Glan Clwyd Hospital

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.

Introduction: Intravenous(IV) immunoglobulin(Ig) treatment is known to alleviate behavioral deficits in the experimentally induced model of sepsis. To delineate the mechanisms by which IVIg treatment prevents neuronal dysfunction, an array of immunological and apoptosis markers was investigated. Methods: Sepsis was induced by cecal ligation perforation(CLP) in rats. The animals were divided into five groups; sham, control, CLP + saline, CLP + immunoglobulin G IgG(250 mg/kg,iv), and CLP + immunoglobulins enriched with immunoglobulin M-IgGAM(250 mg/kg,iv). Blood and brain samples were taken in two sets of experiments after CLP to see the early(24 hrs) and late(10 days) effects of treatment. Total complement activity, complement 3(C3) and soluble complement C5b-9 levels were measured in sera of rats using ELISA-based methods. Cerebral complement content was analyzed by Western Blot. Immune cell infiltration and gliosis were examined by immunohistochemistry using cluster of differentiation 3, CD4, CD8, CD11b, CD19 and glial fibrillary acidic protein antibodies. Apoptotic neuronal death was investigated by TUNEL staining and Western Blot-based semi-quantitative evaluation of brain homogenates by bax and bcl-2 antibodies. Results: IV IgG and IgGAM administration significantly reduced systemic complement activity but increased serum C3 and soluble C5b-9 levels. Likewise, Western Blot data showed slightly increased C5b-9 expression and significantly reduced C1q expression in brain samples of IgGAM-treated but not IgG-treated septic rats especially in the first day of administration. No cerebral cellular infiltrates were observed in treated and non-treated septic rats. By contrast, IV IgG and IgGAM treatment induced considerable amelioration in glial cell proliferation which was increased in non-treated rats. IgG and IgGAM treated rats exhibited significantly reduced numbers of apoptotic neurons and cerebral expression levels of bax and bcl-2 as compared to nontreated rats. Conclusions: We suggest that IV IgG and IgGAM administration ameliorates neuronal dysfunction and behavioral deficits by reducing apoptotic cell death and glial cell proliferation. IgGAM treatment might be suppressing classical complement pathway by reducing C1q expression.

BACKGROUND: The role of prophylactic antibacterial agents after chemotherapy remains controversial. METHODS: We conducted a randomized, double-blind, placebo-controlled trial in patients who were receiving cyclic chemotherapy for solid tumors or lymphoma and who were at risk for temporary, severe neutropenia (fewer than 500 neutrophils per cubic millimeter). Patients were randomly assigned to receive either 500 mg of levofloxacin once daily or matching placebo for seven days during the expected neutropenic period. The primary outcome was the incidence of clinically documented febrile episodes (temperature of more than 38 degrees C) attributed to infection. Secondary outcomes included the incidence of all probable infections, severe infections, and hospitalization but did not include a systematic evaluation of antibacterial resistance. RESULTS: A total of 1565 patients underwent randomization (784 to placebo and 781 to levofloxacin). The tumors included breast cancer (35.4 percent), lung cancer (22.5 percent), testicular cancer (14.4 percent), and lymphoma (12.8 percent). During the first cycle of chemotherapy, 3.5 percent of patients in the levofloxacin group had at least one febrile episode, as compared with 7.9 percent in the placebo group (P<0.001). During the entire chemotherapy course, 10.8 percent of patients in the levofloxacin group had at least one febrile episode, as compared with 15.2 percent of patients in the placebo group (P=0.01); the respective rates of probable infection were 34.2 percent and 41.5 percent (P=0.004). Hospitalization was required for the treatment of infection in 15.7 percent of patients in the levofloxacin group and 21.6 percent of patients in the placebo group (P=0.004). The respective rate of severe infection was 1.0 percent and 2.0 percent (P=0.15), with four infection-related deaths in each group. An organism was isolated in 9.2 percent of probable infections. CONCLUSIONS: Among patients receiving chemotherapy for solid tumors or lymphoma, the prophylactic use of levofloxacin reduces the incidence of fever, probable infection, and hospitalization.

Fundamental processes influencing human growth can be revealed by studying extreme short stature. Using genetic linkage analysis, we find that biallelic loss-of-function mutations in the centrosomal pericentrin (PCNT) gene on chromosome 21q22.3 cause microcephalic osteodysplastic primordial dwarfism type II (MOPD II) in 25 patients. Adults with this rare inherited condition have an average height of 100 centimeters and a brain size comparable to that of a 3-month-old baby, but are of near-normal intelligence. Absence of PCNT results in disorganized mitotic spindles and missegregation of chromosomes. Mutations in related genes are known to cause primary microcephaly (MCPH1, CDK5RAP2, ASPM, and CENPJ).

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7 × 10(-8), HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4 × 10(-8), HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4 × 10(-8), HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2×10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.

BACKGROUND: The incidence of incisional hernias (IHs) following midline abdominal incisions is difficult to estimate. Furthermore recent analyses have reported inconsistent findings on the superiority of absorbable versus non-absorbable sutures. OBJECTIVE: To estimate the mean IH rate following midline laparotomy from the published literature, to identify variables that predict IH rates and to analyse whether the type of suture (absorbable versus non-absorbable) affects IH rates. METHODS: We undertook a systematic review according to PRISMA guidelines. We sought randomised trials and observational studies including patients undergoing midline incisions with standard suture closure. Papers describing two or more arms suitable for inclusion had data abstracted independently for each arm. RESULTS: Fifty-six papers, describing 83 separate groups comprising 14,618 patients, met the inclusion criteria. The prevalence of IHs after midline incision was 12.8% (range: 0 to 35.6%) at a weighted mean of 23.7 months. The estimated risk of undergoing IH repair after midline laparotomy was 5.2%. Two meta-regression analyses (A and B) each identified seven characteristics associated with increased IH rate: one patient variable (higher age), two surgical variables (surgery for AAA and either surgery for obesity surgery (model A) or using an upper midline incision (model B)), two inclusion criteria (including patients with previous laparotomies and those with previous IHs), and two circumstantial variables (later year of publication and specifying an exact significance level). There was no significant difference in IH rate between absorbable and non-absorbable sutures either alone or in conjunction with either regression analysis. CONCLUSIONS: The IH rate estimated by pooling the published literature is 12.8% after about two years. Seven factors account for the large variation in IH rates across groups. However there is no evidence that suture type has an intrinsic effect on IH rates.

Cryptosporidium wrairi was isolated from guinea pigs during a spontaneous outbreak of cryptosporidiosis. Despite the morphological and antigenic similarities to C. parvum, C. wrairi displayed a different host range and site of infection and may represent a separate species or sub-species. We used the polymerase chain reaction to clone two distinct 550 bp-long DNA fragments, Wc-I and Wc-II, of the gene encoding the Cryptosporidium oocyst wall protein (COWP) of C. wrairi, which showed 98% identity to the C. parvum homologue. Within Wc-I, polymorphic Rsal restriction sites were used to develop a polymerase chain reaction-restriction fragment length polymorphism method able to distinguish C. wrairi from C. parvum and to identify two groups of C. parvum isolates differentially associated with animal and human infections.

OBJECTIVE: To test whether steroids reduce respiratory distress in babies born by elective caesarean section at term. DESIGN: Multicentre pragmatic randomised trial. SETTING: 10 maternity units. PARTICIPANTS: 998 consenting women randomised at decision to deliver by elective caesarean section; 503 randomised to treatment group. INTERVENTIONS: The treatment group received two intramuscular doses of 12 mg betamethasone in the 48 hours before delivery. The control group received treatment as usual. OUTCOME MEASURES: The primary outcome was admission to special care baby unit with respiratory distress. Secondary outcomes were severity of respiratory distress and level of care in response. RESULTS: Sex, birth weight, and gestation were not different between the two groups. Of the 35 babies admitted to special baby units with respiratory distress, 24 were in the control group and 11 in the intervention group (P = 0.02). The incidence of admission with respiratory distress was 0.051 in the control group and 0.024 in the treatment group (relative risk 0.46, 95% confidence interval 0.23 to 0.93). The incidence of transient tachypnoea of the newborn was 0.040 in the control group and 0.021 in the treatment group (0.54, 0.26 to 1.12). The incidence of respiratory distress syndrome was 0.011 in the control group and 0.002 in the treatment group (0.21, 0.03 to 1.32). CONCLUSIONS: Antenatal betamethasone and delaying delivery until 39 weeks both reduce admissions to special care baby units with respiratory distress after elective caesarean section at term.

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.

Chronic subdural haematoma is predominantly a disease of the elderly. It usually follows a minor trauma. A history of direct trauma to the head is absent in up to half the cases. The common manifestations are altered mental state and focal neurological deficit. Neurological state at the time of diagnosis is the most important prognostic factor. Morbidity and mortality is higher in the elderly but outcome is good in patients who undergo neurosurgical intervention.

To determine the incidence and possible risk factors for dementia in patients with clinically probable Parkinson's disease (PD), a cohort (n = 86) of nondemented patients over 65 years of age with PD fulfilling the PD Brain Bank clinical diagnostic criteria were determined from community records. A similarly aged group of control subjects (n = 102) were recruited from the same area. Both groups were assessed at baseline and approximately 4 years later for cognition, mood, and motor function (PD patients only). The presence and severity of cognitive impairments was based on subject and informant interview, neuropsychological assessment based on the Cambridge Cognitive Examination (CAMCOG) and the application of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV). At 4 years, 51 (59%) of the PD and 72 (71%) of the control cohort were available for reassessment. Of the PD cohort, 18 (35.3%) had developed dementia and 5 (9.4%) had evidence of mild cognitive impairments. In the control group, 5 (7%) had developed dementia. The incidence of dementia per 1,000 person-years in the PD cohort was 107.1 (95% confidence interval [CI], 59.9-159.8) and in the control group was 17.9 (95% CI, 5.8-31.9). The relative risk of patients developing dementia was 5.1 times that of the controls (95% CI, 2.1-12.5). Increasing age, later age of onset of PD, longer duration of PD symptoms, the presence of hallucinations, and impairment of memory and language function were all predictive factors for the development of dementia (P < 0.05). Dementia was also found to be a significant predictor for institutional placement in the PD group. Compared with similarly aged controls, patients with clinically probable PD have a fivefold-increased risk of developing dementia. This finding has significant implications for successful clinical management of this condition.

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.

OBJECTIVES: To determine the effect on mortality of selective digestive decontamination, selective oropharyngeal decontamination, and topical oropharyngeal chlorhexidine in adult patients in general intensive care units and to compare these interventions with each other in a network meta-analysis. DESIGN: Systematic review, conventional meta-analysis, and network meta-analysis. Medline, Embase, and CENTRAL were searched to December 2012. Previous meta-analyses, conference abstracts, and key journals were also searched. We used pairwise meta-analyses to estimate direct evidence from intervention-control trials and a network meta-analysis within a Bayesian framework to combine direct and indirect evidence. INCLUSION CRITERIA: Prospective randomised controlled trials that recruited adult patients in general intensive care units and studied selective digestive decontamination, selective oropharyngeal decontamination, or oropharyngeal chlorhexidine compared with standard care or placebo. RESULTS: Selective digestive decontamination had a favourable effect on mortality, with a direct evidence odds ratio of 0.73 (95% confidence interval 0.64 to 0.84). The direct evidence odds ratio for selective oropharyngeal decontamination was 0.85 (0.74 to 0.97). Chlorhexidine was associated with increased mortality (odds ratio 1.25, 1.05 to 1.50). When each intervention was compared with the other, both selective digestive decontamination and selective oropharyngeal decontamination were superior to chlorhexidine. The difference between selective digestive decontamination and selective oropharyngeal decontamination was uncertain. CONCLUSION: Selective digestive decontamination has a favourable effect on mortality in adult patients in general intensive care units. In these patients, the effect of selective oropharyngeal decontamination is less certain. Both selective digestive decontamination and selective oropharyngeal decontamination are superior to chlorhexidine, and there is a possibility that chlorhexidine is associated with increased mortality.

It is estimated that there are 1.1–1.5 billion Muslims worldwide, comprising 18–25% of the world population (1,2). Fasting during Ramadan, a holy month of Islam, is an obligatory duty for all healthy adult Muslims. An ∼4.6% prevalence of diabetes worldwide (3) coupled with the results of the population-based Epidemiology of Diabetes and Ramadan 1422/2001 (EPIDIAR) study, which showed (in 12,243 people with diabetes from 13 Islamic countries) that ∼43% of patients with type 1 diabetes and ∼79% of patients with type 2 diabetes fast during Ramadan (4), lead to the estimation that some 40–50 million people with diabetes worldwide fast during Ramadan. Ramadan is a lunar-based month, and its duration varies between 29 and 30 days. Its timing changes with respect to seasons. Depending on the geographical location and season, the duration of the daily fast may range from a few to more than 20 h. Muslims who fast during Ramadan must abstain from eating, drinking, use of oral medications, and smoking from predawn to after sunset; however, there are no restrictions on food or fluid intake between sunset and dawn. Most people consume two meals per day during this month, one after sunset, referred to in Arabic as Iftar (breaking of the fast meal), and the other before dawn, referred to as Suhur (predawn). Fasting is not meant to create excessive hardship on the Muslim individual. The Koran specifically exempts the sick from the duty of fasting (Holy Koran, Al-Bakarah, 183–185), especially if fasting might lead to harmful consequences for the individual. Patients with diabetes fall under this category because their chronic metabolic disorder may place them at high risk for various complications if the pattern and amount of their meal and fluid intake is markedly altered. This exemption represents more than a simple permission not to …

Cryptosporidium spp is now widely accepted as a cause of gastroenteritis. Various methods have been applied to detect oocysts in faeces, but the difficulties of discriminating between non-cryptosporidial bodies, acid fast bodies like cryptosporidia, and cryptosporidia remain. A simple examination in two stages, suitable for routine use is described, using auramine phenol and carbol fuchsine for screening and a modified Ziehl-Neelsen staining method for confirmation. A further method, using Jenner and Giemsa stains, is of value for confirmation of identity, especially where fluorescence microscopy is unavailable. A modification of the formol-ether method of concentration is also described. Immunofluorescence and thin section electron microscopy provide definitive identification. Vomiting can be an important clinical feature of gastroenteritis, and the first description of oocysts in vomit is reported. Preliminary findings, after more than two years of study show that Cryptosporidium is an important pathogenic agent in gastroenteritis, confirm the increased incidence in children, and suggest a possible seasonal trend.

BACKGROUND: We assessed the activity of gemcitabine (G) and cisplatin/gemcitabine (C/G) in patients with locally advanced (LA) or metastatic (M) (advanced) biliary cancers (ABC) for whom there is no standard chemotherapy. METHODS: Patients, aged > or =18 years, with pathologically confirmed ABC, Karnofsky performance (KP) > or =60, and adequate haematological, hepatic and renal function were randomised to G 1000 mg m(-2) on D1, 8, 15 q28d (Arm A) or C 25 mg m(-2) followed by G 1000 mg m(-2) D1, 8 q21d (Arm B) for up to 6 months or disease progression. RESULTS: In total, 86 patients (A/B, n=44/42) were randomised between February 2002 and May 2004. Median age (64/62.5 years), KP, primary tumour site, earlier surgery, indwelling biliary stent and disease stage (LA: 25/38%) are comparable between treatment arms. Grade 3-4 toxicity included (A/B, % patients) anaemia (4.5/2.4), leukopenia (6.8/4.8), neutropenia (13.6/14.3), thrombocytopenia (9.1/11.9), lethargy (9.1/28.6), nausea/vomiting (0/7.1) and anorexia (2.3/4.8). Responses (WHO criteria, % of evaluable patients: A n=31 vs B n=36): no CRs; PR 22.6 vs 27.8%; SD 35.5 vs 47.1% for a tumour control rate (CR+PR+SD) of 58.0 vs 75.0%. The median TTP and 6-month progression-free survival (PFS) (the primary end point) were greater in the C/G arm (4.0 vs 8.0 months and 45.5 vs 57.1% in arms A and B, respectively). CONCLUSION: Both regimens seem active in ABC. C/G is associated with an improved tumour control rate, TTP and 6-month PFS. The study has been extended (ABC-02 study) and powered to determine the effect on overall survival and the quality of life.

OBJECTIVES: to study the diagnostic accuracy for parkinsonism and Parkinson's disease in a community-based sample of subjects on anti-parkinsonian medication. METHODS: computerized prescribing records in general practice were used to create a community-based disease register for Parkinson's disease. Subjects were examined to establish the likely diagnosis using recommended clinical diagnostic criteria. RESULTS: of 402 cases, parkinsonism was confirmed in 74% and clinically probable Parkinson's disease in 53%. The commonest causes of misdiagnosis were essential tremor, Alzheimer's disease and vascular pseudo-parkinsonism. Over one-quarter of subjects did not benefit from anti-parkinsonian medication. CONCLUSIONS: there is difficulty in diagnosing parkinsonism and Parkinson's disease in elderly subjects and we suggest early referral of those suspected of having parkinsonism for specialist assessment.

BACKGROUND: When cure is impossible, cancer treatment should focus on both length and quality of life. Maximisation of time without toxic effects could be one effective strategy to achieve both of these goals. The COIN trial assessed preplanned treatment holidays in advanced colorectal cancer to achieve this aim. METHODS: COIN was a randomised controlled trial in patients with previously untreated advanced colorectal cancer. Patients received either continuous oxaliplatin and fluoropyrimidine combination (arm A), continuous chemotherapy plus cetuximab (arm B), or intermittent (arm C) chemotherapy. In arms A and B, treatment continued until development of progressive disease, cumulative toxic effects, or the patient chose to stop. In arm C, patients who had not progressed at their 12-week scan started a chemotherapy-free interval until evidence of disease progression, when the same treatment was restarted. Randomisation was done centrally (via telephone) by the MRC Clinical Trials Unit using minimisation. Treatment allocation was not masked. The comparison of arms A and B is described in a companion paper. Here, we compare arms A and C, with the primary objective of establishing whether overall survival on intermittent therapy was non-inferior to that on continuous therapy, with a predefined non-inferiority boundary of 1.162. Intention-to-treat (ITT) and per-protocol analyses were done. This trial is registered, ISRCTN27286448. FINDINGS: 1630 patients were randomly assigned to treatment groups (815 to continuous and 815 to intermittent therapy). Median survival in the ITT population (n=815 in both groups) was 15.8 months (IQR 9.4-26.1) in arm A and 14.4 months (8.0-24.7) in arm C (hazard ratio [HR] 1.084, 80% CI 1.008-1.165). In the per-protocol population (arm A, n=467; arm C, n=511), median survival was 19.6 months (13.0-28.1) in arm A and 18.0 months (12.1-29.3) in arm C (HR 1.087, 0.986-1.198). The upper limits of CIs for HRs in both analyses were greater than the predefined non-inferiority boundary. Preplanned subgroup analyses in the per-protocol population showed that a raised baseline platelet count, defined as 400,000 per μL or higher (271 [28%] of 978 patients), was associated with poor survival with intermittent chemotherapy: the HR for comparison of arm C and arm A in patients with a normal platelet count was 0.96 (95% CI 0.80-1.15, p=0.66), versus 1.54 (1.17-2.03, p=0.0018) in patients with a raised platelet count (p=0.0027 for interaction). In the per-protocol population, more patients on continuous than on intermittent treatment had grade 3 or worse haematological toxic effects (72 [15%] vs 60 [12%]), whereas nausea and vomiting were more common on intermittent treatment (11 [2%] vs 43 [8%]). Grade 3 or worse peripheral neuropathy (126 [27%] vs 25 [5%]) and hand-foot syndrome (21 [4%] vs 15 [3%]) were more frequent on continuous than on intermittent treatment. INTERPRETATION: Although this trial did not show non-inferiority of intermittent compared with continuous chemotherapy for advanced colorectal cancer in terms of overall survival, chemotherapy-free intervals remain a treatment option for some patients with advanced colorectal cancer, offering reduced time on chemotherapy, reduced cumulative toxic effects, and improved quality of life. Subgroup analyses suggest that patients with normal baseline platelet counts could gain the benefits of intermittent chemotherapy without detriment in survival, whereas those with raised baseline platelet counts have impaired survival and quality of life with intermittent chemotherapy and should not receive a treatment break. FUNDING: Cancer Research UK.

mAbs have been raised against different epitopes on the protein product of the DMDL gene, which is an autosomal homologue of the X-linked DMD gene for dystrophin. These antibodies provide direct evidence that DMDL protein is localized near acetylcholine receptors at neuromuscular junctions in normal and mdx mouse intercostal muscle. The primary location in tissues other than skeletal muscle is smooth muscle, especially in the vascular system, which may account for the wide tissue distribution previously demonstrated by Western blotting. The DMDL protein was undetectable in the nonjunctional sarcolemma of normal human muscle, but was observed in nonjunctional sarcolemma of Duchenne muscular dystrophy patients, where dystrophin itself is absent or greatly reduced. The expression of DMDL protein is not restricted to smooth and skeletal muscle, however, since relatively large amounts are present in transformed brain cell lines of both glial and Schwann cell origin. This contrasts with the low levels of DMDL protein in adult brain tissue.

BACKGROUND: Pneumonia is the most common hospital-acquired infection affecting patients in the intensive care unit (ICU). However, current national guidelines for the treatment of hospital-acquired pneumonia (HAP) are several years old and the diagnosis of pneumonia in mechanically ventilated patients (VAP) has been subject to considerable recent attention. The optimal duration of antibiotic therapy for HAP in the critically ill is uncertain. OBJECTIVES: To assess the effectiveness of short versus prolonged-course antibiotics for HAP in critically ill adults, including patients with VAP. SEARCH METHODS: We searched CENTRAL (2015, Issue 5), MEDLINE (1946 to June 2015), MEDLINE in-process and other non-indexed citations (5 June 2015), EMBASE (2010 to June 2015), LILACS (1982 to June 2015) and Web of Science (1955 to June 2015). SELECTION CRITERIA: We considered all randomised controlled trials (RCTs) comparing a fixed 'short' duration of antibiotic therapy with a 'prolonged' course for HAP (including patients with VAP) in critically ill adults. DATA COLLECTION AND ANALYSIS: Two review authors conducted data extraction and assessment of risk of bias. We contacted trial authors for additional information. MAIN RESULTS: We identified six relevant studies involving 1088 participants. This included two new studies published after the date of our previous review (2011). There was substantial variation in participants, in the diagnostic criteria used to define an episode of pneumonia, in the interventions and in the reported outcomes. We found no evidence relating to patients with a high probability of HAP who were not mechanically ventilated. For patients with VAP, overall a short seven- or eight-day course of antibiotics compared with a prolonged 10- to 15-day course increased 28-day antibiotic-free days (two studies; N = 431; mean difference (MD) 4.02 days; 95% confidence interval (CI) 2.26 to 5.78) and reduced recurrence of VAP due to multi-resistant organisms (one study; N = 110; odds ratio (OR) 0.44; 95% CI 0.21 to 0.95), without adversely affecting mortality and other recurrence outcomes. However, for cases of VAP specifically due to non-fermenting Gram-negative bacilli (NF-GNB), recurrence was greater after short-course therapy (two studies, N = 176; OR 2.18; 95% CI 1.14 to 4.16), though mortality outcomes were not significantly different. One study found that a three-day course of antibiotic therapy for patients with suspected HAP but a low Clinical Pulmonary Infection Score (CPIS) was associated with a significantly lower risk of superinfection or emergence of antimicrobial resistance, compared with standard (prolonged) course therapy. AUTHORS' CONCLUSIONS: On the basis of a small number of studies and appreciating the lack of uniform definition of pneumonia, we conclude that for patients with VAP not due to NF-GNB a short, fixed course (seven or eight days) of antibiotic therapy appears not to increase the risk of adverse clinical outcomes, and may reduce the emergence of resistant organisms, compared with a prolonged course (10 to 15 days). However, for patients with VAP due to NF-GNB, there appears to be a higher risk of recurrence following short-course therapy. These findings do not differ from those of our previous review and are broadly consistent with current guidelines. There are few data from RCTs comparing durations of therapy in non-ventilated patients with HAP, but on the basis of a single study, short-course (three-day) therapy for HAP appears not to be associated with worse clinical outcome, and may reduce the risk of subsequent infection or the emergence of resistant organisms when there is low probability of pneumonia according to the CPIS.