Broomfield Hospital

BACKGROUND: Lapatinib, a tyrosine kinase inhibitor of human epidermal growth factor receptor type 2 (HER2, also referred to as HER2/neu) and epidermal growth factor receptor (EGFR), is active in combination with capecitabine in women with HER2-positive metastatic breast cancer that has progressed after trastuzumab-based therapy. In this trial, we compared lapatinib plus capecitabine with capecitabine alone in such patients. METHODS: Women with HER2-positive, locally advanced or metastatic breast cancer that had progressed after treatment with regimens that included an anthracycline, a taxane, and trastuzumab were randomly assigned to receive either combination therapy (lapatinib at a dose of 1250 mg per day continuously plus capecitabine at a dose of 2000 mg per square meter of body-surface area on days 1 through 14 of a 21-day cycle) or monotherapy (capecitabine alone at a dose of 2500 mg per square meter on days 1 through 14 of a 21-day cycle). The primary end point was time to progression, based on an evaluation by independent reviewers under blinded conditions. RESULTS: The interim analysis of time to progression met specified criteria for early reporting on the basis of superiority in the combination-therapy group. The hazard ratio for the independently assessed time to progression was 0.49 (95% confidence interval, 0.34 to 0.71; P<0.001), with 49 events in the combination-therapy group and 72 events in the monotherapy group. The median time to progression was 8.4 months in the combination-therapy group as compared with 4.4 months in the monotherapy group. This improvement was achieved without an increase in serious toxic effects or symptomatic cardiac events. CONCLUSIONS: Lapatinib plus capecitabine is superior to capecitabine alone in women with HER2-positive advanced breast cancer that has progressed after treatment with regimens that included an anthracycline, a taxane, and trastuzumab. (ClinicalTrials.gov number, NCT00078572 [ClinicalTrials.gov].).

Abstract Objective: To examine the prevalence, nature, causes, and consequences of suboptimal care before admission to intensive care units, and to suggest possible solutions. Design: Prospective confidential inquiry on the basis of structured interviews and questionnaires. Setting: A large district general hospital and a teaching hospital. Subjects: A cohort of 100 consecutive adult emergency admissions, 50 in each centre. Main outcome measures: Opinions of two external assessors on quality of care especially recognition, investigation, monitoring, and management of abnormalities of airway, breathing, and circulation, and oxygen therapy and monitoring. Results: Assessors agreed that 20 patients were well managed (group 1) and 54 patients received suboptimal care (group 2). Assessors disagreed on quality of management of 26 patients (group 3). The casemix and severity of illness, defined by the acute physiology and chronic health evaluation (APACHE II) score, were similar between centres and the three groups. In groups 1, 2, and 3 intensive care mortalities were 5 (25%), 26 (48%), and 6 (23%) respectively (P=0.04) (group 1 versus group 2, P=0.07). Hospital mortalities were 7 (35%), 30 (56%), and 8 (31%) (P=0.07) and standardised hospital mortality ratios (95% confidence intervals) were 1.23 (0.49 to 2.54), 1.4 (0.94 to 2.0), and 1.26 (0.54 to 2.48) respectively. Admission to intensive care was considered late in 37 (69%) patients in group 2. Overall, a minimum of 4.5% and a maximum of 41% of admissions were considered potentially avoidable. Suboptimal care contributed to morbidity or mortality in most instances. The main causes of suboptimal care were failure of organisation, lack of knowledge, failure to appreciate clinical urgency, lack of supervision, and failure to seek advice. Conclusions: The management of airway, breathing, and circulation, and oxygen therapy and monitoring in severely ill patients before admission to intensive care units may frequently be suboptimal. Major consequences may include increased morbidity and mortality and requirement for intensive care. Possible solutions include improved teaching, establishment of medical emergency teams, and widespread debate on the structure and process of acute care. Key messages Suboptimal management of oxygen therapy, airway, breathing, circulation, and monitoring before admission to intensive care occurred in over half of a consecutive cohort of acute adult emergency patients. This may be associated with increased morbidity, mortality, and avoidable admissions to intensive care At least 39% of acute adult emergency patients were admitted to intensive care late in the clinical course of the illness Major causes of suboptimal care included failure of organisation, lack of knowledge, failure to appreciate clinical urgency, lack of supervision, and failure to seek advice A medical emergency team may be useful in responding pre-emptively to the clinical signs of life threatening dysfunction of airway, breathing, and circulation, rather than relying on a cardiac arrest team The structure and process of acute care and their importance require major re-evaluation and debate

In this review, the clinical features of Parkinson's disease, both motor and non-motor, are described in the context of the progression of the disease. Also briefly discussed are the major treatment strategies and their complications. Parkinson's disease is a slowly progressing neurodegenerative disorder, causing impaired motor function with slow movements, tremor and gait and balance disturbances. A variety of non-motor symptoms are common in Parkinson's disease. They include disturbed autonomic function with orthostatic hypotension, constipation and urinary disturbances, a variety of sleep disorders and a spectrum of neuropsychiatric symptoms. This article describes the different clinical symptoms that may occur and the clinical course of the disease. This article is part of a special issue on Parkinson disease.

BACKGROUND: On the basis of data from a phase 2 trial that compared the checkpoint inhibitor ipilimumab at doses of 0.3 mg, 3 mg, and 10 mg per kilogram of body weight in patients with advanced melanoma, this phase 3 trial evaluated ipilimumab at a dose of 10 mg per kilogram in patients who had undergone complete resection of stage III melanoma. METHODS: After patients had undergone complete resection of stage III cutaneous melanoma, we randomly assigned them to receive ipilimumab at a dose of 10 mg per kilogram (475 patients) or placebo (476) every 3 weeks for four doses, then every 3 months for up to 3 years or until disease recurrence or an unacceptable level of toxic effects occurred. Recurrence-free survival was the primary end point. Secondary end points included overall survival, distant metastasis-free survival, and safety. RESULTS: At a median follow-up of 5.3 years, the 5-year rate of recurrence-free survival was 40.8% in the ipilimumab group, as compared with 30.3% in the placebo group (hazard ratio for recurrence or death, 0.76; 95% confidence interval [CI], 0.64 to 0.89; P<0.001). The rate of overall survival at 5 years was 65.4% in the ipilimumab group, as compared with 54.4% in the placebo group (hazard ratio for death, 0.72; 95.1% CI, 0.58 to 0.88; P=0.001). The rate of distant metastasis-free survival at 5 years was 48.3% in the ipilimumab group, as compared with 38.9% in the placebo group (hazard ratio for death or distant metastasis, 0.76; 95.8% CI, 0.64 to 0.92; P=0.002). Adverse events of grade 3 or 4 occurred in 54.1% of the patients in the ipilimumab group and in 26.2% of those in the placebo group. Immune-related adverse events of grade 3 or 4 occurred in 41.6% of the patients in the ipilimumab group and in 2.7% of those in the placebo group. In the ipilimumab group, 5 patients (1.1%) died owing to immune-related adverse events. CONCLUSIONS: As adjuvant therapy for high-risk stage III melanoma, ipilimumab at a dose of 10 mg per kilogram resulted in significantly higher rates of recurrence-free survival, overall survival, and distant metastasis-free survival than placebo. There were more immune-related adverse events with ipilimumab than with placebo. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00636168 , and EudraCT number, 2007-001974-10 .).

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: Controversy exists concerning the necessary margin of excision for cutaneous melanoma 2 mm or greater in thickness. METHODS: We conducted a randomized clinical trial comparing 1-cm and 3-cm margins. RESULTS: Of the 900 patients who were enrolled, 453 were randomly assigned to undergo surgery with a 1-cm margin of excision and 447 with a 3-cm margin of excision; the median follow-up was 60 months. A 1-cm margin of excision was associated with a significantly increased risk of locoregional recurrence. There were 168 locoregional recurrences (as first events) in the group with 1-cm margins of excision, as compared with 142 in the group with 3-cm margins (hazard ratio, 1.26; 95 percent confidence interval, 1.00 to 1.59; P=0.05). There were 128 deaths attributable to melanoma in the group with 1-cm margins, as compared with 105 in the group with 3-cm margins (hazard ratio, 1.24; 95 percent confidence interval, 0.96 to 1.61; P=0.1); overall survival was similar in the two groups (hazard ratio for death, 1.07; 95 percent confidence interval, 0.85 to 1.36; P=0.6). CONCLUSIONS: A 1-cm margin of excision for melanoma with a poor prognosis (as defined by a tumor thickness of at least 2 mm) is associated with a significantly greater risk of regional recurrence than is a 3-cm margin, but with a similar overall survival rate.

Understanding the pathophysiology of a burn injury is important for effective management. In addition, different causes lead to different injury patterns, which require different management. It is therefore important to understand how a burn was caused and what kind of physiological response it will induce. Burn injuries result in both local and systemic responses. ![][1] Clinical image of burn zones. There is central necrosis, surrounded by the zones of stasis and of hyperaemia ### Local response The three zones of a burn were described by Jackson in 1947. Zone of coagulation —This occurs at the point of maximum damage. In this zone there is irreversible tissue loss due to coagulation of the constituent proteins. Zone of stasis —The surrounding zone of stasis is characterised by decreased tissue perfusion. The tissue in this zone is potentially salvageable. The main aim of burns resuscitation is to increase tissue perfusion here and prevent any damage becoming irreversible. Additional insults—such as prolonged hypotension, infection, or oedema—can convert this zone into an area of complete tissue loss. Zone of hyperaemia —In this outermost zone tissue perfusion is increased. The tissue here will invariably recover unless there is severe sepsis or prolonged hypoperfusion. These three zones of a burn are three dimensional, and loss of tissue in the zone of stasis will lead to the wound deepening as well as widening. ![][2] ackson's burns zones and the effects of adequate and inadequate resuscitation ### Systemic response The release of cytokines and other inflammatory mediators at the site of injury has a systemic effect once the burn reaches 30% of total body surface area. Cardiovascular changes —Capillary permeability is increased, leading to loss of intravascular proteins and fluids into the interstitial compartment. Peripheral and splanchnic vasoconstriction occurs. Myocardial contractility is decreased, possibly due to release of tumour necrosis factor α. These changes, coupled with fluid … [1]: /embed/graphic-1.gif [2]: /embed/graphic-2.gif

A short introduction to the background and theory of synthetic aperture radar (SAR) imaging is given. Some of the key issues in SAR design are discussed and possible future developments involving SAR operation with phased arrays are suggested.

Abstract Changing climate in northern regions is causing permafrost to thaw with major implications for the global mercury (Hg) cycle. We estimated Hg in permafrost regions based on in situ measurements of sediment total mercury (STHg), soil organic carbon (SOC), and the Hg to carbon ratio (R HgC ) combined with maps of soil carbon. We measured a median STHg of 43 ± 30 ng Hg g soil −1 and a median R HgC of 1.6 ± 0.9 μg Hg g C −1 , consistent with published results of STHg for tundra soils and 11,000 measurements from 4,926 temperate, nonpermafrost sites in North America and Eurasia. We estimate that the Northern Hemisphere permafrost regions contain 1,656 ± 962 Gg Hg, of which 793 ± 461 Gg Hg is frozen in permafrost. Permafrost soils store nearly twice as much Hg as all other soils, the ocean, and the atmosphere combined, and this Hg is vulnerable to release as permafrost thaws over the next century. Existing estimates greatly underestimate Hg in permafrost soils, indicating a need to reevaluate the role of the Arctic regions in the global Hg cycle.

after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes-including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)-in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist.

Rates of survival after thermal injury have improved in the past two decades, and rates of wound infections and sepsis have decreased during the same period. Early excision has been advocated as one of the major factors, but its safety and efficacy and the exact timing of burn excision are still under debate. It was hypothesized that acute burn wound excision (in the first 24 hours after burning) would be superior to conservative treatment and delayed excision in preventing bacterial colonization and invasion. Twenty consecutive patients with thermal injuries were studied. Twelve patients underwent acute burn wound excision, and eight patients underwent conservative treatment and delayed excision. The second group of patients received topical treatments in another facility and underwent delayed excision after transfer to our service, on postburn day 6. Quantitative bacteriological assessments of the excised wound and biopsy samples of the wound bed, obtained before autografting and/or homografting, were performed. The effects of time on bacterial counts, differences between superficial and deep biopsy samples, and the effects of early versus late debridement were studied. Patients admitted early exhibited bacterial counts of less than 10 bacteria per gram of tissue. Patients in this group did not experience infection or graft loss. Patients admitted late exhibited counts of more than 10 bacteria (p = 0.001, compared with early admission). Three patients in the late excision group experienced infection and graft loss (p < 0.05, compared with the early excision group). Burn wound excision significantly decreased bacterial colonization for all patients (p < 0.001). Greater bacterial colonization and higher rates of infection were correlated with topical treatment and late excision (p < 0.001). It is concluded that burn wound excision significantly reduces bacterial colonization. Patients who undergo topical treatment and delayed burn wound excision exhibit greater bacterial colonization and increased rates of infection. Acute burn wound excision should be considered for all full-thickness burns.

It is over 20 years since the inaugural deep inferior epigastric perforator (DIEP) flap breast reconstruction. We review the type of flap utilized and indications in 2,850 microvascular breast reconstruction over the subsequent 20 years in the senior author's practice (Robert J. Allen). Data were extracted from a personal logbook of all microsurgical free flap breast reconstructions performed between August 1992 and August 2012. Indication for surgery; mastectomy pattern in primary reconstruction; flap type, whether unilateral or bilateral; recipient vessels; and adjunctive procedures were recorded. The DIEP was the most commonly performed flap (66%), followed by the superior gluteal artery perforator flap (12%), superficial inferior epigastric artery perforator flap (9%), inferior gluteal artery perforator flap (6%), profunda artery perforator flap (3%), and transverse upper gracilis flap (3%). Primary reconstruction accounted for 1,430 flaps (50%), secondary 992 (35%), and tertiary 425 (15%). As simultaneous bilateral reconstructions, 59% flaps were performed. With each flap, there typically ensues a period of enthusiasm which translated into surge in flap numbers. However, each flap has its own nuances and characteristics that influence patient and physician choice. Of note, each newly introduced flap, either buttock or thigh, results in a sharp decline in its predecessor. In this practice, the DIEP flap has remained the first choice in autologous breast reconstruction.

BACKGROUND: Letrozole is safe and effective in postmenopausal women with estrogen receptor-positive early breast cancer, but long-term aromatase inhibitor use may cause bone loss and increase fracture risk. This study evaluated an immediate or delayed strategy of bone protection therapy with zoledronic acid. METHODS: A total of 1065 patients who were receiving adjuvant letrozole were randomized to immediate-start or delayed-start zoledronic acid (4 mg intravenously biannually for 5 years). The delayed group received zoledronic acid if lumbar spine or total hip T-score decreased below -2.0 or when a nontraumatic fracture occurred. The primary endpoint was change in lumbar spine bone mineral density (BMD) at Month 12. Secondary endpoints included changes in total hip BMD, serum bone turnover markers, and safety at Month 12. RESULTS: Lumbar spine BMD increased from baseline in the immediate arm, while it decreased from baseline in delayed-arm patients. At Month 12, the differences between the groups in lumbar spine and total hip BMD were 5.7% (P < .0001; 95% confidence intervals [CI], 5.2% to 6.1%), and 3.6% (P < .0001; 95% CI, 3.3 to 4.0%), respectively. Both regimens were well tolerated with few serious adverse events. Bone pain was higher in the immediate group, as expected, because some patients experienced acute-phase reactions after zoledronic acid infusion. CONCLUSIONS: At 12 months, immediate zoledronic acid therapy prevented bone loss in postmenopausal women who were receiving adjuvant letrozole.

BACKGROUND: Yannas and Burke developed the concept of the dermal regeneration template in the 1970s. It is now a widely accepted tool in the treatment of burns as well as in reconstructive surgery. METHODS: The authors present a previously published study of Integra used in 20 consecutive patients to reconstruct 30 anatomical sites and then analyze the histologic and clinical outcomes. Wound healing was evaluated by examination of weekly punch biopsy specimens with standard and immunohistochemical stains. Patient satisfaction was assessed using a visual analogue scale, and scar appearance was assessed using a modified Vancouver Scar Scale. RESULTS: Four distinct phases of dermal regeneration could be demonstrated histologically: imbibition, fibroblast migration, neovascularization, and remodeling and maturation. Full vascularization of the neodermis occurred at 4 weeks. Patients reported increased range of movement and improvement in appearance compared with their preoperative states. CONCLUSIONS: The color of the matrix reflected the stage of neodermal vascularization. No adnexa, nerve endings, or elastic fibers were seen in any of the specimens. The new collagen was histologically indistinguishable from normal dermal collagen. The authors also present their current protocol and experience with using Integra for a range of reconstructive procedures.

Abstract A multidisciplinary team that is comprised of professionals from industry, academia, and law enforcement who are studying methods to locate clandestine graves has been formed in Colorado. This article describes this team, research conducted, and preliminary results directed toward identifying the most effective means of locating buried bodies.

BACKGROUND: Surgical-site infection increases morbidity, mortality and financial burden. The preferred topical antiseptic agent (chlorhexidine or povidone-iodine) for preoperative skin cleansing is unclear. METHODS: A meta-analysis of clinical trials was conducted to determine whether preoperative antisepsis with chlorhexidine or povidone-iodine reduced surgical-site infection in clean-contaminated surgery. RESULTS: The systematic review identified six eligible studies, containing 5031 patients. Chlorhexidine reduced postoperative surgical-site infection compared with povidone-iodine (pooled odds ratio 0.68, 95 per cent confidence interval 0.50 to 0.94; P = 0.019) . CONCLUSION: Chlorhexidine should be used preferentially for preoperative antisepsis in clean-contaminated surgery.

Abstract Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown 1 to be highly efficient for discovery of genetic associations 2 . Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group 3 . Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling ( JAK1 ), monocyte–macrophage activation and endothelial permeability ( PDE4A ), immunometabolism ( SLC2A5 and AK5 ), and host factors required for viral entry and replication ( TMPRSS2 and RAB2A ).

Angioleiomyoma is a benign tumour arising from the vascular smooth muscle (tunica media) and presents commonly between third and fifth decades of life. Although there are sporadic reports about this tumour in the literature, none describes all the information in detail. This review is an attempt to collate all the facts in one concise article. Angioleiomyoma presents as a painful mass in approximately 60% of the cases. One of the distinct clinical feature noted is the increase in size of the swelling with physical activity of the involved part, especially in the hand. It should be considered in the differential diagnosis of painful nodular lesions of the extremity. Pre-operative diagnosis is difficult, but with a high index of suspicion and awareness, it is possible. The use of ultrasound and magnetic resonance imaging should be considered. It causes minimal morbidity and excision is usually curative. Histological examination using smooth muscle Actin stain portraits the smooth muscle bundles clearly.

Care of the patient with cleft lip and/or palate remains complex. Prior attempts at aggregating data to study the effectiveness of specific interventions or overall treatment protocols have been hindered by a lack of data standards. There exists a critical need to better define the outcomes- particularly those that matter most to patients and their families-and to standardize the methods by which these outcomes will be measured. This report summarizes the recommendations of an international, multidisciplinary working group with regard to which outcomes a typical cleft team could track, how those outcomes could be measured and recorded, and what strategies may be employed to sustainably implement a system for prospective data collection. It is only by agreeing on a common, standard set of outcome measures for the comprehensive appraisal of cleft care that intercenter comparisons can become possible. This is important for quality-improvement endeavors, comparative effectiveness research, and value-based health-care reform.