The impact of a web-based prognostic calculator on prognostic confidence in outpatient palliative care.

PURPOSE: Clinicians are often uncertain about their prognostic estimates, which may impede prognostic communication and clinical decision-making. We assessed the impact of a web-based prognostic calculator on physicians' prognostic confidence. METHODS: In this prospective study, palliative care physicians estimated the prognosis of patients with advanced cancer in an outpatient clinic using the temporal, surprise, and probabilistic approaches for 6 m, 3 m, 2 m, 1 m, 2 w, 1 w, and 3 d. They then reviewed information from www.predictsurvival.com , which calculated survival estimates from seven validated prognostic scores, including the Palliative Prognostic Score, Palliative Prognostic Index, and Palliative Performance Status, and again provided their prognostic estimates after calculator use. The primary outcome was prognostic confidence in temporal CPS (0-10 numeric rating scale, 0 = not confident, 10 = most confident). RESULTS: Twenty palliative care physicians estimated prognoses for 217 patients. The mean (standard deviation) prognostic confidence significantly increased from 5.59 (1.68) before to 6.94 (1.39) after calculator use (p < 0.001). A significantly greater proportion of physicians reported feeling confident enough in their prognosis to share it with patients (44% vs. 74%, p < 0.001) and formulate care recommendations (80% vs. 94%, p < 0.001) after calculator use. Prognostic accuracy did not differ significantly before or after calculator use, ranging from 55-100%, 29-98%, and 48-100% for the temporal, surprise, and probabilistic approaches, respectively. CONCLUSION: This web-based prognostic calculator was associated with increased prognostic confidence and willingness to discuss prognosis. Further research is needed to examine how prognostic tools may augment prognostic discussions and clinical decision-making.

Routinized Syphilis Screening Among Men Living With Human Immunodeficiency Virus: A Stepped Wedge Cluster Randomized Controlled Trial.

BACKGROUND: We implemented an opt-out clinic-based intervention pairing syphilis tests with routine human immunodeficiency virus (HIV) viral load testing. The primary objective was to determine the degree to which this intervention increased the detection of early syphilis. METHODS: The Enhanced Syphilis Screening Among HIV-Positive Men (ESSAHM) Trial was a stepped wedge cluster-randomized controlled trial involving 4 urban HIV clinics in Ontario, Canada, from 2015 to 2017. The population was HIV-positive adult males. The intervention was standing orders for syphilis serological testing with viral loads, and control was usual practice. We obtained test results via linkage with the centralized provincial laboratory and defined cases using a standardized clinical worksheet and medical record review. We employed a generalized linear mixed model with a logit link to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of the intervention. RESULTS: A total of 3895 men were followed over 7471 person-years. The mean number of syphilis tests increased from 0.53 to 2.02 tests per person per year. There were 217 new diagnoses of syphilis (control, 81; intervention, 136), for which 147 (68%) were cases of early syphilis (control, 61 [75%]; intervention, 86 [63%]). The annualized proportion with newly detected early syphilis increased from 0.009 to 0.032 with implementation of the intervention; the corresponding time-adjusted OR was 1.25 (95% CI, .71-2.20). CONCLUSIONS: The implementation of standing orders for syphilis testing with HIV viral loads was feasible and increased testing, yet produced less-than-expected increases in case detection compared to past uncontrolled pre-post trials. CLINICAL TRIALS REGISTRATION: NCT02019043.

Patient perspectives on the implementation of routinised syphilis screening with HIV viral load testing: Qualitative process evaluation of the Enhanced Syphilis Screening Among HIV-positive Men trial.

BACKGROUND: Syphilis infections have been on the rise, affecting men living with HIV in urban centres disproportionately. Since individuals in HIV care undergo routine blood testing, HIV clinics provide practical opportunities to conduct regular and frequent syphilis testing. Following the implementation of a routine syphilis testing intervention in HIV outpatient clinics, we conducted a qualitative process evaluation of patient experiences to measure patient acceptability, barriers to implementation, and facilitators of successful uptake. METHODS: Upon completion of the trial, which took place at four HIV outpatient clinics in Toronto and Ottawa, Canada, we recruited male patients attending these clinics from November 2017 to April 2018. Interviews were conducted on-site and were audio-recorded and transcribed verbatim. All participants provided written informed consent. Interview data were analyzed using grounded theory, assessing qualitative modulators of effective uptake of routinised syphilis testing. RESULTS: A total of 21 male patients were interviewed. Overall, interviewees found the clinical intervention acceptable, endorsing the practice of routinising syphilis testing alongside regular viral load bloodwork. Some men preferred, based on their self-assessment of syphilis risk, to opt out of testing; we considered this as a potential barrier to uptake of population-wide routinised syphilis testing. Interviewees also identified multiple facilitators of successful uptake, including the de-stigmatising of STI testing as a consequence of the universal nature of routinised testing. Participants recommended a routinised syphilis screening intervention to give patients peace of mind surrounding their sexual health. Participants identified HIV care clinics as comfortable and efficient locations to offer testing. CONCLUSIONS: Overall, most men were in support of implementing routinised syphilis testing as part of standard HIV care. From the patient perspective, HIV care clinics are convenient places to be tested for syphilis, and the routine approach was viewed to have a de-stigmatisng effect on syphilis testing. TRIAL REGISTRATION: ClinicalTrials.gov NCT02019043; registered December 23, 2013.

HIV Risk and Protective Factors in the Context of Alcohol and Substance Use During Pride.

This investigation sought to identify HIV-risk and -protective factors among men-who-have-sex-with-men (MSM) who engaged in anal sex following alcohol or substance use during an international Pride Festival. MSM attending World Pride were surveyed regarding (1) alcohol, substance use, and sex during the past 24 h; and (2) HIV-risk and -protective factors. Valid data were provided by 1123 MSM. Anal sex was reported by 195 MSM, among whom the majority (n = 105) consumed alcohol or substances prior to sex. Among MSM aware of their HIV status who consumed alcohol or substances prior to sex (n = 99), those who engaged in serodiscordant condomless anal sex (n = 22) were more likely to be HIV+ (AOR = 10.14, 95% CI 1.48-69.35); report multiple sex partners (AOR = 9.05, 95% CI 1.70-48.12); and possess lower condom efficacy (AOR = 0.47, 95% CI 0.23-0.93) and social support (AOR = 0.08, 95% CI 0.01-0.46). Bolstering condom negotiation skills and social support could potentially reduce HIV acquisition/transmission-risk behavior, even when under the influence of alcohol or substances.

High HIV risk and syndemic burden regardless of referral source among MSM screening for a PrEP demonstration project in Toronto, Canada.

BACKGROUND: To maximize public health impact and cost-effectiveness, HIV pre-exposure prophylaxis (PrEP) must reach individuals at high HIV risk. Referrals for PrEP can be self- or provider-initiated, but there are several challenges to both. We assessed whether HIV risk differed by referral source among gay, bisexual and other men who have sex (gbMSM) screening for an HIV PrEP demonstration project. METHODS: PREPARATORY-5 was an open-label PrEP demonstration project enrolling gbMSM at high risk of HIV acquisition in Toronto, Canada. Study eligibility criteria related to high risk was defined as scoring ≥10 on the HIV Incidence Risk Index for MSM (HIRI-MSM) and engaging in at least 1 act of condomless receptive anal sex within the past 6 months. Recruitment was promoted through self-referrals (ads in a sexual networking app and gay newspaper/website) and provider-referrals (10 community-based organizations, CBOs). HIV risk score (HIRI-MSM) and syndemic health burden were measured among gbMSM screened for study participation and compared according to referral source. RESULTS: Between October 16 and December 30, 2014, online ads generated 1518 click-throughs and CBOs referred 115 individuals. Overall, 165 men inquired about the trial, of which 86 underwent screening. The majority of screened men were self-referrals (60.5%), scored ≥10 on HIRI-MSM (96.5%), and reported condomless receptive anal sex in the past 6 months (74.2%). Self- and provider-referrals had similarly high HIV risk profiles, with a median (IQR) HIRI-MSM score of 26.0 (19.0-32.5) and 28.5 (20.0-34.0) (p = 0.3), and 75.0% and 73.5% reporting condomless receptive anal sex (p = 0.9), respectively. The overall burden of syndemic health problems was also high, with approximately one-third overall identified as having depressive symptoms (39.5%), alcohol-related problems (39.5%), multiple drug use (31.4%), or sexual compulsivity (31.4%). There were no significant differences in syndemic health problems by referral source. CONCLUSIONS: HIV risk and syndemic burden were high among gbMSM presenting for this PrEP demonstration project regardless of referral source. Self-referral may be a useful and efficient strategy for identifying individuals suitable for PrEP use. Online strategies and CBOs working in gay men's health may play important roles in connecting individuals at high HIV risk to PrEP services. TRIAL REGISTRATION: ClinicalTrials.gov NCT02149888 . Registered May 12th 2014.

Decentralizing the delivery of HIV pre-exposure prophylaxis (PrEP) through family physicians and sexual health clinic nurses: a dissemination and implementation study protocol.

BACKGROUND: Gay, bisexual and other men who have sex with men (gbMSM) in Canada continue to experience high rates of incident HIV. Pre-exposure prophylaxis (PrEP, the regular use of anti-HIV medication) reduces HIV acquisition and could reduce incidence. However, there are too few physicians with expertise in HIV care to meet the projected demand for PrEP. To meet demand and achieve greater public health impact, PrEP delivery could be 'decentralized' by incorporating it into front-line prevention services provided by family physicians (FPs) and sexual health clinic nurses. METHODS: This PrEP decentralization project will use two strategies. The first is an innovative knowledge dissemination approach called 'Patient-Initiated CME' (PICME), which aims to empower individuals to connect their family doctors with online, evidence-based, continuing medical education (CME) on PrEP. After learning about the project through community agencies or social/sexual networking applications, gbMSM interested in PrEP will use a uniquely coded card to access an online information module that includes coaching on how to discuss their HIV risk with their FP. They can provide their physician a link to the accredited CME module using the same card. The second strategy involves a pilot implementation program, in which gbMSM who do not have a FP may bring the card to designated sexual health clinics where trained nurses can deliver PrEP under a medical directive. These approaches will be evaluated through quantitative and qualitative methods, including: questionnaires administered to patients and physicians at baseline and at six months; focus groups with patients, FPs, and sexual health clinic staff; and review of sexual health clinic charts. The primary objective is to quantify the uptake of PrEP achieved using each decentralization strategy. Secondary objectives include a) characterizing barriers and facilitators to PrEP uptake for each strategy, b) assessing fidelity to core components of PrEP delivery within each strategy, c) measuring patient-reported outcomes including satisfaction with clinician-patient relationships, and d) conducting a preliminary costing analysis. DISCUSSION: This study will assess the feasibility of a novel strategy for disseminating knowledge about evidence-based clinical interventions, and inform future strategies for scale-up of an underutilized HIV prevention tool.

Discovery of thienoimidazole-based HCV NS5A inhibitors. Part 2: non-symmetric inhibitors with potent activity against genotype 1a and 1b.

The discovery of non-symmetric thienoimidazole-containing HCV NS5A inhibitors is described. The inhibitors herein reported display high potencies against both genotype 1a and 1b. In this follow-up manuscript, we discuss the importance of the linker aromaticity to achieve high potency, particularly against genotype 1a.

Discovery of thienoimidazole-based HCV NS5A inhibitors. Part 1: C2-symmetric inhibitors with diyne and biphenyl linkers.

The discovery of C2-symmetric bis-thienoimidazoles HCV NS5A inhibitors is herein reported. Two straightforward approaches to access the requisite diyne and biphenyl linker moieties are described. This study revealed the paramount importance of the aromatic character of the linker to achieve high genotype 1a potency.

Synthesis and evaluation of NS5A inhibitors containing diverse heteroaromatic cores.

Inhibitors of the HCV NS5A nonstructural protein are showing promising clinical potential in the treatment of hepatitis C when used in combination with other direct-acting antiviral agents. Current NS5A clinical candidates such as daclatasvir, ledipasvir, and ombitasvir share a common pharmacophore that features a pair of (S)-methoxycarbonylvaline capped pyrrolidines linked to various cores by amides, imidazoles and/or benzimidazoles. In this Letter, we describe the evaluation of NS5A inhibitors which contain alternative heteroaromatic replacements for these amide mimetics. The SAR knowledge gleaned in the optimization of scaffolds containing benzoxazoles was parlayed toward the identification of potent NS5A inhibitors containing other heteroaromatic replacements such as indoles and imidazopyridines.

Benzimidazole-containing HCV NS5A inhibitors: effect of 4-substituted pyrrolidines in balancing genotype 1a and 1b potency.

The treatment of HCV with highly efficacious, well-tolerated, interferon-free regimens is a compelling clinical goal. Trials employing combinations of direct-acting antivirals that include NS5A inhibitors have shown significant promise in meeting this challenge. Herein, we describe our efforts to identify inhibitors of NS5A and report on the discovery of benzimidazole-containing analogs with subnanomolar potency against genotype 1a and 1b replicons. Our SAR exploration of 4-substituted pyrrolidines revealed that the subtle inclusion of a 4-methyl group could profoundly increase genotype 1a potency in multiple scaffold classes.

Resistance to AFN-1252 arises from missense mutations in Staphylococcus aureus enoyl-acyl carrier protein reductase (FabI).

AFN-1252 is a potent antibiotic against Staphylococcus aureus that targets the enoyl-acyl carrier protein reductase (FabI). A thorough screen for AFN-1252-resistant strains was undertaken to identify the spectrum of mechanisms for acquired resistance. A missense mutation in fabI predicted to encode FabI(M99T) was isolated 49 times, and a single isolate was predicted to encode FabI(Y147H). AFN-1252 only bound to the NADPH form of FabI, and the close interactions between the drug and Met-99 and Tyr-147 explained how the mutations would result in resistant enzymes. The clone expressing FabI(Y147H) had a pronounced growth defect that was rescued by exogenous fatty acid supplementation, and the purified protein had less than 5% of the enzymatic activity of FabI. FabI(Y147F) was also catalytically defective but retained its sensitivity to AFN-1252, illustrating the importance of the conserved Tyr-147 hydroxyl group in FabI function. The strains expressing FabI(M99T) exhibited normal growth, and the biochemical properties of the purified protein were indistinguishable from those of FabI. The AFN-1252 Ki(app) increased from 4 nm in FabI to 69 nm in FabI(M99T), accounting for the increased resistance of the corresponding mutant strain. The low activity of FabI(Y147H) precluded an accurate Ki measurement. The strain expressing FabI(Y147H) was also resistant to triclosan; however, the strain expressing FabI(M99T) was more susceptible. Strains with higher levels of AFN-1252 resistance were not obtained. The AFN-1252-resistant strains remained sensitive to submicromolar concentrations of AFN-1252, which blocked growth through inhibition of fatty acid biosynthesis at the FabI step.

Dr. Russell Davies (1914-1991): Pioneer of theatre recovery and of anaesthetics in Yugoslavia.

Dr. Russell Davies is a largely forgotten pioneer of both post-operative theatre recovery but also a key figure in the establishment of anaesthetics services in Yugoslavia in the late 1940s. Davies spent the majority of his career working as an anaesthetist at Queen Victoria Hospital, East Grinstead, Sussex, England, later being promoted to the head anaesthetist role. Davies set up one of the first recovery wards in the United Kingdom at Queen Victoria Hospital, the ward being named after him in 1989. Here he became a founding member of the Guinea Pig Club, alongside Dr. Archibald McIndoe. The Guinea Pig Club was founded in 1941 to support airmen in the Second World War undergoing plastic surgery at Queen Victoria Hospital. Davies was crucial to the pastoral care of the Club, providing clinical care and guiding members over access to pensions they would have previously been denied. Little is recognised of Davies's achievement of establishing anaesthetics services in Yugoslavia. Davies and his contributions have been largely overlooked. Davies should be considered one of the foremost British anaesthetists of the 20th century.

Consulting in the dark: Robert Hamilton (1749-1830) and the importance of 'tenderness' towards patients.

Robert Hamilton (1749-1830) was born in Coleraine, Ireland, attended medical school in Edinburgh, Scotland, served in the British army and practised in South-East England. In order to differentiate him from his contemporary and namesake, Hamilton is identified by having worked in Ipswich, Suffolk and Colchester, Essex. This submission considers Hamilton's biography, his 1787 book on the British regimental surgeon and his ideas therein about professionalism. Central to his concept of professionalism is 'tenderness', a notion that broadly equates to empathy. He notes that tenderness brings improvement in clinical outcome and he has the foresight to recognise nurses as key to such care. The authors explore the concept of 'consulting in the dark', i.e. without access to clinical investigations. This is exemplified by doctors of the eighteenth century and earlier. Today general practitioners must still be comfortable 'consulting in the dark', e.g. when attending a patient's home. Hamilton's biography offers a further example of 'consulting in the dark': In later life, he lost his vision but continued to practise successfully. Central to his gift of consulting 'in the dark' was likely to be 'tenderness' for his patients, expressed through language and gentle touch. Hamilton's entreaty for 'tenderness' contrasts with modern medical education where reliance upon clinical tests, technology and pharmacology risksblinding young doctors towards patients and their lives.

Discovery of TNG908: A Selective, Brain Penetrant, MTA-Cooperative PRMT5 Inhibitor That Is Synthetically Lethal with MTAP-Deleted Cancers.

It has been shown that PRMT5 inhibition by small molecules can selectively kill cancer cells with homozygous deletion of the MTAP gene if the inhibitors can leverage the consequence of MTAP deletion, namely, accumulation of the MTAP substrate MTA. Herein, we describe the discovery of TNG908, a potent inhibitor that binds the PRMT5·MTA complex, leading to 15-fold-selective killing of MTAP-deleted (MTAP-null) cells compared to MTAPintact (MTAP WT) cells. TNG908 shows selective antitumor activity when dosed orally in mouse xenograft models, and its physicochemical properties are amenable for crossing the blood-brain barrier (BBB), supporting clinical study for the treatment of both CNS and non-CNS tumors with MTAP loss.

Melaleuca alternifolia concentrate inhibits in vitro entry of influenza virus into host cells.

Influenza virus causes high morbidity among the infected population annually and occasionally the spread of pandemics. Melaleuca alternifolia Concentrate (MAC) is an essential oil derived from a native Australian tea tree. Our aim was to investigate whether MAC has any in vitro inhibitory effect on influenza virus infection and what mechanism does the MAC use to fight the virus infection. In this study, the antiviral activity of MAC was examined by its inhibition of cytopathic effects. In silico prediction was performed to evaluate the interaction between MAC and the viral haemagglutinin. We found that when the influenza virus was incubated with 0.010% MAC for one hour, no cytopathic effect on MDCK cells was found after the virus infection and no immunofluorescence signal was detected in the host cells. Electron microscopy showed that the virus treated with MAC retained its structural integrity. By computational simulations, we found that terpinen-4-ol, which is the major bioactive component of MAC, could combine with the membrane fusion site of haemagglutinin. Thus, we proved that MAC could prevent influenza virus from entering the host cells by disturbing the normal viral membrane fusion procedure.

Trevor Mann (1916-1996): Paediatrician responsible for the development of hospital services for children in Brighton, England.

Trevor Philip Mann (1916-1996) was the first consultant paediatrician at the Royal Alexandra Children's Hospital (RACH) in Brighton, since its foundation in 1881. Here, he was responsible for significant service developments, including establishing a department of paediatric surgery and the first neonatal unit in England outside of London. Mann grew up in South London, and aged 14 had a lengthy admission to hospital with tuberculosis. He studied medicine at St Mary's Hospital, London. During World War II he was a Royal Navy Surgeon-Lieutenant, aboard the Atlantic destroyer, HMS Georgetown, and with the Russian convoys, before completing paediatric training in London. Here, he was involved in treating paediatric tuberculous meningitis; clinical work that formed part of one of the earliest randomised controlled trials. In 1951 Mann moved to the RACH where he researched infantile infectious gastroenteritis and introduced (now commonplace) practices at the hospital, including barrier nursing. He lived in Rottingdean, Sussex, and enjoyed sailing, gardening and wood turning. Mann's impact on paediatric care in Brighton was recognised by the hospital, naming the Trevor Mann Baby Unit in his honour, upon his retirement in 1981. This article seeks to record his contributions and reconnect local clinicians with his memory.

William Attree (died 1846): Royal and army surgeon who underwent amputation of the leg at Brighton, England (1807).

William Attree (1780-1846) came from a prominent family in Brighton, England. He studied medicine at St Thomas' Hospital, London, and there was unwell for nearly 6 months with severe 'spasms' of the hand/arm/chest (1801-1802). Attree qualified Member of the Royal College of Surgeons in 1803 and served as dresser to Sir Astley Paston Cooper (1768-1841). In 1806 Attree is recorded as 'Surgeon and Apothecary' of Prince's street, Westminster. In 1806 Attree's wife died in childbirth and the following year he underwent emergency amputation of the foot in Brighton following a road traffic accident. Attree served as surgeon in the Royal Horse Artillery at Hastings, presumably in a regimental or garrison hospital. He went onto become surgeon to the Sussex County Hospital, Brighton, and Surgeon Extraordinary to two Kings: George IV and William IV. In 1843 Attree was appointed as one of the original 300 Fellows of the Royal College of Surgeons. He died in Sudbury, near Harrow. His son William Hooper Attree (1817-1875) was surgeon to Don Miguel de Braganza, the former King of Portugal. The medical literature appears to lack a history of nineteenth century doctors (especially military surgeons) with physical disability. Attree's biography goes a small way towards developing this field of enquiry.

"It's a win for the clinic, it's a win for the frontline, but, most importantly, it's a win for the client": Task Shifting HIV Prevention Services from Clinicians to Community Health Workers in Ontario, Canada.

Introduction: Despite strong evidence from low- and middle-income countries supporting the use of task shifting to provide quality, cost-effective HIV-related health services, this strategy has been adopted less widely in high-income countries such as Canada. Methods: In 2020, we conducted semi-structured interviews with 19 clinicians (e.g., psychologists, nurses, physicians) and 14 community health workers (CHWs) in Ontario to examine their perspectives on the prospect of shifting HIV/STBBI testing services and PrEP in Ontario, Canada. Interviews were transcribed and then analyzed using content analysis. A community consultation with key stakeholders was also performed to assess the validity of the findings. Results: There was substantial agreement between clinicians and CHWs with respect to shifting specific tasks related to HIV/STBBI testing and PrEP. In particular, most participants felt that rapid HIV testing could and should be provided by CHWs and that ASOs could be ideal sites for clients to obtain and use self-testing kits for STBBIs. Most respondents agreed that CHWs have the skills and expertise required to perform most non-clinical services related to PrEP (e.g., pre-counselling, follow-up, case management). The co-location of clinicians and CHWs could help support the development of task shifting initiatives. Conclusion: Findings indicate that there is enthusiasm among both clinicians and CHWs with respect to shifting HIV prevention services. Creative solutions are required to have a meaningful impact on HIV incidence in this population. Policy Implications: With adequate training and supervision, non-regulated CHWs should be allowed to provide certain HIV prevention services such as rapid HIV testing. A provincial, publicly funded program for PrEP is recommended.

Ubiquitinated PCNA Drives USP1 Synthetic Lethality in Cancer.

CRISPR Cas9-based screening is a powerful approach for identifying and characterizing novel drug targets. Here, we elucidate the synthetic lethal mechanism of deubiquitinating enzyme USP1 in cancers with underlying DNA damage vulnerabilities, specifically BRCA1/2 mutant tumors and a subset of BRCA1/2 wild-type (WT) tumors. In sensitive cells, pharmacologic inhibition of USP1 leads to decreased DNA synthesis concomitant with S-phase-specific DNA damage. Genome-wide CRISPR-Cas9 screens identify RAD18 and UBE2K, which promote PCNA mono- and polyubiquitination respectively, as mediators of USP1 dependency. The accumulation of mono- and polyubiquitinated PCNA following USP1 inhibition is associated with reduced PCNA protein levels. Ectopic expression of WT or ubiquitin-dead K164R PCNA reverses USP1 inhibitor sensitivity. Our results show, for the first time, that USP1 dependency hinges on the aberrant processing of mono- and polyubiquitinated PCNA. Moreover, this mechanism of USP1 dependency extends beyond BRCA1/2 mutant tumors to selected BRCA1/2 WT cancer cell lines enriched in ovarian and lung lineages. We further show PARP and USP1 inhibition are strongly synergistic in BRCA1/2 mutant tumors. We postulate USP1 dependency unveils a previously uncharacterized vulnerability linked to posttranslational modifications of PCNA. Taken together, USP1 inhibition may represent a novel therapeutic strategy for BRCA1/2 mutant tumors and a subset of BRCA1/2 WT tumors.