Andexanet for Factor Xa Inhibitor-Associated Acute Intracerebral Hemorrhage.

BACKGROUND: Patients with acute intracerebral hemorrhage who are receiving factor Xa inhibitors have a risk of hematoma expansion. The effect of andexanet alfa, an agent that reverses the effects of factor Xa inhibitors, on hematoma volume expansion has not been well studied. METHODS: We randomly assigned, in a 1:1 ratio, patients who had taken factor Xa inhibitors within 15 hours before having an acute intracerebral hemorrhage to receive andexanet or usual care. The primary end point was hemostatic efficacy, defined by expansion of the hematoma volume by 35% or less at 12 hours after baseline, an increase in the score on the National Institutes of Health Stroke Scale of less than 7 points (scores range from 0 to 42, with higher scores indicating worse neurologic deficit) at 12 hours, and no receipt of rescue therapy between 3 hours and 12 hours. Safety end points were thrombotic events and death. RESULTS: A total of 263 patients were assigned to receive andexanet, and 267 to receive usual care. Efficacy was assessed in an interim analysis that included 452 patients, and safety was analyzed in all 530 enrolled patients. Atrial fibrillation was the most common indication for factor Xa inhibitors. Of the patients receiving usual care, 85.5% received prothrombin complex concentrate. Hemostatic efficacy was achieved in 150 of 224 patients (67.0%) receiving andexanet and in 121 of 228 (53.1%) receiving usual care (adjusted difference, 13.4 percentage points; 95% confidence interval [CI], 4.6 to 22.2; P = 0.003). The median reduction from baseline to the 1-to-2-hour nadir in anti-factor Xa activity was 94.5% with andexanet and 26.9% with usual care (P<0.001). Thrombotic events occurred in 27 of 263 patients (10.3%) receiving andexanet and in 15 of 267 (5.6%) receiving usual care (difference, 4.6 percentage points; 95% CI, 0.1 to 9.2; P = 0.048); ischemic stroke occurred in 17 patients (6.5%) and 4 patients (1.5%), respectively. There were no appreciable differences between the groups in the score on the modified Rankin scale or in death within 30 days. CONCLUSIONS: Among patients with intracerebral hemorrhage who were receiving factor Xa inhibitors, andexanet resulted in better control of hematoma expansion than usual care but was associated with thrombotic events, including ischemic stroke. (Funded by Alexion AstraZeneca Rare Disease and others; ANNEXA-I ClinicalTrials.gov number, NCT03661528.).

Respiratory Rate Estimation from Thermal Video Data Using Spatio-Temporal Deep Learning.

Thermal videos provide a privacy-preserving yet information-rich data source for remote health monitoring, especially for respiration rate (RR) estimation. This paper introduces an end-to-end deep learning approach to RR measurement using thermal video data. A detection transformer (DeTr) first finds the subject's facial region of interest in each thermal frame. A respiratory signal is estimated from a dynamically cropped thermal video using 3D convolutional neural networks and bi-directional long short-term memory stages. To account for the expected phase shift between the respiration measured using a respiratory effort belt vs. a facial video, a novel loss function based on negative maximum cross-correlation and absolute frequency peak difference was introduced. Thermal recordings from 22 subjects, with simultaneous gold standard respiratory effort measurements, were studied while sitting or standing, both with and without a face mask. The RR estimation results showed that our proposed method outperformed existing models, achieving an error of only 1.6 breaths per minute across the four conditions. The proposed method sets a new State-of-the-Art for RR estimation accuracy, while still permitting real-time RR estimation.

Prevalence of and factors associated with scrub typhus exposure among the hill tribe population living in high incidence areas in Thailand: a cross-sectional study.

BACKGROUND: Scrub typhus is a significant tropical disease, occurring in rural settings and therefore usually afflicting remote agricultural populations who have lower socioeconomic status and limited access to medical care. A large proportion of the hill tribe people in Thailand are financially poor, have limited education, and do not have adequate health care access. This study aimed to estimate the prevalence of and determine factors associated with scrub typhus exposure among the hill tribe population living in high-incidence areas in northern Thailand. METHODS: A cross-sectional study design was used to gather information from hill tribe people aged 18 years and over living in ten hill tribe villages in Mae Fah Luang, Chiang Rai Province, Thailand. Participants who met the inclusion criteria were invited to participate in the study. A validated questionnaire was used as the research instrument, and 5 mL blood samples were taken. Orientia tsutsugamushi IgM and IgG antibodies were detected by enzyme-linked immunosorbent assay (ELISA) and then confirmed by immunofluorescence assay (IFA). Logistic regression was used to detect associations between variables at a significance level of α = 0.05. RESULTS: A total of 485 hill tribe people participated in the study; 57.1% were female, 29.9% were over 60 years of age, 46.4% were from the Akha tribe, and 74.2% had never attended school. The overall prevalence of scrub typhus exposure was 48.0%. In the multivariate model, five variables were found to be associated with scrub typhus exposure. Participants aged over 60 years had a 4.31-fold increased risk (95% CI = 1.73-10.72) of scrub typhus exposure compared to those who were younger than 30 years. Those who were illiterate had a 3.46-fold increased risk (95% CI = 1.93-6.21) of scrub typhus exposure than those who had at least a primary education level. Participants from the Akha tribe had a 2.20-fold increased risk (95% CI = 1.31-3.72) of scrub typhus exposure than those from the Lahu tribe. Subjects who had a history of cutting grass had a 1.85-fold increased risk (95% CI = 1.20-2.84) of scrub typhus exposure. Those who never wore gloves for farming had a 2.12-fold increased risk (95% CI = 1.28-3.49) of scrub typhus exposure than those who wore gloves daily. CONCLUSIONS: There is a high prevalence of scrub typhus exposure among the hill tribe in Thailand. Effective public health interventions to promote scrub typhus awareness and prevention are urgently needed in these populations.

ELF5 modulates the estrogen receptor cistrome in breast cancer.

Acquired resistance to endocrine therapy is responsible for half of the therapeutic failures in the treatment of breast cancer. Recent findings have implicated increased expression of the ETS transcription factor ELF5 as a potential modulator of estrogen action and driver of endocrine resistance, and here we provide the first insight into the mechanisms by which ELF5 modulates estrogen sensitivity. Using chromatin immunoprecipitation sequencing we found that ELF5 binding overlapped with FOXA1 and ER at super enhancers, enhancers and promoters, and when elevated, caused FOXA1 and ER to bind to new regions of the genome, in a pattern that replicated the alterations to the ER/FOXA1 cistrome caused by the acquisition of resistance to endocrine therapy. RNA sequencing demonstrated that these changes altered estrogen-driven patterns of gene expression, the expression of ER transcription-complex members, and 6 genes known to be involved in driving the acquisition of endocrine resistance. Using rapid immunoprecipitation mass spectrometry of endogenous proteins, and proximity ligation assays, we found that ELF5 interacted physically with members of the ER transcription complex, such as DNA-PKcs. We found 2 cases of endocrine-resistant brain metastases where ELF5 levels were greatly increased and ELF5 patterns of gene expression were enriched, compared to the matched primary tumour. Thus ELF5 alters ER-driven gene expression by modulating the ER/FOXA1 cistrome, by interacting with it, and by modulating the expression of members of the ER transcriptional complex, providing multiple mechanisms by which ELF5 can drive endocrine resistance.

The effects of whole-body vibration and head supported mass on performance and muscular demand.

For military rotary-wing aircrew, little is known about the interactive effects of vibration exposure and the addition of head supported mass (HSM) on target acquisition performance, head kinematics, and muscular demand. Sixteen healthy male participants wore an aviator helmet with replica night vision goggles and completed rapid aiming head movements to acquire visual targets in axial and off-axis movement trajectories while secured in a Bell-412 helicopter seat mounted to a human-rated shaker platform. HSM configuration (with or without a counterweight (CW)) and vertical whole-body vibration (WBV) conditions (vibration or no vibration exposure) were manipulated as independent variables. WBV exposure degraded target acquisition performance and lengthened time to peak velocity of head movements. For yaw peak velocity in the axial movement trajectory, peak velocity was 9.9%, 11.6%, and 8.4% higher in the noCW + WBV condition compared to the CW + WBV, CW + noWBV, and noCW + noWBV conditions, respectively.Practitioner summary: The majority of military helicopter aircrew use a counterweight to counteract the anteriorly displaced load of night vision googles. This study was undertaken to better understand how helicopter vibration and counterweight use interactively affect performance and health-related measures during rapid scanning head movements.

Activation of the viral sensor oligoadenylate synthetase 2 (Oas2) prevents pregnancy-driven mammary cancer metastases.

BACKGROUND: The interferon response can influence the primary and metastatic activity of breast cancers and can interact with checkpoint immunotherapy to modulate its effects. Using N-ethyl-N-nitrosourea mutagenesis, we found a mouse with an activating mutation in oligoadenylate synthetase 2 (Oas2), a sensor of viral double stranded RNA, that resulted in an interferon response and prevented lactation in otherwise healthy mice. METHODS: To determine if sole activation of Oas2 could alter the course of mammary cancer, we combined the Oas2 mutation with the MMTV-PyMT oncogene model of breast cancer and examined disease progression and the effects of checkpoint immunotherapy using Kaplan-Meier survival analysis with immunohistochemistry and flow cytometry. RESULTS: Oas2 mutation prevented pregnancy from increasing metastases to lung. Checkpoint immunotherapy with antibodies against programmed death-ligand 1 was more effective when the Oas2 mutation was present. CONCLUSIONS: These data establish OAS2 as a therapeutic target for agents designed to reduce metastases and increase the effectiveness of checkpoint immunotherapy.

Endothelin type B receptor promotes cofilin rod formation and dendritic loss in neurons by inducing oxidative stress and cofilin activation.

Endothelin-1 (ET-1) is a neuroactive peptide produced by neurons, reactive astrocytes, and endothelial cells in the brain. Elevated levels of ET-1 have been detected in the post-mortem brains of individuals with Alzheimer's disease (AD). We have previously demonstrated that overexpression of astrocytic ET-1 exacerbates memory deficits in aged mice or in APPK670/M671 mutant mice. However, the effects of ET-1 on neuronal dysfunction remain elusive. ET-1 has been reported to mediate superoxide formation in the vascular system via NADPH oxidase (NOX) and to regulate the actin cytoskeleton of cancer cell lines via the cofilin pathway. Interestingly, oxidative stress and cofilin activation were both reported to mediate one of the AD histopathologies, cofilin rod formation in neurons. This raises the possibility that ET-1 mediates neurodegeneration via oxidative stress- or cofilin activation-driven cofilin rod formation. Here, we demonstrate that exposure to 100 nm ET-1 or to a selective ET type B receptor (ETB) agonist (IRL1620) induces cofilin rod formation in dendrites of primary hippocampal neurons, accompanied by a loss of distal dendrites and a reduction in dendritic length. The 100 nm IRL1620 exposure induced superoxide formation and cofilin activation, which were abolished by pretreatment with a NOX inhibitor (5 µm VAS2870). Moreover, IRL1620-induced cofilin rod formation was partially abolished by pretreatment with a calcineurin inhibitor (100 nm FK506), which suppressed cofilin activation. In conclusion, our findings suggest a role for ETB in neurodegeneration by promoting cofilin rod formation and dendritic loss via NOX-driven superoxide formation and cofilin activation.

Proteogenomic analysis of Inhibitor of Differentiation 4 (ID4) in basal-like breast cancer.

BACKGROUND: Basal-like breast cancer (BLBC) is a poorly characterised, heterogeneous disease. Patients are diagnosed with aggressive, high-grade tumours and often relapse with chemotherapy resistance. Detailed understanding of the molecular underpinnings of this disease is essential to the development of personalised therapeutic strategies. Inhibitor of differentiation 4 (ID4) is a helix-loop-helix transcriptional regulator required for mammary gland development. ID4 is overexpressed in a subset of BLBC patients, associating with a stem-like poor prognosis phenotype, and is necessary for the growth of cell line models of BLBC through unknown mechanisms. METHODS: Here, we have defined unique molecular insights into the function of ID4 in BLBC and the related disease high-grade serous ovarian cancer (HGSOC), by combining RIME proteomic analysis, ChIP-seq mapping of genomic binding sites and RNA-seq. RESULTS: These studies reveal novel interactions with DNA damage response proteins, in particular, mediator of DNA damage checkpoint protein 1 (MDC1). Through MDC1, ID4 interacts with other DNA repair proteins (γH2AX and BRCA1) at fragile chromatin sites. ID4 does not affect transcription at these sites, instead binding to chromatin following DNA damage. Analysis of clinical samples demonstrates that ID4 is amplified and overexpressed at a higher frequency in BRCA1-mutant BLBC compared with sporadic BLBC, providing genetic evidence for an interaction between ID4 and DNA damage repair deficiency. CONCLUSIONS: These data link the interactions of ID4 with MDC1 to DNA damage repair in the aetiology of BLBC and HGSOC.

Understanding childhood obesity in the US: the NIH environmental influences on child health outcomes (ECHO) program.

BACKGROUND: Few resources exist for prospective, longitudinal analysis of the relationships between early life environment and later obesity in large diverse samples of children in the United States (US). In 2016, the National Institutes of Health launched the Environmental influences on Child Health Outcomes (ECHO) program to investigate influences of environmental exposures on child health and development. We describe demographics and overweight and obesity prevalence in ECHO, and ECHO's potential as a resource for understanding how early life environmental factors affect obesity risk. METHODS: In this cross-sectional study of 70 extant US and Puerto Rico cohorts, 2003-2017, we examined age, race/ethnicity, and sex in children with body mass index (BMI) data, including 28,507 full-term post-birth to <2 years and 38,332 aged 2-18 years. Main outcomes included high BMI for age <2 years, and at 2-18 years overweight (BMI 85th to <95th percentile), obesity (BMI ≥ 95th percentile), and severe obesity (BMI ≥ 120% of 95th percentile). RESULTS: The study population had diverse race/ethnicity and maternal demographics. Each outcome was more common with increasing age and varied with race/ethnicity. High BMI prevalence (95% CI) was 4.7% (3.5, 6.0) <1 year, and 10.6% (7.4, 13.7) for 1 to <2 years; overweight prevalence increased from 13.9% (12.4, 15.9) at 2-3 years to 19.9% (11.7, 28.2) at 12 to <18 years. ECHO has the statistical power to detect relative risks for 'high' BMI ranging from 1.2 to 2.2 for a wide range of exposure prevalences (1-50%) within each age group. CONCLUSIONS: ECHO is a powerful resource for understanding influences of chemical, biological, social, natural, and built environments on onset and trajectories of obesity in US children. The large sample size of ECHO cohorts adopting a standardized protocol for new data collection of varied exposures along with longitudinal assessments will allow refined analyses to identify drivers of childhood obesity.

An eQTL in the cystathionine beta synthase gene is linked to osteoporosis in laying hens.

BACKGROUND: Skeletal damage is a challenge for laying hens because the physiological adaptations required for egg laying make them susceptible to osteoporosis. Previously, we showed that genetic factors explain 40% of the variation in end of lay bone quality and we detected a quantitative trait locus (QTL) of large effect on chicken chromosome 1. The aim of this study was to combine data from the commercial founder White Leghorn population and the F2 mapping population to fine-map this QTL and understand its function in terms of gene expression and physiology. RESULTS: Several single nucleotide polymorphisms on chromosome 1 between 104 and 110 Mb (galGal6) had highly significant associations with tibial breaking strength. The alternative genotypes of markers of large effect that flanked the region had tibial breaking strengths of 200.4 vs. 218.1 Newton (P < 0.002) and, in a subsequent founder generation, the higher breaking strength genotype was again associated with higher breaking strength. In a subsequent generation, cortical bone density and volume were increased in individuals with the better bone genotype but with significantly reduced medullary bone quality. The effects on cortical bone density were confirmed in a further generation and was accompanied by increased mineral maturity of the cortical bone as measured by infrared spectrometry and there was evidence of better collagen cross-linking in the cortical bone. Comparing the transcriptome of the tibia from individuals with good or poor bone quality genotypes indicated four differentially-expressed genes at the locus, one gene, cystathionine beta synthase (CBS), having a nine-fold higher expression in the genotype for low bone quality. The mechanism was cis-acting and although there was an amino-acid difference in the CBS protein between the genotypes, there was no difference in the activity of the enzyme. Plasma homocysteine concentration, the substrate of CBS, was higher in the poor bone quality genotype. CONCLUSIONS: Validated markers that predict bone strength have been defined for selective breeding and a gene was identified that may suggest alternative ways to improve bone health in addition to genetic selection. The identification of how genetic variants affect different aspects of bone turnover shows potential for translational medicine.

A mutation in the viral sensor 2'-5'-oligoadenylate synthetase 2 causes failure of lactation.

We identified a non-synonymous mutation in Oas2 (I405N), a sensor of viral double-stranded RNA, from an ENU-mutagenesis screen designed to discover new genes involved in mammary development. The mutation caused post-partum failure of lactation in healthy mice with otherwise normally developed mammary glands, characterized by greatly reduced milk protein synthesis coupled with epithelial cell death, inhibition of proliferation and a robust interferon response. Expression of mutant but not wild type Oas2 in cultured HC-11 or T47D mammary cells recapitulated the phenotypic and transcriptional effects observed in the mouse. The mutation activates the OAS2 pathway, demonstrated by a 34-fold increase in RNase L activity, and its effects were dependent on expression of RNase L and IRF7, proximal and distal pathway members. This is the first report of a viral recognition pathway regulating lactation.

Differential Growth in Periclinal and Anticlinal Walls during Lobe Formation in Arabidopsis Cotyledon Pavement Cells.

Lobe development in the epidermal pavement cells of Arabidopsis thaliana cotyledons and leaves is thought to take place via tip-like growth on the concave side of lobes driven by localized concentrations of actin filaments and associated proteins, with a predicted role for cortical microtubules in establishing the direction of restricted growth at the convex side. We used homologous landmarks fixed to the outer walls of pavement cells and thin-plate spline analysis to demonstrate that lobes form by differential growth of both the anticlinal and periclinal walls. Most lobes formed within the first 24 h of the cotyledons unfurling, during the period of rapid cell expansion. Cortical microtubules adjacent to the periclinal wall were persistently enriched at the convex side of lobes during development where growth was anisotropic and were less concentrated or absent at the concave side where growth was promoted. Alternating microtubule-enriched and microtubule-free zones at the periclinal wall in neighboring cells predicted sites of new lobes. There was no particular arrangement of cortical actin filaments that could predict where lobes would form. However, drug studies demonstrate that both filamentous actin and microtubules are required for lobe formation.

ELF5 Drives Lung Metastasis in Luminal Breast Cancer through Recruitment of Gr1+ CD11b+ Myeloid-Derived Suppressor Cells.

During pregnancy, the ETS transcription factor ELF5 establishes the milk-secreting alveolar cell lineage by driving a cell fate decision of the mammary luminal progenitor cell. In breast cancer, ELF5 is a key transcriptional determinant of tumor subtype and has been implicated in the development of insensitivity to anti-estrogen therapy. In the mouse mammary tumor virus-Polyoma Middle T (MMTV-PyMT) model of luminal breast cancer, induction of ELF5 levels increased leukocyte infiltration, angiogenesis, and blood vessel permeability in primary tumors and greatly increased the size and number of lung metastasis. Myeloid-derived suppressor cells, a group of immature neutrophils recently identified as mediators of vasculogenesis and metastasis, were recruited to the tumor in response to ELF5. Depletion of these cells using specific Ly6G antibodies prevented ELF5 from driving vasculogenesis and metastasis. Expression signatures in luminal A breast cancers indicated that increased myeloid cell invasion and inflammation were correlated with ELF5 expression, and increased ELF5 immunohistochemical staining predicted much shorter metastasis-free and overall survival of luminal A patients, defining a group who experienced unexpectedly early disease progression. Thus, in the MMTV-PyMT mouse mammary model, increased ELF5 levels drive metastasis by co-opting the innate immune system. As ELF5 has been previously implicated in the development of antiestrogen resistance, this finding implicates ELF5 as a defining factor in the acquisition of the key aspects of the lethal phenotype in luminal A breast cancer.

Punctal occlusion for dry eye syndrome.

BACKGROUND: Dry eye syndrome is a disorder of the tear film that is associated with symptoms of ocular discomfort. Punctal occlusion is a mechanical treatment that blocks the tear drainage system in order to aid in the preservation of natural tears on the ocular surface. OBJECTIVES: To assess the effects of punctal plugs versus no punctal plugs, different types of punctal plugs, and other interventions for managing dry eye. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2016, Issue 11), MEDLINE Ovid (1946 to 8 December 2016), Embase.com (1947 to 8 December 2016), PubMed (1948 to 8 December 2016), LILACS (Latin American and Caribbean Health Sciences Literature Database) (1982 to 8 December 2016), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com; last searched 18 November 2012 - this resource is now archived), ClinicalTrials.gov (www.clinicaltrials.gov; searched 8 December 2016), and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en; searched 8 December 2016). We did not use any date or language restrictions in the electronic searches for trials. We also searched the Science Citation Index-Expanded database and reference lists of included studies. The evidence was last updated on 8 December 2016 SELECTION CRITERIA: We included randomized and quasi-randomized controlled trials of collagen or silicone punctal plugs in symptomatic participants diagnosed with aqueous tear deficiency or dry eye syndrome. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. We contacted study investigators for additional information when needed. MAIN RESULTS: We included 18 trials (711 participants, 1249 eyes) from Austria, Canada, China, Greece, Japan, Mexico, Netherlands, Turkey, the UK, and the USA in this review. We also identified one ongoing trial. Overall we judged these trials to be at unclear risk of bias because they were poorly reported. We assessed the evidence for eight comparisons.Five trials compared punctal plugs with no punctal plugs (control). Three of these trials employed a sham treatment and two trials observed the control group. Two trials did not report outcome data relevant to this review. There was very low-certainty evidence on symptomatic improvement. The three trials that reported this outcome used different scales to measure symptoms. In all three trials, there was little or no improvement in symptom scores with punctal plugs compared with no punctal plugs. Low-certainty evidence from one trial suggested less ocular surface staining in the punctal plug group compared with the no punctal plug group however this difference was small and possibly clinically unimportant (mean difference (MD) in fluorescein staining score -1.50 points, 95% CI -1.88 to -1.12; eyes = 61). Similarly there was a small difference in tear film stability with people in the punctal plug group having more stability (MD 1.93 seconds more, 95% CI 0.67 to 3.20; eyes = 28, low-certainty evidence). The number of artificial tear applications was lower in the punctal plug group compared with the no punctal plugs group in one trial (MD -2.70 applications, 95% CI -3.11 to -2.29; eyes = 61, low-certainty evidence). One trial with low-certainty evidence reported little or no difference between the groups in Schirmer scores, but did not report any quantitative data on aqueous tear production. Very low-certainty evidence on adverse events suggested that events occurred reasonably frequently in the punctal plug group and included epiphora, itching, tenderness and swelling of lids with mucous discharge, and plug displacement.One trial compared punctal plugs with cyclosporine (20 eyes) and one trial compared punctal plugs with oral pilocarpine (55 eyes). The evidence was judged to be very low-certainty due to a combination of risk of bias and imprecision.Five trials compared punctal plugs with artificial tears. In one of the trials punctal plugs was combined with artificial tears and compared with artificial tears alone. There was very low-certainty evidence on symptomatic improvement. Low-certainty evidence of little or no improvement in ocular surface staining comparing punctal plugs with artificial tears (MD right eye 0.10 points higher, 0.56 lower to 0.76 higher, MD left eye 0.60 points higher, 0.10 to 1.10 higher) and low-certainty evidence of little or no difference in aqueous tear production (MD 0.00 mm/5 min, 0.33 lower to 0.33 higher)Three trials compared punctal plugs in the upper versus the lower puncta, and none of them reported the review outcomes at long-term follow-up. One trial with very low-certainty evidence reported no observed complications, but it was unclear which complications were collected.One trial compared acrylic punctal plugs with silicone punctal plugs and the trial reported outcomes at approximately 11 weeks of follow-up (36 eyes). The evidence was judged to be very low-certainty due to a combination of risk of bias and imprecision.One trial compared intracanalicular punctal plugs with silicone punctal plugs at three months follow-up (57 eyes). The evidence was judged to be very low-certainty due to a combination of risk of bias and imprecision.Finally, two trials with very low-certainty evidence compared collagen punctal plugs versus silicone punctal plugs (98 eyes). The evidence was judged to be very low-certainty due to a combination of risk of bias and imprecision. AUTHORS' CONCLUSIONS: Although the investigators of the individual trials concluded that punctal plugs are an effective means for treating dry eye signs and symptoms, the evidence in this systematic review suggests that improvements in symptoms and commonly tested dry eye signs are inconclusive. Despite the inclusion of 11 additional trials, the findings of this updated review are consistent with the previous review published in 2010. The type of punctal plug investigated, the type and severity of dry eye being treated, and heterogeneity in trial methodology confounds our ability to make decisive statements regarding the effectiveness of punctal plug use. Although punctal plugs are believed to be relatively safe, their use is commonly associated with epiphora and, less commonly, with inflammatory conditions such as dacryocystitis.

Different-sized incisions for phacoemulsification in age-related cataract.

BACKGROUND: Age-related cataract is the principal cause of blindness and visual impairment in the world. Phacoemulsification is the main surgical procedure used to treat cataract. The comparative effectiveness and safety of different-sized incisions for phacoemulsification has not been determined. OBJECTIVES: The aim of this systematic review was to assess the effectiveness and safety of smaller versus larger incisions for phacoemulsification in age-related cataract. The primary outcome of this review was surgically induced astigmatism at three months after surgery. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2016, Issue 10), MEDLINE Ovid (1946 to 28 October 2016), Embase Ovid (1947 to 28 October 2016), PubMed (1948 to 28 October 2016), LILACS (Latin American and Caribbean Health Sciences Literature Database) (1982 to 28 October 2016), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com; last searched 13 May 2013), ClinicalTrials.gov (www.clinicaltrials.gov; searched 28 October 2016), and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp; searched 28 October 2016). We did not use any date or language restrictions in the electronic searches for trials. SELECTION CRITERIA: We included randomized controlled trials (RCTs) comparing different-sized incisions in people with age-related cataract undergoing phacoemulsification. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included 26 RCTs with a total of 2737 participants (3120 eyes). These trials were conducted in Bosnia and Herzegovina, China, France, India, Italy, Korea, Spain, Switzerland, and Turkey. Half of the 26 trials were conducted in China. We judged all trials as mostly at unclear to low risk of bias. The included RCTs compared four different-sized incisions:<= 1.5 mm, 1.8 mm, 2.2 mm, and approximately 3.0 mm. These incisions were performed using three different techniques: coaxial and biaxial microincision phacoemulsification (C-MICS and B-MICS) and standard phacoemulsification. Not all studies provided data in a form that could be included in this review. Five studies had three arms.Fifteen trials compared C-MICS (2.2 mm) with standard phacoemulsification (about 3.0 mm). Very low-certainty evidence suggested less surgically induced astigmatism in the C-MICS group at three months compared with standard phacoemulsification (mean difference (MD) -0.19 diopters (D), 95% confidence interval (CI) -0.30 to -0.09; 996 eyes; 8 RCTs). There was low-certainty evidence that both groups achieved similar best-corrected visual acuity (MD 0.00 logMAR, 95% CI -0.02 to 0.02; 242 eyes; 3 RCTs). There was low-certainty evidence of little or no difference in endothelial cell loss and central corneal thickness comparing C-MICS with standard phacoemulsification (MD -7.23 cells/mm2, 95% CI -78.66 to 64.20; 596 eyes; 4 RCTs) and (MD -0.68 µm, 95% CI -3.26 to 1.90; 487 eyes; 5 RCTs).Nine trials compared C-MICS (1.8 mm) with standard phacoemulsification (about 3.0 mm). Very low-certainty evidence suggested less astigmatism at three months in the C-MICS group compared with standard phacoemulsification group (MD -0.23 D, 95% CI -0.34 to -0.13; 561 eyes; 5 RCTs). Low-certainty evidence suggested little or no difference in best-corrected visual acuity, endothelial cell loss, and central corneal thickness in the two groups at three months (MD -0.02 logMAR, 95% CI -0.03 to -0.00; 192 eyes; 3 RCTs), (MD 7.56 cells/mm2, 95% CI -67.65 to 82.77; 380 eyes; 5 RCTs), and (MD -1.52 µm, 95% CI -6.29 to 3.25; 245 eyes; 3 RCTs).Six studies compared C-MICS (1.8 mm) with C-MICS (2.2 mm). There was low-certainty evidence that astigmatism, visual acuity, and central corneal thickness were similar in the two groups at three months (MD 0.04 D, 95% CI -0.09 to 0.16; 259 eyes; 3 RCTs), (MD 0.01 logMAR, 95% CI -0.01 to 0.04; 200 eyes; 3 RCTs), and (MD 0.45 µm, 95% CI -2.70 to 3.60; 100 eyes; 1 RCT). Very low-certainty evidence suggested higher endothelial cell loss in the 1.8 mm group (MD 213.00 cells/mm2, 95% CI 11.15 to 414.85; 70 eyes; 1 RCT).Four studies compared B-MICS (<= 1.5 mm) with standard phacoemulsification (about 3.0 mm). Astigmatism was similar in the two groups at three months (MD -0.01 D, 95% CI -0.03 to 0.01; 368 eyes; 2 RCTs; moderate-certainty evidence). There was low-certainty evidence on visual acuity, suggesting little or no difference between the two groups (MD -0.02 logMAR, 95% CI -0.04 to -0.00; 464 eyes; 3 RCTs). Low-certainty evidence on endothelial cell loss and central corneal thickness also suggested little or no difference between the two groups (MD 55.83 cells/mm2, 95% CI -34.93 to 146.59; 280 eyes; 1 RCT) and (MD 0.10 µm, 95% CI -14.04 to 14.24; 90 eyes; 1 RCT).None of the trials reported on quality of life. One trial reported that no participants experienced endophthalmitis or posterior capsule rupture; they also reported little or no difference between incision groups regarding corneal edema (risk ratio 1.02, 95% CI 0.40 to 2.63; 362 eyes). AUTHORS' CONCLUSIONS: Phacoemulsification with smaller incisions was not consistently associated with less surgically induced astigmatism compared with phacoemulsification with larger incisions. Coaxial microincision phacoemulsification may be associated with less astigmatism than standard phacoemulsification, but the difference was small, in the order of 0.2 D, and the evidence was uncertain. Safety outcomes and quality of life were not adequately reported; these should be addressed in future studies.

Acupuncture for acute hordeolum.

BACKGROUND: Hordeolum is an acute, purulent inflammation of the eyelid margin usually caused by obstructed orifices of the sebaceous glands of the eyelid. The condition, which affects sebaceous glands internally or externally, is common. When the meibomian gland in the tarsal plate is affected, internal hordeolum occurs, while when the glands of Zeis or Moll associated with eyelash follicles are affected, external hordeolum, or stye occurs. The onset of hordeolum is usually self limited, and may resolve in about a week with spontaneous drainage of the abscess. When the condition is severe, it can spread to adjacent glands and tissues. Recurrences are very common. As long as an internal hordeolum remains unresolved, it can develop into a chalazion or generalized eyelid cellulitis. Acupuncture is a traditional Chinese medical therapy aimed to treat disease by using fine needles to stimulate specific points on the body. However, it is unclear if acupuncture is an effective and safe treatment for acute hordeolum. OBJECTIVES: The objective of this review was to investigate the effectiveness and safety of acupuncture to treat acute hordeolum compared with no treatment, sham acupuncture, or other active treatment. We also compared the effectiveness and safety of acupuncture plus another treatment with that treatment alone. SEARCH METHODS: We searched CENTRAL, Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE, Embase, PubMed, Latin American and Caribbean Health Sciences Literature Database (LILACS), three major Chinese databases, as well as clinical trial registers all through 7 June 2016. We reviewed the reference lists from potentially eligible studies to identify additional randomised clinical trials (RCTs). SELECTION CRITERIA: We included RCTs of people diagnosed with acute internal or external hordeola. We included RCTs comparing acupuncture with sham acupuncture or no treatment, other active treatments, or comparing acupuncture plus another treatment versus another treatment alone. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures used by Cochrane. MAIN RESULTS: We included 6 RCTs with a total of 531 participants from China. The mean age of the participants ranged from 18 to 28 years. Four RCTs included participants diagnosed with initial acute hordeolum with a duration of less than seven days; one RCT included participants diagnosed with initial acute hordeolum without specifying the duration; and one RCT included participants with recurrent acute hordeolum with a mean duration of 24 days. About 55% (291/531) of participants were women. Three RCTs included participants with either external or internal hordeolum; one RCT included participants with only external hordeolum; and two RCTs did not specify the type of hordeolum. Follow-up was no more than seven days after treatment in all included RCTs; no data were available for long-term outcomes. Overall, the certainty of the evidence for all outcomes was low to very low, and we judged all RCTs to be at high or unclear risk of bias.Three RCTs compared acupuncture with conventional treatments. We did not pool the data from these RCTs because the conventional treatments were not similar among trials. Two trials showed that resolution of acute hordeolum was more likely in the acupuncture group when compared with topical antibiotics (1 RCT; 32 participants; risk ratio (RR) 3.60; 95% confidence interval (CI) 1.34 to 9.70; low-certainty of evidence) or oral antibiotics plus warm compresses (1 RCT; 120 participants; RR 1.45; 95% CI 1.18 to 1.78; low-certainty of evidence). In the third trial, little or no difference in resolution of hordeolum was observed when acupuncture was compared with topical antibiotics plus warm compresses (1 RCT; 109 participants; RR 1.00; 95% CI 0.96 to 1.04; low-certainty of evidence). One RCT mentioned adverse outcomes, stating that there was no adverse event associated with acupuncture.Three RCTs compared acupuncture plus conventional treatments (two RCTs used topical antibiotics and warm compresses, one RCT used topical antibiotics only) versus the conventional treatments alone. One of the three RCTs, with very low-certainty evidence, did not report the resolution of acute hordeolum; however, it reported that acute hordeolum relief might be higher when acupuncture was combined with conventional treatments than with conventional treatments alone group (60 participants; RR 1.80; 95% CI 1.00 to 3.23). Pooled analysis of the remaining two RCTs, with low-certainty evidence, estimated resolution of acute hordeolum was slightly higher in the combined treatment group compared with the conventional treatment alone group at 7-day follow-up (210 participants; RR 1.12; 95% CI 1.03 to 1.23; I2 = 0%). None of the three RCTs reported adverse outcomes. Among the included RCTs, four participants, two from the acupuncture plus conventional treatments group and two from the conventional treatments alone group, withdrew due to exacerbation of symptoms. AUTHORS' CONCLUSIONS: Low-certainty evidence suggests that acupuncture with or without conventional treatments may provide short-term benefits for treating acute hordeolum when compared with conventional treatments alone. The certainty of the evidence was low to very low mainly due to small sample sizes, inadequate allocation concealment, lack of masking of the outcome assessors, inadequate or unclear randomization method, and a high or unreported number of dropouts. All RCTs were conducted in China, which may limit their generalizability to non-Chinese populations.Because no RCTs included a valid sham acupuncture control, we cannot rule out a potential expectation/placebo effect associated with acupuncture. As resolution is based on clinical observation, the outcome could be influenced by the observer's knowledge of the assigned treatment. Adverse effects of acupuncture were reported sparsely in the included RCTs, and, when reported, were rare. RCTs with better methodology, longer follow-up, and which are conducted among other populations are warranted to provide more general evidence regarding the benefit of acupuncture to treat acute hordeolum.

MCL-1 inhibition provides a new way to suppress breast cancer metastasis and increase sensitivity to dasatinib.

BACKGROUND: Metastatic disease is largely resistant to therapy and accounts for almost all cancer deaths. Myeloid cell leukemia-1 (MCL-1) is an important regulator of cell survival and chemo-resistance in a wide range of malignancies, and thus its inhibition may prove to be therapeutically useful. METHODS: To examine whether targeting MCL-1 may provide an effective treatment for breast cancer, we constructed inducible models of BIMs2A expression (a specific MCL-1 inhibitor) in MDA-MB-468 (MDA-MB-468-2A) and MDA-MB-231 (MDA-MB-231-2A) cells. RESULTS: MCL-1 inhibition caused apoptosis of basal-like MDA-MB-468-2A cells grown as monolayers, and sensitized them to the BCL-2/BCL-XL inhibitor ABT-263, demonstrating that MCL-1 regulated cell survival. In MDA-MB-231-2A cells, grown in an organotypic model, induction of BIMs2A produced an almost complete suppression of invasion. Apoptosis was induced in such a small proportion of these cells that it could not account for the large decrease in invasion, suggesting that MCL-1 was operating via a previously undetected mechanism. MCL-1 antagonism also suppressed local invasion and distant metastasis to the lung in mouse mammary intraductal xenografts. Kinomic profiling revealed that MCL-1 antagonism modulated Src family kinases and their targets, which suggested that MCL-1 might act as an upstream modulator of invasion via this pathway. Inhibition of MCL-1 in combination with dasatinib suppressed invasion in 3D models of invasion and inhibited the establishment of tumors in vivo. CONCLUSION: These data provide the first evidence that MCL-1 drives breast cancer cell invasion and suggests that MCL-1 antagonists could be used alone or in combination with drugs targeting Src kinases such as dasatinib to suppress metastasis.

Genome-wide association reveals QTL for growth, bone and in vivo carcass traits as assessed by computed tomography in Scottish Blackface lambs.

BACKGROUND: Improving meat quality including taste and tenderness is critical to the protection and development of markets for sheep meat. Phenotypic selection for such measures of meat quality is constrained by the fact that these parameters can only be measured post-slaughter. Carcass composition has an impact on meat quality and can be measured on live animals using advanced imaging technologies such as X-ray computed tomography (CT). Since carcass composition traits are heritable, they are potentially amenable to improvement through marker-assisted and genomic selection. We conducted a genome-wide association study (GWAS) on about 600 Scottish Blackface lambs for which detailed carcass composition phenotypes, including bone, fat and muscle components, had been captured using CT and which were genotyped for ~40,000 single nucleotide polymorphisms (SNPs) using the Illumina OvineSNP50 chip. RESULTS: We confirmed that the carcass composition traits were heritable with moderate to high (0.19-0.78) heritabilities. The GWAS analyses revealed multiple SNPs and quantitative trait loci (QTL) that were associated with effects on carcass composition traits and were significant at the genome-wide level. In particular, we identified a region on ovine chromosome 6 (OAR6) associated with bone weight and bone area that harboured SNPs with p values of 5.55 × 10(-8) and 2.63 × 10(-9), respectively. The same region had effects on fat area, fat density, fat weight and muscle density. We identified plausible positional candidate genes for these OAR6 QTL. We also detected a SNP that reached the genome-wide significance threshold with a p value of 7.28 × 10(-7) and was associated with muscle density on OAR1. Using a regional heritability mapping approach, we also detected regions on OAR3 and 24 that reached genome-wide significance for bone density. CONCLUSIONS: We identified QTL on OAR1, 3, 24 and particularly on OAR6 that are associated with effects on muscle, fat and bone traits. Based on available evidence that indicates that these traits are genetically correlated with meat quality traits, these associated SNPs have potential applications in selective breeding for improved meat quality. Further research is required to determine whether the effects associated with the OAR6 QTL are caused by a single gene or several closely-linked genes.

Perceived frailty and measured frailty among adults undergoing hemodialysis: a cross-sectional analysis.

BACKGROUND: Frailty, a validated measure of physiologic reserve, predicts adverse health outcomes among adults with end-stage renal disease. Frailty typically is not measured clinically; instead, a surrogate-perceived frailty-is used to inform clinical decision-making. Because correlations between perceived and measured frailty remain unknown, the aim of this study was to assess their relationship. METHODS: 146 adults undergoing hemodialysis were recruited from a single dialysis center in Baltimore, Maryland. Patient characteristics associated with perceived (reported by nephrologists, nurse practitioners (NPs), or patients) or measured frailty (using the Fried criteria) were identified using ordered logistic regression. The relationship between perceived and measured frailty was assessed using percent agreement, kappa statistic, Pearson's correlation coefficient, and prevalence of misclassification of frailty. Patient characteristics associated with misclassification were determined using Fisher's exact tests, t-tests, or median tests. RESULTS: Older age (adjusted OR [aOR] = 1.36, 95%CI:1.11-1.68, P = 0.003 per 5-years older) and comorbidity (aOR = 1.49, 95%CI:1.27-1.75, P < 0.001 per additional comorbidity) were associated with greater likelihood of nephrologist-perceived frailty. Being non-African American was associated with greater likelihood of NP- (aOR = 5.51, 95%CI:3.21-9.48, P = 0.003) and patient- (aOR = 4.20, 95%CI:1.61-10.9, P = 0.003) perceived frailty. Percent agreement between perceived and measured frailty was poor (nephrologist, NP, and patient: 64.1%, 67.0%, and 55.5%). Among non-frail participants, 34.4%, 30.0%, and 31.6% were perceived as frail by a nephrologist, NP, or themselves. Older adults (P < 0.001) were more likely to be misclassified as frail by a nephrologist; women (P = 0.04) and non-African Americans (P = 0.02) were more likely to be misclassified by an NP. Neither age, sex, nor race was associated with patient misclassification. CONCLUSIONS: Perceived frailty is an inadequate proxy for measured frailty among patients undergoing hemodialysis.