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.

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.

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.

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.

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.

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.

'Disciples of Aesclepius': Glimpses into lives of the 'Gentlemen of the Faculty' of medicine in Brighton, England 1800-1809.

Here we present newspaper accounts from the Sussex Advertiser to consider hitherto largely unknown Brighton doctors active between 1800 and 1809. This body of physicians, surgeons and apothecaries comprised Brighton's 'Gentlemen of the [medical] Faculty', whom the newspaper also dubbed the 'Disciples of Aesclepius'. Members are considered under three broad categories. First, are Brighton-based clinicians (Mr Barratt, Mr Bond, Charles Bankhead, Thomas Guy, John Hall, John Newton, Benjamin Scutt and Sir Matthew Tierney). Second are London clinicians, probably in attendance to the Prince of Wales (John Hunter and Thomas Keate), More widely, two dentists (Dr Durlacher and Mr Bew) and two Royal Navy surgeons (Robert Chambers and Thomas Thong) also recorded at Brighton are considered. Other aspects of medical life are described: recruiting an apprentice, anatomy training at Joshua Brooke's London museum, midwifery, a description of a surgeon's bag and the last reference to the Royal Sussex Jennerian Society (which disappears from the newspaper record in 1807). Clinical cases described include: resuscitation from near-drowning, post-mortem examinations, death from the 'gravel and stone' and accounts of suicide. The primary sources presented in this paper offer rare glimpses into medical life in Brighton at the very start of the nineteenth century.

Robert Henderson: Scottish doctor who was appointed Physician to the Forces (1795) and practised at Brighton, England.

Robert Henderson was a Scottish physician who qualified Doctor of Medicine at Aberdeen in 1786. By 1792, Henderson was working in Brighton on the south coast of England. He was admitted Licentiate of the College of Physicians of London in 1793. At Brighton he probably worked as a parish doctor. In 1795 Henderson was appointed Physician to the Forces and probably served as a garrison doctor. In Brighton, he is noted as an advocate of chalybeate water therapy (i.e. mineral spring water containing iron salts). Henderson undertook basic experiments into the chemistry of mineral water and a few, very brief, clinical observations may be his. In Henderson's time, the chalybeate in question was part of the 'Wick estate' to the North West of Brighton. Today the site of the spring is located within St Ann's Well Gardens, Hove and this article briefly considers its history. Circumstances link Henderson to Sir Lucas Pepys MD (1742-1830), physician-general to the army and closely associated with both the College of Physicians and the town of Brighton. Henderson died in Brighton on the 3rd April 1808. Henderson's daughter Sophia Janet married Captain William John Thompson Hood who served at Trafalgar aged eleven.

Leslie Wallace Lauste MBE (1908-2001): Brighton surgeon and prisoner of war in occupied Europe.

Leslie Wallace Lauste (1908-2001) was an English surgeon of French ancestry who practised in Brighton. This article used his memoirs and interviews to describe his life during the Second World War. In 1940, after declining evacuation by the Royal Navy, he was captured at Boulogne- Sur-Mer. Lauste went on to work in the following hospitals, of which most were attached to prisoner of war (POW) camps: Dannes-Camiers (France), Lille (France), Enghien (Belgium), Malines (Belgium), Dieberg (Germany), Klein-Zimmern (Germany), Stadtroda (Germany), Treysa (Germany), Kloster Haina (Germany), Lamsdorf (Poland), and Moosburg (Germany). Lauste's memoirs indicate that most surgical work was routine rather than trauma-related. He gained considerable freedoms in camp and attended external hospitals to give a surgical opinion. Lauste witnessed the consequences of allied bombing raids on German cities and considered these a "genocide." Lauste's life offers insight into the Nazi mistreatment of Russian prisoners, management of a typhus outbreak, camp liberation, and extraordinary journeys within occupied Europe. His memoirs provide new insight into the life of a British POW surgeon and reveals personal courage, kindness to others, and passion for medicine. Lauste never married. He died in Brighton in 2001.

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.

Developing a combat-relevant translatable large animal model of heterotopic ossification.

Heterotopic ossification (HO) refers to ectopic bone formation, typically in residual limbs following trauma and injury. A review of injuries from Operation Iraqi Freedom (OIF) and Operation Enduring Freedom (OEF) indicated that approximately 70% of war wounds involved the musculoskeletal system, largely in part from the use of improvised explosive devices (IED) and rocket-propelled grenades (RPG). HO is reported to occur in approximately 63%-65% of wounded warriors from OIF and OEF. Symptomatic HO may delay rehabilitation regimens since it often requires modifications to prosthetic limb componentry and socket size. There is limited evidence indicating a mechanism for preventing HO. This may be due to inadequate models, which do not produce HO bone structure that is morphologically similar to HO samples obtained from wounded warfighters injured in theatre. We hypothesized that using a high-power blast of air (shockwave) and simulated battlefield trauma (i.e. bone damage, tourniquet, bacteria, negative pressure wound therapy) in a large animal model, HO would form and have similar morphology to ectopic bone observed in clinical samples. Initial radiographic and micro-computed tomography (CT) data demonstrated ectopic bone growth in sheep 24 weeks post-procedure. Advanced histological and backscatter electron (BSE) analyses showed that 5 out of 8 (63%) sheep produced HO with similar morphology to clinical samples. We conclude that not all ectopic bone observed by radiograph or micro-CT in animal models is HO. Advanced histological and BSE analyses may improve confirmation of HO presence and morphology, which we demonstrated can be produced in a large animal model.

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.

Decentralizing PrEP delivery: Implementation and dissemination strategies to increase PrEP uptake among MSM in Toronto, Canada.

Pre-exposure prophylaxis (PrEP) is traditionally prescribed by HIV specialist physicians. Given finite specialist resources, there is a need to scale up PrEP delivery by decentralizing services via other healthcare professionals. We aimed to assess the feasibility of delivering PrEP to men who have sex with men (MSM) through primary care physicians and sexual health clinic nurses. We piloted a multi-component, implementation and dissemination research program to increase provision of PrEP through primary care physicians and sexual health clinic nurses in Toronto, Canada. Community-based organizations (CBOs) provided prospective participants with information cards that contained links to an online module on engaging providers in a conversation about PrEP. In our patient-initiated continuing medical education (PICME) strategy, participants saw their family doctors and gave them the card, which also contained a link to a Continuing Medical Education module. In the nurse-led strategy, participants visited one of two participating clinics to obtain PrEP. We administered an optional online questionnaire to patients and providers at baseline and six months. CBOs distributed 3043 cards. At least 339 men accessed the online module and 196 completed baseline questionnaires. Most (55%) intended to visit nurses while 21% intended to consult their physicians. Among 45 men completing follow-up questionnaires at 6 months, 31% reported bringing cards to their physicians and obtaining PrEP through them; sexual health clinics delivered PrEP to 244 patients. Participants who went through the PICME approach reported no changes in relationships with their providers. Nurses showed fidelity to PrEP prescribing guidelines. Nurse-led PrEP and patient-initiated continuing medical education (PICME) for primary care physicians are feasible strategies to increase PrEP uptake. Nurse-led PrEP delivery was preferred by most patients.

Assessing the safety of an epiphyseal plate biopsy in a translational lamb model.

The literature demonstrates that obtaining a biopsy of the physis may be beneficial for diagnostic purposes. A small biopsy of the epiphyseal plate may allow for earlier detection of certain conditions and be used to monitor the healing of diseased and/or damaged physes. However, due to the fear of a growth arrest in a growing child, biopsies are not currently performed. In this study, we investigated the effects of a biopsy of the epiphyseal plate in 3-month-old lambs. A total of 4.2 mm biopsy samples were captured in the proximal tibiae and distal femora physes. The lambs were monitored 12- and 24-week post-biopsy. Computed tomography (CT) and micro-CT scans were obtained to determine if any angular deformities occurred, while scanning electron microscope (SEM) and histological analysis were utilized to assess the bone response due to the biopsy. The contralateral limbs served as unaltered controls for direct comparison within each lamb. The data demonstrated no signs of angular deformities following a 4.2 mm biopsy of the physis. Bone growth/elongation was confirmed by CT, SEM, and fluorochrome analyses and indicated that the lambs were in fact immature and still growing at the time of the biopsy. Clinical Significance: This investigation demonstrated that a small biopsy of the epiphyseal plate can be obtained safely without the cause of growth arrest and angular deformities. The ability to precisely diagnose, treat, and/or monitor at-risk children at an earlier timepoint by way of a biopsy sample could be an important advancement in regard to researching diseased and/or damaged physes.

GPS: A Randomized Controlled Trial of Sexual Health Counseling for Gay and Bisexual Men Living With HIV.

Gay, bisexual, and other men who have sex with men (GBM) continue to have high rates of HIV and sexually transmitted infections, including syphilis. GBM have therefore been identified by public health agencies as a high-priority population to reach with prevention initiatives. Despite the importance of mental health in preventing HIV and related infections, there is a shortage of credentialed mental health professionals to deliver behavioral Counseling interventions. The current study evaluated the efficacy of GPS, a community-based and peer-delivered sexual health promotion motivational interviewing-based intervention for HIV-positive GBM who engaged in condomless anal sex (CAS) in the past 2 months. GPS prevention counseling demonstrated a 43% relative reduction at 3-month follow-up in CAS with serodiscordant partners and significant reductions in sexual compulsivity. The study demonstrated that community-based counselors can administer an efficacious motivational interviewing program, and suggests a continued benefit of counseling methods to promote the sexual health of higher risk populations.

Dealing with prognostic uncertainty: the role of prognostic models and websites for patients with advanced cancer.

PURPOSE OF REVIEW: To provide an updated overview of prognostic models in advanced cancer and highlight the role of prognostic calculators. RECENT FINDINGS: In the advanced cancer setting, many important healthcare decisions are driven by a patient's prognosis. However, there is much uncertainty in formulating prognosis, particularly in the era of novel cancer therapeutics. Multiple prognostic models have been validated for patients seen by palliative care and have a life expectancy of a few months or less, such as the Palliative Performance Scale, Palliative Prognostic Score, Palliative Prognostic Index, Objective Prognostic Score, and Prognosis in Palliative Care Study Predictor. However, these models are seldom used in clinical practice because of challenges related to limited accuracy when applied individually and difficulties with model selection, computation, and interpretation. Online prognostic calculators emerge as tools to facilitate knowledge translation by overcoming the above challenges. For example, www.predictsurvival.com provides the output for seven prognostic indexes simultaneously based on 11 variables. SUMMARY: Prognostic models and prognostic websites are currently available to augment prognostication in the advanced cancer setting. Further studies are needed to examine their impact on prognostic accuracy, confidence, and clinical outcomes.

Acceptability and tolerability of and adherence to HIV preexposure prophylaxis among Toronto gay and bisexual men: a pilot study.

BACKGROUND: Preexposure prophylaxis is efficacious at preventing HIV infection, but concerns persist about adherence and sexually transmitted infections (STIs). We assessed preexposure prophylaxis acceptability, adherence and clinical outcomes in a pilot demonstration project. METHODS: HIV-uninfected adult gay and bisexual men who scored 10 or higher on a validated HIV risk score (HIV Incidence Risk Index for MSM) and reported condomless receptive anal sex were sequentially enrolled into a 1-year open-label single-arm pilot study of daily oral therapy with tenofovir disoproxil fumarate/emtricitabine in Toronto. The primary outcome was acceptability of preexposure prophylaxis. Secondary outcomes were preexposure prophylaxis adherence (4-d recall, pill count and dried blood spot analysis), HIV seroconversion, STIs and adverse events. RESULTS: Of the 86 men screened, 52 were enrolled. Participants were mostly young (median age 33 yr [interquartile range (IQR) 28-37 yr) white (38 [73%]) gay (49 [94%]) men. Preexposure prophylaxis acceptability was high: all participants reported their experience as "good" or "very good." The median adherence rate was high, at 100% (IQR 95%-100%) by self-report and 96.9% (IQR 93.4%-98.4%) by pill count. Dried blood spot analysis suggested that doses were taken 4-7 days/week at 88.7% (173/195) of month 3-12 visits. No cases of HIV seroconversion occurred, but 25 participants (48%) experienced at least 1 bacterial STI, with incidence rates per 100 person-years of 32.8, 32.8, 8.2 and 8.2 for chlamydia, gonorrhea, syphilis and lymphogranuloma venereum, respectively. No adverse events led to discontinuation of prophylaxis, but the estimated glomerular filtration rate declined by 0.22 mL/min per month. INTERPRETATION: Preexposure prophylaxis was associated with high adherence and acceptability and no HIV infections in this study. Frequent STIs and clinically unapparent toxic renal effects reinforce the need for ongoing vigilance. TRIAL REGISTRATION: ClinicalTrials. gov, no. NCT02149888.

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.

Myelopathy Improvement Following Removal of Cervical Sublaminar Wiring.

Posterior cervical wiring has been used by spine surgeons in fixation procedures for patients with spinal instability. It is historically considered an effective method of treating cervical instability with a low risk of complications leading to neurological deterioration. We experienced a case of delayed neurological decline associated with myelopathy, lower extremity spasticity, and associated syringomyelia secondary to instrumentation failure and resultant sublaminar wire protrusion into the cervical spinal cord. In the present case, the construct was removed and the patient underwent a durotomy repair and a posterior fusion of cervical levels 1 and 2 via screw placement under image guidance with a subsequent functional improvement back to baseline. We report this case and review the literature on the complications associated with cervical wire fusion and the methods of minimizing these risks.