Tenofovir alafenamide or tenofovir disoproxil fumarate in pregnancy to prevent HBV transmission: Maternal ALT trajectory and infant outcomes.

BACKGROUND: The use of antiviral agents, specifically tenofovir disoproxil fumarate (TDF), in pregnant women to prevent mother-to-child HBV transmission is a key step towards hepatitis elimination. However, data on using tenofovir alafenamide (TAF) is insufficient. The frequent occurrence of postpartum ALT flares may impact the clinical implementation. METHODS: The maternal and infant outcomes were compared in multi-centre trials of high viral load HBsAg/HBeAg+ pregnant women receiving TAF or TDF from the third trimester until 2 weeks postpartum with intensive follow-ups. To explore the dynamic pre- and postpartum changes in ALT levels, we used a group-based trajectory model for analysing data of 332 women from three prospective studies. RESULTS: After treatment, the maternal HBV DNA levels significantly decreased from baseline to delivery: 7.87 ± 0.59 to 3.99 ± 1.07 Log10 IU/mL TAF (n = 78) and 8.30 ± 0.36 to 4.47 ± 0.86 Log10 IU/mL (TDF, n = 53), with viral load reductions of 3.87 versus 3.83 Log10 IU/mL. The HBsAg-positive rates among 12-month-old infants were 1.28% (1/78) versus 1.82% (1/55) respectively (p = 1.00). Of the TAF or TDF-treated mothers, 25.64% versus 16.98% experienced ALT > 2X ULN, and 11.54% versus 1.89% received extended antiviral treatment. Our model revealed four distinct ALT patterns: stable ALT (87.2%), moderate (8.0%) or marked (2.4%) postpartum flares, or prepartum elevations (2.4%). CONCLUSIONS: TAF effectively reduces mother-to-child HBV transmission, but prophylaxis failure still occurred in few cases. Postpartum ALT flares are common in women receiving TAF or TDF during pregnancy. Approximately 12.8% of mothers may require extended postpartum antiviral treatment. CLINICAL TRIAL NUMBER: NCT03695029 (ClinicalTrials.gov).

Metagenomic discovery of CRISPR-associated transposons.

CRISPR-associated Tn7 transposons (CASTs) co-opt cas genes for RNA-guided transposition. CASTs are exceedingly rare in genomic databases; recent surveys have reported Tn7-like transposons that co-opt Type I-F, I-B, and V-K CRISPR effectors. Here, we expand the diversity of reported CAST systems via a bioinformatic search of metagenomic databases. We discover architectures for all known CASTs, including arrangements of the Cascade effectors, target homing modalities, and minimal V-K systems. We also describe families of CASTs that have co-opted the Type I-C and Type IV CRISPR-Cas systems. Our search for non-Tn7 CASTs identifies putative candidates that include a nuclease dead Cas12. These systems shed light on how CRISPR systems have coevolved with transposases and expand the programmable gene-editing toolkit.

Ab interno supraciliary microstent surgery for open-angle glaucoma.

BACKGROUND: Glaucoma is the leading cause of global irreversible blindness, often associated with raised intraocular pressure (IOP). Where medical or laser treatment has failed or is not tolerated, surgery is often required. Minimally-invasive surgical approaches have been developed in recent years to reduce IOP with lower surgical risks. Supraciliary microstent surgery for the treatment of open-angle glaucoma (OAG) is one such approach. OBJECTIVES: To evaluate the efficacy and safety of supraciliary microstent surgery for the treatment of OAG, and to compare with standard medical, laser or surgical treatments. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; which contains the Cochrane Eyes and Vision Trials Register; 2020, Issue 8); Ovid MEDLINE; Ovid Embase; the ISRCTN registry; ClinicalTrials.gov and the WHO ICTRP. The date of the search was 27 August 2020. SELECTION CRITERIA: We searched for randomised controlled trials (RCTs) of supraciliary microstent surgery, alone or with cataract surgery, compared to other surgical treatments (cataract surgery alone, other minimally invasive glaucoma device techniques, trabeculectomy), laser treatment or medical treatment. DATA COLLECTION AND ANALYSIS: Two review authors independently screened titles and abstracts from the database search to identify studies that met the selection criteria. Data extraction, analysis, and evaluation of risk of bias from selected studies was performed independently and according to standard Cochrane methodology. MAIN RESULTS: One study met the inclusion criteria of this review, evaluating the efficacy and safety of the Cypass supraciliary microstent surgery for the treatment of OAG, comparing phacoemulsification + supraciliary microstent surgery with phacoemulsification alone over 24 months. This study comprised 505 eyes of 505 participants with both OAG and cataract, 374 randomised to the phacoemulsification + microstent group.  In this study, the perceived risk of bias from random sequence generation, allocation concealment and selective reporting was low. However, we considered the study to be at high risk of performance bias as surgeons/investigators were unmasked. Attrition bias was unclear, with 448/505 participants contributing to per protocol analysis. Insertion of a Cypass supraciliary microstent combined with phacoemulsification probably increases the proportion of participants who are medication-free (not using eye-drops) at 24 months compared with phacoemulsification alone (85% versus 59%, risk ratio (RR) 1.27, 95% confidence interval (CI) 1.09 to 1.49, moderate-certainty evidence). There is high-certainty evidence that a greater improvement in mean IOP occurs in the phacoemulsification + microstent group - mean (SD) change in IOP from baseline of -5.4 (3.9) mmHg in the phacoemulsification group, compared to -7.4 (4.4) mmHg in the phacoemulsification + microstent group at 24 months (mean difference -2.0 mmHg, 95% CI -2.85 to -1.15). There is moderate-certainty evidence that insertion of a microstent is probably associated with a greater reduction in use of IOP-lowering drops (mean reduction of 0.7 medications in the phacoemulsification group, compared to a mean reduction of 1.2 medications in the phacoemulsification + microstent group). Insertion of a microstent during phacoemulsification may reduce the requirement for further glaucoma intervention to control IOP at a later stage compared to phacoemulsification alone (RR 0.26, 95% CI 0.07 to 1.04, low-certainty evidence). There is no evidence relating to the rate of visual field progression, or proportion of participants whose visual field loss progressed in this study. There is moderate-certainty evidence showing little or no difference in the proportion of participants experiencing postoperative complications over 24 months between participants in the microstent group compared to those who received phacoemulsification alone (RR 1.1, 95% CI 0.8 to 1.4). Five year post-approval data regarding the safety of the Cypass supraciliary microstent showed increased endothelial cell loss, associated with the position of the microstent in the anterior chamber. There were no reported health-related quality of life (HRQoL) outcomes in the included study. AUTHORS' CONCLUSIONS: Data from this single RCT show superiority of supraciliary microstent surgery when combined with phacoemulsification compared to phacoemulsification alone in achieving medication-free control of OAG. However, there are long-term safety concerns with the device used in this trial, relating to the observed significant loss of corneal endothelial cells at five years following device implantation. At the time of this review, this device has been withdrawn from the market. This review has found that few high-quality studies exist comparing supraciliary microstent surgery to standard medical, laser or surgical glaucoma treatments. This should be addressed by further appropriately designed RCTs with sufficient long-term follow-up to ensure robust safety data are obtained. Consideration of health-related quality of life outcomes should also feature in trial design.

Ab interno trabecular bypass surgery with Trabectome for open-angle glaucoma.

BACKGROUND: Glaucoma is the leading cause of irreversible blindness. Minimally invasive surgical techniques, such as ab interno trabecular bypass surgery, have been introduced to prevent glaucoma from progressing.   OBJECTIVES: In light of the potential benefits for people with open-angle glaucoma and the widespread uptake of the technique, it is important to critically evaluate the evidence for whether treatment with ab interno trabecular bypass surgery with Trabectome is both efficacious and safe. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; which contains the Cochrane Eyes and Vision Trials Register; 2020, Issue 7); Ovid MEDLINE; Ovid Embase; the ISRCTN registry; ClinicalTrials.gov and the WHO ICTRP. The date of the search was 17 July 2020. SELECTION CRITERIA: We searched for randomised controlled trials (RCTs) of ab interno trabecular bypass surgery with Trabectome compared to other surgical treatments (other minimally invasive glaucoma device techniques, trabeculectomy), laser treatment, or medical treatment. We also included trials in which these devices were combined with phacoemulsification compared to phacoemulsification in combination with other glaucoma surgery or alone. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by Cochrane. Our primary outcome was proportion of participants who were medication-free (not using eye drops). Secondary outcomes included mean change in intraocular pressure (IOP), proportion of participants who required further glaucoma surgery, mean change in quality of life, proportion of participants who achieved an IOP of 21 mmHg or less, 17 mmHg or less, or 14 mmHg or less and rate of visual field progression. Adverse effects were the proportion of participants experiencing intra- and postoperative complications. All outcomes were measured in the short term (6 to 18 months), medium term (18 to 36 months), and long term (36 months or longer). MAIN RESULTS: In this update, we included one RCT which had previously been identified as an ongoing study in our 2016 publication. This trial was a single-centre, single-surgeon RCT set in Canada with 19 participants. Participants were adults who had open-angle glaucoma, open angles, and had inadequately controlled IOP that required surgical intervention. The study was terminated before the intended sample size was reached 'due to slow recruitment and increasing lack of clinical equipoise over time'. This reduced the power of the study to detect clinically important effects. We assessed the trial as being at high risk of attrition, reporting, and other potential sources of biases. The risks of performance and detection bias are unclear. The intervention group of 10 people had Trabectome ab interno trabeculotomy combined with cataract extraction (phaco-AIT) and the comparator group of 9 people had trabeculectomy with mitomycin C combined with cataract extraction (phaco-Trab), one of whom was lost to follow-up. Seven of 10 participants in the phaco-AIT group and 4 of 8 in the phaco-Trab group were medication-free (not using drops) at 12 months (odds ratio (OR) 2.33, 95% confidence interval (CI) 0.34 to 16.2; very low-certainty evidence). At 12 months, the mean change in IOP was worse for phaco-AIT than for phaco-Trab, but this evidence was very uncertain (mean difference (MD) 3.70 mmHg, 95% CI -1.44 to 8.84; very low-certainty evidence) in the phaco-AIT group, as was the difference in the mean number of IOP-lowering drops taken per day (MD -0.41, 95% CI -1.22 to 0.40; very low-certainty evidence). Only one participant in the phaco-AIT group required further glaucoma surgery. The study protocol declared that quality of life and visual field progression were measured, but they were not reported All 8 participants with complete data in the phaco-Trab group and 8 of 10 in the phaco-AIT had at least one early or late postoperative complication (e.g. day 1 IOP spike, hypotony, choroidal effusion, bleb leak or encapsulation, uveitis, or peripheral anterior synechiae). The evidence was very low-certainty due to high risk of bias for several domains for this study and for large imprecision of all estimates. We also identified one ongoing study, identified from the International Clinical Trials Registry Platform (ICTRP): a multicentre, open, RCT comparing Trabectome to ab interno trabeculectomy using microhook. The study investigators plan to recruit 120 adults between 20 and 90 years of age. The primary outcome is duration of treatment success. Secondary outcomes include postoperative IOP, number of anti-glaucoma medications, and adverse events. AUTHORS' CONCLUSIONS: There is currently no high-quality evidence for the outcomes of ab interno trabecular bypass surgery with Trabectome for open-angle glaucoma. Properly designed RCTs are needed to assess the long-term efficacy and safety of this technique.

Ab interno trabecular bypass surgery with Schlemm´s canal microstent (Hydrus) for open angle glaucoma.

BACKGROUND: Glaucoma is a leading cause of irreversible blindness. A number of minimally-invasive surgical techniques have been introduced as a treatment to prevent glaucoma from progressing; ab interno trabecular bypass surgery with the Schlemm's canal Hydrus microstent is one of them. OBJECTIVES: To evaluate the efficacy and safety of ab interno trabecular bypass surgery with the Hydrus microstent in treating people with open angle glaucoma (OAG). SEARCH METHODS: On 7 May 2019, we searched CENTRAL (2019, Issue 5), which contains the Cochrane Eyes and Vision Trials Register; Ovid MEDLINE; Ovid Embase; the ISRCTN registry; ClinicalTrials.gov; and the WHO ICTRP. SELECTION CRITERIA: We searched for randomised controlled trials (RCTs) of the Hydrus microstent, alone or with cataract surgery, compared to other surgical treatments (cataract surgery alone, other minimally-invasive glaucoma device techniques, trabeculectomy), laser treatment, or medical treatment. DATA COLLECTION AND ANALYSIS: A minimum of three authors independently extracted data from reports of included studies, using a data collection form and analysed data, based on standard Cochrane methods. MAIN RESULTS: We included three published studies, with 808 people randomised. Two studies had multiple international recruitment centres in the USA and other countries. The third study had several sites based in Europe. All three studies were sponsored by the Hydrus manufacturer Ivantis Inc. All studies included participants with mainly mild or moderate OAG (mean deviation between -3.6 dB (decibel) and -8.4 dB in all study arms), which was controlled with medication in many participants (mean medicated intraocular pressure (IOP) 17.9 mmHg to 19.1 mmHg). There were no concerns regarding allocation concealment bias, but masking of outcome assessors was high or unclear risk in all studies; masking of participants was achieved, and losses to follow-up were not a concern. Two studies compared the Hydrus microstent combined with cataract surgery to cataract surgery alone, in participants with visually significant cataracts and OAG. We found moderate-certainty evidence that adding the Hydrus microstent to cataract surgery increased the proportion of participants who were medication-free from about half to more than three quarters at 12-month, short-term follow-up (risk ratio (RR) 1.59, 95% confidence interval (CI) 1.39 to 1.83; 2 studies, 639 participants; I² = 0%; and 24-month, medium-term follow-up (RR 1.63, 95% CI 1.40 to 1.88; 2 studies, 619 participants; I² = 0%). The Hydrus microstent combined with cataract surgery reduced the medium-term mean change in unmedicated IOP (after washout) by 2 mmHg more compared to cataract surgery alone (mean difference (MD) -2.00, 95% CI -2.69 to -1.31; 2 studies, 619 participants; I² = 0%; moderate-certainty evidence), and the mean change in IOP-lowering drops (MD -0.41, 95% CI -0.56 to -0.27; 2 studies, 619 participants; I² = 0%; low-certainty evidence). We also found low-certainty evidence that adding a Hydrus microstent to cataract surgery reduced the need for secondary glaucoma surgery from about 2.5% to less than 1% (RR 0.17, 95% CI 0.03 to 0.86; 2 studies, 653 participants; I² = 27%; low-certainty evidence). Intraocular bleeding, loss of 2 or more visual acuity (VA) lines, and IOP spikes of 10 mmHg or more were rare in both groups; estimates were imprecise, and included both beneficial and harmful effects. There were no cases of endophthalmitis in either group. No data were available on the proportion of participants achieving IOP less than 21 mmHg, 17 mmHg, or 14 mmHg; health-related quality of life (HRQOL), or visual field progression. One study provided short-term data for the Hydrus microstent compared with the iStent trabecular micro-bypass stent (iStent: implantation of two devices in a single procedure) in 152 participants with OAG (148 in analyses). Use of the Hydrus increased the proportion of medication-free participants from about a quarter to about half compared to those who received iStent, but this estimate was imprecise (RR 1.94, 95% CI 1.21 to 3.11; low-certainty evidence). Use of the Hydrus microstent reduced unmedicated IOP (after washout) by about 3 mmHg more than the iStent (MD -3.10, 95% CI -4.17 to -2.03; moderate-certainty evidence), and the use of IOP-lowering medication (MD -0.60, 95% CI -0.99 to -0.21; low-certainty evidence). Both devices achieved a final IOP < 21 mmHg in most participants (Hydrus microstent: 91.8%; iStent: 84%; RR 1.09, 95% CI 0.97 to 1.23; low-certainty evidence). None of the participants who received the Hydrus microstent (N = 74) required additional glaucoma surgery; two participants who received the iStent (N = 76) did. Few adverse events were found in either group. No data were available on the proportion of participants achieving IOP less than 17 mmHg or 14 mmHg, or on HRQOL. AUTHORS' CONCLUSIONS: In people with cataracts and generally mild to moderate OAG, there is moderate-certainty evidence that the Hydrus microstent with cataract surgery compared to cataract surgery alone, likely increases the proportion of participants who do not require IOP lowering medication, and may further reduce IOP at short- and medium-term follow-up. There is moderate-certainty evidence that the Hydrus microstent is probably more effective than the iStent in lowering IOP of people with OAG in the short-term. Few studies were available on the effects of the Hydrus microstent, therefore the results of this review may not be applicable to all people with OAG, particularly in selected people with medically uncontrolled glaucoma, since IOP was controlled with medication in many participants in the included studies. Complications may be rare using the Hydrus microstent, as well as the comparator iStent, but larger studies are needed to investigate its safety.

Decreased Colorectal Adenoma Risk After Helicobacter pylori Eradication: A Retrospective Cohort Study.

BACKGROUND: Helicobacter pylori infection is associated with colorectal adenoma and confers a 1.3- to 2.26-fold increased risk. We evaluated the association between H. pylori and the progression of colorectal adenoma. METHODS: This retrospective cohort study included 615 adults with no history of colorectal adenoma or cancer at baseline who participated in a repeated, regular health screening examination, which included a bidirectional gastrointestinal endoscopy, between July 2006 and June 2015. A gastric biopsy specimen from each subject was tested for H. pylori. RESULTS: During follow-up, the incidence rates of colorectal adenoma progression in participants with persistent H. pylori infections (persistent group) and those whose infections had previously been successfully eradicated (eradication group) were 160.52 and 51.60 per 1000 person-years, respectively (P = .0003). After adjustment for confounding factors, the persistent group exhibited a higher risk of colorectal adenoma than the eradication group (hazard ratio = 3.04, 95% CI 1.899, 5.864). The colorectal adenoma ratio of patients uninfected with H. pylori was similar to that of the eradication group (23.93% vs 20.12%, P = .328). CONCLUSIONS: Persistent H. pylori infection was associated significantly with the independent development of colorectal adenoma. H. pylori infection may have a pathophysiological role in colorectal adenoma development and, after successful eradication of H. pylori, the colorectal adenoma ratio might decrease.

Endoscopic cyclophotocoagulation (ECP) for open angle glaucoma and primary angle closure.

BACKGROUND: Glaucoma is a leading cause of irreversible blindness. A number of minimally invasive surgical techniques have been introduced as a treatment to prevent glaucoma progressing. Among them, endoscopic cyclophotocoagulation (ECP) is a cyclodestructive procedure developed by Martin Uram in 1992. OBJECTIVES: To evaluate the efficacy and safety of ECP in people with open angle glaucoma (OAG) and primary angle closure whose condition is inadequately controlled with drops. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2018, Issue 6); Ovid MEDLINE; Ovid Embase; the ISRCTN registry; ClinicalTrials.gov and the WHO ICTRP. The date of the search was 12 July 2018. SELECTION CRITERIA: We searched for randomised controlled trials (RCTs) of ECP compared to other surgical treatments (other minimally invasive glaucoma device techniques, trabeculectomy), laser treatment or medical treatment. We also planned to include trials where these devices were combined with phacoemulsification compared to phacoemulsification alone. DATA COLLECTION AND ANALYSIS: Two review authors planned to independently extract data from reports of included studies using a data collection form and analyse data based on methods expected by Cochrane. Our primary outcome was proportion of participants who were drop-free (not using eye drops). Secondary outcomes included mean change in IOP; proportion of participants who achieved an IOP of 21 mmHg or less, 17 mmHg or less or 14 mmHg or less; and proportion of participants experiencing intra- and postoperative complications, We planned to measure all outcomes in the short-term (six to 18 months), medium-term (18 to 36 months), and long-term (36 months onwards). MAIN RESULTS: We found one ongoing study that met our inclusion criteria (ChiCTR-TRC-14004233). The study compares combined phacoemulsification with ECP to phacoemulsification alone in people with primary angle closure glaucoma. The primary outcome is intraocular pressure (IOP) and number of IOP-lowering drugs. A total of 50 people have been enrolled. The study started in February 2014 and the trialists have completed recruitment and are in the process of collecting data. AUTHORS' CONCLUSIONS: There is currently no high-quality evidence for the effects of ECP for OAG and primary angle closure. Properly designed RCTs are needed to assess the medium and long-term efficacy and safety of this technique.

Subconjunctival draining minimally-invasive glaucoma devices for medically uncontrolled glaucoma.

BACKGROUND: Glaucoma is a leading cause of irreversible blindness. Subconjunctival draining minimally-invasive glaucoma devices such as the Xen gelatin implant and InnFocus stent have been introduced as a treatment to prevent glaucoma progressing.These implants provide a channel to allow aqueous humour from the anterior chamber of the eye to drain into the subconjunctival space on the surface of the eye thus reducing intraocular pressure (IOP) and mimicking the mechanism of the most commonly undertaken glaucoma surgery, trabeculectomy. OBJECTIVES: To evaluate the efficacy and safety of subconjunctival draining minimally-invasive glaucoma devices in treating people with open angle glaucoma and ocular hypertension whose condition is inadequately controlled with drops. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; which contains the Cochrane Eyes and Vision Trials Register; 2018, Issue 6); Ovid MEDLINE; Ovid Embase; the ISRCTN registry; ClinicalTrials.gov and the WHO ICTRP. The date of the search was 10 July 2018. SELECTION CRITERIA: We searched for randomised controlled trials (RCTs) of Xen gelatin implant or InnFocus MicroShunt to other surgical treatments (other minimally-invasive glaucoma device techniques, trabeculectomy), laser treatment or medical treatment. We also planned to include trials where these devices were combined with phacoemulsification compared to phacoemulsification alone. DATA COLLECTION AND ANALYSIS: We planned to have two review authors independently extract data from reports of included studies using a data collection form and analyse data based on methods expected by Cochrane. Our primary outcome was mean change in IOP. Secondary outcomes included proportion of participants who were drop-free; proportion of participants who achieved an IOP of 21 mmHg or less, 17 mmHg or less or 14 mmHg or less; and proportion of participants experiencing intra- and postoperative complications. We planned to measure all outcomes in the short-term (six to 18 months), medium-term (18 to 36 months), and long-term (36 months onwards). MAIN RESULTS: We found no completed RCTs that met our inclusion criteria. We found one ongoing study (NCT01881425). The study compares InnFocus MicroShunt to trabeculectomy in people with primary open angle glaucoma. The primary outcome is greater than 20% IOP reduction from baseline to 12 months' follow-up. A total of 889 people aged between 40 and 85 years have been enrolled. The estimated study completion date is November 2019. AUTHORS' CONCLUSIONS: There is currently no high-quality evidence for the effects of subconjunctival draining minimally-invasive glaucoma devices for medically uncontrolled open angle glaucoma. Properly designed RCTs are needed to assess the medium- and long-term efficacy and safety of this technique.

Ab interno trabecular bypass surgery with Trabectome for open angle glaucoma.

BACKGROUND: Glaucoma is the leading cause of irreversible blindness. Minimally invasive surgical techniques, such as ab interno trabecular bypass surgery, have been introduced to prevent glaucoma progressing. OBJECTIVES: The main objective was to assess the results at two years of ab interno trabecular bypass surgery with Trabectome for open angle glaucoma in comparison to conventional medical, laser, or surgical treatment in terms of efficacy and safety. A secondary objective was to examine the effects of Trabectome surgery in people who have concomitant phacoemulsification in comparison to those who do not have concomitant phacoemulsification. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register) (2016, Issue 4), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to May 2016), EMBASE (January 1980 to May 2016), the ISRCTN registry (www.isrctn.com/editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov), and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 12 May 2016. SELECTION CRITERIA: We included only randomised controlled trials (RCTs) of ab interno trabecular bypass surgery with Trabectome. DATA COLLECTION AND ANALYSIS: We planned to have two review authors independently extract data from reports of included studies using a data collection form. MAIN RESULTS: One randomised controlled trial identified from ClinicalTrials.gov, NCT00901108, met the criteria for inclusion. This study has subsequently been terminated. The ClinicalTrials.gov record indicates that the investigators plan to complete 12 months of follow-up and analysis on 19 participants already recruited into the trial. AUTHORS' CONCLUSIONS: There is currently no high-quality evidence for the outcomes of ab interno trabecular bypass surgery with Trabectome for open angle glaucoma. Properly designed RCTs are needed to assess the long-term efficacy and safety of this technique.

Grouper interleukin-12, linked by an ancient disulfide-bond architecture, exhibits cytokine and chemokine activities.

Interleukin-12 (IL-12) is a pleiotropic cytokine which bridges innate and adaptive immunity in defense against pathogens. IL-12 proved to be an effective and successful adjuvant to enhance both the innate and adaptive immune responses and could be applicable for a rationale vaccine formulation in fish against pathogen infection. We have cloned the p35 and p40 cDNAs of IL-12 from orange-spotted grouper (Epinephelus coioides). Grouper IL-12 most resembles with sea bass orthologues; moderate to low identity with other teleost and mammalian counterparts. The structural model of grouper IL-12 heterodimer revealed NC(141)F three amino acid patch of grouper p35, which is present in teleost p35 but absent in mammalian and avian p35, and is spatially nearby the conserved cysteine residue located at A-helix of p35 to form a disulfide bond when the 14aa peptide located at loop 1 of grouper p35 was aligned with human corresponding exon 4, instead of exon 5. The results indicated that the loss of this 3aa patch during evolution was compensated by the duplication of exon 4 in mammalian p35 to gain another cysteine residue to form a disulfide bond, evidenced by chicken p35 which does not contain NCF corresponding 3-aa patch nor exon 4 duplication. Accordingly, the inter-chain disulfide bond of IL-12 heterodimer is conserved from teleost to mammalian IL-12. A single chain grouper IL-12 (scgIL-12) construct linked by (G4S)3 was successfully expressed in baculovirus-insect cell system; its identity has been confirmed by LC/MS/MS. In addition, the biological activity of recombinant scgIL-12 (rscgIL-12) are demonstrated for its stimulation of PBL proliferation, chemotactic migration, induction of TNF-α gene expression and a plausible adjuvant effect of prolonged protection against parasite infection in fish. We illustrated the first time in lower vertebrate that grouper IL-12 possesses both cytokine and chemokine activities.

Clinical presentations of patients from different age cohorts with biliary tract stone diseases.

BACKGROUND AND AIM: The role of clinical symptoms, transabdominal ultrasound scan (USS), and liver function tests (LFTs) in evaluating common bile duct (CBD) stones in patients suspected to have pancreatobiliary disease has been studied. However, it is unclear whether these predictive models are useful in different age cohorts. The aim of this study is to investigate the clinical presentations from different age cohorts with and without CBD stones. METHODS: Four hundred and forty-three patients with pancreatobiliary diseases were divided into cohorts according to decades as follows: young (Y, 18-64 years old, n = 143), young-old (YO, 65-74 years old, n = 168), old-old (OO, 75-84 years old, n = 97), and very old (VO, ≥ 85 years old, n = 35). The clinical symptoms, LFTs, and USS findings were demonstrated and compared among patients. RESULTS: Y- and YO-group patients were more likely to develop symptoms such as biliary colic in the presence of CBD stones. The proportion of abnormal serum aspartate aminotransferase and alanine aminotransferase were significantly greater in Y-, YO-, and OO-group patients with than in those without CBD stones. Sensitivity of USS for CBD stones in Y: 0.15; YO: 0.45; OO: 0.57; and VO: 0.68. Accuracy of USS for detected CBD stone in Y: 48%; YO: 62.5%; OO: 70.1%; and VO: 71.4%. CONCLUSION: Combined evaluation of clinical symptoms, biochemical and USS findings may help predict the presence of CBD stones. In Y, YO, and OO patients with CBD stones, the incidences of abnormal LFTs were higher. The sensitivity and accuracy of USS in detecting CBD stones were increased according to age.

Priorities for health outcomes in glaucoma in an ethnically diverse UK cohort: an observational study.

OBJECTIVES: To assess whether patients from minority ethnic groups have different perceptions about the quality-of-life outcomes that matter most to them. DESIGN: Cross-sectional observational study. SETTING: High volume eye centres serving the most ethnically diverse region in the UK, recruiting from July 2021 to February 2022. PARTICIPANTS: 511 patients with primary open-angle glaucoma and the predisease state of ocular hypertension. MAIN OUTCOME MEASURES: The main outcome was participants' self-reported priorities for health outcomes. RESULTS: Participants fell into one of four clusters with differing priorities for health outcomes, namely: (1) vision, (2) drop freedom, (3) intraocular pressure and (4) one-time treatment. Ethnicity was the strongest determinant of cluster membership after adjusting for potential confounders. Compared with white patients prioritising vision alone, the OR for black/black British patients was 7.31 (95% CI 3.43 to 15.57, p<0.001) for prioritising drop freedom; 5.95 (2.91 to 12.16, p<0.001) for intraocular pressure; and 2.99 (1.44 to 6.18, p=0.003) for one-time treatment. For Asian/Asian British patients, the OR was 3.17 (1.12 to 8.96, p=0.030) for prioritising intraocular pressure as highly as vision. Other ethnic minority groups also had higher ORs for prioritising health outcomes other than vision alone: 4.50 (1.03 to 19.63, p=0.045) for drop freedom and 5.37 (1.47 to 19.60, p=0.011) for intraocular pressure. CONCLUSIONS: Ethnicity is strongly associated with differing perceptions about the health outcomes that matter. An individualised and ethnically inclusive approach is needed when selecting and evaluating treatments in clinical and research settings.

Interaction of Colorectal Neoplasm Risk Factors and Association with Metabolic Health Status Focusing on Normal Waist-to-Hip Ratio in Adults.

BACKGROUND: We aimed to evaluate the interaction between colorectal adenoma risks among asymptomatic individuals in terms of metabolic health status and obesity, and examine the normal waist-to-hip ratio (WHR) in adults with colorectal adenoma risk. METHODS: A cross-sectional, retrospective study was conducted at MacKay Memorial Hospital involving 16,996 participants who underwent bidirectional gastrointestinal endoscopy between 2013 and 2023. The study recorded important clinicopathological characteristics, including age, body mass index and WHR, Framingham Risk Score (FRS), blood glucose level, and Helicobacter pylori (H. pylori) infection status. RESULTS: Multivariate logistic regression analysis demonstrated that elevated hemoglobin A1C (HbA1c), increased FRS, positive H. pylori infection, and WHR ≥ 0.9 are independent risk factors for colorectal adenoma. In examining the interaction between FRS and WHR using multivariate logistic regression to evaluate adenoma risk, the OR for the interaction term was 0.95, indicating a decline in adenoma risk when considering the interaction between these two factors. Incorporating HbA1c into the analysis, evaluating the interaction between FRS and WHR still demonstrated a statistically significant impact on adenoma risk (OR 0.96, p < 0.001). Participants with WHR < 0.9, elevated FRS, positive H. pylori infection, and increased HbA1c levels were associated with a higher risk of colorectal adenoma formation. Remarkably, the increased risk of adenoma due to rising HbA1c levels was statistically significant only for those with a WHR < 0.9. CONCLUSIONS: An increase in FRS and HbA1c or a positive H. pylori infection still warrants vigilance for colorectal adenoma risk when WHR is 0.9. These factors interacted with each other and were found to have a minimal decline in adenoma risk when considering the interaction between WHR and FRS.

Gene expression profiling of breast cancer survivability by pooled cDNA microarray analysis using logistic regression, artificial neural networks and decision trees.

BACKGROUND: Microarray technology can acquire information about thousands of genes simultaneously. We analyzed published breast cancer microarray databases to predict five-year recurrence and compared the performance of three data mining algorithms of artificial neural networks (ANN), decision trees (DT) and logistic regression (LR) and two composite models of DT-ANN and DT-LR. The collection of microarray datasets from the Gene Expression Omnibus, four breast cancer datasets were pooled for predicting five-year breast cancer relapse. After data compilation, 757 subjects, 5 clinical variables and 13,452 genetic variables were aggregated. The bootstrap method, Mann-Whitney U test and 20-fold cross-validation were performed to investigate candidate genes with 100 most-significant p-values. The predictive powers of DT, LR and ANN models were assessed using accuracy and the area under ROC curve. The associated genes were evaluated using Cox regression. RESULTS: The DT models exhibited the lowest predictive power and the poorest extrapolation when applied to the test samples. The ANN models displayed the best predictive power and showed the best extrapolation. The 21 most-associated genes, as determined by integration of each model, were analyzed using Cox regression with a 3.53-fold (95% CI: 2.24-5.58) increased risk of breast cancer five-year recurrence. CONCLUSIONS: The 21 selected genes can predict breast cancer recurrence. Among these genes, CCNB1, PLK1 and TOP2A are in the cell cycle G2/M DNA damage checkpoint pathway. Oncologists can offer the genetic information for patients when understanding the gene expression profiles on breast cancer recurrence.

The add-on N-acetylcysteine is more effective than dimethicone alone to eliminate mucus during narrow-band imaging endoscopy: a double-blind, randomized controlled trial.

OBJECTIVE: Recent studies have shown that pronase can improve mucosal visibility, but this agent is not uniformly available for human use worldwide. This study aimed to assess the efficacy of N-acetylcysteine (NAC), a mucolytic agent, in improving mucus elimination as measured by decreased endoscopic water flushes during narrow-band imaging (NBI) endoscopy. MATERIAL AND METHODS: A consecutive series of patients scheduled for upper gastrointestinal endoscopy at outpatient clinics were enrolled in this double-blind, randomized controlled trial. The control group drank a preparation of 100 mg dimethicone (5 ml at 20 mg/ml) plus water up to 100 ml, and the NAC group drank 300 mg NAC plus 100 mg dimethicone and water up to 100 ml. During the endoscopy, the endoscopist used as many flushes of water as deemed necessary to produce a satisfactory NBI view of the entire gastric mucosa. RESULTS: In all, 177 patients with a mean age of 51 years were evaluated in this study. Significantly lesser water was used for flushing during NBI endoscopy for the NAC group than the control group; 40 ml (30-70, 0-120) versus 50 ml (30-100, 0-150) (median (interquartile range, range), p = 0.0095). CONCLUSIONS: Considering the safety profile of NAC, decreasing the number of water flushes for optimal vision and unavailability of pronase in some areas, the authors suggest the use of add-on NAC to eliminate mucus during NBI endoscopy.

Gender-specific association of the interleukin 18 gene with symptomatic gallstone disease.

BACKGROUND AND AIM: Symptomatic gallstone disease (SGSD) induced several inflammatory responses and affected extrahepatic bile ducts. Although the pathology and environmental risk factors of gallstone disease are well documented, immune or inflammatory responses in SGSD development are still inconclusive. Interleukin 18 (IL18) is a pro-inflammatory cytokine that plays an important role in immune, infectious, and inflammatory diseases because of the induction of interferon-γ. In this study, we investigated whether polymorphisms of the IL18 gene were associated with SGSD susceptibility. METHODS: Genomic DNA was isolated from the whole blood samples of 445 patients with SGSD and 1121 gallstone-free controls. The IL18 rs549908T>G, rs5744247C>G, rs187238G>C, rs1946518T>G, and rs360719A>G polymorphisms were genotyped using predeveloped TaqMan allelic discrimination assay. RESULTS: We found IL18 rs5744247G allele conferred protection against SGSD in female patients (odds ratio = 0.75, corrected P-value = 0.015). Haplotype analysis revealed that TGGTA protected females from SGSD development (odds ratio = 0.75, corrected P-value = 0.02). CONCLUSIONS: Based on our findings, IL18 rs5744247C>G polymorphism could be a potential genetic marker to predict SGSD susceptibility in Han Chinese women.

Treatment expectations in glaucoma: what matters most to patients?

BACKGROUND/OBJECTIVES: Recent clinical trials in glaucoma have used patient-reported outcome measures (PROMs) of health-related quality of life to evaluate interventions. However, existing PROMs may not be sufficiently sensitive to capture changes in health status. This study aims to determine what really matters to patients by directly exploring their treatment expectations and preferences. SUBJECTS/METHODS: We conducted a qualitative study using one-to-one semi-structured interviews to elicit patients' preferences. Participants were recruited from two NHS clinics serving urban, suburban and rural populations in the UK. To be relevant across glaucoma patients under NHS care, participants were sampled to include a full range of demographic profiles, disease severities and treatment histories. Interview transcripts were evaluated using thematic analysis until no new themes emerged (saturation). Saturation was established when 25 participants with ocular hypertension, mild, moderate and advanced glaucoma had been interviewed. RESULTS: Themes identified were: Patients' experiences of living with glaucoma, patients' experiences of having glaucoma treatment, most important outcomes to patients, and COVID-related concerns. Participants specifically expressed their most important concerns, which were (i) disease-related outcomes (intraocular pressure control, maintaining vision, and being independent); and (ii) treatment-related outcomes (treatment that does not change, drop-freedom, and one-time treatment). Both disease-related and treatment-related experiences were covered prominently in interviews with patients across the spectrum of glaucoma severity. CONCLUSIONS: Outcomes related both to the disease and its treatment are important to patients with different severities of glaucoma. To accurately evaluate quality of life in glaucoma, PROMs may need to assess both disease-related and treatment-related outcomes.

Distinct horizontal transfer mechanisms for type I and type V CRISPR-associated transposons.

CRISPR-associated transposons (CASTs) co-opt CRISPR-Cas proteins and Tn7-family transposons for RNA-guided vertical and horizontal transmission. CASTs encode minimal CRISPR arrays but can't acquire new spacers. Here, we show that CASTs instead co-opt defense-associated CRISPR arrays for horizontal transmission. A bioinformatic analysis shows that all CAST sub-types co-occur with defense-associated CRISPR-Cas systems. Using an E. coli quantitative transposition assay, we show that CASTs use CRISPR RNAs (crRNAs) from these defense systems for horizontal gene transfer. A high-resolution structure of the type I-F CAST-Cascade in complex with a type III-B crRNA reveals that Cas6 recognizes direct repeats via sequence-independent π - π interactions. In addition to using heterologous CRISPR arrays, type V CASTs can also transpose via a crRNA-independent unguided mechanism, even when the S15 co-factor is over-expressed. Over-expressing S15 and the trans-activating CRISPR RNA (tracrRNA) or a single guide RNA (sgRNA) reduces, but does not abrogate, off-target integration for type V CASTs. Exploiting new spacers in defense-associated CRISPR arrays explains how CASTs horizontally transfer to new hosts. More broadly, this work will guide further efforts to engineer the activity and specificity of CASTs for gene editing applications.

Clinical prognosis of surgical resection versus transarterial chemoembolization for single large hepatocellular carcinoma (≥5 cm): A propensity score matching analysis.

Favorable prognostic factors and therapeutic strategies are important for patients with single large hepatocellular carcinoma (HCC). This retrospective study aimed to investigate the prognostic factors in patients with single large (≥5 cm) HCC with Child-Pugh (CP) class A patients and to recommend therapeutic strategies. Overall, 298 HCC patients with single and large (≥5 cm) tumors with CP class A, but without distant metastasis and macrovascular invasion were included, and their clinicopathological data, overall survival (OS), and progression-free survival (PFS) were recorded. OS and PFS was analyzed by the Kaplan-Meier method and Cox regression analysis. Propensity score matching (PSM) analysis was performed. The 298 HCC patients were 79.2% male and median age of 64 years. For the initial treatment, surgical resection (SR) and transarterial chemoembolization (TACE) was 50.8% and 49.2%, respectively. The OS and PFS were significantly higher in patients receiving SR than those receiving TACE before and after PSM. Furthermore, in multivariate analysis, cirrhosis (Hazard ratio [HR]: 2.04; 95% confidence interval [CI]: 1.35-3.03, p < 0.001, CP class A5/6 [HR: 4.01; 95% CI: 2.43-6.66, p < 0.001], and initial treatment [SR vs. TACE HR = 3.23; 95% CI: 2.13-5.01, p < 0.001]) remained significantly associated with mortality. Moreover, in multivariate analysis, CP class A5/6 (HR: 3.23; 95% CI: 1.89-5.88, p < 0.001), and initial treatment (Resection vs. TACE; HR = 4.17; 95% CI: 1.64-8.33, p = 0.039) remained significantly associated with recurrence. In conclusion, SR was associated with significantly higher OS and PFS rates than TACE before and after PSM for single large HCC patients.