Real-world effectiveness of ustekinumab and vedolizumab in TNF-exposed pediatric patients with ulcerative colitis.

OBJECTIVES: Vedolizumab (VDZ) and ustekinumab (UST) are second-line treatments in pediatric patients with ulcerative colitis (UC) refractory to antitumor necrosis factor (anti-TNF) therapy. Pediatric studies comparing the effectiveness of these medications are lacking. Using a registry from ImproveCareNow (ICN), a global research network in pediatric inflammatory bowel disease, we compared the effectiveness of UST and VDZ in anti-TNF refractory UC. METHODS: We performed a propensity-score weighted regression analysis to compare corticosteroid-free clinical remission (CFCR) at 6 months from starting second-line therapy. Sensitivity analyses tested the robustness of our findings to different ways of handling missing outcome data. Secondary analyses evaluated alternative proxies of response and infection risk. RESULTS: Our cohort included 262 patients on VDZ and 74 patients on UST. At baseline, the two groups differed on their mean pediatric UC activity index (PUCAI) (p = 0.03) but were otherwise similar. At Month 6, 28.3% of patients on VDZ and 25.8% of those on UST achieved CFCR (p = 0.76). Our primary model showed no difference in CFCR (odds ratio: 0.81; 95% confidence interval [CI]: 0.41-1.59) (p = 0.54). The time to biologic discontinuation was similar in both groups (hazard ratio: 1.26; 95% CI: 0.76-2.08) (p = 0.36), with the reference group being VDZ, and we found no differences in clinical response, growth parameters, hospitalizations, surgeries, infections, or malignancy risk. Sensitivity analyses supported these findings of similar effectiveness. CONCLUSIONS: UST and VDZ are similarly effective for inducing clinical remission in anti-TNF refractory UC in pediatric patients. Providers should consider safety, tolerability, cost, and comorbidities when deciding between these therapies.

Sequential regression and simulation: a method for estimating causal effects from heterogeneous clinical trials without a common control group.

BACKGROUND: The advent of clinical trial data sharing platforms has created opportunities for making new discoveries and answering important questions using already collected data. However, existing methods for meta-analyzing these data require the presence of shared control groups across studies, significantly limiting the number of questions that can be confidently addressed. We sought to develop a method for meta-analyzing potentially heterogeneous clinical trials even in the absence of a common control group. METHODS: This work was conducted within the context of a broader effort to study comparative efficacy in Crohn's disease. Following a search of clnicaltrials.gov we obtained access to the individual participant data from nine trials of FDA-approved treatments in Crohn's Disease (N = 3392). We developed a method involving sequences of regression and simulation to separately model the placebo- and drug-attributable effects, and to simulate head-to-head trials against an appropriately normalized background. We validated this method by comparing the outcome of a simulated trial comparing the efficacies of adalimumab and ustekinumab against the recently published results of SEAVUE, an actual head-to-head trial of these drugs. This study was pre-registered on PROSPERO (#157,827) prior to the completion of SEAVUE. RESULTS: Using our method of sequential regression and simulation, we compared the week eight outcomes of two virtual cohorts subject to the same patient selection criteria as SEAVUE and treated with adalimumab or ustekinumab. Our primary analysis replicated the corresponding published results from SEAVUE (p = 0.9). This finding proved stable under multiple sensitivity analyses. CONCLUSIONS: This new method may help reduce the bias of individual participant data meta-analyses, expand the scope of what can be learned from these already-collected data, and reduce the costs of obtaining high-quality evidence to guide patient care.

Retrospective analysis of 34 febrile neutropenia episodes - therapeutic implication of multiplex polymerase chain reaction in infection diagnosis.

BACKGROUND: Hemato-oncologic patients on chemotherapy or undergoing bone marrow transplantation are susceptible to infections due to neutropenia. Incidences of febrile neutropenia (FN) in these patients are common, contributing to high mortality and morbidity. Lack of diagnosis of pathogens responsible for infections in these patients is a major healthcare challenge. Newer molecular diagnostics are increasingly becoming relevant. The objective of this retrospective study was to evaluate the effectiveness of Syndrome Evaluation System (SES), a multiplex molecular diagnostic platform for diagnosis of pathogens, and its impact on the management of FN. METHODS: In total, 34 neutropenic episodes from 21 patients admitted during September 2013 to April 2015 were analyzed in this study. Clinical samples from patients were tested on SES and routine culture. Treatment was as per standard of care. RESULTS: SES showed a 5-fold higher clinical sensitivity (55.9%) as compared to automated culture (11.1%). SES results were available within 14 hours as compared to >72 hours for culture, and elucidated change in antimicrobial therapy in 50% of episodes. Mortality rates were lower when SES was used early in the episode. De-escalation of antimicrobials according to SES results was possible, which translated into substantial cost saving. CONCLUSION: Newer non-culture-based molecular technologies like SES are changing the way we manage FN. It is faster, has a higher diagnostic yield as compared to traditional culture, and helps in making rapid, evidence-based therapeutic decision-making including de-escalation of antimicrobials. It would potentially lead to a reduction in mortality and healthcare cost in the long run.

Studies on the synthesis, characterization, human serum albumin binding and biological activity of single chain surfactant-cobalt(III) complexes.

The interaction of surfactant-cobalt(III) complexes [Co(bpy)(dien)TA](ClO4)3 · 3H2O (1) and [Co(dien)(phen)TA](ClO4)3 · 4H2O (2), where bpy = 2,2'-bipyridine, dien = diethylenetriamine, phen = 1,10-phenanthroline and TA = tetradecylamine with human serum albumin (HSA) under physiological conditions was analyzed using steady state, synchronous, 3D fluorescence, UV/visabsorption and circular dichroism spectroscopic techniques. The results show that these complexes cause the fluorescence quenching of HSA through a static mechanism. The binding constant (Kb ) and number of binding-sites (n) were obtained at different temperatures. The corresponding thermodynamic parameters (∆G°, ∆H° and ∆S°) and Ea were also obtained. According to Förster's non-radiation energy transfer theory, the binding distance (r) between the complexes and HSA were calculated. The results of synchronous and 3D fluorescence spectroscopy indicate that the binding process has changed considerably the polarity around the fluorophores, along with changes in the conformation of the protein. The antimicrobial and anticancer activities of the complexes were tested and the results show that the complexes have good activities against pathogenic microorganisms and cancer cells.

Biological and protein-binding studies of newly synthesized polymer-cobalt(III) complexes.

The polymer-cobalt(III) complexes, [Co(bpy)(dien)BPEI]Cl3 · 4H2O (bpy = 2,2'-bipyridine, dien = diethylentriamine, BPEI = branched polyethyleneimine) were synthesized and characterized. The interaction of these complexes with human serum albumin (HSA) and bovine serum albumin (BSA) was investigated under physiological conditions using various physico-chemical techniques. The results reveal that the fluorescence quenching of serum albumins by polymer-cobalt(III) complexes took place through static quenching. The binding of these complexes changed the molecular conformation of the protein considerably. The polymer-cobalt(III) complex with x = 0.365 shows antimicrobial activity against several human pathogens. This complex also induces cytotoxicity against MCF-7 through apoptotic induction. However, further studies are needed to decipher the molecular mode of action of polymer-cobalt(III) complex and for its possible utilization in anticancer therapy.

Congenital hypothyroidism presenting as menorrhagia in adulthood.

Although hypothyroidism is a common cause of menorrhagia, it is an uncommon presentation of congenital hypothyroidism. We report a case of congenital hypothyroidism presenting in adulthood with severe menorrhagia. Despite the late presentation, she had features to suggest hypothyroidism since birth.