A multi-centre study of therapeutic efficacy and safety of platelet components treated with amotosalen and ultraviolet A pathogen inactivation stored for 6 or 7 d prior to transfusion

Bacteria in platelet components (PC) may result in transfusion-related sepsis (TRS). Pathogen inactivation of PC with amotosalen (A-PC) can abrogate the risk of TRS and hence facilitate storage to 7 d. A randomized, controlled, double-blinded trial to evaluate the efficacy and safety of A-PC stored for 6-7 d was conducted. Patients were randomized to receive one transfusion of conventional PC (C-PC) or A-PC stored for 6-7 d. The primary endpoint was the 1 h corrected count increment (CCI) with an acceptable inferiority of 30%. Secondary endpoints included 1- and 24-h count increment (CI), 24-h CCI, time to next PC transfusion, red blood cell (RBC) use, bleeding and adverse events. 101 and 100 patients received A-PC or C-PC respectively. The ratio of 1-h CCI (A-PC:C-PC) was 0·87 (95% confidence interval: 0·73, 1·03) demonstrating non-inferiority (P = 0·007), with respective mean 1-h CCIs of 8163 and 9383; mean 1-h CI was not significantly different. Post-transfusion bleeding and RBC use were not significantly different (P = 0·44, P = 0·82 respectively). Median time to the next PC transfusion after study PC was not significantly different between groups: (2·2 vs. 2·3 d, P = 0·72). Storage of A-PCs for 6-7 d had no impact on platelet efficacy.     

Therapeutic efficacy of platelet components treated with amotosalen and ultraviolet A pathogen inactivation method: results of a meta‐analysis of randomized controlled trials

Background and Objectives There are conflicting data regarding the therapeutic efficacy of platelets inactivated using amotosalen and ultraviolet A light. We have performed a meta‐analysis to summarize the results of different randomized controlled trials (RCT). Materials and Methods Five RCTs reported through March 2011 met the criteria for meta‐analysis. Weighted mean difference (WMD) in corrected count increment (CCI) at 1 h, CCI‐24 h, and transfusion interval (days) and summary odds ratio (OR) of bleeding in inactivated platelet (I‐P) group vs. noninactivated platelet (C‐P) group were calculated across studies. Results Randomized controlled trials were statistically homogeneous when we analysed CCI‐24 h, and the transfusion of C‐P was associated with a higher CCI‐24 h when compared with the transfusion of I‐P (WMD, 3 × 10³; 95% CI, 2·32 × 10³–3·69 × 10³; P < 0·00001). RCTs were statistically heterogeneous when we analysed CCI‐1 h, transfusion interval and OR of bleeding. Regarding the OR of bleeding in the I‐P and C‐P groups, it varied by as much as a multiple of four among the trials, from 0·66 to 2·66. When we combined double‐blinded and high methodologic quality score RCTs, the use of I‐P was not statistically associated with an increase in the OR of bleeding when compared with the use of C‐P (OR, 0·97; 95% CI, 0·75–1·27; P = 0·84). Conclusion Although the transfusion of I‐P was associated with lower CCI‐24 h when compared with the transfusion of C‐P, this was not associated with differences in the OR of bleeding between I‐P and C‐P.     

A comparison of artificially-depleted, lyophilized coumarin and fresh coumarin plasmas in thromboplastin calibration

Artificially-depleted lyophilized plasmas and lyophilized coumarin plasmas were prepared and compared with fresh coumarin plasmas to assess their comparative reliability in local thromboplastin calibration using the manual prothrombin time (PT) technique. Their certified PT values were inserted in turn on the vertical axis in place of the PT obtained with fresh coumarin plasmas. PT results were obtained at eight ECAA national laboratories ('test centres') and inserted on the horizontal axis. The resulting thromboplastin calibration slopes were compared with conventional fresh coumarin plasma calibration slopes at the same 'test centres'. When 60 artificially-depleted plasmas were substituted for 60 fresh plasmas, the mean calibration slopes with the human plain International Reference Preparation (IRP) were 4.2% higher. For comparison with 20 lyophilized coumarins, three sets of 20 artificially-depleted plasmas were selected in sequential order from the 60. The lyophilized coumarin plasmas gave a mean deviation of 9.6% from the fresh plasma calibration slopes compared with values of 2.0%, 6.1% and 11.7% for the three sets of 20 depleted plasmas.
Although both types of lyophilized plasma calibration slopes give measurable differences from conventional fresh plasmas, these may be regarded as acceptable in clinical terms.     

Two cases of fatal methemoglobinemia caused by self-poisoning with sodium nitrite: A case report

Rationale:Sodium nitrite intoxication reportedly causes severe methemoglobinemia. Recent studies reported that most clinically significant cases resulted from intentional exposure in suicidal attempts. We describe 2 cases of severe methemoglobinemia secondary to intentional sodium nitrite intoxication in suicidal attempts.Patients concerns:A 26-year-old man and 20-year-old woman attempted suicide by taking sodium nitrite, and were brought to the emergency department.Diagnosis:The male patient collapsed at the scene. He ingested approximately 18 g of sodium nitrate, and his methemoglobin level was 90.3%. The female patient was conscious, but was cyanotic. She ingested approximately 12.5 g of sodium nitrite, and her methemoglobin level was 54.6%.Interventions:The male patient received advanced cardiac life support in the emergency department. Methylene blue was immediately administered for the female patient.Outcomes:The male patient died despite aggressive resuscitation. The female patient''s cyanosis resolved, and her methemoglobin level decreased to 1.2% 3 hours later.Lessons:The immediate administration of methylene blue in severe methemoglobinemia patients prevented fatal consequences. The public should be informed about the accessibility and toxicity of sodium nitrite.     

A comparison of IFNgamma detection methods used in tuberculosis vaccine trials

Interferon gamma (IFNγ) is a critical component of the pro-inflammatory immune response that provides protection against Mycobacterium tuberculosis. In the absence of an immunological correlate of protection, antigen-specific production of IFNγ is a commonly used marker of a protective immune response. To facilitate the evaluation of tuberculosis candidate vaccines three different IFNγ detection methods were compared. The cultured whole blood ELISA, ex vivo IFNγ ELISpot and whole blood ex vivo intracellular cytokine staining (ICS) assays were performed head-to-head during a Phase I clinical trial using the candidate vaccine MVA85A. Whilst all three assays detected significant increases in IFNγ production immediately following vaccination, distinctions between the assays were apparent. Higher baseline IFNγ responses were detected using the cultured whole blood ELISA, whereas the ex vivo ELISpot assay was the most sensitive in detecting long-term (52 weeks) post-vaccination responses. The whole blood ex vivo ICS assay provided novel information by dissecting the IFNγ response into responding CD4, CD8 and γ/δ T cell subsets.Future tuberculosis vaccine trials and immunology studies should ideally include a combination of ex vivo and cultured assays to ensure a thorough and multifaceted evaluation of the immune response is achieved.     

Comparison between sodium–glucose cotransporter 2 inhibitors and pioglitazone as additions to insulin therapy in type 2 diabetes patients: A systematic review with an indirect comparison meta‐analysis

Aims/Introduction

We aimed to evaluate the efficacy and safety of pioglitazone (PIO) and sodium–glucose cotransporter 2 inhibitors (SGLT2i) as additions to insulin therapy for the management of type 2 diabetes mellitus.

Materials and Methods

We searched PubMed, EMBASE, the Cochrane Central Register of Controlled Trials and ClinicalTrials.gov through December 2016. Randomized controlled trials published in English that compared SGLT2i plus insulin (SGLT2i/INS) or PIO plus insulin (PIO/INS) with placebo plus insulin (PCB/INS) in type 2 diabetes mellitus patients were included. We compared the efficacy and safety between SGLT2i/INS and PIO/INS indirectly.

Results

A total of 14 randomized controlled trials comparing 7,226 participants were included (8 SGLT2i and 6 PIO studies). SGLT2i/INS achieved similar reductions in hemoglobin A1c (weighted mean difference [WMD] ?0.01% [?0.1 mmol/mol], 95% confidence interval [CI] ?0.25 to 0.22% [?2.7 to ?2.4 mmol/mol]; P = 0.896) and fasting plasma glucose (WMD ?0.90 mg/dL, 95% CI: ?15.50 to 13.71 mg/dL; P = 0.904), and a similar proportion of participants achieved hemoglobin A1c <7.0% (<53.0 mmol/mol; relative risk 0.98, 95% CI: 0.73 to 1.33; P = 0.917) as compared with the PIO/INS group, with greater weight reduction (WMD ?4.54 kg, 95% CI: ?5.67 to ?3.41 kg; P < 0.001). PIO/INS showed non‐significant trends toward a higher risk of hypoglycemia (relative risk 1.15, 95% CI: 0.97 to 1.35; P = 0.102) and higher reduction of total daily insulin doses (WMD ?2.45 IU/day, 95% CI: ?7.30 to 2.40 IU/day; P = 0.438).

Conclusions

Both PIO and SGLT2i are feasible adjunctive oral agents to pre‐existing insulin therapy in individuals with inadequately controlled type 2 diabetes mellitus.

     

Kinetic evidence for modulation by glycophorin A of a conformational equilibrium between two states of band 3 (SLC4A1) bound reversibly by the competitive inhibitor DIDS

Recent evidence has suggested that erythrocytes naturally deficient in glycophorin A (GPA) have a reduced V_max for monovalent anion exchange. Unanswered is whether miss-folding of band 3 during biosynthesis, or the absence of GPA modulation of properly folded band 3 is responsible. Here, I determine the effect of selective depletion of GPA on the kinetics of reversible binding of the competitive transport inhibitor DIDS (4,4′-diisothiocyanato-2,2′-stilbenedisulfonate) to properly folded band 3. Reversible binding of DIDS follows biphasic kinetics: a fast phase {DIDS + band 3  (DIDS − band 3), k₁, k_− 1} and a slower phase {(DIDS − band 3)  (DIDS − band 3), k₂, k_− 2}. Selective depletion of GPA was accomplished by pretreating membranes with Triton X-100, over a range where erythrocyte hemolysis is inhibited by the detergent (0% to 0.03%, v/v). Pretreatment with sublytic Triton X-100: (a) virtually completely depleted GPA, (b) did not deplete membrane-bound band 3, and (c) slowed the overall rate of reversible binding of DIDS to band 3. Data analysis and model simulation studies indicated that the decrease in the rate of binding of DIDS was due exclusively to a decrease in k_− 2, with no change in the initial rate of binding. Thus, depletion of GPA does not alter the native conformation of band 3 at the DIDS binding site, but rather modulates a conformational equilibrium between two states of the binary complex formed by the competitive inhibitor DIDS, reversibly bound to properly folded band 3.     

Treatment of atypical pacemaker‐mediated tachycardia with ablation of the retrograde atrioventricular nodal pathway

A 25‐year‐old runner received a single‐lead, VDD pacemaker after ablation of AV nodal reentrant tachycardia complicated by intermittent AV block. The rate‐adaptive AV delay algorithm (RAAV), which shortens the sensed AV interval (SAV) at faster atrial rates, was programmed to provide a physiologic SAV with exercise. She developed repetitive, atypical, long‐RP pacemaker‐mediated tachycardia (PMT) because the RAAV shortened the antegrade SAV and retrograde conduction occurred over the slow AV nodal pathway. PMT was refractory to usual programming solutions. Using high‐density electroanatomic mapping, we were able to ablate the retrograde limb of PMT without further damaging AV conduction.