was the only one found to be required for intestinal colonization, emphasizing the importance of this protein to enterococcal adaptation to the GIT. By studying Δ
ireK
suppressor mutants that recovered the ability to colonize the GIT, we identified two conserved enterococcal proteins (OG1RF_11271 and OG1RF_11272) that function antagonistically to IreK and interfere with cell envelope integrity, antimicrobial resistance, and GIT colonization. Our data suggest that IreK, through its kinase activity, inhibits the actions of these proteins. IreK, OG1RF_11271, and OG1RF_11272 are found in all enterococci, suggesting that their effect on GIT colonization is universal across enterococci. Thus, we have defined conserved genes in the enterococcal core genome that influence GIT colonization through their effect on enterococcal envelope integrity and antimicrobial resistance.
Plasmodium falciparum PfEMP1 Modulates Monocyte/Macrophage Transcription Factor Activation and Cytokine and Chemokine Responses
Authors: Sampaio Natália Guimarães , Eriksson Emily Marie , Schofield Louis
Published: October 2017

Immunity to
Plasmodium falciparum
malaria is slow to develop, and it is often asserted that malaria suppresses host immunity, although this is poorly understood and the molecular basis for such activity remains unknown.
P. falciparum
erythrocyte membrane protein 1 (PfEMP1) is a virulence factor that plays a key role in parasite-host interactions. We investigated the immunosuppressive effect of PfEMP1 on monocytes/macrophages, which are central to the antiparasitic innate response. RAW macrophages and human primary monocytes were stimulated with wild-type 3D7 or CS2 parasites or transgenic PfEMP1-null parasites. To study the immunomodulatory effect of PfEMP1, transcription factor activation and cytokine and chemokine responses were measured. The level of activation of NF-κB was significantly lower in macrophages stimulated with parasites that express PfEMP1 at the red blood cell surface membrane than in macrophages stimulated with PfEMP1-null parasites. Modulation of additional transcription factors, including CREB, also occurred, resulting in reduced immune gene expression and decreased tumor necrosis factor (TNF) and interleukin-10 (IL-10) release. Similarly, human monocytes released less IL-1β, IL-6, IL-10, monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein 1α (MIP-1α), MIP-1β, and TNF specifically in response to VAR2CSA PfEMP1-containing parasites than in response to PfEMP1-null parasites, suggesting that this immune regulation by PfEMP1 is important in naturally occurring infections. These results indicate that PfEMP1 is an immunomodulatory molecule that affects the activation of a range of transcription factors, dampening cytokine and chemokine responses. Therefore, these findings describe a potential molecular basis for immune suppression by
P. falciparum
.
Transcervical Inoculation with Chlamydia trachomatis Induces Infertility in HLA-DR4 Transgenic and Wild-Type Mice
Authors: Pal Sukumar , Tifrea Delia F. , Zhong Guangming , de la Maza Luis M.
Published: October 2017

Chlamydia trachomatisis the leading cause of infection-induced infertility in women. Attempts to control this epidemic with screening programs and antibiotic therapy have failed. Currently, a vaccine to preventC. trachomatisinfections is not available. In order to develop an animal model for evaluating vaccine antigens that can be applied to humans, we usedC. trachomatisserovar D (strain UW-3/Cx) to induce infertility in mice whose major histocompatibility complex class II antigen was replaced with the human leukocyte antigen DR4 (HLA-DR4). Transcervical inoculation of medroxyprogesterone-treated HLA-DR4 transgenic mice with 5 × 105C. trachomatisD inclusion forming units (IFU) induced a significant reduction in fertility, with a mean number of embryos/mouse of 4.4 ± 1.3 compared to 7.8 ± 0.5 for the uninfected control mice (P< 0.05). A similar fertility reduction was elicited in the wild-type (WT) C57BL/6 mice (4.3 ± 1.4 embryos/mouse) compared to the levels of the WT controls (9.1 ± 0.4 embryos/mouse) (P< 0.05). Following infection, WT mice mounted more robust humoral and cellular immune responses than HLA-DR4 mice. As determined by vaginal shedding, HLA-DR4 mice were more susceptible to a transcervicalC. trachomatisD infection than WT mice. To assess if HLA-DR4 transgenic and WT mice could be protected by vaccination, 104IFU ofC. trachomatisD was delivered intranasally, and mice were challenged transcervically 6 weeks later with 5 × 105IFU ofC. trachomatisD. As determined by severity and length of vaginal shedding, WT C57BL/6 and HLA-DR4 mice were significantly protected by vaccination. The advantages and limitations of the HLA-DR4 transgenic mouse model for evaluating humanC. trachomatisvaccine antigens are discussed.
Native or Proteolytically Activated NanI Sialidase Enhances the Binding and Cytotoxic Activity of Clostridium perfringens Enterotoxin and Beta Toxin
Authors: Theoret James R. , Li Jihong , Navarro Mauricio A. , Garcia Jorge P. , Uzal Francisco A. , McClane Bruce A.
Published: October 2017

Many
Clostridium perfringens
strains produce NanI as their major sialidase. Previous studies showed that NanI could potentiate
C. perfringens
epsilon toxin cytotoxicity by enhancing the binding of this toxin to host cells. The present study first determined that NanI exerts similar cytotoxicity-enhancing effects on
C. perfringens
enterotoxin and beta toxin, which are also important toxins for
C. perfringens
diseases (enteritis and enterotoxemia) originating in the gastrointestinal (GI) tract. Building upon previous work demonstrating that purified trypsin can activate NanI activity, this study next determined that purified chymotrypsin or mouse intestinal fluids can also activate NanI activity. Amino acid sequencing then showed that this effect involves the N-terminal processing of the NanI protein. Recombinant NanI (rNanI) species corresponding to major chymotrypsin- or small intestinal fluid-generated NanI fragments possessed more sialidase activity than did full-length rNanI, further supporting the proteolytic activation of NanI activity. rNanI species corresponding to proteolysis products also promoted the cytotoxic activity and binding of enterotoxin and beta toxin more strongly than did full-length rNanI. Since enterotoxin and beta toxin are produced in the intestines during human and animal disease, these findings suggest that intestinal proteases may enhance NanI activity, which in turn could further potentiate the activity of intestinally active toxins during disease. Coupling these new results with previous findings demonstrating that NanI is important for the adherence of
C. perfringens
to enterocyte-like cells, NanI sialidase is now emerging as a potential auxiliary virulence factor for
C. perfringens
enteritis and enterotoxemia.
A Single-Cell View of the BtsSR/YpdAB Pyruvate Sensing Network in Escherichia coli and Its Biological Relevance
Authors: Vilhena Cláudia , Kaganovitch Eugen , Shin Jae Yen , Grünberger Alexander , Behr Stefan , Kristoficova Ivica , Brameyer Sophie , Kohlheyer Dietrich , Jung Kirsten
Published: October 2017

Fluctuating environments and individual physiological diversity force bacteria to constantly adapt and optimize the uptake of substrates. We focus here on two very similar two-component systems (TCSs) of
Escherichia coli
belonging to the LytS/LytTR family: BtsS/BtsR (formerly YehU/YehT) and YpdA/YpdB. Both TCSs respond to extracellular pyruvate, albeit with different affinities, typically during postexponential growth, and each system regulates expression of a single transporter gene,
yjiY
and
yhjX
, respectively. To obtain insights into the biological significance of these TCSs, we analyzed the activation of the target promoters at the single-cell level. We found unimodal cell-to-cell variability; however, the degree of variance was strongly influenced by the available nutrients and differed between the two TCSs. We hypothesized that activation of either of the TCSs helps individual cells to replenish carbon resources. To test this hypothesis, we compared wild-type cells with the
btsSR ypdAB
mutant under two metabolically modulated conditions: protein overproduction and persister formation. Although all wild-type cells were able to overproduce green fluorescent protein (GFP), about half of the
btsSR ypdAB
population was unable to overexpress GFP. Moreover, the percentage of persister cells, which tolerate antibiotic stress, was significantly lower in the wild-type cells than in the
btsSR ypdAB
population. Hence, we suggest that the BtsS/BtsR and YpdA/YpdB network contributes to a balancing of the physiological state of all cells within a population.

IMPORTANCE
Histidine kinase/response regulator (HK/RR) systems enable bacteria to respond to environmental and physiological fluctuations.
Escherichia coli
and other members of the
Enterobacteriaceae
possess two similar LytS/LytTR-type HK/RRs, BtsS/BtsR (formerly YehU/YehT) and YpdA/YpdB, which form a functional network. Both systems are activated in response to external pyruvate, typically when cells face overflow metabolism during post-exponential growth. Single-cell analysis of the activation of their respective target genes
yjiY
and
yhjX
revealed cell-to-cell variability, and the range of variation was strongly influenced by externally available nutrients. Based on the phenotypic characterization of a
btsSR ypdAB
mutant compared to the parental strain, we suggest that this TCS network supports an optimization of the physiological state of the individuals within the population.
Conversion of Norepinephrine to 3,4-Dihdroxymandelic Acid in Escherichia coli Requires the QseBC Quorum-Sensing System and the FeaR Transcription Factor
Authors: Pasupuleti Sasikiran , Sule Nitesh , Manson Michael D. , Jayaraman Arul
Published: October 2017

The detection of norepinephrine (NE) as a chemoattractant by
Escherichia coli
strain K-12 requires the combined action of the TynA monoamine oxidase and the FeaB aromatic aldehyde dehydrogenase. The role of these enzymes is to convert NE into 3,4-dihydroxymandelic acid (DHMA), which is a potent chemoattractant sensed by the Tsr chemoreceptor. These two enzymes must be induced by prior exposure to NE, and cells that are exposed to NE for the first time initially show minimal chemotaxis toward it. The induction of TynA and FeaB requires the QseC quorum-sensing histidine kinase, and the signaling cascade requires new protein synthesis. Here, we demonstrate that the cognate response regulator for QseC, the transcription factor QseB, is also required for induction. The related quorum-sensing kinase QseE appears not to be part of the signaling pathway, but its cognate response regulator, QseF, which is also a substrate for phosphotransfer from QseC, plays a nonessential role. The promoter of the
feaR
gene, which encodes a transcription factor that has been shown to be essential for the expression of
tynA
and
feaB
, has two predicted QseB-binding sites. One of these sites appears to be in an appropriate position to stimulate transcription from the P
1
promoter of the
feaR
gene. This study unites two well-known pathways: one for expression of genes regulated by catecholamines (QseBC) and one for expression of genes required for metabolism of aromatic amines (FeaR, TynA, and FeaB). This cross talk allows
E. coli
to convert the host-derived and chemotactically inert NE into the potent bacterial chemoattractant DHMA.

IMPORTANCE
The chemotaxis of
E. coli
K-12 to norepinephrine (NE) requires the conversion of NE to 3,4-dihydroxymandleic acid (DHMA), and DHMA is both an attractant and inducer of virulence gene expression for a pathogenic enterohemorrhagic
E. coli
(EHEC) strain. The induction of virulence by DHMA and NE requires QseC. The results described here show that the cognate response regulator for QseC, QseB, is also required for conversion of NE into DHMA. Production of DHMA requires induction of a pathway involved in the metabolism of aromatic amines. Thus, the QseBC sensory system provides a direct link between virulence and chemotaxis, suggesting that chemotaxis to host signaling molecules may require that those molecules are first metabolized by bacterial enzymes to generate the actual chemoattractant.
Evaluation of a type 2 diabetes prevention program using a commercial weight management provider for non-diabetic hyperglycemic patients referred by primary care in the UK
Authors: Piper Carolyn , Marossy Agnes , Griffiths Zoe , Adegboye Amanda
Published: October 2017

Objectives

To determine if a diabetes prevention program (DPP) delivered by a commercial weight management provider using a UK primary care referral pathway could reduce the progression to type 2 diabetes (T2D) in those diagnosed with non-diabetic hyperglycemia (NDH—being at high risk of developing T2D).

Research design

This is a quasi-experimental translational research study.

Methods

14 primary care practices identified, recruited and referred patients with NDH (fasting plasma glucose ≥5.5 to ≤6.9 mmol/L and/or glycated hemoglobin (HbA1c) ≥42 to 47 mmol/mol (6.0%–6.4%)) and a body mass index (BMI) ≥30 kg/m2to a DPP. Eligible patients were asked to contact Weight Watchers to book onto their DPP, an intensive lifestyle intervention which included a 90 min activation session followed by the offer of 48 weekly Weight Watchers community group meetings. Patients’ blood tests were repeated by primary care, weight change plus self-reported data was recorded by Weight Watchers.

Results

166 patients were referred to the program and 149 were eligible. 79% of eligible patients attended an activation session (117 eligible patients) and 77% started the weekly sessions. The study sample was primarily female (75%), white (90%), with 5% living in the most deprived quintile in the UK. Using intention-to-treat analysis, the DPP resulted in a mean reduction in HbA1c of 2.84 mmol/mol at 12 months (from 43.42±1.28 to 40.58±3.41, p<0.01). 38% of patients returned to normoglycemia and 3% developed T2D at 12 months. There was a mean weight reduction in BMI of 3.2 kg/m2at 12 months (35.5 kg/m2±5.4 to 32.3 kg/m2±5.2, p<0.01).

Conclusion

A UK primary care referral route partnered with this commercial weight management provider can deliver an effective DPP. The lifestyle changes and weight loss achieved in the intervention translated into considerable reductions in diabetes risk, with an immediate and significant public health impact.
Prevalence of substandard and falsified artemisinin-based combination antimalarial medicines on Bioko Island, Equatorial Guinea
Authors: Kaur Harparkash , Allan Elizabeth Louise , Mamadu Ibrahim , Hall Zoe , Green Michael D , Swamidos Isabel , Dwivedi Prabha , Culzoni Maria Julia , Fernandez Facundo M , Garcia Guillermo , Hergott Dianna , Monti Feliciano
Published: October 2017

Introduction

Poor-quality artemisinin-containing antimalarials (ACAs), including falsified and substandard formulations, pose serious health concerns in malaria endemic countries. They can harm patients, contribute to the rise in drug resistance and increase the public’s mistrust of health systems. Systematic assessment of drug quality is needed to gain knowledge on the prevalence of the problem, to provide Ministries of Health with evidence on which local regulators can take action.

Methods

We used three sampling approaches to purchase 677 ACAs from 278 outlets on Bioko Island, Equatorial Guinea as follows: convenience survey using mystery client (n=16 outlets, 31 samples), full island-wide survey using mystery client (n=174 outlets, 368 samples) and randomised survey using an overt sampling approach (n=88 outlets, 278 samples). The stated active pharmaceutical ingredients (SAPIs) were assessed using high-performance liquid chromatography and confirmed by mass spectrometry at three independent laboratories.

Results

Content analysis showed 91.0% of ACAs were of acceptable quality, 1.6% were substandard and 7.4% falsified. No degraded medicines were detected. The prevalence of medicines without the SAPIs was higher for ACAs purchased in the convenience survey compared with the estimates obtained using the full island-wide survey-mystery client and randomised-overt sampling approaches. Comparable results were obtained for full island survey-mystery client and randomised overt.

However, the availability of purchased artesunate monotherapies differed substantially according to the sampling approach used (convenience, 45.2%; full island-wide survey-mystery client, 32.6%; random-overt sampling approach, 21.9%). Of concern is that 37.1% (n=62) of these were falsified.

Conclusion

Falsified ACAs were found on Bioko Island, with the prevalence ranging between 6.1% and 16.1%, depending on the sampling method used. These findings underscore the vital need for national authorities to track the scale of ineffective medicines that jeopardise treatment of life-threatening diseases and value of a representative sampling approach to obtain/measure the true prevalence of poor-quality medicines.
Prevalence of anxiety, depression and post-traumatic stress disorder in the Kashmir Valley
Authors: Housen Tambri , Lenglet Annick , Ariti Cono , Shah Showkat , Shah Helal , Ara Shabnum , Viney Kerri , Janes Simon , Pintaldi Giovanni
Published: October 2017

Background

Following the partition of India in 1947, the Kashmir Valley has been subject to continual political insecurity and ongoing conflict, the region remains highly militarised. We conducted a representative cross-sectional population-based survey of adults to estimate the prevalence and predictors of anxiety, depression and post-traumatic stress disorder (PTSD) in the 10 districts of the Kashmir Valley.

Methods

Between October and December 2015, we interviewed 5519 out of 5600 invited participants, ≥18 years of age, randomly sampled using a probability proportional to size cluster sampling design. We estimated the prevalence of a probable psychological disorder using the Hopkins Symptom Checklist (HSCL-25) and the Harvard Trauma Questionnaire (HTQ-16). Both screening instruments had been culturally adapted and translated. Data were weighted to account for the sampling design and multivariate logistic regression analysis was conducted to identify risk factors for developing symptoms of psychological distress.

Findings

The estimated prevalence of mental distress in adults in the Kashmir Valley was 45% (95% CI 42.6 to 47.0). We identified 41% (95% CI 39.2 to 43.4) of adults with probable depression, 26% (95% CI 23.8 to 27.5) with probable anxiety and 19% (95% CI 17.5 to 21.2) with probable PTSD. The three disorders were associated with the following characteristics: being female, over 55 years of age, having had no formal education, living in a rural area and being widowed/divorced or separated. A dose–response association was found between the number of traumatic events experienced or witnessed and all three mental disorders.

Interpretation

The implementation of mental health awareness programmes, interventions aimed at high risk groups and addressing trauma-related symptoms from all causes are needed in the Kashmir Valley.
Mandated reporters’ experiences with reporting child maltreatment: a meta-synthesis of qualitative studies
Authors: McTavish Jill R , Kimber Melissa , Devries Karen , Colombini Manuela , MacGregor Jennifer C D , Wathen C Nadine , Agarwal Arnav , MacMillan Harriet L
Published: October 2017

Objective

To systematically search for research about the effectiveness of mandatory reporting of child maltreatment and to synthesise qualitative research that explores mandated reporters’ (MRs) experiences with reporting.

Design

As no studies assessing the effectiveness of mandatory reporting were retrieved from our systematic search, we conducted a meta-synthesis of retrieved qualitative research. Searches in Medline (Ovid), Embase, PsycINFO, Cumulative Index to Nursing and Allied Health Literature, Sociological Abstracts, Education Resources Information Center, Criminal Justice Abstracts and Cochrane Library yielded over 6000 citations, which were deduplicated and then screened by two independent reviewers. English-language, primary qualitative studies that investigated MRs’ experiences with reporting of child maltreatment were included. Critical appraisal involved a modified checklist from the Critical Appraisal Skills Programme and qualitative meta-synthesis was used to combine results from the primary studies.

Setting

All healthcare and social-service settings implicated by mandatory reporting laws were included. Included studies crossed nine high-income countries (USA, Australia, Sweden, Taiwan, Canada, Norway, Finland, Israel and Cyprus) and three middle-income countries (South Africa, Brazil and El Salvador). Participants: The studies represent the views of 1088 MRs.

Outcomes

Factors that influence MRs’ decision to report and MRs’ views towards and experiences with mandatory reporting of child maltreatment.

Results

Forty-four articles reporting 42 studies were included. Findings indicate that MRs struggle to identify and respond to less overt forms of child maltreatment. While some articles (14%) described positive experiences MRs had with the reporting process, negative experiences were reported in 73% of articles and included accounts of harm to therapeutic relationships and child death following removal from their family of origin.

Conclusions

The findings of this meta-synthesis suggest that there are many potentially harmful experiences associated with mandatory reporting and that research on the effectiveness of this process is urgently needed.
Better early functional outcome after short stem total hip arthroplasty? A prospective blinded randomised controlled multicentre trial comparing the Collum Femoris Preserving stem with a Zweymuller straight cementless stem total hip replacement for the treatment of primary osteoarthritis of the hip
Authors: van Oldenrijk Jakob , Scholtes Vanessa A B , van Beers Loes W A H , Geerdink Carel H , Niers Bob B A M , Runne Wouter , Bhandari Mohit , Poolman Rudolf W
Published: October 2017

Objectives

Primary aim was to compare the functional results at 3 months and 2 years between short and conventional cementless stem total hip arthroplasty (THA). Secondary aim was to determine the feasibility of a double-blind implant-related trial.

Design

A prospective blinded randomised controlled multicentre trial in patients with osteoarthritis of the hip. All patients, research assistants, clinical assessors, investigators and data analysts were blinded to the type of prosthesis. Population: 150 patients between 18 and 70 years with osteoarthritis of the hip, 75 in the short stem and 75 in the conventional stem group. Mean age: 60 years (SD 7). Interventions: the Collum Femoris Preserving short stem versus the Zweymuller Alloclassic conventional stem.

Main outcome measures

The Dutch version of the Hip Disability and Osteoarthritis Outcome Score (HOOS). Secondary outcomes measures: Harris Hip Score, the Physical Component Scale of the SF12, the Timed Up and Go test, Pain and the EQ-5D. Feasibility outcomes: continued blinding, protocol adherence and follow-up success rate.

Results

No significant difference between the two groups. Mean HOOS total score in the short stem group increased 32.7 points from 36.6 (95% CI 32.9 to 40.2) preoperatively to 69.3 (95% CI 66.4 to 72.1) at 3 months follow-up. Mean HOOS total score in the conventional straight stem group increased 36.3 points from 37.1 (95% CI 33.9 to 40.3) preoperatively to 73.4 (95% CI 70.3 to 76.4) at 3 months follow-up. 91.2% of patients remained blinded at 2 years follow-up. Both protocol adherence and follow-up success rate were 98%.

Conclusions

Functional result at 3 months and 2 years after short stem THA is not superior to conventional cementless THA. There were more perioperative and postoperative complications in the short stem group. Direct comparison of two hip implants in a double-blinded randomised controlled trial is feasible.

Trial registration number

NTR1560.
Non-invasive brain stimulation interventions for management of chronic central neuropathic pain: a scoping review protocol
Authors: Chen Mei Lin , Yao Lin , Boger Jennifer , Mercer Kathryn , Thompson Benjamin , Jiang Ning
Published: October 2017

Introduction

Pain can affect people regardless of age, gender or ethnicity. Chronic central neuropathic pain (CCNP) is a debilitating condition that affects populations such as stroke survivors, amputees, spinal cord injury patients and patients with multiple sclerosis, with prevalence rates between 30% and 80%. This condition can be caused by a lesion or disease affecting the somatosensory system. CCNP is notoriously drug resistant, and few effective CCNP treatment or management strategies exist. The emergence of non-invasive brain stimulation and neuromodulation techniques provide novel avenues for managing chronic central neuropathic pain. This scoping review aims to systematically identify the methods and effectiveness of non-invasive brain stimulation techniques for treating and managing chronic central neuropathic pain.

Methods and analysis

The following databases will be searched systematically: PubMed, EMBASE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Institute of Electric and Electronic Engineers (IEEE), Association of Computing Machinary (ACM) and Scopus. Additional literature will be identified by searching the reference lists of identified studies. Studies will include reviews and original research in both published and grey literatures. Two reviewers will independently screen identified studies for final inclusion. A quantitative analysis on the intervention type, application and efficacy will be synthesised along with a qualitative analysis to describe the effectiveness of each intervention.

Ethics and dissemination

No primary data will be collected and hence formal ethics review is not required. The results of the scoping review will be presented at relevant national and international conferences, published in a peer-reviewed journal and provided to the stakeholders with plain language to be posted on their websites. This scoping review will provide a foundation to guide the development of future primary research on non-invasive brain stimulation and CCNP.
Effectiveness and meaningful use of paediatric surgical safety checklists and their implementation strategies: a systematic review with narrative synthesis
Authors: Lagoo Janaka , Lopushinsky Steven R , Haynes Alex B , Bain Paul , Flageole Helene , Skarsgard Erik D , Brindle Mary E
Published: October 2017

Objective

To examine the effectiveness and meaningful use of paediatric surgical safety checklists (SSCs) and their implementation strategies through a systematic review with narrative synthesis.

Summary background data

Since the launch of the WHO SSC, checklists have been integrated into surgical systems worldwide. Information is sparse on how SSCs have been integrated into the paediatric surgical environment.

Methods

A broad search strategy was created using Pubmed, Embase, CINAHL, Cochrane Central, Web of Science, Science Citation Index and Conference Proceedings Citation Index. Abstracts and full texts were screened independently, in duplicate for inclusion. Extracted study characteristic and outcomes generated themes explored through subgroup analyses and idea webbing.

Results

1826 of 1921 studies were excluded after title and abstract review (kappa 0.77) and 47 after full-text review (kappa 0.86). 20 studies were of sufficient quality for narrative synthesis. Clinical outcomes were not affected by SSC introduction in studies without implementation strategies. A comprehensive SSC implementation strategy in developing countries demonstrated improved outcomes in high-risk surgeries. Narrative synthesis suggests that meaningful compliance is inconsistently measured and rarely achieved. Strategies involving feedback improved compliance. Stakeholder-developed implementation strategies, including team-based education, achieved greater acceptance. Three studies suggest that parental involvement in the SSC is valued by parents, nurses and physicians and may improve patient safety.

Conclusions

A SSC implementation strategy focused on paediatric patients and their families can achieve high acceptability and good compliance. SSCs’ role in improving measures of paediatric surgical outcome is not well established, but they may be effective when used within a comprehensive implementation strategy especially for high-risk patients in low-resource settings.
Association between polypharmacy and falls in older adults: a longitudinal study from England
Authors: Dhalwani Nafeesa N , Fahami Radia , Sathanapally Harini , Seidu Sam , Davies Melanie J , Khunti Kamlesh
Published: October 2017

Objectives

Assess the longitudinal association between polypharmacy and falls and examine the differences in this association by different thresholds for polypharmacy definitions in a nationally representative sample of adults aged over 60 years from England.

Design

Longitudinal cohort study.

Setting

The English Longitudinal Study of Ageing waves 6 and 7.

Participants

5213 adults aged 60 or older.

Main outcome measures

Rates, incidence rate ratio (IRR) and 95% CI for falls in people with and without polypharmacy.

Results

A total of 5213 participants contributed 10 502 person-years of follow-up, with a median follow-up of 2.02 years (IQR 1.9–2.1 years). Of the 1611 participants with polypharmacy, 569 reported at least one fall within the past 2 years (rate: 175 per 1000 person-years, 95% CI 161 to 190), and of the 3602 participants without polypharmacy 875 reported at least one fall (rate: 121 per 1000 person-years, 95% CI 113 to 129). The rate of falls was 21% higher in people with polypharmacy compared with people without polypharmacy (adjusted IRR 1.21, 95% CI 1.11 to 1.31). Using ≥4 drugs threshold the rate of falls was 18% higher in people with polypharmacy compared with people without (adjusted IRR 1.18, 95% CI 1.08 to 1.28), whereas using ≥10 drugs threshold polypharmacy was associated with a 50% higher rate of falls (adjusted IRR 1.50, 95% CI 1.34 to 1.67).

Conclusions

We found almost one-third of the total population using five or more drugs, which was significantly associated with 21% increased rate of falls over a 2-year period. Further exploration of the effects of these complex drug combinations in the real world with a detailed standardised assessment of polypharmacy is greatly required along with pragmatic studies in primary care, which will help inform whether the threshold for a detailed medication review should be lowered.
Potentially inappropriate prescribing and its association with health outcomes in middle-aged people: a prospective cohort study in Ireland
Authors: Moriarty Frank , Cahir Caitriona , Bennett Kathleen , Hughes Carmel M , Kenny Rose Anne , Fahey Tom
Published: October 2017

Objectives

To determine the prevalence of potentially inappropriate prescribing (PIP) in a cohort of community-dwelling middle-aged people and assess the relationship between PIP and emergency department (ED) visits, general practitioner (GP) visits and quality of life (QoL).

Design

Prospective cohort study.

Setting

The Irish Longitudinal Study on Ageing (TILDA), a nationally representative cohort study of ageing.

Participants

Individuals aged 45–64 years recruited to TILDA who were eligible for the means-tested General Medical Services scheme and followed up after 2 years.

Exposure

PIP was determined in the 12 months preceding baseline and follow-up TILDA data collection by applying the PRescribing Optimally in Middle-aged People’s Treatments (PROMPT) criteria to participants’ medication dispensing data.

Outcome measures

At follow-up, the reported rates of ED and GP visits over 12 months (primary outcome) and the CASP-R12 (Control Autonomy Self-realisation Pleasure) measure of QoL (secondary outcome).

Analysis

Multivariate negative binomial (rates) and linear regression (CASP-R12) models controlling for potential confounders.

Results

At 2-year follow-up (n=808), PIP was detected in 42.9% by the PROMPT criteria. An ED visit was reported by 18.7% and 94.4% visited a GP (median 4 visits, IQR 2–6). Exposure to ≥2 PROMPT criteria was associated with higher rates of healthcare utilisation and lower QoL in unadjusted regression. However, in multivariate analysis, the associations between PIP and rates of ED visits (adjusted incidence rate ratio (IRR) 0.92, 95% CI 0.53 to 1.58), and GP visits (IRR 1.06, 95% CI 0.87 to 1.28), and CASP-R12 score (adjusted β coefficient 0.35, 95% CI −0.93 to 1.64) were not statistically significant. Numbers of medicines and comorbidities were associated with higher healthcare utilisation.

Conclusions

Although PIP was prevalent in this study population, there was no evidence of a relationship with ED and GP visits and QoL. Further research should evaluate whether the PROMPT criteria are related to these and other adverse outcomes in the general middle-aged population.
Associations between major chain fast-food outlet availability and change in body mass index: a longitudinal observational study of women from Victoria, Australia
Authors: Lamb Karen E , Thornton Lukar E , Olstad Dana Lee , Cerin Ester , Ball Kylie
Published: October 2017

Objectives

The residential neighbourhood fast-food environment has the potential to lead to increased levels of obesity by providing opportunities for residents to consume energy-dense products. This longitudinal study aimed to examine whether change in body mass index (BMI) differed dependent on major chain fast-food outlet availability among women residing in disadvantaged neighbourhoods.

Setting

Eighty disadvantaged neighbourhoods in Victoria, Australia.

Participants

Sample of 882 women aged 18–46 years at baseline (wave I: 2007/2008) who remained at the same residential location at all three waves (wave II: 2010/2011; wave III: 2012/2013) of the Resilience for Eating and Activity Despite Inequality study.

Primary outcome

BMI based on self-reported height and weight at each wave.

Results

There was no evidence of an interaction between time and the number of major chain fast-food outlets within 2 (p=0.88), 3 (p=0.66) or 5 km (p=0.24) in the multilevel models of BMI. Furthermore, there was no evidence of an interaction between time and change in availability at any distance and BMI.

Conclusions

Change in BMI was not found to differ by residential major chain fast-food outlet availability among Victorian women residing in disadvantaged neighbourhoods. It may be that exposure to fast-food outlets around other locations regularly visited influence change in BMI. Future research needs to consider what environments are the key sources for accessing and consuming fast food and how these relate to BMI and obesity risk.
Health education for patients with acute coronary syndrome and type 2 diabetes mellitus: an umbrella review of systematic reviews and meta-analyses
Authors: Liu Xian-liang , Shi Yan , Willis Karen , Wu Chiung-Jung (Jo) , Johnson Maree
Published: October 2017

Objectives

This umbrella review aimed to identify the current evidence on health education-related interventions for patients with acute coronary syndrome (ACS) or type two diabetes mellitus (T2DM); identify the educational content, delivery methods, intensity, duration and setting required. The purpose was to provide recommendations for educational interventions for high-risk patients with both ACS and T2DM.

Design

Umbrella review of systematic reviews and meta-analyses.

Setting

Inpatient and postdischarge settings.

Participants

Patients with ACS and T2DM.

Data sources

CINAHL, Cochrane Library, Joanna Briggs Institute, Journals@Ovid, EMBase, Medline, PubMed and Web of Science databases from January 2000 through May 2016.

Outcomes measures

Clinical outcomes (such as glycated haemoglobin), behavioural outcomes (such as smoking), psychosocial outcomes (such as anxiety) and medical service use.

Results

Fifty-one eligible reviews (15 for ACS and 36 for T2DM) consisting of 1324 relevant studies involving 2 88 057 patients (15 papers did not provide the total sample); 30 (58.8%) reviews were rated as high quality. Nurses only and multidisciplinary teams were the most frequent professionals to provide education, and most educational interventions were delivered postdischarge. Face-to-face sessions were the most common delivery formats, and many education sessions were also delivered by telephone or via web contact. The frequency of educational sessions was weekly or monthly, and an average of 3.7 topics was covered per education session. Psychoeducational interventions were generally effective at reducing smoking and admissions for patients with ACS. Culturally appropriate health education, self-management educational interventions, group medical visits and psychoeducational interventions were generally effective for patients with T2DM.

Conclusions

Results indicate that there is a body of current evidence about the efficacy of health education, its content and delivery methods for patients with ACS or T2DM. These results provide recommendations about the content for, and approach to, health education intervention for these high-risk patients.