CCL19-CCR7-dependent reverse transendothelial migration of myeloid cells clears Chlamydia muridarum from the arterial intima.

Regions of the normal arterial intima predisposed to atherosclerosis are sites of ongoing monocyte trafficking and also contain resident myeloid cells with features of dendritic cells. However, the pathophysiological roles of these cells are poorly understood. Here we found that intimal myeloid cells underwent reverse transendothelial migration (RTM) into the arterial circulation after systemic stimulation of pattern-recognition receptors (PRRs). This process was dependent on expression of the chemokine receptor CCR7 and its ligand CCL19 by intimal myeloid cells. In mice infected with the intracellular pathogen Chlamydia muridarum, blood monocytes disseminated infection to the intima. Subsequent CCL19-CCR7-dependent RTM was critical for the clearance of intimal C. muridarum. This process was inhibited by hypercholesterolemia. Thus, RTM protects the normal arterial intima, and compromised RTM during atherogenesis might contribute to the intracellular retention of pathogens in atherosclerotic lesions.

Azithromycin or Doxycycline for Asymptomatic Rectal Chlamydia trachomatis.

BACKGROUND: Rectal chlamydia is a common bacterial sexually transmissible infection among men who have sex with men. Data from randomized, controlled trials are needed to guide treatment. METHODS: In this double-blind trial conducted at five sexual health clinics in Australia, we randomly assigned men who have sex with men and who had asymptomatic rectal chlamydia to receive doxycycline (100 mg twice daily for 7 days) or azithromycin (1-g single dose). Asymptomatic chlamydia was selected as the trial focus because more than 85% of men with rectal chlamydia infection are asymptomatic, and clinical guidelines recommend a longer treatment course for symptomatic infection. The primary outcome was a negative nucleic acid amplification test for rectal chlamydia (microbiologic cure) at 4 weeks. RESULTS: From August 2016 through August 2019, we enrolled 625 men (314 in the doxycycline group and 311 in the azithromycin group). Primary outcome data were available for 290 men (92.4%) in the doxycycline group and 297 (95.5%) in the azithromycin group. In the modified intention-to-treat population, a microbiologic cure occurred in 281 of 290 men (96.9%; 95% confidence interval [CI], 94.9 to 98.9) in the doxycycline group and in 227 of 297 (76.4%; 95% CI, 73.8 to 79.1) in the azithromycin group, for an adjusted risk difference of 19.9 percentage points (95% CI, 14.6 to 25.3; P<0.001). Adverse events that included nausea, diarrhea, and vomiting were reported in 98 men (33.8%) in the doxycycline group and in 134 (45.1%) in the azithromycin group (risk difference, -11.3 percentage points; 95% CI, -19.5 to -3.2). CONCLUSIONS: A 7-day course of doxycycline was superior to single-dose azithromycin in the treatment of rectal chlamydia infection among men who have sex with men. (Funded by the National Health and Medical Research Council; RTS Australian New Zealand Clinical Trials Registry number, ACTRN12614001125617.).

Rectal chlamydia infections: implications for reinfection risk, screening, and treatment guidelines.

PURPOSE OF REVIEW: Rectal chlamydia is a prevalent sexually transmissible infection in both men who have sex with men (MSM) and in women. Screening is recommended for MSM but remains controversial for women. The optimal treatment for rectal chlamydia is now conclusive but interpreting and managing positive results remains challenging. Infections among MSM are increasing and strategies are needed to reduce incident infections. This review summarizes recent developments for the screening and management of rectal chlamydia and its implications on reinfection. RECENT FINDINGS: Reinfections in MSM may be occurring due to resumption of sex soon after treatment whereas repeat infections in women may occur due to autoinoculation in the absence of sex. Doxycycline is now first-line treatment but its role in chemoprophylaxis remains unclear. False positive results remain an issue, but the development of viability assays may prove useful in future to determine true infections. SUMMARY: Doxycycline is the first-line treatment for rectal chlamydia and in women may prevent infections at the urogenital site. Viability assays can help to reduce antibiotic use once developed. The role of routine screening of rectal chlamydia in women remains unclear and this debate may soon include asymptomatic infections in MSM.

Sexual behaviour during COVID-19: a repeated cross-sectional survey in Victoria, Australia.

BACKGROUND: During 2020, the State of Victoria (Australia) experienced two COVID-19 waves. Both resulted in community lockdowns followed by eased restrictions. We examined variation of sexual behaviour in Victorians over time during COVID-19. METHODS: We conducted a repeated online survey at four timepoints corresponding with two lockdown (LD1, LD2) and two reduced restriction (RR1, RR2) periods in Victoria. A convenience sample of participants aged ≥18years was recruited via social media and asked about their recent (past 4weeks) sexual behaviour. Using multivariable logistic regression, we investigated variation in sexual behaviour between surveys. RESULTS: A total of 1828 surveys were completed; 72% identified as female, 69% were aged 18-29years, 90% were metropolitan residents. The proportion reporting recent partnered sex ranged from 54.9% (LD2) to 70.2% (RR1). Across all timepoints, the most common sexual partners were regular (81.5%, n =842) and 10.8% (n =111) reported casual partners (e.g. hook-ups). Compared with LD1, respondents were >2-fold more likely to report casual partner(s) during reduced restrictions (RR1: aOR 2.0; 95% CI 1.1-3.7; RR2: aOR 2.8; 95% CI 1.3-5.9). Across all timepoints, 26.6% (n =486) reported using dating apps. Compared with LD1, dating app use for face-to-face activities (e.g. dates, hook-ups) was >4-fold higher during reduced restrictions (RR1: aOR 4.3; 95% CI 2.3-8.0; RR2: aOR 4.1; 95% CI 1.9-8.8). App use for distanced activities (e.g. sexting, virtual dates) was highest during LD1 (48.8%) than other periods. CONCLUSIONS: In this convenience sample, self-reported sexual behaviours fluctuated between lockdowns and reduced restrictions. While dating apps may provide a mechanism for virtual connections, this may be temporary until physical connections are possible.

Engineering Pseudomonas putida for efficient aromatic conversion to bioproduct using high throughput screening in a bioreactor.

Pseudomonas putida KT2440 is an emerging biomanufacturing host amenable for use with renewable carbon streams including aromatics such as para-coumarate. We used a pooled transposon library disrupting nearly all (4,778) non-essential genes to characterize this microbe under common stirred-tank bioreactor parameters with quantitative fitness assays. Assessing differential fitness values by monitoring changes in mutant strain abundance identified 33 gene mutants with improved fitness across multiple stirred-tank bioreactor formats. Twenty-one deletion strains from this subset were reconstructed, including GacA, a regulator, TtgB, an ABC transporter, and PP_0063, a lipid A acyltransferase. Thirteen deletion strains with roles in varying cellular functions were evaluated for conversion of para-coumarate, to a heterologous bioproduct, indigoidine. Several mutants, such as the ΔgacA strain improved fitness in a bioreactor by 35 fold and showed an 8-fold improvement in indigoidine production (4.5 g/L, 0.29 g/g, 23% of maximum theoretical yield) from para-coumarate as the carbon source.

Love during lockdown: findings from an online survey examining the impact of COVID-19 on the sexual health of people living in Australia.

INTRODUCTION: Australia recorded its first case of COVID-19 in late January 2020. On 22P March 2020, amid increasing daily case numbers, the Australian Government implemented lockdown restrictions to help 'flatten the curve'. Our study aimed to understand the impact of lockdown restrictions on sexual and reproductive health. Here we focus on sexual practices. METHODS: An online survey was open from the 23PP April 2020 to 11P May 2020. Participants were recruited online via social media and other networks and were asked to report on their sexual practices in 2019 and during lockdown. Logistic regression was used to calculate the difference (diff) (including 95% CIs) in the proportion of sex practices between time periods. RESULTS: Of the 1187 who commenced the survey, 965 (81.3%) completed it. Overall, 70% were female and 66.3% were aged 18-29 years. Most (53.5%) reported less sex during lockdown than in 2019. Compared with 2019, participants were more likely to report sex with a spouse (35.3% vs 41.7%; diff=6.4%; 95% CI 3.6 to 9.2) and less likely to report sex with a girl/boyfriend (45.1% vs 41.8%; diff=-3.3%; 95% CI -7.0 to -0.4) or with casual hook-up (31.4% vs 7.8%; 95% CI -26.9 to -19.8). Solo sex activities increased; 14.6% (123/840) reported using sex toys more often and 26.0% (218/838) reported masturbating more often. Dating app use decreased during lockdown compared with 2019 (42.1% vs 27.3%; diff= -14.8%; 95% CI -17.6 to -11.9). Using dating apps for chatting/texting (89.8% vs 94.5%; diff=4.7%; 95% CI 1.0 to 8.5) and for setting up virtual dates (2.6% vs 17.2%; diff=14.6%; 95% CI 10.1 to 19.2) increased during lockdown. CONCLUSION: Although significant declines in sexual activity during lockdown were reported, people did not completely stop engaging in sexual activities, highlighting the importance of ensuring availability of normal sexual and reproductive health services during global emergencies.

Contraceptive use and pregnancy plans among women of reproductive age during the first Australian COVID-19 lockdown: findings from an online survey.

PURPOSE: Australia introduced 'lockdown' measures to control COVID-19 on 22 March 2020 which continued for a period of two months. We aimed to investigate the impact this had on sexual and reproductive health (SRH). MATERIALS AND METHODS: Australians aged 18+ were eligible to participate in an online survey from 23 April to 11 May 2020. We report on the experiences of 518 female participants aged <50 years. Pregnancy intentions and contraceptive use were analysed using descriptive statistics. Odds ratios and 95% confidence intervals were calculated to investigate difficulty accessing SRH products and services. Qualitative data were analysed using conventional content analysis. RESULTS: Most participants were aged 18-24 years, and indicated they were trying to avoid pregnancy. The oral contraceptive pill was the most common single method used however nearly 20% reported they were not using contraception. Women who were employed had less trouble accessing contraception during lockdown. Participants reported delaying childbearing or deciding to remain childfree due to COVID-19. CONCLUSION: COVID-19 lockdown impacted the SRH of Australian women. Findings highlight the importance of continued access to SRH services and products during global emergencies.

The prevalence of oropharyngeal squamous cell carcinoma in patients admitted with symptoms of peritonsillar abscess or cellulitis: A retrospective multicentre study.

OBJECTIVES: Anecdotal evidence suggests that oropharyngeal squamous cell carcinoma (OPSCC) should be suspected in patients presenting with symptoms of peritonsillar abscess (PTA) or cellulitis (PTC). The aim of this study was to estimate the prevalence of OPSCC in patients presenting with symptoms of PTA/PTC. METHOD, SETTING AND PARTICIPANTS: We retrospectively identified all adults with a coded diagnosis of PTA or PTC who presented between 2012 and 2016 inclusive, across six ENT units in Merseyside. Records were compared to that of the centralised regional head and neck cancer database. The clinical records of a subset of patients were reviewed for the purposes of data validation. RESULTS: A total of 1975 patients with PTA/PTC were identified. Three patients were subsequently diagnosed with OPSCC. None of the three actually had an objective underlying diagnosis of PTA/PTC on the same side. The prevalence of OPSCC in patients admitted with symptoms of PTA/PTC was 0.15% or approximately 1:650 admissions. The records of 510 patients who presented over a one-year period (2016) were reviewed in even greater detail. There were 298 patients with PTA (59.4%) and 151 with PTC (29.1%) and 61 had an alternative diagnosis (11.9%). High-risk features (age ≥40, tonsillar asymmetry or tonsillar lesion) were present in 106 patients (24%). Urgent follow-up was expedited for 77 patients (73%). CONCLUSION: This study estimates the risk of OPSCC in patients with peritonsillar symptoms. The prevalence is low, even in a region with a relatively heavy disease burden. Clinicians should, however, retain a high level of suspicion in patients with persistent symptoms.

A prospective multicentre external validation study of the Liverpool Peritonsillar abscess Score (LPS) with a no-examination COVID-19 modification.

OBJECTIVES: Our primary aim was to validate the Liverpool Peritonsillar abscess Score (LPS) externally in a new patient cohort. Our secondary aim was to modify the LPS in the light of the COVID-19 pandemic to produce a no-examination variant for use in this instance. DESIGN: Prospective multicentre external validation study. SETTING: Six different secondary care institutions across the United Kingdom. PARTICIPANTS: Patients over 16 years old who were referred to ENT with any uncomplicated sore throat such a tonsillitis or peritonsillar abscess (PTA). MAIN OUTCOME MEASURES: Sensitivity, specificity, positive predictive value and negative predictive value for both the original LPS model and the modified model for COVID-19. RESULTS: The LPS model had sensitivity and specificity calculated at 98% and 79%, respectively. The LPS has a high negative predictive value (NPV) of 99%. The positive predictive value (PPV) was slightly lower at 63%. Receiver operating characteristic (ROC) curve, including the area under the curve (AUROC), was 0.888 which indicates very good accuracy. CONCLUSIONS: External validation of the LPS against an independent geographically diverse population yields high NPV. This may support non-specialist colleagues who may have concerns about mis-diagnosing a PTA. The COVID-19 modification of the LPS has a similar NPV, which may be of use where routine oral examination is to be avoided during the COVID-19 pandemic.

Treatment efficacy for pharyngeal Neisseria gonorrhoeae: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Rising gonorrhoea rates require highly effective treatments to reduce transmission and prevent development of antimicrobial resistance. Currently the most effective treatments for pharyngeal gonorrhoea remain unclear. This review aimed to estimate treatment efficacy for pharyngeal gonorrhoea. METHODS: Online bibliographic databases were searched for the period 1 January 2000 to 17 September 2019 for treatments of gonorrhoea. All randomized controlled trials (RCTs) with data on pharyngeal gonorrhoea among participants aged 15 years or above, published in English, were included. Meta-analyses (random effects) were used to estimate the treatment efficacy, defined as microbiological cure, among currently recommended monotherapies and dual therapies, previously recommended but no longer used regimens and emerging drugs under evaluation. Side effects were also summarized. The study protocol was registered on PROSPERO (CRD42020149278). RESULTS: There were nine studies that included 452 participants studying 19 treatment regimens. The overall treatment efficacy for pharyngeal gonorrhoea was 98.1% (95% CI: 93.8%-100%; I2 = 57.3%; P < 0.01). Efficacy was similar for single (97.1%; 95% CI: 90.8%-100.0%; I2 = 15.6%; P = 0.29) and dual therapies (98.0%; 95% CI: 91.4%-100%; I2 = 79.1%; P < 0.01). Regimens containing azithromycin 2 g or ceftriaxone were similarly efficacious. The summary efficacy estimate for emerging drugs was 88.8% (95% CI: 76.9%-97.5%; I2 = 11.2%; P = 0.34). Small sample sizes in each trial was a major limitation. CONCLUSIONS: Regimens containing ceftriaxone or azithromycin 2 g, alone or as part of dual therapies are the most efficacious for pharyngeal gonorrhoea. Further pharyngeal-specific RCTs with adequate sample sizes are needed.

Factors Associated With Early Resumption of Condomless Anal Sex Among Men Who Have Sex With Men After Rectal Chlamydia Treatment.

BACKGROUND: The resumption of sexual activity shortly after commencing treatment for sexually transmitted infections (STIs) is poorly described despite contributing to onward transmission. With azithromycin remaining an option for rectal Chlamydia trachomatis, resuming sex too early after treatment may contribute to antimicrobial resistance because of exposure of newly acquired STIs to subinhibitory concentrations. METHODS: Clinical and sexual behavioral data were collected from men participating in a trial assessing treatment efficacy for rectal chlamydia. Data were collected at recruitment and weekly for 3 weeks after commencing treatment. Outcome measures were resumption of any sexual activity or condomless receptive anal sex within 1, 2, or 3 weeks after commencing treatment. Generalized linear regression was used to calculate adjusted risk ratios (aRR) to identify associated factors. RESULTS: Almost 1 in 10 men (9.5%; 95% confidence interval [CI], 7.2-12.1) resumed condomless receptive anal sex within 1 week of commencing treatment. This was associated with current preexposure prophylaxis use (aRR, 3.4; 95% CI, 2.5-4.8]) and having 9 or more sexual partners in the last 3 months (aRR, 3.2; 95% CI, 1.6-5.0). Most men (75.0%; 95% CI, 71.3-78.5) resumed any sexual activity within 3 weeks; this was associated with a greater number of sexual partners (4-8 partners; aRR, 1.2; 95% CI, 1.1-1.5; ≥9 partners; aRR, 1.5; 95% CI, 1.3-1.7). CONCLUSIONS: Resuming condomless receptive anal sex early after treatment may facilitate onward transmission and promote antimicrobial resistance for STIs. Although azithromycin remains a treatment option, this analysis highlights the need for new health promotion messages regarding early resumption of sex and continued surveillance for antimicrobial resistance.

Factors associated with anorectal Chlamydia trachomatis or Neisseria gonorrhoeae test positivity in women: a systematic review and meta-analysis.

OBJECTIVES: There has been considerable discussion about anorectal Chlamydia trachomatis (CT) in women, with some calling for anorectal CT screening, but little about anorectal Neisseria gonorrhoeae (NG). Given that urogenital NG is more strongly associated with pelvic inflammatory disease, this is an evidence gap. This systematic review and meta-analysis investigates the associations between anorectal CT in women and CT positivity at other sites (urogenital/oropharyngeal) and with anal intercourse, and compares these with anorectal NG within the same study populations. METHODS: Electronic databases were searched for English-language studies published to October 2018 using the following terms: ("Chlamydia" OR "Chlamydia trachomatis") AND (("anal" OR "rect*" OR "anorect*") OR ("extra?genital" OR "multi?site")). Studies were included if anorectal NG data were available. Random-effects meta-analyses calculated pooled estimates; heterogeneity was investigated using meta-regression. RESULTS: 25 studies were eligible. Anorectal CT positivity ranged from 0% to 17.5%, with a summary estimate of 8.0% (95% CI 7.0 to 9.1; I2=88.5%). Anorectal NG positivity ranged from 0% to 17.0%, with a summary estimate of 2.1% (95% CI 1.6 to 2.8; I2=92.7%). The association between urogenital and anorectal positivity was stronger for NG than CT (summary prevalence ratio (PR)=89.3 (95% CI 53.1 to 150.3; I2=80.1%), PR=32.2 (95% CI 25.6 to 40.7; I2=70.3%), respectively), and between oropharyngeal and anorectal positivity it was stronger for NG than CT (PR=34.8 (95% CI 10.2 to 118.2; I2=89.9%), PR=8.8 (95% CI 6.8 to 11.5; I2=58.1%), respectively). Anal intercourse was associated with anorectal NG (PR=4.3; 95% CI 2.2 to 8.6; I2=0.0%) but not with anorectal CT (PR=1.0; 95% CI 0.7 to 1.4; I2=0.0%). CONCLUSIONS: Anorectal CT is more common than anorectal NG, but anorectal NG is more strongly associated with anal intercourse, urogenital and oropharyngeal NG, suggesting that ongoing discussion about anorectal CT should also include NG. Longitudinal data are required to further understanding of the aetiology of anorectal STIs and assess whether anorectal screening is needed in women. TRIAL REGISTRATION NUMBER: CRD42df017080188.

The effects of an expanded cognitive stimulation therapy model on the improvement of cognitive ability of elderly with mild stage Dementia living in a community - a randomized waitlist controlled trial.

OBJECTIVE: This research study aims to evaluate the effectiveness of an expanded cognitive stimulation therapy (CST) model that combines a CST group and tai chi on improving the cognitive ability of community-dwelling Chinese elderly with mild stage dementia (EwMD). METHOD: A randomized waitlist controlled trial design was adopted in this study. The treatment group participated in a structured CST group followed by tai chi twice a week, with a total of 14 sessions throughout the study period. The waitlist control group received treatment as usual at the initial stage and expanded CST model at a later stage. The Chinese Mattis Dementia Rating Scale (DRS) and the Chinese Mini Mental State Examination (MMSE) were used to assess the cognitive ability of EwMD in the pre- and post- treatment periods. RESULTS: At baseline, the treatment group (n = 51) and control group (n = 50) did not differ significantly in any demographic or clinical variables. Overall, the participants had a mean baseline MMSE score of 20.67 (SD = 2.30). The 2 × 2 repeated measures ANCOVA demonstrated that the treatment group was significantly more effective than the control group in improving the MMSE score (F = 12.31, p< .01) with a moderate effect size (partial eta square = .11) after controlling for group difference in age, gender, education, and having a diagnosis of dementia. CONCLUSION: The present study demonstrates the effectiveness of the expanded CST model on the improvement of cognitive ability of community-dwelling EwMD. More research is needed to further investigate this intervention model across cultures and societies.

Long-term soft tissue outcomes for hydroxyapatite-coated bone-anchored hearing implant surgery.

PURPOSE: To investigate skin-related postoperative outcomes following a tissue preservation technique in percutaneous hydroxyapatite-coated bone-anchored hearing aid (BAHA) abutment implantation. METHODS: A retrospective medical records review of adult patients, who underwent single-stage BAHA implantation between July 2013 and November 2017 at a tertiary centre was conducted. Surgical procedures were performed by a single surgeon using a linear incision soft tissue preservation technique. Patients were reviewed at 1 week, 4 weeks, 3 months, 6 months, and annually postoperatively and soft tissue reactions were graded using Holger's score RESULTS: There were 102 patients included with a slight female preponderance (female:male 56:46). There were 586 follow-up episodes during the study period. From the recorded follow-up episodes, Holger's scores were documented as follows: Holger score 0 (89%); 1 (7%); 2 (2%); 3 (1.9%). Three patients (3%) required peri-abutment soft tissue excision (Holger 3) and insertion of longer abutments. One patient (1%) reported atraumatic implant loss. The BAHA was re-implanted in two patients (2%) due to traumatic dislodgement. There was a statistically significant association (p = 0.009) when the mean time to minor skin complications was compared with mean time to a significant skin reaction. CONCLUSION: Tissue preservation technique is the procedure of choice for BAHA abutment implant surgery. It confers excellent soft tissue outcomes and an excellent implant survival rate.

The Liverpool Peritonsillar abscess Score: Development of a predictive score through a prospective multicentre observational study.

OBJECTIVES: While uncommon in the population at large, peritonsillar abscess (PTA) is a common subject of ENT referrals. Missed or uncertain diagnosis is a source of concern for non-specialist referrers. In line with the NHS England Second Sepsis Action Plan, we aimed to develop a predictive score for the presence of PTA. This would help to improve non-specialist colleagues' diagnostic certainty as well as to support ENT surgeons' triage of these referrals. DESIGN: Prospective, multicentre observational study. SETTING: Primary and secondary care. PARTICIPANTS: Patients >16 years with symptoms of sore throat. DATA: We prospectively collected comprehensive data on patient demographics, symptoms and clinical status. We documented whether the patient had aspiration-proven PTA or not. We performed binary logistic regression analysis, iterative development of a predictive score which we validated internally. RESULTS: 100 patients were included (46 PTA and 54 tonsillitis). Five variables added significantly to the logistic regression model: unilateral sore throat; trismus; male gender; pharyngeal voice change; and uvular deviation. Using the odds ratio outputs, we developed the Liverpool Peritonsillar abscess Score (LPS) iteratively. We validated the latest (third) iteration of the LPS internally (ie, on the same sample), yielding sensitivity 96%; specificity 85%; positive predictive value 85%; and negative predictive value 96%. The area under the receiver operating characteristics (AUROC) curve was 0.970. CONCLUSIONS: We have developed the first predictive score for PTA based on symptoms and signs that do not require the user to have specialist experience. Its high negative predictive value may be particularly helpful to non-specialist colleagues.

Sinew acupuncture for knee osteoarthritis: study protocol for a randomized sham-controlled trial.

BACKGROUND: Sinew acupuncture is a new modality of acupuncture in which needles are inserted into acupoints, ashi points or spasm points of sinew and muscles along the meridian sinew pathway. A previous observational study revealed that sinew acupuncture has immediate analgesic effects on various soft tissue injuries, including knee injuries. However, no rigorous trials have been conducted. This study aims to examine whether sinew acupuncture can safely relieve pain and symptoms of knee osteoarthritis (KOA) and improve patients' functional movement and quality of life. METHODS/DESIGN: A randomized, sham-controlled, patient- and assessor-blinded trial will be conducted to compare the efficacy of sinew acupuncture and sham acupuncture. Subjects will be assessed by the physician and acupuncturists. A sample of eighty-six eligible subjects will be randomized into either the sinew acupuncture group or the sham acupuncture group. The intervention will be performed in the Hong Kong Tuberculosis Association Chinese Medicine Clinic cum Training Centre of the University of Hong Kong by acupuncturists with over 3 years of acupuncture experience. Subjects will receive 10 sessions of interventions for 4 weeks, followed by a 6-week follow-up. The visual analogue scale (VAS) score at week 4 will be the primary outcome. The Western Ontario and McMasters University Osteoarthritis Index (WOMAC), Timed Up & Go Test (TUG), 8-step Stair Climb Test (SCT) and the 36-Item Short Form Survey (SF-36) will be secondary outcomes. DISCUSSION: Sinew acupuncture is a potential alternative non-pharmacological therapy for KOA. This rigorous trial will expand our knowledge of whether sinew acupuncture reduces pain intensity and improves symptoms, functional movements, and quality of life of KOA patients. TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov (Identifier: NCT03099317) in March 2017.

Endothelial cells suppress monocyte activation through secretion of extracellular vesicles containing antiinflammatory microRNAs.

The blood contains high concentrations of circulating extracellular vesicles (EVs), and their levels and contents are altered in several disease states, including cardiovascular disease. However, the function of circulating EVs, especially the microRNAs (miRNAs) that they contain, are poorly understood. We sought to determine the effect of secreted vesicles produced by quiescent endothelial cells (ECs) on monocyte inflammatory responses and to assess whether transfer of microRNAs occurs between these cells. We observed that monocytic cells cocultured (but not in contact) with ECs were refractory to inflammatory activation. Further characterization revealed that endothelium-derived EVs (EC-EVs) suppressed monocyte activation by enhancing immunomodulatory responses and diminishing proinflammatory responses. EVs isolated from mouse plasma also suppressed monocyte activation. Importantly, injection of EC-EVs in vivo repressed monocyte/macrophage activation, confirming our in vitro findings. We found that several antiinflammatory microRNAs were elevated in EC-EV-treated monocytes. In particular, miR-10a was transferred to monocytic cells from EC-EVs and could repress inflammatory signaling through the targeting of several components of the NF-κB pathway, including IRAK4. Our findings reveal that ECs secrete EVs that can modulate monocyte activation and suggest that altered EV secretion and/or microRNA content may affect vascular inflammation in the setting of cardiovascular disease.

Differential role of an NF-κB transcriptional response element in endothelial versus intimal cell VCAM-1 expression.

RATIONALE: Human and murine Vcam1 promoters contain 2 adjacent nuclear factor-κB (NF-κB)-binding elements. Both are essential for cytokine-induced transcription of transiently transfected promoter-reporter constructs. However, the relevance of these insights to regulation of the endogenous Vcam1 gene and to pathophysiological processes in vivo remained unknown. OBJECTIVE: Determine the role of the 5' NF-κB-binding element in expression of the endogenous Vcam1 gene. METHODS AND RESULTS: Homologous recombination in embryonic stem cells was used to inactivate the 5' NF-κB element in the Vcam1 promoter and alter 3 nucleotides in the 5' untranslated region to allow direct comparison of wild-type versus mutant allele RNA expression and chromatin configuration in heterozygous mice. Systemic treatment with inflammatory cytokines or endotoxin (lipopolysaccharide) induced lower expression of the mutant allele relative to wild-type by endothelial cells in the aorta, heart, and lungs. The mutant allele also showed lower endothelial expression in 2-week atherosclerotic lesions in Vcam1 heterozygous/low-density lipoprotein receptor-deficient mice fed a cholesterol-rich diet. In vivo chromatin immunoprecipitation assays of heart showed diminished lipopolysaccharide-induced association of RNA polymerase 2 and NF-κB p65 with the mutant promoter. In contrast, expression of mutant and wild-type alleles was comparable in intimal cells of wire-injured carotid artery and 4- to 12-week atherosclerotic lesions. CONCLUSIONS: This study highlights differences between in vivo and in vitro promoter analyses, and reveals a differential role for a NF-κB transcriptional response element in endothelial vascular cell adhesion molecule-1 expression induced by inflammatory cytokines or a cholesterol-rich diet versus intimal cell expression in atherosclerotic lesions and injured arteries.

Treatment efficacy of azithromycin 1 g single dose versus doxycycline 100 mg twice daily for 7 days for the treatment of rectal chlamydia among men who have sex with men - a double-blind randomised controlled trial protocol.

BACKGROUND: Rectal infection with Chlamydia trachomatis is one of the most common bacterial sexually transmissible infections among men who have sex with men (MSM) with diagnosis rates continuing to rise. Current treatment guidelines recommend either azithromycin 1 g single dose or doxycycline 100 mg twice daily for 7 days. However, there are increasing concerns about treatment failure with azithromycin. We are conducting the first randomised controlled trial (RCT) to compare treatment efficacy of azithromycin versus doxycycline for the treatment of rectal chlamydia in MSM. METHODS/DESIGN: The Rectal Treatment Study will recruit 700 MSM attending Australian sexual health clinics for the treatment of rectal chlamydia. Participants will be asked to provide rectal swabs and will be randomised to either azithromycin 1 g single dose or doxycycline 100 mg twice daily for 7 days. Participants will be asked to complete questionnaires about adverse drug reactions, sexual behaviour and drug adherence via short message service and online survey. The primary outcome is the treatment efficacy as determined by a negative chlamydia nucleic acid amplification test at 4 weeks post treatment. Secondary outcomes will utilise whole genome sequencing and mRNA assay to differentiate between treatment failure, reinfection or false positive results. DISCUSSION: Rectal chlamydia is an increasing public health concern as use of pre-exposure prophylaxis against HIV becomes commonplace. Optimal, evidence-based treatment is critical to halting ongoing transmission. This study will provide the first RCT evidence comparing azithromycin and doxycycline for the treatment of rectal chlamydia. The results of this trial will establish which treatment is more efficacious and inform international management guidelines. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12614001125617.