Intrahepatic cholangiocarcinoma hidden within cancer of unknown primary.

BACKGROUND: Many patients referred with a provisional diagnosis of cancer of unknown primary (pCUP) present with presumed metastatic disease to the liver. Due to the lack of definitive histological markers, intrahepatic cholangiocarcinoma (iCCA) may be overlooked. This study assessed the frequency of iCCA within a pCUP cohort. METHODS: A single UK cancer-center study of sequential patients referred with pCUP from January 2017 to April 2020. Baseline diagnostic imaging was reviewed independently by a radiologist and oncologist; those with radiological features of iCCA (dominant liver lesion, capsular retraction) were identified. RESULTS: Of 228 patients referred with pCUP, 72 (32%) had malignancy involving the liver. 24/72 patients had radiological features consistent with iCCA; they were predominantly female (75%) with an average age of 63 years and 63% had an ECOG PS ≤ 2. The median overall survival (OS) of the iCCA group and the remaining liver-involved CUP group were similar (OS 4.1 vs 4.4 months, p-value = 0.805). Patients, where a primary diagnosis was subsequently determined, had better OS (10.2 months, p-values: iCCA = 0.0279: cCUP = 0.0230). CONCLUSIONS: In this study, 34% of patients with liver-involved pCUP, fulfilled the radiological criteria for an iCCA diagnosis. Consideration of an iCCA diagnosis in patients with CUP could improve timely diagnosis, molecular characterisation and treatment.

The impact of health literacy on psychosocial and behavioural outcomes among people at low risk of cardiovascular disease.

This study aimed to explore the impact of health literacy on psychosocial and behavioural outcomes for people who were not at high risk of cardiovascular disease receiving a hypothetical blood pressure reading of 135/85 mmHg. We performed a secondary analysis of data from a national sample of Australians aged 40 to 50 years (n = 1318) recruited online. Health literacy was measured using the validated Newest Vital Sign (inadequate: 0-3; adequate: 4-6). Analysed outcomes included: willingness to increase exercise and accept medication; perceived severity; positive and negative affect; illness perceptions and impacts on life and motivation. Participants with inadequate levels of health literacy perceived a blood pressure reading of 135/85 mmHg to be less serious compared to individuals with adequate health literacy (Mean Difference [MD]:0.21; 95%CI 0.03-0.39; p = .024; d = 0.13), and reported less motivation to eat well (MD:0.44; 95%CI 0.31-0.58; p < .001; d = 0.38) and exercise (MD:0.43; 95%CI 0.31-0.58; p < .001; d = 0.36). However, they were more willing to accept medication (MD:0.20; 95%CI 0.07-0.34; p = .004; d = 0.17). Participants with inadequate health literacy also perceived the condition to have fewer negative impacts on aspects of life and work than individuals with adequate health literacy, but reported greater negative emotion and more negative illness perceptions (all p < .001). Tailored communication and behaviour change support may be needed when communicating blood pressure information to people with lower health literacy and not at high risk of cardiovascular disease given the differential impacts on medication (increased willingness) and healthy exercise and diet behaviours (decreased willingness) observed in this study.

An effective strategy to diagnose HIV infection: findings from a national audit of HIV partner notification outcomes in sexual health and infectious disease clinics in the UK.

OBJECTIVES: Partner notification (PN) is a key public health intervention in the control of STIs. Data regarding its clinical effectiveness in the context of HIV are lacking. We sought to audit HIV PN outcomes across the UK. METHODS: All UK sexual health and HIV services were invited to participate. Clinical audit consisted of retrospective case-note review for up to 40 individuals diagnosed with HIV per site during 2011 (index cases) and a review of PN outcomes for up to five contacts elicited by PN per index case. RESULTS: 169/221 (76%) clinical services participated (93% sexual health/HIV services, 7% infectious diseases/HIV units). Most (97%) delivered PN for HIV. Data were received regarding 2964 index cases (67% male; 50% heterosexual, 52% white). PN was attempted for 88% of index cases, and outcomes for 3211 contacts were audited (from an estimated total of 6400): 519 (16%) were found not to be at risk of undiagnosed HIV infection, 1399 (44%) were informed of their risk and had an HIV test, 310 (10%) were informed of the risk but not known to have tested and 983 (30%) were not informed of their risk of HIV infection. Of 1399 contacts tested through PN, 293 (21%) were newly diagnosed with HIV infection. Regular partners were most likely to test positive (p<0.001). CONCLUSIONS: HIV PN is a highly effective diagnostic strategy. Non-completion of PN thus represents a missed opportunity to diagnose HIV in at-risk populations. Vigorous efforts should be made to pursue PN to identify people living with, and at risk of, HIV infection.

A cross-sectional study showing differences in the clinical diagnosis of pelvic inflammatory disease according to the experience of clinicians: implications for training and audit.

OBJECTIVES: Pelvic inflammatory disease (PID) generates diagnostic difficulty even for experienced doctors. Junior doctors and nurses also assess women with symptoms suggestive of PID. We aimed to determine if and how PID diagnoses vary between clinicians with different experience levels. METHODS: Cross-sectional study conducted in U.K. sexual health clinic, nested within a Chlamydia trachomatis (CT), and Neisseria gonorrhoea diagnostic test accuracy study. Proportions and characteristics of women diagnosed clinically with PID by clinicians with varying experience were compared. Outcomes included demographics, presenting symptoms and signs and CT, and CT and/or gonococcal (GC) (CT/GC) positivity. RESULTS: In 3804 women assessed by 36 clinicians, rates of PID, CT and GC were 4.4%, 10.5%, and 2.5%, with no differences between experienced and inexperienced clinicians (p=0.84, p=0.13 and p=0.07, respectively). 63.7% of PID diagnosed by experienced clinicians met Centers for Disease Control and Prevention (CDC) key clinical criteria versus 41.2% by inexperienced; experienced versus inexperienced OR 2.51; 95% CI 1.16 to 5.40). Proportions of CT (CT/GC)-positive PID increased with experience (5.9% (11.8%) to 31.9% (34.1%)); experienced versus inexperienced (OR 3.90; 95% CI 1.12 to 13.5). Percentages of women with CT (CT/GC) who were diagnosed with PID also rose with experience (2.2% (3.9%) to 14.2% (13.7%)), but CT prevalence in PID cases diagnosed by inexperienced clinicians (8.8%) was no greater than in all women they assessed (9.0%), suggesting poorer discriminative skills. CONCLUSIONS: Clinical diagnostic acumen for PID improves with experience. Inexperienced clinicians should focus on the presence of lower abdominal pain with pelvic tenderness and consider additional supportive symptoms, to improve specificity of their diagnoses. TRIAL REGISTRATION NUMBER: ISRCTN 42867448.

Private sector quality of care for maternal, new-born, and child health in low-and-middle-income countries: a secondary review.

The private sector has emerged as a crucial source of maternal, newborn, and child health (MNCH) care in many low- and middle-income countries (LMICs). Quality within the MNCH private sector varies and has not been established systematically. This study systematically reviews findings on private-sector delivery of quality MNCH care in LMICs through the six domains of quality care (QoC) (i.e., efficiency, equity, effectiveness, people-centered care, safety, and timeliness). We registered the systematic review with PROSPERO international prospective register of systematic reviews (registration number CRD42019143383) and followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) Statement for clear and transparent reporting of systematic reviews and meta-analyses. Searches were conducted in eight electronic databases and two websites. For inclusion, studies in LMICs must have examined at least one of the following outcomes using qualitative, quantitative, and/or mixed-methods: maternal morbidity, maternal mortality, newborn morbidity, newborn mortality, child morbidity, child mortality, service utilization, quality of care, and/or experience of care including respectful care. Outcome data was extracted for descriptive statistics and thematic analysis. Of the 139 included studies, 110 studies reported data on QoC. Most studies reporting on QoC occurred in India (19.3%), Uganda (12.3%), and Bangladesh (8.8%). Effectiveness was the most widely measured quality domain with 55 data points, followed by people-centered care (n = 52), safety (n = 47), timeliness (n = 31), equity (n = 24), and efficiency (n = 4). The review showed inconsistencies in care quality across private and public facilities, with quality varying across the six domains. Factors such as training, guidelines, and technical competence influenced the quality. There were also variations in how domains like "people-centered care" have been understood and measured over time. The review underscores the need for clearer definitions of "quality" and practical QoC measures, central to the success of Sustainable Development Goals (SDGs) and equitable health outcomes. This research addresses how quality MNCH care has been defined and operationalized to understand how quality is delivered across the private health sector and the larger health system. Numerous variables and metrics under each QoC domain highlight the difficulty in systematizing QoC. These findings have practical significance to both researchers and policymakers. Systematic Review Registration: https://bmjopen.bmj.com/content/10/2/e033141.long, Identifier [CRD42019143383].

Viricidal Efficacy of a 405-nm Environmental Decontamination System for Inactivation of Bacteriophage Phi6: Surrogate for SARS-CoV-2.

The highly transmittable nature of SARS-CoV-2 has increased the necessity for novel strategies to safely decontaminate public areas. This study investigates the efficacy of a low irradiance 405-nm light environmental decontamination system for the inactivation of bacteriophage phi6 as a surrogate for SARS-CoV-2. Bacteriophage phi6 was exposed to increasing doses of low irradiance (~0.5 mW cm-2 ) 405-nm light while suspended in SM buffer and artificial human saliva at low (~103-4 PFU mL-1 ) and high (~107-8 PFU mL-1 ) seeding densities, to determine system efficacy for SARS-CoV-2 inactivation and establish the influence of biologically relevant suspension media on viral susceptibility. Complete/near-complete (≥99.4%) inactivation was demonstrated in all cases, with significantly enhanced reductions observed in biologically relevant media (P < 0.05). Doses of 43.2 and 172.8 J cm-2 were required to achieve ~3 log10 reductions at low density, and 97.2 and 259.2 J cm-2 achieved ~6 log10 reductions at high density, in saliva and SM buffer, respectively: 2.6-4 times less dose was required when suspended in saliva compared to SM buffer. Comparative exposure to higher irradiance (~50 mW cm-2 ) 405-nm light indicated that, on a per unit dose basis, 0.5 mW cm-2 treatments were capable of achieving up to 5.8 greater log10 reductions with up to 28-fold greater germicidal efficiency than that of 50 mW cm-2 treatments. These findings establish the efficacy of low irradiance 405-nm light systems for inactivation of a SARS-CoV-2 surrogate and demonstrate the significant enhancement in susceptibility when suspended in saliva, which is a major vector in COVID-19 transmission.

Outcomes and experiences of using oral voriconazole with or without concomitant topical agents to treat refractory vulvovaginal yeast infections.

BACKGROUND: We describe 11 cases of refractory vulvovaginal yeast infections (RVVYI) treated using oral voriconazole with or without concomitant topical agents. METHODS: Retrospective case-note review of all women prescribed oral voriconazole to treat RVVYI in five Sexual Health Clinics from Jan 2010-March 2020. Demographic details, clinical features, diagnostic results and treatment outcomes were collected. RESULTS: 11 women with vulvovaginal symptoms for a median of 1 year were treated with voriconazole. RVVYI was diagnosed clinically and confirmed on microscopy and culture with speciation. 10/11 isolates were fluconazole resistant, 1 intermediately sensitive, 10/11 were either fully or intermediately sensitive to voriconazole. All had received prior fluconazole and clotrimazole and 10/11 had used at least 2-weeks of one or more second-line antifungals with non-clearance of the yeast. Oral voriconazole 400 mg BD day-1, then 200 mg BD 13-days was prescribed and 10/11 women completed the course. Concomitant topical treatment was used by 6/11. Liver and renal function were monitored at 0, 7, 14 days. One woman stopped voriconazole after 5-days due to perioral tingling. Other transient side-effects were nausea (n = 2), photosensitivity, muscle aches, hair thinning (all n = 1), peripheral visual disturbance (n = 2). 8/11 experienced both symptom reduction and yeast clearance. Two women had an initial partial response but experienced resolution of symptoms following a second course of voriconazole. CONCLUSIONS: Our observational data adds to the limited evidence to support voriconazole treatment for RVVYI. A 2-week course of voriconazole was tolerated and completed by 10/11 women. Eight women, five using concomitant topical agents, achieved mycological cure.

Benefits and Harms of Hypertension and High-Normal Labels: A Randomized Experiment.

BACKGROUND: Recent US guidelines lowered the threshold for diagnosing hypertension while other international guidelines use alternative/no labels for the same group (blood pressure [BP], <140/90 mm Hg). We investigated potential benefits and harms of hypertension and high-normal BP labels, compared with control, among people at lower risk of cardiovascular disease. METHODS: We conducted a randomized experiment using a national sample of Australians (n=1318) 40 to 50 years of age recruited from an online panel. Participants were randomized to 1 of 3 hypothetical scenarios where a general practitioner told them they had a BP reading of 135/85 mm Hg, using either hypertension/high-normal BP/control (general BP description) labels. Participants were then randomized to receive an additional absolute risk description or nothing. Primary outcomes were willingness to change diet and worry. Secondary outcomes included exercise/medication intentions, risk perceptions, and other psychosocial outcomes. RESULTS: There was no difference in willingness to change diet across label groups (P=0.22). The hypertension label (mean difference [MD], 0.74 [95% CI, 0.41-1.06]; P<0.001) and high-normal BP label (MD, 0.45 [95% CI, 0.12-0.78]; P=0.008) had increased worry about cardiovascular disease risk compared with control. There was no evidence that either label increased willingness to exercise (P=0.80). However, the hypertension (MD, 0.20 [95% CI, 0.04-0.36]; P=0.014), but not high-normal label (MD, 0.06 [95% CI, -0.10 to 0.21]; P=0.49), increased willingness to accept BP-lowering medication compared with control. Psychosocial differences including lower control, higher risk perceptions, and more negative affect were found for the hypertension and high-normal labels compared with control. Providing absolute risk information decreased willingness to change diet (MD, 0.25 [95% CI, 0.10-0.41]; P=0.001) and increase exercise (MD, 0.28 [95% CI, 0.11-0.45]; P=0.001) in the hypertension group. CONCLUSIONS: Neither hypertension nor high-normal labels motivated participants to change their diet or exercise more than control, but both labels had adverse psychosocial outcomes. Labeling people with systolic BP of 130 to 140 mm Hg, who are otherwise at low risk of cardiovascular disease, may cause harms that outweigh benefit. Registration: URL: http://www.anzctr.org.au/; Unique identifier: ACTRN12618001700224.

Microbicides and HIV prevention: lessons from the past, looking to the future.

PURPOSE OF REVIEW: This review provides an update on developments in HIV microbicide research in the light of recent phase 3 efficacy studies and discusses how lessons learnt from early generation microbicide candidates can assist the development of future agents. RECENT FINDINGS: Results of an interim analysis of a phase 3 trial suggested that cellulose sulfate increased the risk of HIV acquisition compared with placebo. Carraguard, SAVVY and Buffergel also failed to show any HIV protection in human efficacy trials. Recent research has focused on elucidating the reasons behind these failures as well as improving the assessment of safety and efficacy for the next generation of microbicide candidates. PRO 2000 0.5% gel is the only HIV microbicide candidate for which there are preliminary data suggesting efficacy in women. Antiretroviral agents and entry inhibitors may provide the key in the future to developing an effective HIV microbicide both for vaginal and rectal use. SUMMARY: Development of a protective 'barrier' which can be controlled by the receptive partner independent of time of coitus remains a key goal in HIV prevention. A gel or ring-delivered combination of active anti-HIV agents may prove more efficacious than a single agent alone. Challenges in evaluating and manufacturing new candidates must be overcome before a well tolerated, effective, acceptable and affordable microbicide can be produced.

Translational research on parenting of adolescents: Linking theory to valid observation measures for family centered prevention and treatment.

Parental monitoring and family problem solving are key parenting practices targeted in evidence-based interventions targeting adolescents and families, yet the constructs have yet to be validated across ethnic groups. The study's objective was to promote translational research by evaluating convergent, discriminant, and predictive validity of the two constructs at age 16-17 years through the use of multiple observation indicators and methods and as a function of ethnic status. Videotaped parent-adolescent family interactions were coded for monitoring and problem solving in a sample of 714 European American (EA; 59.2 %) and African American (AA; 40.8 %) males (53.8 %) and females (46.2 %). Structural equation models established convergent and discriminant validity of parental monitoring and problem solving among parent, youth, and observation measures for AA and EA families. Low levels of parent monitoring was highly predictive of antisocial behavior in EA and in AA youths (p < 0.001) and moderately predicted future drug use (p < 0.001) for both groups at age 18-19. Poorer family problem solving was also moderately predictive of antisocial behavior (p < 0.001 for EA; p < 0.05 for AA) and drug use (p < 0.01 for EA; p < 0.05 for AA) at age 18-19. These findings suggest that interventions targeting parental monitoring and family problem solving can be reliably evaluated through various measurement methods and that such interventions are of value in efforts to prevent and treat problem behavior in adolescence. These family processes are readily observable in videotaped family interaction tasks in both EA and AA families.

Comparative Immunogenicity of HIV-1 gp140 Vaccine Delivered by Parenteral, and Mucosal Routes in Female Volunteers; MUCOVAC2, A Randomized Two Centre Study.

BACKGROUND: Defining optimal routes for induction of mucosal immunity represents an important research priority for the HIV-1 vaccine field. In particular, it remains unclear whether mucosal routes of immunization can improve mucosal immune responses. METHODS: In this randomized two center phase I clinical trial we evaluated the systemic and mucosal immune response to a candidate HIV-1 Clade C CN54gp140 envelope glycoprotein vaccine administered by intramuscular (IM), intranasal (IN) and intravaginal (IVAG) routes of administration in HIV negative female volunteers. IM immunizations were co-administered with Glucopyranosyl Lipid Adjuvant (GLA), IN immunizations with 0.5% chitosan and IVAG immunizations were administered in an aqueous gel. RESULTS: Three IM immunizations of CN54 gp140 at either 20 or 100 µg elicited significantly greater systemic and mucosal antibodies than either IN or IVAG immunizations. Following additional intramuscular boosting we observed an anamnestic antibody response in nasally primed subjects. Modest neutralizing responses were detected against closely matched tier 1 clade C virus in the IM groups. Interestingly, the strongest CD4 T-cell responses were detected after IN and not IM immunization. CONCLUSIONS: These data show that parenteral immunization elicits systemic and mucosal antibodies in women. Interestingly IN immunization was an effective prime for IM boost, while IVAG administration had no detectable impact on systemic or mucosal responses despite IM priming. CLINICAL TRIALS REGISTRATION: EudraCT 2010-019103-27 and the UK Clinical Research Network (UKCRN) Number 11679.

MABGEL 1: first phase 1 trial of the anti-HIV-1 monoclonal antibodies 2F5, 4E10 and 2G12 as a vaginal microbicide.

BACKGROUND: Monoclonal antibodies (mAbs) which potently neutralize a broad range of HIV isolates are potential microbicide candidates. To date, topical application of mAbs in humans and their stability in vaginal secretions has not been studied. OBJECTIVES: To assess the pharmacokinetics and safety of the mAbs 2F5, 4E10 and 2G12 when applied vaginally in women. DESIGN: A randomized, double-blind, placebo-controlled phase 1 trial. METHODS: Twenty-eight healthy, sexually abstinent women administered 2.5 g of gel daily for 12 days containing either 10 or 20 mg/g of each mAb (MABGEL) or placebo. Main clinical evaluations and sampling occurred at baseline, 1, 8, and 24 hours post-1st dose and 12 and 36 hours post-12th dose. RESULTS: After adjustment for dilution factors, median levels of 2F5, 4E10 and 2G12 in vaginal secretions at 1 hour post high-dose MABGEL were 7.74, 5.28 and 7.48 mg/ml respectively. Levels of 2F5 and 4E10 declined exponentially thereafter with similar estimated half-lives (4.6 and 4.3 hours). In contrast, 2G12 levels declined more rapidly in the first 8 hours, with an estimated half-life of 1.4 hours during this period. There was no evidence of systemic absorption. There were no significant differences in local or systemic adverse event rates or vaginal flora changes (by qPCR) between active and placebo gel arms. Whilst at least 1 adverse event was recorded in 96% of participants, 95% were mild and none were serious. CONCLUSIONS: Vaginal application of 50 mg of each mAb daily was safe over a 12 day period. Median mAb concentrations detected at 8 hours post dose were potentially sufficient to block HIV transmission.2G12 exhibited more rapid elimination from the human vagina than 4E10 and 2F5, likely due to poor stability of 2G12 in acidic human vaginal secretions. Further research is needed to develop mAb-based vaginal microbicides and delivery systems. TRIAL REGISTRATION: ISRCTN 64808733 UK CRN Portfolio 6470.