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The book offers a fresh and distinctive account of the transformation of provincial English medicine from the late eighteenth to the mid nineteenth centuries. Written by one of the leading scholars in the field it demonstrates how the roots of modern medicine can be located in the cultural, political and ideological upheavals of the age of reform.

Dabrafenib is an inhibitor of BRAF kinase that is selective for mutant BRAF. We aimed to assess its safety and tolerability and to establish a recommended phase 2 dose in patients with incurable solid tumours, especially those with melanoma and untreated, asymptomatic brain metastases. We undertook a phase 1 trial between May 27, 2009, and March 20, 2012, at eight study centres in Australia and the USA. Eligible patients had incurable solid tumours, were 18 years or older, and had adequate organ function. BRAF mutations were mandatory for inclusion later in the study because of an absence of activity in patients with wild-type BRAF. We used an accelerated dose titration method, with the first dose cohort receiving 12 mg dabrafenib daily in a 21-day cycle. Once doses had been established, we expanded the cohorts to include up to 20 patients. On the basis of initial data, we chose a recommended phase 2 dose. Efficacy at the recommended phase 2 dose was studied in patients with BRAF-mutant tumours, including those with non-Val600Glu mutations, in three cohorts: metastatic melanoma, melanoma with untreated brain metastases, and non-melanoma solid tumours. This study is registered with ClinicalTrials.gov, number NCT00880321. We enrolled 184 patients, of whom 156 had metastatic melanoma. The most common treatment-related adverse events of grade 2 or worse were cutaneous squamous-cell carcinoma (20 patients, 11%), fatigue (14, 8%), and pyrexia (11, 6%). Dose reductions were necessary in 13 (7%) patients. No deaths or discontinuations resulted from adverse events, and 140 (76%) patients had no treatment-related adverse events worse than grade 2. Doses were increased to 300 mg twice daily, with no maximum tolerated dose recorded. On the basis of safety, pharmacokinetic, and response data, we selected a recommended phase 2 dose of 150 mg twice daily. At the recommended phase 2 dose in 36 patients with Val600 BRAF-mutant melanoma, responses were reported in 25 (69%, 95% CI 51·9–83·7) and confirmed responses in 18 (50%, 32·9–67·1). 21 (78%, 57·7–91·4) of 27 patients with Val600Glu BRAF-mutant melanoma responded and 15 (56%, 35·3–74·5) had a confirmed response. In Val600 BRAF-mutant melanoma, responses were durable, with 17 patients (47%) on treatment for more than 6 months. Responses were recorded in patients with non-Val600Glu BRAF mutations. In patients with melanoma and untreated brain metastases, nine of ten patients had reductions in size of brain lesions. In 28 patients with BRAF-mutant non-melanoma solid tumours, apparent antitumour activity was noted in a gastrointestinal stromal tumour, papillary thyroid cancers, non-small-cell lung cancer, ovarian cancer, and colorectal cancer. Dabrafenib is safe in patients with solid tumours, and an active inhibitor of Val600-mutant BRAF with responses noted in patients with melanoma, brain metastases, and other solid tumours. GlaxoSmithKline.

The orally available BRAF kinase inhibitor vemurafenib, compared with dacarbazine, shows improved response rates, progression-free survival (PFS), and overall survival in patients with metastatic melanoma that has a BRAFV600 mutation. We assessed vemurafenib in patients with advanced metastatic melanoma with BRAFV600 mutations who had few treatment options. In an open-label, multicentre study, patients with untreated or previously treated melanoma and a BRAFV600 mutation received oral vemurafenib 960 mg twice a day. The primary endpoint was safety. All analyses were done on the safety population, which included all patients who received at least one dose of vemurafenib. This report is the third interim analysis of this study. This study is registered with ClinicalTrials.gov, number NCT01307397. Between March 1, 2011, and Jan 31, 2013, 3226 patients were enrolled in 44 countries. 3222 patients received at least one dose of vemurafenib (safety population). At data cutoff, 868 (27%) patients were on study treatment and 2354 (73%) had withdrawn, mainly because of disease progression. Common adverse events of all grades included rash (1592 [49%]), arthralgia (1259 [39%]), fatigue (1093 [34%]), photosensitivity reaction (994 [31%]), alopecia (826 [26%]), and nausea (628 [19%]). 1480 (46%) patients reported grade 3 or 4 adverse events, including cutaneous squamous cell carcinoma (389 [12%]), rash (155 [5%]), liver function abnormalities (165 [5%]), arthralgia (106 [3%]), and fatigue (93 [3%]). Grade 3 and 4 adverse events were reported more frequently in patients aged 75 years and older (n=257; 152 [59%, 95% CI 53–65] and ten [4%, 2–7], respectively) than in those younger than 75 years (n=2965; 1286 [43%, 42–45] and 82 [3%, 2–3], respectively). Vemurafenib safety in this diverse population of patients with BRAFV600 mutated metastatic melanoma, who are more representative of routine clinical practice, was consistent with the safety profile shown in the pivotal trials of this drug. F Hoffmann-La Roche.

Obesity is a complex chronic disease in which abnormal or excess body fat (adiposity) impairs health, increases the risk of long-term medical complications and reduces lifespan. Epidemiologic studies define obesity using the body mass index (BMI), which can stratify obesity-related health risks at the population level. Obesity is operationally defined as a BMI exceeding 30 kg/m2 and is subclassified into class 1 (30-34.9), class 2 (35-39.9) and class 3 (≥ 40). At the population level, health complications from excess body fat increase as BMI increases. At the individual level, complications occur because of excess adiposity, location and distribution of adiposity and many other factors, including environmental, genetic, biologic and socioeconomic factors. Here, Wharton et al discuss the Canadian clinical practice guideline for assessing and treating people living with obesity.

First discovered in 1999 in Malaysia, Nipah virus (NiV) causes yearly outbreaks throughout south and southeast Asia with associated mortality rates of 40–75%. Due to the structural and sequence similarities between the NiV and Hendra virus (HeV) attachment G glycoproteins, and the extensive extant evidence of the ability of a recombinant soluble glycoprotein G (HeV-sG) to provide heterologous cross-protective immunity when used as vaccine (HeV-sG-V), this study aimed to evaluate HeV-sG-V for safety, tolerability, and immunogenicity against NiV. We conducted a phase 1, single-centre, randomised, observer-blind, placebo-controlled study. Eligible participants were aged 18–49 years, healthy, and not pregnant; participants were ineligible if they were immunocompromised, had received blood products within 6 months of enrolment, had potential exposure to NiV or HeV, or had known allergies to components of the vaccine. Participants were randomly assigned in a 5:1 ratio to receive either one or two doses of the vaccine candidate (at 10 μg for the first cohort; 30 μg at days 1 and either days 8 or 29 for cohort 2; and 100 μg with the same timing for cohort 3) or placebo. The primary endpoints were solicited and unsolicited adverse events, clinically significant laboratory test result abnormalities, medically attended adverse events, and serious adverse events. Secondary endpoints were serum IgG binding via ELISA and neutralising antibody responses against prototypical NiV Bangladesh (NiVB) and NiV Malaysia (NiVM) reporter viruses. Between Feb 24, 2020, and Oct 6, 2021, 268 participants were screened, and 192 were enrolled. 173 (90%) participants met the per-protocol criteria. Mild-to-moderate injection site pain was the most commonly reported adverse event. No serious adverse events, hospitalisations, or deaths were reported. The immune response to HeV-sG-V was dose-dependent; a single administration was not sufficiently immunogenic, whereas two administrations were immunogenic, with the highest response rates observed among vaccinees that received two administrations of the 100 μg HeV-sG-V 28 days apart (neutralising antibody geometric mean titres rose dramatically 7 days after the second investigational product dose, reaching 1485·6 (990·5–2228·1) and 2581·9 (147·1–3194·2) for NiVB and NiVM, respectively). All three doses and regimens of HeV-sG-V had a tolerable risk profile and were able to induce an immune response. The induction of antibodies within 1 month of vaccination, along with the persistence afforded by two dosages, suggests the vaccine candidate has potential for reactive outbreak control and preventive use. Coalition for Epidemic Preparedness Innovations (CEPI).

There is growing evidence that pre-exposure prophylaxis (PrEP) prevents HIV acquisition. However, in the United States, approximately only 4% of people who could benefit from PrEP are currently receiving it, and it is estimated only 1 in 5 physicians has ever prescribed PrEP. We conducted a scoping review to gain an understanding of physician-identified barriers to PrEP provision. Four overarching barriers presented in the literature: Purview Paradox, Patient Financial Constraints, Risk Compensation, and Concern for ART Resistance. Considering the physician-identified barriers, we make recommendations for how physicians and students may work to increase PrEP knowledge and competence along each stage of the PrEP cascade. We recommend adopting HIV risk assessment as a standard of care, improving physician ability to identify PrEP candidates, improving physician interest and ability in encouraging PrEP uptake, and increasing utilization of continuous care management to ensure retention and adherence to PrEP.

Traumatic brain injury (TBI) is the leading cause of long-term disability in children and young adults worldwide. However, accurate information about its incidence does not exist. We aimed to estimate the burden of TBI in rural and urban populations in New Zealand across all ages and TBI severities. We did a population-based incidence study in an urban (Hamilton) and rural (Waikato District) population in New Zealand. We registered all cases of TBI (admitted to hospital or not, fatal or non-fatal) that occurred in the population between March 1, 2010, and Feb 28, 2011, using multiple overlapping sources of information. We calculated incidence per 100 000 person-years with 95% CIs using a Poisson distribution. We calculated rate ratios [RRs] to compare the age-standardised rates between sex, ethnicity, and residency (urban, rural) groups. We used direct standardisation to age-standardise the rates to the world population. The total incidence of TBI per 100 000 person-years was 790 cases (95% CI 749–832); incidence per 100 000 person-years of mild TBI was 749 cases (709–790) and of moderate to severe TBI was 41 cases (31–51). Children (aged 0–14 years) and adolescents and young adults (aged 15–34 years) constituted almost 70% of all TBI cases. TBI affected boys and men more than women and girls (RR 1·77, 95% CI 1·58–1·97). Most TBI cases were due to falls (38% [516 of 1369]), mechanical forces (21% [288 of 1369]), transport accidents (20% [277 of 1369]), and assaults (17% [228 of 1369]). Compared with people of European origin, Maori people had a greater risk of mild TBI (RR 1·23, 95% CI 1·08–1·39). Incidence of moderate to severe TBI in the rural population (73 per 100 000 person-years [95% CI 50–107) was almost 2·5 times greater than in the urban population (31 per 100 000 person-years [23–42]). Our findings suggest that the incidence of TBI, especially mild TBI, in New Zealand is far greater than would be estimated from the findings of previous studies done in other high-income countries. Our age-specific and residency-specific data for TBI incidence overall and by mechanism of injury should be considered when planning prevention and TBI care services. Health Research Council of New Zealand.

Despite preventive vaccines for oncogenic human papillomaviruses (HPVs), cervical intraepithelial neoplasia (CIN) is common, and current treatments are ablative and can lead to long-term reproductive morbidity. We assessed whether VGX-3100, synthetic plasmids targeting HPV-16 and HPV-18 E6 and E7 proteins, delivered by electroporation, would cause histopathological regression in women with CIN2/3. Efficacy, safety, and immunogenicity of VGX-3100 were assessed in CIN2/3 associated with HPV-16 and HPV-18, in a randomised, double-blind, placebo-controlled phase 2b study. Patients from 36 academic and private gynaecology practices in seven countries were randomised (3:1) to receive 6 mg VGX-3100 or placebo (1 mL), given intramuscularly at 0, 4, and 12 weeks. Randomisation was stratified by age (<25 vs ≥25 years) and CIN2 versus CIN3 by computer-generated allocation sequence (block size 4). Funder and site personnel, participants, and pathologists were masked to treatment. The primary efficacy endpoint was regression to CIN1 or normal pathology 36 weeks after the first dose. Per-protocol and modified intention-to-treat analyses were based on patients receiving three doses without protocol violations, and on patients receiving at least one dose, respectively. The safety population included all patients who received at least one dose. The trial is registered at ClinicalTrials.gov (number NCT01304524) and EudraCT (number 2012-001334-33). Between Oct 19, 2011, and July 30, 2013, 167 patients received either VGX-3100 (n=125) or placebo (n=42). In the per-protocol analysis 53 (49·5%) of 107 VGX-3100 recipients and 11 (30·6%) of 36 placebo recipients had histopathological regression (percentage point difference 19·0 [95% CI 1·4–36·6]; p=0·034). In the modified intention-to-treat analysis 55 (48·2%) of 114 VGX-3100 recipients and 12 (30·0%) of 40 placebo recipients had histopathological regression (percentage point difference 18·2 [95% CI 1·3–34·4]; p=0·034). Injection-site reactions occurred in most patients, but only erythema was significantly more common in the VGX-3100 group (98/125, 78·4%) than in the placebo group (24/42, 57·1%; percentage point difference 21·3 [95% CI 5·3–37·8]; p=0·007). VGX-3100 is the first therapeutic vaccine to show efficacy against CIN2/3 associated with HPV-16 and HPV-18. VGX-3100 could present a non-surgical therapeutic option for CIN2/3, changing the treatment outlook for this common disease. Inovio Pharmaceuticals.

Encephalitis has many causes, but for most patients the cause is unknown. We aimed to establish the cause and identify the clinical differences between causes in patients with encephalitis in England. Patients of all ages and with symptoms suggestive of encephalitis were actively recruited for 2 years (staged start between October, 2005, and November, 2006) from 24 hospitals by clinical staff. Systematic laboratory testing included PCR and antibody assays for all commonly recognised causes of infectious encephalitis, investigation for less commonly recognised causes in immunocompromised patients, and testing for travel-related causes if indicated. We also tested for non-infectious causes for acute encephalitis including autoimmunity. A multidisciplinary expert team reviewed clinical presentation and hospital tests and directed further investigations. Patients were followed up for 6 months after discharge from hospital. We identified 203 patients with encephalitis. Median age was 30 years (range 0–87). 86 patients (42%, 95% CI 35–49) had infectious causes, including 38 (19%, 14–25) herpes simplex virus, ten (5%, 2–9) varicella zoster virus, and ten (5%, 2–9) Mycobacterium tuberculosis; 75 (37%, 30–44) had unknown causes. 42 patients (21%, 15–27) had acute immune-mediated encephalitis. 24 patients (12%, 8–17) died, with higher case fatality for infections from M tuberculosis (three patients; 30%, 7–65) and varicella zoster virus (two patients; 20%, 2–56). The 16 patients with antibody-associated encephalitis had the worst outcome of all groups—nine (56%, 30–80) either died or had severe disabilities. Patients who died were more likely to be immunocompromised than were those who survived (OR=3·44). Early diagnosis of encephalitis is crucial to ensure that the right treatment is given on time. Extensive testing substantially reduced the proportion with unknown cause, but the proportion of cases with unknown cause was higher than that for any specific identified cause. The Policy Research Programme, Department of Health, UK.