Safety and efficacy of antibiotics compared with appendicectomy for treatment of uncomplicated acute appendicitis: meta-analysis of randomised controlled trials

Objective To compare the safety and efficacy of antibiotic treatment versus appendicectomy for the primary treatment of uncomplicated acute appendicitis. Design Meta-analysis of randomised controlled trials. Population Randomised controlled trials of adult patients presenting with uncomplicated acute appendicitis, diagnosed by haematological and radiological investigations. Interventions Antibiotic treatment versus appendicectomy. Outcome measures The primary outcome measure was complications. The secondary outcome measures were efficacy of treatment, length of stay, and incidence of complicated appendicitis and readmissions. Results Four randomised controlled trials with a total of 900 patients (470 antibiotic treatment, 430 appendicectomy) met the inclusion criteria. Antibiotic treatment was associated with a 63% (277/438) success rate at one year. Meta-analysis of complications showed a relative risk reduction of 31% for antibiotic treatment compared with appendicectomy (risk ratio (Mantel-Haenszel, fixed) 0.69 (95% confidence interval 0.54 to 0.89); I2=0%; P=0.004). A secondary analysis, excluding the study with crossover of patients between the two interventions after randomisation, showed a significant relative risk reduction of 39% for antibiotic therapy (risk ratio 0.61 (0.40 to 0.92); I2=0%; P=0.02). Of the 65 (20%) patients who had appendicectomy after readmission, nine had perforated appendicitis and four had gangrenous appendicitis. No significant differences were seen for treatment efficacy, length of stay, or risk of developing complicated appendicitis. Conclusion Antibiotics are both effective and safe as primary treatment for patients with uncomplicated acute appendicitis. Initial antibiotic treatment merits consideration as a primary treatment option for early uncomplicated appendicitis

N-acetylcysteine (NAC), an anti-oxidant, does not improve bone mechanical properties in a rat model of progressive chronic kidney disease-mineral bone disorder

Individuals with chronic kidney disease have elevated levels of oxidative stress and are at a significantly higher risk of skeletal fracture. Advanced glycation end products (AGEs), which accumulate in bone and compromise mechanical properties, are known to be driven in part by oxidative stress. The goal of this study was to study effects of N-acetylcysteine (NAC) on reducing oxidative stress and improving various bone parameters, most specifically mechanical properties, in an animal model of progressive CKD. Male Cy/+ (CKD) rats and unaffected littermates were untreated (controls) or treated with NAC (80 mg/kg, IP) from 30 to 35 weeks of age. Endpoint measures included serum biochemistries, assessments of systemic oxidative stress, bone morphology, and mechanical properties, and AGE levels in the bone. CKD rats had the expected phenotype that included low kidney function, elevated parathyroid hormone, higher cortical porosity, and compromised mechanical properties. NAC treatment had mixed effects on oxidative stress markers, significantly reducing TBARS (a measure of lipid peroxidation) while not affecting 8-OHdG (a marker of DNA oxidation) levels. AGE levels in the bone were elevated in CKD animals and were reduced with NAC although this did not translate to a benefit in bone mechanical properties. In conclusion, NAC failed to significantly improve bone architecture/geometry/mechanical properties in our rat model of progressive CKD

Effect of a Cold Margin on Ice Flow at the Terminus of Storglaciaren, Sweden: Implications for Sediment Transfer

The cold-based termini of polythermal glaciers are usually assumed to adhere strongly to an immobile substrate and thereby supply significant resistance to the flow of warm-based ice upglacier. This compressive environment is commonly thought to uplift basal sediment to the surface of the glacier by folding and thrust faulting. We present model and field evidence from the terminus of Storglaciaren, Sweden, showing that the cold margin provides limited resistance to flow from up-glacier. Ice temperatures indicate that basal freezing occurs in this zone at 10−1 –10−2 ma−1, but model results indicate that basal motion at rates greater than 1ma−1 must, nevertheless, persist there for surface and basal velocities to be consistent with measurements. Estimated longitudinal compressive stresses of 20– 25 kPa within the terminus further indicate that basal resistance offered by the cold-based terminus is small. These results indicate that where polythermal glaciers are underlain by unlithified sediments, ice-flow trajectories and sediment transport pathways may be affected by subglacial topography and hydrology more than by the basal thermal regime

Prospective, randomized, multi-institutional clinical trial of a silver alginate dressing to reduce lower extremity vascular surgery wound complications

ObjectiveWound complications negatively affect outcomes of lower extremity arterial reconstruction. By way of an investigator initiated clinical trial, we tested the hypothesis that a silver-eluting alginate topical surgical dressing would lower wound complication rates in patients undergoing open arterial procedures in the lower extremity.MethodsThe study block-randomized 500 patients at three institutions to standard gauze or silver alginate dressings placed over incisions after leg arterial surgery. This original operating room dressing remained until gross soiling, clinical need to remove, or postoperative day 3, whichever was first. Subsequent care was at the provider's discretion. The primary end point was 30-day wound complication incidence generally based on National Surgical Quality Improvement Program guidelines. Demographic, clinical, quality of life, and economic end points were also collected. Wound closure was at the surgeon's discretion.ResultsParticipants (72% male) were 84% white, 45% were diabetic, 41% had critical limb ischemia, and 32% had claudication (with aneurysm, bypass revision, other). The overall 30-day wound complication incidence was 30%, with superficial surgical site infection as the most common. In intent-to-treat analysis, silver alginate had no effect on wound complications. Multivariable analysis showed that Coumadin (Bristol-Myers Squibb, Princeton, NJ; odds ratio [OR], 1.72; 95% confidence interval [CI], 1.03-2.87; P = .03), higher body mass index (OR, 1.05; 95% CI, 1.01-1.09; P = .01), and the use of no conduit/material (OR, 0.12; 95% CI, 0.82-3.59; P < .001) were independently associated with wound complications.ConclusionsThe incidence of wound complications remains high in contemporary open lower extremity arterial surgery. Under the study conditions, a silver-eluting alginate dressing showed no effect on the incidence of wound complications

Immunohistochemical inflammation in histologically normal appendices in patients with right iliac fossa pain

BackgroundHistologically normal appendices resected for right iliac fossa pain in children demonstrate immunohistochemical markers of inflammation. We aimed to establish if subclinical inflammation was present in histologically normal appendices resected from adults with right iliac fossa pain.MethodsImmunohistochemistry was performed on formalin-fixed paraffin-embedded appendices for tumour necrosis factor (TNF)-α, interleukin (IL)-6, IL-2R and serotonin in four groups: Group I (n = 120): uncomplicated appendicitis, Group II (n = 118): complicated appendicitis (perforation or gangrene), Group III (n = 104): histologically normal appendices resected for right iliac fossa pain and Group IV (n = 106) appendices resected at elective colectomy. Expression was quantified using the H-scoring system.ResultsMedian, interquartile range expression of TNF-α was increased in Groups I (5.9, 3.1–9.8), II (6.8, 3.6–12.1) and III (9.8, 6.2–15.2) when compared with Group IV (3.0, 1.4–4.7, p ≤ 0.01). Epithelial expression of IL-6 in Groups II (44.0, 8.0–97.0) and III (71.0, 18.5–130.0) was increased when compared with Group IV (9.5, 1.0–60.2, p ≤ 0.01). Expression of mucosal IL-2R in Groups I (47.4, 34.8–69.0), II (37.8, 25.4–60.4) and III (18.4, 10.1–34.7) was increased when compared with Group IV (2.8, 1.2–5.7, p ≤ 0.01). Serotonin content in Groups I (3.0, 0–30.0) and II (0, 0–8.5) was decreased when compared with Groups III (49.7, 16.7–107.5) and IV (43.5, 9.5–115.8, p ≤ 0.01).ConclusionHistologically normal appendices resected from symptomatic patients exhibited increased proinflammatory cytokine expression on immunohistochemistry suggesting the presence of an inflammatory process not detected on conventional microscopy

SynthoPlate: A platelet-inspired hemostatic nanotechnology for treatment of bleeding complications

Platelet transfusions are routinely used in the clinic to treat bleeding complications stemming from trauma, surgery, malignancy-related bone marrow dysfunctions, and congenital or drug-related defects platelet defects. These transfusions primarily use allogeneic platelet concentrates (PCs) that pose issues of limited availability and portability, high risk of bacterial contamination, very short shelf life (~3-5 days), need for antigen matching and several biologic side effects. While robust research is being directed at resolving some of these issues, there is in parallel a significant clinical interest in synthetic platelet substitutes that can render efficient hemostasis by leveraging and amplifying endogenous clotting mechanisms while avoiding the above issues. To this end, we have developed a unique platelet-inspired synthetic hemostat technology called the SynthoPlate® (US Patent 9107845). Since platelets promote primary hemostasis via adhesion to vWF and collagen at the injury site and concomitant aggregation via fibrinogen binding to integrin GPIIb-IIIa on active platelets, we have mimicked and integrated these key hemostatic mechanisms on the SynthoPlate® by heteromultivalent surface-engineering of a liposomal platform with vWF-binding peptides (VBP), collagen-binding peptides (CBP) and fibrinogen-mimetic peptides (FMP). These ~150nm diameter SynthoPlate® vesicles are sterilizable and can be stored as lyophilized powder for long periods of time. We demonstrated, in vitro, that this platelet-mimetic integrative design renders hemostatically relevant functions at levels significantly higher than designs that mimic platelet’s adhesion function only or aggregation function only. We further demonstrated in vitro that SynthoPlate®-mediated site-selective amplification of primary hemostatic mechanisms (active platelet recruitment and aggregation) in effect results in site-selective enhancement of secondary hemostatic function (fibrin generation). We also established that SynthoPlate® does not activate and aggregate resting platelets or trigger coagulation mechanisms in plasma, suggesting that this technology will not have systemic pro-thrombotic and coagulatory risks. The hemostatic efficacy of SynthoPlate® was tested in appropriate tail-transection and liver bleeding models in mice, as well as, pilot studies in arterial bleeding model in pigs. In tail-transection bleeding model in normal as well as thrombocytopenic mice, prophylactically administered SynthoPlate® was able to significantly reduce bleeding time by 60-70%. In laparotomy traumatic bleeding model in mice, prophylactically administered SynthoPlate® was able to reduce blood volume loss by ~30%, reduced hypotension effects and increased survival by \u3e80%. In pilot pig models of arterial bleeding, emergency administration of SynthoPlate® has shown substantial reduction in blood volume loss. Immunohistological evaluation of tissues from various treated animals have shown marked co-localization of red fluorescent SynthoPlate® with green fluorescent platelets localized at the clot site. Biodistribution studies in animals indicate that SynthoPlate® is cleared primarily by liver and spleen, similar to clinically known liposomal technologies. We have also demonstrated that the platelet-mimetic heteromultivalent surface-decoration approach can be adapted to other biomedically relevant particle platforms. Altogether, our studies establish the promise of SynthoPlate® nanotechnology as a platelet-mimetic intravenous hemostat for treatment of bleeding complications in prophylactic and emergency scenarios. Ongoing studies are focused on evaluating this technology in clinically motivated large animal bleeding models, with a vision for translation

5-Azacytidine Acts Directly on Both Erythroid Precursors and Progenitors to Increase Production of Fetal Hemoglobin

Abstract The effect of 5-azacytidine on erythroid precursors and progenitors was studied in nine patients with sickle cell anemia or severe thalassemia. Each patient received the drug intravenously for 5 or 7 d. 5-Azacytidine caused a four-to sixfold increase in y-messenger RNA concentration in bone marrow cells of eight of the nine patients and decreased the methylation frequency of a specific cytosine residue in th

Changes in serogroup and genotype prevalence among carried meningococci in the United Kingdom during vaccine implementation.

BACKGROUND: Herd immunity is important in the effectiveness of conjugate polysaccharide vaccines against encapsulated bacteria. A large multicenter study investigated the effect of meningococcal serogroup C conjugate vaccine introduction on the meningococcal population. METHODS: Carried meningococci in individuals aged 15-19 years attending education establishments were investigated before and for 2 years after vaccine introduction. Isolates were characterized by multilocus sequence typing, serogroup, and capsular region genotype and changes in phenotypes and genotypes assessed. RESULTS: A total of 8462 meningococci were isolated from 47 765 participants (17.7%). Serogroup prevalence was similar over the 3 years, except for decreases of 80% for serogroup C and 40% for serogroup 29E. Clonal complexes were associated with particular serogroups and their relative proportions fluctuated, with 12 statistically significant changes (6 up, 6 down). The reduction of ST-11 complex serogroup C meningococci was probably due to vaccine introduction. Reasons for a decrease in serogroup 29E ST-254 meningococci (from 1.8% to 0.7%) and an increase in serogroup B ST-213 complex meningococci (from 6.7% to 10.6%) were less clear. CONCLUSIONS: Natural fluctuations in carried meningococcal genotypes and phenotypes a can be affected by the use of conjugate vaccines, and not all of these changes are anticipatable in advance of vaccine introduction

Phase variation mediates reductions in expression of surface proteins during persistent meningococcal carriage

Asymptomatic and persistent colonization of the upper respiratory tract by Neisseria meningitidis occurs despite elicitation of adaptive immune responses against surface antigens. A putative mechanism for facilitating host persistence of this bacterial commensal and pathogen is alterations in expression of surface antigens by simple sequence repeat (SSR)-mediated phase variation. We investigated how often phase variation occurs during persistent carriage by analyzing the SSRs of eight loci in multiple isolates from 21 carriers representative of 1 to 6 months carriage. Alterations in repeat number were detected by a GeneScan analysis and occurred at 0.06 mutations/gene/month of carriage. The expression states were determined by Western blotting and two genes, fetA and nadA, exhibited trends toward low expression states. A critical finding from our unique examination of combinatorial expression states, “phasotypes,” was for significant reductions in expression of multiple phase-variable surface proteins during persistent carriage of some strains. The immune responses in these carriers were examined by measuring variant-specific PorA IgG antibodies, capsular group Y IgG antibodies and serum bactericidal activity in concomitant serum samples. Persistent carriage was associated with high levels of specific IgG antibodies and serum bactericidal activity while recent strain acquisition correlated with a significant induction of antibodies. We conclude that phase-variable genes are driven into lower expression states during long-term persistent meningococcal carriage, in part due to continuous exposure to antibody-mediated selection, suggesting localized hypermutation has evolved to facilitate host persistence

8th Annual Seminar on Legal Issues for Financial Institutions

Outline of speakers\u27 presentations from the 8th Annual Seminar on Legal Issues for Financial Institutions held by UK/CLE on March 11-12, 1988