Haloperidol for the Treatment of Delirium in ICU Patients.

BACKGROUND: Haloperidol is frequently used to treat delirium in patients in the intensive care unit (ICU), but evidence of its effect is limited. METHODS: In this multicenter, blinded, placebo-controlled trial, we randomly assigned adult patients with delirium who had been admitted to the ICU for an acute condition to receive intravenous haloperidol (2.5 mg 3 times daily plus 2.5 mg as needed up to a total maximum daily dose of 20 mg) or placebo. Haloperidol or placebo was administered in the ICU for as long as delirium continued and as needed for recurrences. The primary outcome was the number of days alive and out of the hospital at 90 days after randomization. RESULTS: A total of 1000 patients underwent randomization; 510 were assigned to the haloperidol group and 490 to the placebo group. Among these patients, 987 (98.7%) were included in the final analyses (501 in the haloperidol group and 486 in the placebo group). Primary outcome data were available for 963 patients (97.6%). At 90 days, the mean number of days alive and out of the hospital was 35.8 (95% confidence interval [CI], 32.9 to 38.6) in the haloperidol group and 32.9 (95% CI, 29.9 to 35.8) in the placebo group, with an adjusted mean difference of 2.9 days (95% CI, -1.2 to 7.0) (P = 0.22). Mortality at 90 days was 36.3% in the haloperidol group and 43.3% in the placebo group (adjusted absolute difference, -6.9 percentage points [95% CI, -13.0 to -0.6]). Serious adverse reactions occurred in 11 patients in the haloperidol group and in 9 patients in the placebo group. CONCLUSIONS: Among patients in the ICU with delirium, treatment with haloperidol did not lead to a significantly greater number of days alive and out of the hospital at 90 days than placebo. (Funded by Innovation Fund Denmark and others; AID-ICU ClinicalTrials.gov number, NCT03392376; EudraCT number, 2017-003829-15.).

Higher vs lower doses of dexamethasone in patients with COVID-19 and severe hypoxia (COVID STEROID 2) trial: Protocol and statistical analysis plan.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has resulted in millions of deaths and overburdened healthcare systems worldwide. Systemic low-dose corticosteroids have proven clinical benefit in patients with severe COVID-19. Higher doses of corticosteroids are used in other inflammatory lung diseases and may offer additional clinical benefits in COVID-19. At present, the balance between benefits and harms of higher vs. lower doses of corticosteroids for patients with COVID-19 is unclear. METHODS: The COVID STEROID 2 trial is an investigator-initiated, international, parallel-grouped, blinded, centrally randomised and stratified clinical trial assessing higher (12 mg) vs. lower (6 mg) doses of dexamethasone for adults with COVID-19 and severe hypoxia. We plan to enrol 1,000 patients in Denmark, Sweden, Switzerland and India. The primary outcome is days alive without life support (invasive mechanical ventilation, circulatory support or renal replacement therapy) at day 28. Secondary outcomes include serious adverse reactions at day 28; all-cause mortality at day 28, 90 and 180; days alive without life support at day 90; days alive and out of hospital at day 90; and health-related quality of life at day 180. The primary outcome will be analysed using the Kryger Jensen and Lange test adjusted for stratification variables and reported as adjusted mean differences and median differences. The full statistical analysis plan is outlined in this protocol. DISCUSSION: The COVID STEROID 2 trial will provide evidence on the optimal dosing of systemic corticosteroids for COVID-19 patients with severe hypoxia with important implications for patients, their relatives and society.

Volume of ropivacaine 0.2% and common peroneal nerve block duration: a randomised, double-blind cohort trial in healthy volunteers.

The volume-duration relationship using low concentrations of ropivacaine for peripheral nerve blocks is unknown, even though low concentrations of ropivacaine are increasingly used clinically. We investigated the effect of ropivacaine 0.2% on common peroneal nerve block duration. With ethical committee approval, 60 consenting, healthy volunteers were randomly allocated to receive one of five volumes of ropivacaine 0.2% (2.5, 5.0, 10, 15 or 20 ml) administered by ultrasound-guided, catheter-based injection (at 10 ml.min-1 ) near the common peroneal nerve. Our primary outcome was duration of sensory block, defined by insensitivity to a cold stimulus. Our secondary outcome was duration of motor block. Outcomes were assessed every hour from onset of block to complete remission. Intergroup differences were tested using one-way ANOVA followed by regression analyses using the 20 ml intervention group as reference. Block durations varied significantly (p < 0.0001) between groups. Mean (SD) sensory block durations were 9.2 (3.3), 12.5 (3.0), 15.5 (4.4), 17.3 (3.5) and 17.3 (4.6) h. Mean (SD) motor block durations were 3.3 (2.1), 7.2 (2.5), 9.2 (2.2), 12.7 (2.5) and 12.5 (2.5) h. Regression analysis showed that the effect of volume on block duration was progressively smaller with increasing volume, reaching a threshold volume above which there was no effect on nerve block duration (10 ml for sensory block and 15 ml for motor block). We conclude that there is a ceiling effect of increasing volume of ropivacaine 0.2% on both sensory and motor block duration of the common peroneal nerve.

Maternal systemic or cord blood inflammation is associated with birth anthropometry in a Tanzanian prospective cohort.

OBJECTIVES: HIV infection is associated with chronic systemic inflammation, with or without antiretroviral therapy. Consequences for foetal growth are not understood, particularly in settings where multiple maternal infections and malnutrition are common. The study was designed to examine maternal systemic circulating and umbilical cord blood cytokine concentrations in relation to birth anthropometry in a Tanzanian prospective cohort. METHODS: A 9-plex panel of maternal plasma cytokines in HIV-positive (n = 44) and HIV-negative (n = 70) mothers and the same cytokines in umbilical cord blood collected at delivery was assayed. Linear regression modelled associations between maternal or cord blood cytokines and birth anthropometry. RESULTS: Health indicators (haemoglobin, mid-upper-arm circumference, body mass index) in HIV-positive mothers without considerable immunosuppression did not differ from HIV-negative women. Despite this, HIV-exposed infants had lower birthweight and length. Subgroup analyses indicated that HIV management using HAART was associated with lower plasma TNF-α, as were longer durations of any antiretroviral therapy (≥2 months). Greater maternal plasma TNF-α was associated with earlier delivery (-1.7 weeks, P = 0.039) and lower birthweights (-287 g; P = 0.020), while greater umbilical cord TNF-α (-1.43 cm; P = 0.036) and IL-12p70 (-2.4 cm; P = 0.008) were associated with shorter birth length. Birthweight was inversely associated with cord IL-12p70 (-723 g; P = 0.001) and IFN-γ (-482 g, P = 0.007). Maternal cytokines during pregnancy did not correlate with umbilical cord cytokines at delivery. CONCLUSIONS: Systemic inflammation identified in maternal plasma or umbilical cord blood was associated with poorer birth anthropometrics in HIV-exposed and HIV-unexposed infants. Controlling maternal and/or foetal systemic inflammation may improve birth anthropometry.

Initial placement and secondary displacement of a new suture-method catheter for sciatic nerve block in healthy volunteers: a randomised, double-blind pilot study.

We performed a randomised double-blind pilot study in 16 healthy volunteers to investigate the success rate for placing a new suture-method catheter for sciatic nerve block. A catheter was inserted into both legs of volunteers and each was randomly allocated to receive 15 ml lidocaine 2% through the catheter in one leg and 15 ml saline in the other leg. Successful placement of the catheter was defined as a 20% decrease in maximum voluntary isometric contraction for dorsiflexion of the ankle. Secondary outcomes were maximum voluntary isometric contraction for plantar flexion at the ankle, surface electromyography and cold sensation. After return of motor and sensory function, volunteers performed standardised physical exercises; injection of the same study medication was repeated in the same leg and followed by motor and sensory assessments. Fifteen of 16 (94%; 95%CI 72-99%) initial catheter placements were successful. The reduction in maximum voluntary isometric contraction and surface electromyography affected the peroneal nerve more often than the tibial nerve. Eleven of 15 (73%; 95%CI 54-96%) catheters remained functional with motor and sensory block after physical exercise, and the maximal displacement was 5 mm. Catheters with secondary block failure were displaced between 6 and 10 mm. One catheter was displaced 1.8 mm that resulted in a decrease in maximum voluntary isometric contraction of less than 20%. After repeat test injection, 14 of the 16 volunteers had loss of cold sensation. Neither motor nor sensory functions were affected in the legs injected with placebo. We conclude that the suture-method catheter can be placed with a high success rate, but that physical exercise may cause displacement.

Comparison of innate and Th1-type host immune responses in Oesophagostomum dentatum and Trichuris suis infections in pigs.

This study investigated the details of the innate and Th1/Treg-type-associated host immune responses in Trichuris suis and Oesophagostomum dentatum mono- and co-infected pigs and in vitro in stimulated porcine dendritic cell cultures. Forty-eight pigs were allocated into a 2-factorial design with two groups trickle-inoculated with 10 T. suis eggs/kg/day (Group T) or 20 O. dentatum L3/kg/day (O). Another group (OT) was infected with both parasites. Group C remained uninfected. Expression of innate and Th1/Treg-cell-associated genes in gut mucosa and associated lymph nodes was determined by qPCR at necropsy day 35 and 71. Gene expression showed suppressed/inhibited Th1 and Treg-type immune reactions, in accordance with previous findings of a predominant Th2-type immune response to both nematodes. The in vitro part examined the production of TNF-α in porcine dendritic cells (DC) exposed to T. suis and/or O. dentatum excretory/secretory (E/S) products. Further, binding capacity and structure of E/S products were characterized. Glycan and lectin-binding capacity were generally lower in O. dentatum E/S products compared to T. suis which may explain the earlier found weaker Th2 response to the former. Surprisingly, O. dentatum E/S products induced a significant (P < 0·0001) increase in TNF-α DC production, potentially indicating a new mode of helminth-host immune response interaction.

Plasma follistatin is elevated in patients with type 2 diabetes: relationship to hyperglycemia, hyperinsulinemia, and systemic low-grade inflammation.

BACKGROUND: Plasma follistatin is elevated in patients with low-grade inflammation and insulin resistance as observed with polycystic ovary syndrome. In the present study, we evaluated plasma follistatin in patients with type 2 diabetes characterised by low-grade inflammation and assessed the acute effects of hyperglycemia, hyperinsulinemia and LPS on plasma follistatin. METHODS: Baseline plasma follistatin and inflammatory biomarkers were measured in a cross-sectional study that involved 95 patients with type 2 diabetes and 103 matched controls. To determine the acute effect of hyperglycemia and hyperinsulinemia on follistatin, hyperglycemic and hyperinsulinemic-euglycemic clamps were performed in five healthy males. Furthermore, 15 patients with type 2 diabetes and 22 healthy controls were challenged with low-dose LPS to determine the effect on follistatin. RESULTS: Patients with type 2 diabetes have higher HOMA2-IR values mean [95% CI] 1.64 [1.40-1.93] versus mean 0.86 [0.75-0.99], p < 0.001 and inflammatory markers compared with controls. Baseline plasma follistatin is elevated in patients with type 2 diabetes compared with controls mean 1564 [1456-1680] versus mean 1328 [1225-1440] ng/L, p = 0.003 and correlates with fasting glucose levels (r = 0.44, p < 0.0001), 2 h glucose (r = 0.48, p < 0.0001), HbA1c (r = 0.41, p < 0.0001), triacylglycerol (r = 0.28, p = 0.008) and total cholesterol (r = 0.33, p = 0.004) in patients but not in controls. No correlation exists between plasma follistatin and inflammatory biomarkers in either of the groups. Neither hyperglycemia, hyperinsulinemia nor LPS increase plasma follistatin. CONCLUSIONS: Plasma follistatin is moderately elevated in patients with type 2 diabetes. Our findings suggest that this is not likely caused by hyperglycemia, hyperinsulinemia or systemic low-grade inflammation.

Growth hormone effects on cortical bone dimensions in young adults with childhood-onset growth hormone deficiency.

UNLABELLED: Growth hormone (GH) treatment in young adults with childhood-onset GH deficiency has beneficial effects on bone mass. The present study shows that cortical bone dimensions also benefit from GH treatment, with endosteal expansion and increased cortical thickness leading to improved bone strength. INTRODUCTION: In young adults with childhood-onset growth hormone deficiency (CO GHD), GH treatment after final height is reached has been shown to have beneficial effects on spine and hip bone mineral density. The objective of the study was to evaluate the influence of GH on cortical bone dimensions. METHODS: Patients (n = 160; mean age, 21.2 years; 63% males) with CO GHD were randomised 2:1 to GH or no treatment for 24 months. Cortical bone dimensions were evaluated by digital x-ray radiogrammetry of the metacarpal bones every 6 months. RESULTS: After 24 months, cortical thickness was increased compared with the controls (6.43%, CI 3.34 to 9.61%; p = 0.0001) and metacarpal index (MCI) (6.14%, CI 3.95 to 8.38%; p < 0.0001), while the endosteal diameter decreased (-4.64%, CI -7.15 to -2.05; p < 0.001). Total bone width did not change significantly (0.68%, CI -1.17 to 2.57%; not significant (NS)). A gender effect was seen on bone width (p < 0.0001), endosteal diameter (p < 0.01) and cortical thickness (p < 0.01), but not with MCI (NS). CONCLUSIONS: Cortical bone reacts promptly to reinstitution of GH beyond the attainment of final height by increasing the cortical thickness through endosteal bone growth. This leads to a higher peak bone mass and may reduce the risk of cortical bone fragility later in life.

A nationwide study on anastomotic leakage after colonic cancer surgery.

AIM: Anastomotic leakage (AL) is a major challenge in colorectal cancer surgery due to increased morbidity and mortality. Possible risk factors should be investigated differentially, distinguishing between rectal and colonic surgery in large-scale studies to avoid selection bias and confounding. METHOD: The incidence and risk factors associated with AL were analysed in an unselected nationwide prospective cohort of patient subjected to curative colonic cancer surgery with primary anastomosis and entered into The Danish Colorectal Cancer Group database between May 2001 and December 2008. RESULTS: AL occurred in 593 (6.4%) of 9333 patients. Laparoscopic surgery [odds ratio (OR) 1.34; 95% confidence interval (CI) 1.05-1.70; P=0.03); left hemicolectomy (OR 2.02; 95% CI 1.50-2.72; P=0.01) or sigmoid colectomy (OR 1.69; 95% CI 1.32-2.17; P=0.01); intra-operative blood loss (OR 1.04; 95% CI 1.01-1.07; P=0.03); blood transfusion (OR 10.27; 95% CI 6.82-15.45; P<0.001) and male gender (OR 1.41; 95% CI 1.12-1.75; P=0.02) were associated with AL in the multivariate analysis. CONCLUSION: The main finding that a laparoscopic approach was associated with an increased risk of AL should prompt close future monitoring. There was no evidence that centralization of surgery to high-volume hospitals reduced the rate of AL.

The effect of exercise therapy on fatigue in multiple sclerosis.

BACKGROUND: Fatigue occurs in the majority of patients with multiple sclerosis (MS) and therapeutic possibilities are few. Exercise therapy is a therapeutic option but no studies have systematically reviewed the existing literature evaluating the effect of exercise therapy on MS fatigue. OBJECTIVE: To determine the effect of exercise therapy on MS fatigue by systematically reviewing the literature. METHODS: A comprehensive literature search (PubMed, SweMed +, Embase, Cochrane, CINAHL, PEDro, Sport Discuss and Bibliotek.dk) was conducted. RESULTS: Studies evaluating the effect of exercise therapy on MS fatigue show heterogeneous results and only few studies have evaluated MS fatigue as the primary outcome. The heterogeneous findings seem to be related to the selected study population, which in many studies are non-fatigued. Most studies that have included fatigued patients with MS show positive effects, although it is not clear whether any exercise modalities are superior to others because there are no comparative studies regarding different exercise interventions. CONCLUSION: Exercise therapy has the potential to induce a positive effect on MS fatigue, but findings are heterogeneous probably because many studies have applied non-fatigued study populations. Furthermore, only few studies have evaluated MS fatigue as the primary outcome measure, emphasizing the need for future studies within this field.

Flt3 ligand induces tumor regression and antitumor immune responses in vivo.

Daily treatment of mice with recombinant human Flt3 ligand (huFlt3L) results in a dramatic numerical increase in the number of dendritic cells (DCs) in vivo. Since DCs are pivotal in the induction of immune responses, we tested whether Flt3L treatment of mice challenged with a syngeneic methylcholanthrene (MCA)-induced fibrosarcoma would augment the generation of effective antitumor immune responses in vivo. Flt3L treatment not only induced complete tumor regression in a significant proportion of mice, but also decreased tumor growth rate in the remaining mice. A preliminary characterization of the cellular mechanisms involved suggests that Flt3L may be important in the treatment of cancer in situ through the generation of specific antitumor immune responses.

Regional brain atrophy in primary fatigued patients with multiple sclerosis.

OBJECTIVE: To examine the relationship between fatigue, regional brain atrophy and normal appearing white matter damage in patients with multiple sclerosis. METHODS: Primary fatigued (PF) (n, 17) and non-fatigued (NF) (n, 17) patients with relapsing remitting multiple sclerosis and moderate disability were grouped according to their subjective fatigue score. Also, they were examined with respect to processing speed and central motor activation during isometric contraction. Using 3 Tesla MRI quantitative analyses were performed on normal appearing brain tissue and of brain structure volumes with tensor based morphometry. RESULTS: Between the PF and NF patients there was no significant differences in brain parenchymal fraction (81.5% vs. 82.4%), lesion load (0.53% vs. 0.36%) and NAA/Cr ratio (1.29 vs. 1.32 respectively). Eleven clusters of atrophy in PF versus NF involved gray and nearby white matter, the majority being located in areas functionally related to attentional control. Central motor activation was associated with atrophy in five regions in PF patients, three clusters involving the premotor and primary motor cortex. Normal appearing white matter did not differ between groups. CONCLUSION: Primary fatigued patients with multiple sclerosis have extended regional atrophy of supratentorial brain parenchyma, involving the cerebral cortex, nearby white matter and the caudate head, areas which are functionally related to attentional control. We suggest that impaired central motor activation is due to interruption of the cortico-subcortical motor circuits involving the motor cortex.

Validation of a 5-year risk score of hip fracture in postmenopausal women. The Danish Nurse Cohort Study.

SUMMARY: We evaluated the Women's Health Initiative (WHI) hip fracture risk score in 15,648 postmenopausal Danish nurses. The algorithm was well calibrated for Denmark. However, the sensitivity was poor at common decision making thresholds. Obtaining sensitivity better than 80% led to a low specificity of 61.4%. INTRODUCTION: A new score based on data from the WHI has been designed to predict 5-year risk of hip fracture in postmenopausal women. The performance of the algorithm has not been validated in populations with different lifestyle characteristics and ethnicity. The aim of this study was to test the clinical performance of the algorithm in a large Danish cohort of postmenopausal Caucasian women against hip fracture. METHODS: The Danish Nurse Cohort is a prospective risk factor and hormone therapy (HT) study established in 1993. Participants in the present analysis were 15,648 postmenopausal nurses. The calibration and diagnostic performance of the WHI algorithm was evaluated using fracture events captured in the Danish National Hospital Registry. RESULTS: During 5 years of follow-up, 122 participants suffered a hip fracture (1.8/1,000 person years). The WHI algorithm predicted that 107 hip fractures would occur, indicating an underestimation of the number of fractures by 12%. To obtain sensitivity better than 80%, the cut-off value for 5-year risk was set to 0.5%, which was accompanied by a low positive predictive value of 1.9% and a low specificity of 61.4%. The algorithm predicted too many fractures in HT-users (12 observed, 22 expected) and too few in non HT-users (107 observed, 81 expected). CONCLUSIONS: While the WHI algorithm was well calibrated on the Danish population, the clinical utility of the WHI algorithm in Danish postmenopausal women was limited by poor sensitivity at common decision-making thresholds and suboptimal in non-HT-users.

Fatigue and processing speed are related in multiple sclerosis.

BACKGROUND: Fatigue is common in multiple sclerosis (MS) and could be related to impaired processing speed caused by MS specific brain alterations. The objective of this study was to examine the relationship between processing speed and fatigue in patients with relapsing remitting MS. METHODS: Patients with EDSS score < or =3.5 were grouped as fatigued [Fatigue Severity Scale (FSS) score > or =5.0] or non-fatigued (FSS score < or =4.0). Patients with FSS scores > or =5 were categorized as primary or secondary fatigued according to various indices. A cognitive test battery obtained from Wechsler's Adult Intelligence Scale-III/Wechsler's Memory Scale-III was applied. RESULTS: Processing speed (Digit Symbol Coding) was lower amongst all MS patients being 9.4(2.9) in primary fatigued, 8.3(2.8) in secondary fatigued and 10.3(2.7) in non-fatigued versus 12.3(3.0) in healthy controls. In the combined group of primary and secondary fatigued MS patients, processing speed was slower than that in non-fatigued MS patients and inversely related to fatigue (r = -0.35; P < 0.05). No such relationship could be established in non-fatigued MS patients or in healthy controls. CONCLUSION: The degree of fatigue in MS is related to processing speed impairment and longitudinal studies should clarify their mutual dependency.

Serum concentrations of matrix metalloproteinase-9, tissue inhibitor of matrix metalloproteinase-1 and alpha2-macroglobulin in healthy subjects after supplementation with different doses of marine n-3 fatty acids.

OBJECTIVE: Extracellular matrix modification by matrix metalloproteinase-9 (MMP-9), tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) and alpha2-macroglobulin may affect the stability of atherosclerotic plaques. Marine n-3 polyunsaturated fatty acids (n-3 PUFA) may protect against plaque rupture. The aim was to investigate the effect of marine n-3 PUFA supplementation on serum levels of MMP-9, TIMP-1, and alpha2-macroglobulin. METHODS: Healthy volunteers were randomized to receive capsules contributing either 6.6 g marine n-3 PUFA/day, 2.0 g marine n-3 PUFA/day or 6.6 g of olive oil (control). Serum MMP-9, TIMP-1 and alpha2-macroglobulin was measured at baseline and after 12 weeks of supplementation. One way ANOVA or Kruskal-Wallis test was used to compare groups. RESULTS: 60 healthy volunteers were enrolled and no subjects dropped out of the 12 week study. There were no statistically significant changes in serum levels of MMP-9, TIMP-1, and alpha2-macroglobulin in any of the three treatment groups (P=0.85, P=0.23 and P=0.87, respectively). CONCLUSION: Supplementation with marine n-3 PUFA had no effect on serum levels of MMP-9, TIMP-1 and alpha2-macroglobulin in healthy subjects. The possible protection offered by marine n-3 PUFA against plaque rupture is therefore unlikely to be mediated through a change in serum levels of MMP-9, TIMP-1 and alpha2-macroglobulin.

Anastomotic leakage after anterior resection for rectal cancer: risk factors.

OBJECTIVE: The study aimed to identify risk factors for clinical anastomotic leakage (AL) after anterior resection for rectal cancer in a consecutive national cohort. METHOD: All patients with an initial first diagnosis of colorectal adenocarcinoma were prospectively registered in a national database. The register included 1495 patients who had had a curative anterior resection between May 2001 and December 2004. The association of a number of patient- and procedure-related factors with clinical AL after anterior resection was analysed in a cohort design. RESULTS: Anastomotic leakages occurred in 163 (11%) patients. In a multivariate analysis, the risk of AL was significantly increased in patients with tumours located below 10 cm from the anal verge if no faecal diversion was undertaken (OR 5.37 5 cm (tumour level from anal verge), 95% CI 2.10-13.7, OR 3.57 7 cm, CI 1.81-7.07 and OR 1.96 10 cm, CI 1.22-3.10), in male patients (OR 2.36, CI 1.18-4.71), in smokers (OR 1.88, CI 1.02-3.46), and perioperative bleeding (OR 1.05 for intervals of 100 ml blood loss, CI 1.02-1.07). CONCLUSION: Anastomotic leakage after anterior resection for low rectal tumours is related to the level, male gender, smoking and perioperative bleeding. Faecal diversion is advisable after total mesorectal excision of low rectal tumours in order to prevent AL.

Anastomotic leakage after curative anterior resection for rectal cancer: short and long-term outcome.

OBJECTIVE: The influence of symptomatic anastomotic leakage (AL) after anterior resection (AR) for rectal cancer on short and long-term mortality and local and distant recurrence was analysed. METHOD: All patients with a first diagnosis of rectal carcinoma were prospectively registered in a national database. This comprised 1494 Danish citizens who had had a curative AR between May 2001 and December 2004. Data on survival and recurrence were obtained from the National Patient Register. Multivariate analyses were performed. RESULTS: Anastomotic leakage increased the 30-day mortality [odds ratio (OR) 4.01 (95% CI 2.24-7.17)]. Of other possible risk factors, only age had a significant interaction with leakage, as the risk of death within 30 days of AR decreased with increasing age. Long-term survival decreased significantly after AL [hazard ratio (HR) of 1.63, CI 1.21-2.19]. A total of 97 (6.7%) and 258 (18.0%) patients had local and distant recurrence respectively in the follow-up period. The risk of local and distant recurrence after AL was not different with HR of 1.50 (CI 0.84-2.69) and 1.13 (CI 0.76-1.69) respectively. No other factors influenced the risk of recurrence due to AL. CONCLUSION: Anastomotic leakage after AR for rectal cancer increases the 30-day and long-term mortality, but AL did not increase the risk of local and distant recurrence.

Prevalence of HIV, HCV and sexually transmitted infections among injecting drug users in Rawalpindi and Abbottabad, Pakistan: evidence for an emerging injection-related HIV epidemic.

OBJECTIVES: To measure the prevalence of hepatitis C virus (HCV), HIV and sexually transmitted infections (STI) among injecting drug users (IDUs) in Rawalpindi and Abbottabad and to examine risk factors associated with HIV and HCV. METHODS: Two cross-sectional surveys were performed of community-recruited IDUs with collection of clinical specimens for testing of HCV, HIV and other STIs. Behavioural data were collected through interviewer-administered questionnaires. Characteristics and risk behaviours were compared across cities. Univariate and multivariate analyses explored risk factors associated with HIV and HCV. RESULTS: The prevalence of HIV was 2.6% (95% CI 0.83% to 4.5%) in Rawalpindi (n = 302) and zero in Abbottabad (n = 102). The prevalence of HCV was significantly higher in Rawalpindi at 17.3% (95% CI 13.0% to 21.6%) than in Abbottabad at 8% (95% CI 2.6% to 13.4%). The prevalence of other STIs was low in both cities, with <2% of participants having current gonorrhoea or Chlamydia and <3% with active syphilis. Injecting risk behaviours were greater in Rawalpindi. An increased risk of HCV was associated with using informal sources as a main source of new needles/syringes (OR 2.8, 95% CI 1.3 to 6.0) compared with pharmacies and a history of drug treatment (OR 3.7, 95% CI 0.9 to 11.6). Reporting symptoms of an STI was associated with decreased odds of HIV in Rawalpindi (OR 0.02, 95% CI 0.03 to 0.9). CONCLUSIONS: The findings suggest recent transmission of HIV and HCV and point to the urgent need for the provision of clean needles/syringes to IDUs and a review of how needles/syringes are currently provided via healthcare establishments.

HIV and other sexually transmitted infections among men, transgenders and women selling sex in two cities in Pakistan: a cross-sectional prevalence survey.

OBJECTIVES: The extent and possibilities of spread of the HIV epidemic are not fully understood in Pakistan. A survey was conducted among men, women and transgender populations selling sex in Rawalpindi (Punjab) and Abbottabad (North West Frontier Province) in order to inform evidence-based programme planning. METHODS: A cross-sectional survey was performed with participants recruited through respondent-driven sampling. Male and transgender sex workers were analysed in three gender groups; women were analysed as one group. Behavioural surveys were conducted and clinical specimens collected. Laboratory tests looked for evidence of acute infection (gonorrhoea, Chlamydia, syphilis, Trichomonas) and infection over the lifetime (HIV, herpes simplex virus-2, syphilis). Predictors of infection were explored using univariable and multivariable logistic regression. RESULTS: The prevalence of HIV was low in 917 male and transgender sex workers and absent in 533 female sex workers in the study. High levels of current sexually transmitted infections were found, predominantly among transgender sex workers. Risk behaviours were common and knowledge of HIV was extremely low. Multivariable analysis found a large number of factors associated with higher levels of infection, including experience of forced first sex. Protection against risk was low, but those sex workers who reported using condoms at last sex had lower rates of infection. CONCLUSIONS: The HIV epidemic is currently in its early stages among people who sell sex, but there may be potential for a much greater spread given the levels of other sexually transmitted infections found and the concomitant low levels of both protective knowledge and risk-reducing behaviours. Action is needed now to avert an epidemic. Framing interventions by upholding the recognition and protection of human rights is vital.

Human endotoxemia as a model of systemic inflammation.

Systemic inflammation is a pathogenetic component in a vast number of acute and chronic diseases such as sepsis, trauma, type 2 diabetes, atherosclerosis, and Alzheimer's disease, all of which are associated with a substantial morbidity and mortality. However, the molecular mechanisms and physiological significance of the systemic inflammatory response are still not fully understood. The human endotoxin model, an in vivo model of systemic inflammation in which lipopolysaccharide is injected or infused intravenously in healthy volunteers, may be helpful in unravelling these issues. The present review addresses the basic changes that occur in this model. The activation of inflammatory cascades as well as organ-specific haemodynamic and functional changes after lipopolysaccharide are described, and the limitations of human-experimental models for the study of clinical disease are discussed. Finally, we outline the ethical considerations that apply to the use of human endotoxin model.