James Cook University Hospital

BACKGROUND: The SARS outbreak of 2002-2003 presented clinicians with a new, life-threatening disease for which they had no experience in treating and no research on the effectiveness of treatment options. The World Health Organization (WHO) expert panel on SARS treatment requested a systematic review and comprehensive summary of treatments used for SARS-infected patients in order to guide future treatment and identify priorities for research. METHODS AND FINDINGS: In response to the WHO request we conducted a systematic review of the published literature on ribavirin, corticosteroids, lopinavir and ritonavir (LPV/r), type I interferon (IFN), intravenous immunoglobulin (IVIG), and SARS convalescent plasma from both in vitro studies and in SARS patients. We also searched for clinical trial evidence of treatment for acute respiratory distress syndrome. Sources of data were the literature databases MEDLINE, EMBASE, BIOSIS, and the Cochrane Central Register of Controlled Trials (CENTRAL) up to February 2005. Data from publications were extracted and evidence within studies was classified using predefined criteria. In total, 54 SARS treatment studies, 15 in vitro studies, and three acute respiratory distress syndrome studies met our inclusion criteria. Within in vitro studies, ribavirin, lopinavir, and type I IFN showed inhibition of SARS-CoV in tissue culture. In SARS-infected patient reports on ribavirin, 26 studies were classified as inconclusive, and four showed possible harm. Seven studies of convalescent plasma or IVIG, three of IFN type I, and two of LPV/r were inconclusive. In 29 studies of steroid use, 25 were inconclusive and four were classified as causing possible harm. CONCLUSIONS: Despite an extensive literature reporting on SARS treatments, it was not possible to determine whether treatments benefited patients during the SARS outbreak. Some may have been harmful. Clinical trials should be designed to validate a standard protocol for dosage and timing, and to accrue data in real time during future outbreaks to monitor specific adverse effects and help inform treatment.

BACKGROUND: Methylxanthines reduce the frequency of apnea of prematurity and the need for mechanical ventilation during the first seven days of therapy. It is uncertain whether methylxanthines have other short- and long-term benefits or risks in infants with very low birth weight. METHODS: We randomly assigned 2006 infants with birth weights of 500 to 1250 g during the first 10 days of life to receive either caffeine or placebo, until drug therapy for apnea of prematurity was no longer needed. We evaluated the short-term outcomes before the first discharge home. RESULTS: Of 963 infants who were assigned to caffeine and who remained alive at a postmenstrual age of 36 weeks, 350 (36 percent) received supplemental oxygen, as did 447 of the 954 infants (47 percent) assigned to placebo (adjusted odds ratio, 0.63; 95 percent confidence interval, 0.52 to 0.76; P<0.001). Positive airway pressure was discontinued one week earlier in the infants assigned to caffeine (median postmenstrual age, 31.0 weeks; interquartile range, 29.4 to 33.0) than in the infants in the placebo group (median postmenstrual age, 32.0 weeks; interquartile range, 30.3 to 34.0; P<0.001). Caffeine reduced weight gain temporarily. The mean difference in weight gain between the group receiving caffeine and the group receiving placebo was greatest after two weeks (mean difference, -23 g; 95 percent confidence interval, -32 to -13; P<0.001). The rates of death, ultrasonographic signs of brain injury, and necrotizing enterocolitis did not differ significantly between the two groups. CONCLUSIONS: Caffeine therapy for apnea of prematurity reduces the rate of bronchopulmonary dysplasia in infants with very low birth weight. (ClinicalTrials.gov number, NCT00182312.).

Patients with neuropathic pain secondary to failed back surgery syndrome (FBSS) typically experience persistent pain, disability, and reduced quality of life. We hypothesised that spinal cord stimulation (SCS) is an effective therapy in addition to conventional medical management (CMM) in this patient population. We randomised 100 FBSS patients with predominant leg pain of neuropathic radicular origin to receive spinal cord stimulation plus conventional medical management (SCS group) or conventional medical management alone (CMM group) for at least 6 months. The primary outcome was the proportion of patients achieving 50% or more pain relief in the legs. Secondary outcomes were improvement in back and leg pain, health-related quality of life, functional capacity, use of pain medication and non-drug pain treatment, level of patient satisfaction, and incidence of complications and adverse effects. Crossover after the 6-months visit was permitted, and all patients were followed up to 1 year. In the intention-to-treat analysis at 6 months, 24 SCS patients (48%) and 4 CMM patients (9%) (p<0.001) achieved the primary outcome. Compared with the CMM group, the SCS group experienced improved leg and back pain relief, quality of life, and functional capacity, as well as greater treatment satisfaction (p<or=0.05 for all comparisons). Between 6 and 12 months, 5 SCS patients crossed to CMM, and 32 CMM patients crossed to SCS. At 12 months, 27 SCS patients (32%) had experienced device-related complications. In selected patients with FBSS, SCS provides better pain relief and improves health-related quality of life and functional capacity compared with CMM alone.

Abstract The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19 1,2 , host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases 3–7 . They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

BACKGROUND: Ovarian cancer has a poor prognosis, with just 40% of patients surviving 5 years. We designed this trial to establish the effect of early detection by screening on ovarian cancer mortality. METHODS: In this randomised controlled trial, we recruited postmenopausal women aged 50-74 years from 13 centres in National Health Service Trusts in England, Wales, and Northern Ireland. Exclusion criteria were previous bilateral oophorectomy or ovarian malignancy, increased risk of familial ovarian cancer, and active non-ovarian malignancy. The trial management system confirmed eligibility and randomly allocated participants in blocks of 32 using computer-generated random numbers to annual multimodal screening (MMS) with serum CA125 interpreted with use of the risk of ovarian cancer algorithm, annual transvaginal ultrasound screening (USS), or no screening, in a 1:1:2 ratio. The primary outcome was death due to ovarian cancer by Dec 31, 2014, comparing MMS and USS separately with no screening, ascertained by an outcomes committee masked to randomisation group. All analyses were by modified intention to screen, excluding the small number of women we discovered after randomisation to have a bilateral oophorectomy, have ovarian cancer, or had exited the registry before recruitment. Investigators and participants were aware of screening type. This trial is registered with ClinicalTrials.gov, number NCT00058032. FINDINGS: Between June 1, 2001, and Oct 21, 2005, we randomly allocated 202,638 women: 50,640 (25·0%) to MMS, 50,639 (25·0%) to USS, and 101,359 (50·0%) to no screening. 202,546 (>99·9%) women were eligible for analysis: 50,624 (>99·9%) women in the MMS group, 50,623 (>99·9%) in the USS group, and 101,299 (>99·9%) in the no screening group. Screening ended on Dec 31, 2011, and included 345,570 MMS and 327,775 USS annual screening episodes. At a median follow-up of 11·1 years (IQR 10·0-12·0), we diagnosed ovarian cancer in 1282 (0·6%) women: 338 (0·7%) in the MMS group, 314 (0·6%) in the USS group, and 630 (0·6%) in the no screening group. Of these women, 148 (0·29%) women in the MMS group, 154 (0·30%) in the USS group, and 347 (0·34%) in the no screening group had died of ovarian cancer. The primary analysis using a Cox proportional hazards model gave a mortality reduction over years 0-14 of 15% (95% CI -3 to 30; p=0·10) with MMS and 11% (-7 to 27; p=0·21) with USS. The Royston-Parmar flexible parametric model showed that in the MMS group, this mortality effect was made up of 8% (-20 to 31) in years 0-7 and 23% (1-46) in years 7-14, and in the USS group, of 2% (-27 to 26) in years 0-7 and 21% (-2 to 42) in years 7-14. A prespecified analysis of death from ovarian cancer of MMS versus no screening with exclusion of prevalent cases showed significantly different death rates (p=0·021), with an overall average mortality reduction of 20% (-2 to 40) and a reduction of 8% (-27 to 43) in years 0-7 and 28% (-3 to 49) in years 7-14 in favour of MMS. INTERPRETATION: Although the mortality reduction was not significant in the primary analysis, we noted a significant mortality reduction with MMS when prevalent cases were excluded. We noted encouraging evidence of a mortality reduction in years 7-14, but further follow-up is needed before firm conclusions can be reached on the efficacy and cost-effectiveness of ovarian cancer screening. FUNDING: Medical Research Council, Cancer Research UK, Department of Health, The Eve Appeal.

BACKGROUND: The incidence of human papillomavirus (HPV)-positive oropharyngeal cancer, a disease affecting younger patients, is rapidly increasing. Cetuximab, an epidermal growth factor receptor inhibitor, has been proposed for treatment de-escalation in this setting to reduce the toxicity of standard cisplatin treatment, but no randomised evidence exists for the efficacy of this strategy. METHODS: ). The primary outcome was overall severe (grade 3-5) toxicity events at 24 months from the end of treatment. The primary outcome was assessed by intention-to-treat and per-protocol analyses. This trial is registered with the ISRCTN registry, number ISRCTN33522080. FINDINGS: Between Nov 12, 2012, and Oct 1, 2016, 334 patients were recruited (166 in the cisplatin group and 168 in the cetuximab group). Overall (acute and late) severe (grade 3-5) toxicity did not differ significantly between treatment groups at 24 months (mean number of events per patient 4·8 [95% CI 4·2-5·4] with cisplatin vs 4·8 [4·2-5·4] with cetuximab; p=0·98). At 24 months, overall all-grade toxicity did not differ significantly either (mean number of events per patient 29·2 [95% CI 27·3-31·0] with cisplatin vs 30·1 [28·3-31·9] with cetuximab; p=0·49). However, there was a significant difference between cisplatin and cetuximab in 2-year overall survival (97·5% vs 89·4%, hazard ratio 5·0 [95% CI 1·7-14·7]; p=0·001) and 2-year recurrence (6·0% vs 16·1%, 3·4 [1·6-7·2]; p=0·0007). INTERPRETATION: Compared with the standard cisplatin regimen, cetuximab showed no benefit in terms of reduced toxicity, but instead showed significant detriment in terms of tumour control. Cisplatin and radiotherapy should be used as the standard of care for HPV-positive low-risk patients who are able to tolerate cisplatin. FUNDING: Cancer Research UK.

A postal questionnaire was sent to 10,000 patients more than one year after their total knee replacement (TKR). They were assessed using the Oxford knee score and were asked whether they were satisfied, unsure or unsatisfied with their TKR. The response rate was 87.4% (8231 of 9417 eligible questionnaires) and a total of 81.8% (6625 of 8095) of patients were satisfied. Multivariable regression modelling showed that patients with higher scores relating to the pain and function elements of the Oxford knee score had a lower level of satisfaction (p < 0.001), and that ongoing pain was a stronger predictor of this. Female gender and a primary diagnosis of osteoarthritis were found to be predictors of lower levels of patient satisfaction. Differences in the rate of satisfaction were also observed in relation to age, the American Society of Anesthesiologists grade and the type of prosthesis. This study has provided data on the Oxford knee score and the expected levels of satisfaction at one year after TKR. The results should act as a benchmark of practice in the United Kingdom and provide a baseline for peer comparison between institutions.

BACKGROUND: Methylxanthine therapy is commonly used for apnea of prematurity but in the absence of adequate data on its efficacy and safety. It is uncertain whether methylxanthines have long-term effects on neurodevelopment and growth. METHODS: We randomly assigned 2006 infants with birth weights of 500 to 1250 g to receive either caffeine or placebo until therapy for apnea of prematurity was no longer needed. The primary outcome was a composite of death, cerebral palsy, cognitive delay (defined as a Mental Development Index score of <85 on the Bayley Scales of Infant Development), deafness, or blindness at a corrected age of 18 to 21 months. RESULTS: Of the 937 infants assigned to caffeine for whom adequate data on the primary outcome were available, 377 (40.2%) died or survived with a neurodevelopmental disability, as compared with 431 of the 932 infants (46.2%) assigned to placebo for whom adequate data on the primary outcome were available (odds ratio adjusted for center, 0.77; 95% confidence interval [CI], 0.64 to 0.93; P=0.008). Treatment with caffeine as compared with placebo reduced the incidence of cerebral palsy (4.4% vs. 7.3%; adjusted odds ratio, 0.58; 95% CI, 0.39 to 0.87; P=0.009) and of cognitive delay (33.8% vs. 38.3%; adjusted odds ratio, 0.81; 95% CI, 0.66 to 0.99; P=0.04). The rates of death, deafness, and blindness and the mean percentiles for height, weight, and head circumference at follow-up did not differ significantly between the two groups. CONCLUSIONS: Caffeine therapy for apnea of prematurity improves the rate of survival without neurodevelopmental disability at 18 to 21 months in infants with very low birth weight. (ClinicalTrials.gov number, NCT00182312 [ClinicalTrials.gov].).

ABSTRACT Background Coronavirus disease 2019 (COVID-19) is associated with diffuse lung damage. Corticosteroids may modulate immune-mediated lung injury and reducing progression to respiratory failure and death. Methods The Randomised Evaluation of COVID-19 therapy (RECOVERY) trial is a randomized, controlled, open-label, adaptive, platform trial comparing a range of possible treatments with usual care in patients hospitalized with COVID-19. We report the preliminary results for the comparison of dexamethasone 6 mg given once daily for up to ten days vs. usual care alone. The primary outcome was 28-day mortality. Results 2104 patients randomly allocated to receive dexamethasone were compared with 4321 patients concurrently allocated to usual care. Overall, 454 (21.6%) patients allocated dexamethasone and 1065 (24.6%) patients allocated usual care died within 28 days (age-adjusted rate ratio [RR] 0.83; 95% confidence interval [CI] 0.74 to 0.92; P&lt;0.001). The proportional and absolute mortality rate reductions varied significantly depending on level of respiratory support at randomization (test for trend p&lt;0.001): Dexamethasone reduced deaths by one-third in patients receiving invasive mechanical ventilation (29.0% vs. 40.7%, RR 0.65 [95% CI 0.51 to 0.82]; p&lt;0.001), by one-fifth in patients receiving oxygen without invasive mechanical ventilation (21.5% vs. 25.0%, RR 0.80 [95% CI 0.70 to 0.92]; p=0.002), but did not reduce mortality in patients not receiving respiratory support at randomization (17.0% vs. 13.2%, RR 1.22 [95% CI 0.93 to 1.61]; p=0.14). Conclusions In patients hospitalized with COVID-19, dexamethasone reduced 28-day mortality among those receiving invasive mechanical ventilation or oxygen at randomization, but not among patients not receiving respiratory support. Trial registrations The RECOVERY trial is registered with ISRCTN (50189673) and clinicaltrials.gov ( NCT04381936 ). Funding Medical Research Council and National Institute for Health Research (Grant ref: MC_PC_19056).

BACKGROUND: Ovarian cancer has a high case-fatality ratio, with most women not diagnosed until the disease is in its advanced stages. The United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) is a randomised controlled trial designed to assess the effect of screening on mortality. This report summarises the outcome of the prevalence (initial) screen in UKCTOCS. METHODS: Between 2001 and 2005, a total of 202 638 post-menopausal women aged 50-74 years were randomly assigned to no treatment (control; n=101 359); annual CA125 screening (interpreted using a risk of ovarian cancer algorithm) with transvaginal ultrasound scan as a second-line test (multimodal screening [MMS]; n=50 640); or annual screening with transvaginal ultrasound (USS; n=50 639) alone in a 2:1:1 ratio using a computer-generated random number algorithm. All women provided a blood sample at recruitment. Women randomised to the MMS group had their blood tested for CA125 and those randomised to the USS group were sent an appointment to attend for a transvaginal scan. Women with abnormal screens had repeat tests. Women with persistent abnormality on repeat screens underwent clinical evaluation and, where appropriate, surgery. This trial is registered as ISRCTN22488978 and with ClinicalTrials.gov, number NCT00058032. FINDINGS: In the prevalence screen, 50 078 (98.9%) women underwent MMS, and 48 230 (95.2%) underwent USS. The main reasons for withdrawal were death (two MMS, 28 USS), non-ovarian cancer or other disease (none MMS, 66 USS), removal of ovaries (five MMS, 29 USS), relocation (none MMS, 39 USS), failure to attend three appointments for the screen (72 MMS, 757 USS), and participant changing their mind (483 MMS, 1490 USS). Overall, 4355 of 50 078 (8.7%) women in the MMS group and 5779 of 48 230 (12.0%) women in the USS group required a repeat test, and 167 (0.3%) women in the MMS group and 1894 (3.9%) women in the USS group required clinical evaluation. 97 of 50 078 (0.2%) women from the MMS group and 845 of 48 230 (1.8%) from the USS group underwent surgery. 42 (MMS) and 45 (USS) primary ovarian and tubal cancers were detected, including 28 borderline tumours (eight MMS, 20 USS). 28 (16 MMS, 12 USS) of 58 (48.3%; 95% CI 35.0-61.8) of the invasive cancers were stage I/II, with no difference (p=0.396) in stage distribution between the groups. A further 13 (five MMS, eight USS) women developed primary ovarian cancer during the year after the screen. The sensitivity, specificity, and positive-predictive values for all primary ovarian and tubal cancers were 89.4%, 99.8%, and 43.3% for MMS, and 84.9%, 98.2%, and 5.3% for USS, respectively. For primary invasive epithelial ovarian and tubal cancers, the sensitivity, specificity, and positive-predictive values were 89.5%, 99.8%, and 35.1% for MMS, and 75.0%, 98.2%, and 2.8% for USS, respectively. There was a significant difference in specificity (p<0.0001) but not sensitivity between the two screening groups for both primary ovarian and tubal cancers as well as primary epithelial invasive ovarian and tubal cancers. INTERPRETATION: The sensitivity of the MMS and USS screening strategies is encouraging. Specificity was higher in the MMS than in the USS group, resulting in lower rates of repeat testing and surgery. This in part reflects the high prevalence of benign adnexal abnormalities and the more frequent detection of borderline tumours in the USS group. The prevalence screen has established that the screening strategies are feasible. The results of ongoing screening are awaited so that the effect of screening on mortality can be determined.

OBJECTIVE: To estimate the global number of excess deaths due to diabetes in the year 2000. RESEARCH DESIGN AND METHODS: We used a computerized generic formal disease model (DisMod II), used by the World Health Organization to assess disease burden through modeling the relationships between incidence, prevalence, and disease-specific mortality. Baseline input data included population structure, age- and sex-specific estimates of diabetes prevalence, and available published estimates of relative risk of death for people with diabetes compared with people without diabetes. The results were validated with population-based observations and independent estimates of relative risk of death. RESULTS: The excess global mortality attributable to diabetes in the year 2000 was estimated to be 2.9 million deaths, equivalent to 5.2% of all deaths. Excess mortality attributable to diabetes accounted for 2-3% of deaths in poorest countries and over 8% in the U.S., Canada, and the Middle East. In people 35-64 years old, 6-27% of deaths were attributable to diabetes. CONCLUSIONS: These are the first global estimates of mortality attributable to diabetes. Globally, diabetes is likely to be the fifth leading cause of death.

IMPORTANCE: High-dose immunosuppressive therapy and autologous hematopoietic stem cell transplantation (HSCT) have shown efficacy in systemic sclerosis in phase 1 and small phase 2 trials. OBJECTIVE: To compare efficacy and safety of HSCT vs 12 successive monthly intravenous pulses of cyclophosphamide. DESIGN, SETTING, AND PARTICIPANTS: The Autologous Stem Cell Transplantation International Scleroderma (ASTIS) trial, a phase 3, multicenter, randomized (1:1), open-label, parallel-group, clinical trial conducted in 10 countries at 29 centers with access to a European Group for Blood and Marrow Transplantation-registered transplant facility. From March 2001 to October 2009, 156 patients with early diffuse cutaneous systemic sclerosis were recruited and followed up until October 31, 2013. INTERVENTIONS: HSCT vs intravenous pulse cyclophosphamide. MAIN OUTCOMES AND MEASURES: The primary end point was event-free survival, defined as time from randomization until the occurrence of death or persistent major organ failure. RESULTS: A total of 156 patients were randomly assigned to receive HSCT (n = 79) or cyclophosphamide (n = 77). During a median follow-up of 5.8 years, 53 events occurred: 22 in the HSCT group (19 deaths and 3 irreversible organ failures) and 31 in the control group (23 deaths and 8 irreversible organ failures). During the first year, there were more events in the HSCT group (13 events [16.5%], including 8 treatment-related deaths) than in the control group (8 events [10.4%], with no treatment-related deaths). At 2 years, 14 events (17.7%) had occurred cumulatively in the HSCT group vs 14 events (18.2%) in the control group; at 4 years, 15 events (19%) had occurred cumulatively in the HSCT group vs 20 events (26%) in the control group. Time-varying hazard ratios (modeled with treatment × time interaction) for event-free survival were 0.35 (95% CI, 0.16-0.74) at 2 years and 0.34 (95% CI, 0.16-0.74) at 4 years. CONCLUSIONS AND RELEVANCE: Among patients with early diffuse cutaneous systemic sclerosis, HSCT was associated with increased treatment-related mortality in the first year after treatment. However, HCST conferred a significant long-term event-free survival benefit. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN54371254.

BACKGROUND: Chronic mucocutaneous candidiasis (CMC) is characterized by susceptibility to candida infection of skin, nails, and mucous membranes. Patients with recessive CMC and autoimmunity have mutations in the autoimmune regulator AIRE. The cause of autosomal dominant CMC is unknown. METHODS: We evaluated 14 patients from five families with autosomal dominant CMC. We incubated their peripheral-blood mononuclear cells with different combinations of stimuli to test the integrity of pathways that mediate immunity, which led to the selection of 100 genes that were most likely to contain the genetic defect. We used an array-based sequence-capture assay, followed by next-generation sequencing, to identify mutations. RESULTS: The mononuclear cells from the affected patients were characterized by poor production of interferon-γ, interleukin-17, and interleukin-22, suggesting that the defect lay within the interleukin-12 receptor and interleukin-23 receptor signaling pathways. We identified heterozygous missense mutations in the DNA sequence encoding the coiled-coil (CC) domain of signal transducer and activator of transcription 1 (STAT1) in the patients. These mutations lead to defective responses in type 1 and type 17 helper T cells (Th1 and Th17). The interferon-γ receptor pathway was intact in these patients. CONCLUSIONS: Mutations in the CC domain of STAT1 underlie autosomal dominant CMC and lead to defective Th1 and Th17 responses, which may explain the increased susceptibility to fungal infection. (Funded by the Netherlands Organization for Scientific Research and others.).

OBJECTIVE: After randomizing 100 failed back surgery syndrome patients to receive spinal cord stimulation (SCS) plus conventional medical management (CMM) or CMM alone, the results of the 6-month Prospective Randomized Controlled Multicenter Trial of the Effectiveness of Spinal Cord Stimulation (i.e., PROCESS) showed that SCS offered superior pain relief, health-related quality of life, and functional capacity. Because the rate of crossover favoring SCS beyond 6 months would bias a long-term randomized group comparison, we present all outcomes in patients who continued SCS from randomization to 24 months and, for illustrative purposes, the primary outcome (>50% leg pain relief) per randomization and final treatment. METHODS: Patients provided data on pain, quality of life, function, pain medication use, treatment satisfaction, and employment status. Investigators documented adverse events. Data analysis included inferential comparisons and multivariate regression analyses. RESULTS: The 42 patients continuing SCS (of 52 randomized to SCS) reported significantly improved leg pain relief (P < 0.0001), quality of life (P <or= 0.01), and functional capacity (P = 0.0002); and 13 patients (31%) required a device-related surgical revision. At 24 months, of 46 of 52 patients randomized to SCS and 41 of 48 randomized to CMM who were available, the primary outcome was achieved by 17 (37%) randomized to SCS versus 1 (2%) to CMM (P = 0.003) and by 34 (47%) of 72 patients who received SCS as final treatment versus 1 (7%) of 15 for CMM (P = 0.02). CONCLUSION: At 24 months of SCS treatment, selected failed back surgery syndrome patients reported sustained pain relief, clinically important improvements in functional capacity and health-related quality of life, and satisfaction with treatment.

Contrary to the commonly held misconception, bone is a relatively dynamic organ that undergoes significant turnover as compared to other organs in the body. This review details how complex intercellular signalling, between the osteoprogenitor cells and mature osteoblasts, osteocytes and osteoclasts, regulates and balances activities of bone cells during remodelling and growth. Both systemic, as well as local autocrine and paracrine factors are discussed. A number of recent important advances in cell biology of bone have led to a new paradigm in understanding of the subject. In this regard, the interaction between the immune system and bone cells is of particular interest, leading to the emergence of a new discipline termed osteoimmunology. The role of lymphocytes and a number of key cytokines in the regulation of osteoclastogenesis and osteoblast function is critically examined. The intracellular signalling regulating key cellular pathways involved in cell differentiation and activity are outlined. The emerging evidence of osteocytes as mechanosensors as well as regulators of mineralisation is discussed.

The Obstetric Anaesthetists' Association and Difficult Airway Society have developed the first national obstetric guidelines for the safe management of difficult and failed tracheal intubation during general anaesthesia. They comprise four algorithms and two tables. A master algorithm provides an overview. Algorithm 1 gives a framework on how to optimise a safe general anaesthetic technique in the obstetric patient, and emphasises: planning and multidisciplinary communication; how to prevent the rapid oxygen desaturation seen in pregnant women by advocating nasal oxygenation and mask ventilation immediately after induction; limiting intubation attempts to two; and consideration of early release of cricoid pressure if difficulties are encountered. Algorithm 2 summarises the management after declaring failed tracheal intubation with clear decision points, and encourages early insertion of a (preferably second-generation) supraglottic airway device if appropriate. Algorithm 3 covers the management of the 'can't intubate, can't oxygenate' situation and emergency front-of-neck airway access, including the necessity for timely perimortem caesarean section if maternal oxygenation cannot be achieved. Table 1 gives a structure for assessing the individual factors relevant in the decision to awaken or proceed should intubation fail, which include: urgency related to maternal or fetal factors; seniority of the anaesthetist; obesity of the patient; surgical complexity; aspiration risk; potential difficulty with provision of alternative anaesthesia; and post-induction airway device and airway patency. This decision should be considered by the team in advance of performing a general anaesthetic to make a provisional plan should failed intubation occur. The table is also intended to be used as a teaching tool to facilitate discussion and learning regarding the complex nature of decision-making when faced with a failed intubation. Table 2 gives practical considerations of how to awaken or proceed with surgery. The background paper covers recommendations on drugs, new equipment, teaching and training.

Obesity is rising in the obstetric population, yet there is an absence of services and guidance for the management of maternal obesity. This systematic review aimed to investigate relationships between obesity and impact on obstetric care. Literature was systematically searched for cohort studies of pregnant women with anthropometric measurements recorded within 16-weeks gestation, followed up for the term of the pregnancy, with at least one obese and one comparison group. Two researchers independently data-extracted and quality-assessed each included study. Outcome measures were those that directly or indirectly impacted on maternity resources. Primary outcomes included instrumental delivery, caesarean delivery, duration of hospital stay, neonatal intensive care, neonatal trauma, haemorrhage, infection and 3rd/4th degree tears. Meta-analysis shows a significant relationship between obesity and increased odds of caesarean and instrumental deliveries, haemorrhage, infection, longer duration of hospital stay and increased neonatal intensive care requirement. Maternal obesity significantly contributes to a poorer prognosis for mother and baby during delivery and in the immediate post-partum period. National clinical guidelines for management of obese pregnant women, and public health interventions to help safeguard the health of mothers and their babies are urgently required.

IMPORTANCE: The need for surgery for the majority of patients with displaced proximal humeral fractures is unclear, but its use is increasing. OBJECTIVE: To evaluate the clinical effectiveness of surgical vs nonsurgical treatment for adults with displaced fractures of the proximal humerus involving the surgical neck. DESIGN, SETTING, AND PARTICIPANTS: A pragmatic, multicenter, parallel-group, randomized clinical trial, the Proximal Fracture of the Humerus Evaluation by Randomization (PROFHER) trial, recruited 250 patients aged 16 years or older (mean age, 66 years [range, 24-92 years]; 192 [77%] were female; and 249 [99.6%] were white) who presented at the orthopedic departments of 32 acute UK National Health Service hospitals between September 2008 and April 2011 within 3 weeks after sustaining a displaced fracture of the proximal humerus involving the surgical neck. Patients were followed up for 2 years (up to April 2013) and 215 had complete follow-up data. The data for 231 patients (114 in surgical group and 117 in nonsurgical group) were included in the primary analysis. INTERVENTIONS: Fracture fixation or humeral head replacement were performed by surgeons experienced in these techniques. Nonsurgical treatment was sling immobilization. Standardized outpatient and community-based rehabilitation was provided to both groups. MAIN OUTCOMES AND MEASURES: Primary outcome was the Oxford Shoulder Score (range, 0-48; higher scores indicate better outcomes) assessed during a 2-year period, with assessment and data collection at 6, 12, and 24 months. Sample size was based on a minimal clinically important difference of 5 points for the Oxford Shoulder Score. Secondary outcomes were the Short-Form 12 (SF-12), complications, subsequent therapy, and mortality. RESULTS: There was no significant mean treatment group difference in the Oxford Shoulder Score averaged over 2 years (39.07 points for the surgical group vs 38.32 points for the nonsurgical group; difference of 0.75 points [95% CI, -1.33 to 2.84 points]; P = .48) or at individual time points. There were also no significant between-group differences over 2 years in the mean SF-12 physical component score (surgical group: 1.77 points higher [95% CI, -0.84 to 4.39 points]; P = .18); the mean SF-12 mental component score (surgical group: 1.28 points lower [95% CI, -3.80 to 1.23 points]; P = .32); complications related to surgery or shoulder fracture (30 patients in surgical group vs 23 patients in nonsurgical group; P = .28), requiring secondary surgery to the shoulder (11 patients in both groups), and increased or new shoulder-related therapy (7 patients vs 4 patients, respectively; P = .58); and mortality (9 patients vs 5 patients; P = .27). Ten medical complications (2 cardiovascular events, 2 respiratory events, 2 gastrointestinal events, and 4 others) occurred in the surgical group during the postoperative hospital stay. CONCLUSIONS AND RELEVANCE: Among patients with displaced proximal humeral fractures involving the surgical neck, there was no significant difference between surgical treatment compared with nonsurgical treatment in patient-reported clinical outcomes over 2 years following fracture occurrence. These results do not support the trend of increased surgery for patients with displaced fractures of the proximal humerus. TRIAL REGISTRATION: isrctn.com Identifier: ISRCTN50850043.

BACKGROUND: Localised prostate cancer is commonly treated with external-beam radiotherapy. Moderate hypofractionation has been shown to be non-inferior to conventional fractionation. Ultra-hypofractionated stereotactic body radiotherapy would allow shorter treatment courses but could increase acute toxicity compared with conventionally fractionated or moderately hypofractionated radiotherapy. We report the acute toxicity findings from a randomised trial of standard-of-care conventionally fractionated or moderately hypofractionated radiotherapy versus five-fraction stereotactic body radiotherapy for low-risk to intermediate-risk localised prostate cancer. METHODS: PACE is an international, phase 3, open-label, randomised, non-inferiority trial. In PACE-B, eligible men aged 18 years and older, with WHO performance status 0-2, low-risk or intermediate-risk prostate adenocarcinoma (Gleason 4 + 3 excluded), and scheduled to receive radiotherapy were recruited from 37 centres in three countries (UK, Ireland, and Canada). Participants were randomly allocated (1:1) by computerised central randomisation with permuted blocks (size four and six), stratified by centre and risk group, to conventionally fractionated or moderately hypofractionated radiotherapy (78 Gy in 39 fractions over 7·8 weeks or 62 Gy in 20 fractions over 4 weeks, respectively) or stereotactic body radiotherapy (36·25 Gy in five fractions over 1-2 weeks). Neither participants nor investigators were masked to allocation. Androgen deprivation was not permitted. The primary endpoint of PACE-B is freedom from biochemical or clinical failure. The coprimary outcomes for this acute toxicity substudy were worst grade 2 or more severe Radiation Therapy Oncology Group (RTOG) gastrointestinal or genitourinary toxic effects score up to 12 weeks after radiotherapy. Analysis was per protocol. This study is registered with ClinicalTrials.gov, NCT01584258. PACE-B recruitment is complete and follow-up is ongoing. FINDINGS: Between Aug 7, 2012, and Jan 4, 2018, we randomly assigned 874 men to conventionally fractionated or moderately hypofractionated radiotherapy (n=441) or stereotactic body radiotherapy (n=433). 432 (98%) of 441 patients allocated to conventionally fractionated or moderately hypofractionated radiotherapy and 415 (96%) of 433 patients allocated to stereotactic body radiotherapy received at least one fraction of allocated treatment. Worst acute RTOG gastrointestinal toxic effect proportions were as follows: grade 2 or more severe toxic events in 53 (12%) of 432 patients in the conventionally fractionated or moderately hypofractionated radiotherapy group versus 43 (10%) of 415 patients in the stereotactic body radiotherapy group (difference -1·9 percentage points, 95% CI -6·2 to 2·4; p=0·38). Worst acute RTOG genitourinary toxicity proportions were as follows: grade 2 or worse toxicity in 118 (27%) of 432 patients in the conventionally fractionated or moderately hypofractionated radiotherapy group versus 96 (23%) of 415 patients in the stereotactic body radiotherapy group (difference -4·2 percentage points, 95% CI -10·0 to 1·7; p=0·16). No treatment-related deaths occurred. INTERPRETATION: Previous evidence (from the HYPO-RT-PC trial) suggested higher patient-reported toxicity with ultrahypofractionation. By contrast, our results suggest that substantially shortening treatment courses with stereotactic body radiotherapy does not increase either gastrointestinal or genitourinary acute toxicity. FUNDING: Accuray and National Institute of Health Research.