A coordinated approach for managing polypharmacy among children with medical complexity: rationale and design of the Pediatric Medication Therapy Management (pMTM) randomized controlled trial.

BACKGROUND: Children with medical complexity (CMC) often rely upon the use of multiple medications to sustain quality of life and control substantial symptom burden. Pediatric polypharmacy (≥ 5 concurrent medications) is prevalent and increases the risk of medication-related problems (MRPs). Although MRPs are associated with pediatric morbidity and healthcare utilization, polypharmacy is infrequently assessed during routine clinical care for CMC. The aim of this randomized controlled trial is to determine if a structured pharmacist-led Pediatric Medication Therapy Management (pMTM) intervention reduces MRP counts, as well as the secondary outcomes of symptom burden and acute healthcare utilization. METHODS: This is a hybrid type 2 randomized controlled trial assessing the effectiveness of pMTM compared to usual care in a large, patient-centered medical home for CMC. Eligible patients include all children ages 2-18 years old, with ≥ 1 complex chronic condition, and with ≥ 5 active medications, as well as their English-speaking primary caregivers. Child participants and their primary parental caregivers will be randomized to pMTM or usual care before a non-acute primary care visit and followed for 90 days. Using generalized linear models, the overall effectiveness of the intervention will be evaluated using total MRP counts at 90 days following pMTM intervention or usual care visit. Following attrition, a total of 296 CMC will contribute measurements at 90 days, which provides > 90% power to detect a clinically significant 1.0 reduction in total MRPs with an alpha level of 0.05. Secondary outcomes include Parent-Reported Outcomes of Symptoms (PRO-Sx) symptom burden scores and acute healthcare visit counts. Program replication costs will be assessed using time-driven activity-based scoring. DISCUSSION: This pMTM trial aims to test hypotheses that a patient-centered medication optimization intervention delivered by pediatric pharmacists will result in lower MRP counts, stable or improved symptom burdens, and fewer cumulative acute healthcare encounters at 90 days following pMTM compared to usual care. The results of this trial will be used to quantify medication-related outcomes, safety, and value for a high-utilization group of CMC, and outcomes may elucidate the role of integrated pharmacist services as a key component of outpatient complex care programs for this priority pediatric population. TRIAL REGISTRATION: This trial was prospectively registered at clinicaltrials.gov (NCT05761847) on Feb 25, 2023.

Complete genome and plasmid sequence of a novel Bacillus sp. BD59S, a parasporal protein synthesizing bacterium.

Parasporal crystalline inclusion proteins of some Bacillus spp. are of paramount importance due to their insecticidal, nematocidal, and cancer cell killing capabilities. Here, we present a brief report of the complete genome sequence of Bacillus sp. BD59S, a bacterium that produced HeLa cell-killing parasporal crystalline inclusion proteins. From genome sequencing and assembly, we found that the bacterium has one circular chromosome and two large plasmids, pBTBD59S1 and pBTBD59S2. The size of the chromosome is 5283,933 bp with a 35.4% GC content, consisting of 5938 genes and 5550 protein-coding sequences (CDSs), 25 complete rRNAs (5S, 16S, 23S), 98 tRNAs, 5 ncRNAs, 260 pseudo-genes, and 356 subsystems. Complete plasmid sequence of pBTBD59S1 comprises a total size of 162,149 bp with 33.4% GC content, 192 CDSs, and 13 subsystems. The other plasmid pBTBD59S2, is 199,209 bp long with 32.9% GC content, 179 CDSs, and 11 subsystems. Analyses by NCBI microbial genome BLAST, phylogenetic genome tree, and BLAST ring image generator (BRIG) revealed that BD59S belongs to Bacillus cereus group, and is more close to B. thuringiensis. Further, the strain possesses 57.04 kDa and 54.42 kDa Cry protein-coding genes, which show significant similarities with cancer cell-killing parasporin proteins of B. thuringiensis strains.

Parasporin 1Ac2, a novel cytotoxic crystal protein isolated from Bacillus thuringiensis B0462 strain.

Two novel parasporin (PS) genes were cloned from Bacillus thuringiensis B0462 strain. One was 100 % identical even in nucleotide sequence level with that of parasporin-1Aa (PS1Aa1) from B. thuringiensis A1190 strain. The other (PS1Ac2) showed significant homology (99 % identity) to that of PS1Ac1 from B. thuringiensis 87-29 strain. The 15 kDa (S(113)-R(250)) and 60 kDa (I(251)-S(777)) fragments consisting of an active form of PS1Ac2 were expressed as His-tag fusion. Upon purification under denaturing condition and refolding, the recombinant polypeptides were applied to cancer cells to analyze their cytotoxicities. 3-(4,5-Dimethyl-2-thiazoyl)-2,5-diphenyl-2H-tetrazolium bromide assay revealed that either of 15 or 60 kDa polypeptide exhibited no cytotoxicity to HeLa cells, but they became cytotoxic upon mixed together. Our results suggested that PS1Ac2 was responsible for the cytotoxicity of B. thuringiensis B0462 strain, and that the formation of hetero-dimer of 15 and 60 kDa polypeptide was required for their cytotoxicity.

Prevention of gestational diabetes mellitus by continuing metformin therapy throughout pregnancy in women with polycystic ovary syndrome.

AIM: The aim of the present study was to assess whether continuation of metformin therapy throughout pregnancy can reduce the development of gestational diabetes in women with polycystic ovarian syndrome (PCOS). METHODS: This experimental study was conducted in a private tertiary level infertility care center between June 2002 and December 2006. Fifty-nine non-diabetic PCOS patients who conceived while taking metformin and different ovulation-inducing agents comprised the sample group. Twenty-nine of them continued metformin throughout pregnancy and 30 did not The main outcome measure was development of gestational diabetes in women with PCOS and their fetal outcome. RESULTS: Basic parameters such as age, body mass index, levels of follicle-stimulating hormone and luteinizing hormone, free testosterone, dihydroepiandrosterone sulfate, fasting sugar and fasting insulin did not differ between the two groups. Among 29 women who received metformin, gestational diabetes developed during one of 29 pregnancies (3.44%) versus nine of 30 pregnancies (30%) without metformin. The odds ratio for gestational diabetes in women without metformin versus with metformin was 12 (95% confidence interval: 6.20-18.08). All babies born in the metformin group had average birthweight and those in the control group 4 (13.33%) were large for date. CONCLUSION: In PCOS use of metformin throughout pregnancy is associated with and might be responsible for a ninefold reduction (30-3.44%) of gestational diabetes.

Comparison of efficacy of aromatase inhibitor and clomiphene citrate in induction of ovulation in polycystic ovarian syndrome.

OBJECTIVE: To compare the effectiveness of letrozole and clomiphene citrate (CC) in induction of ovulation in polycystic ovary syndrome (PCOS). DESIGN: Prospective, randomized, not blinded, controlled trial. SETTING: A tertiary level infertility care center. PATIENT(S): Sixty-four anovulatory patients with PCOS, who failed to ovulate when taking 100 mg/day CC in previous cycles. INTERVENTION(S): Patients were randomly divided into two groups by lottery and treated with either 7.5 mg/day letrozole (an aromatase inhibitor) or 150 mg/day CC for 5 days starting from day 3 of the menstrual cycle. MAIN OUTCOME MEASURE(S): Occurrence of ovulation, endometrial thickness, and pregnancy rate (PR). RESULT(S): Twenty (62.5%) patients from the letrozole group and 12 (37.50%) patients from the CC group ovulated during the observation period. Mean serum E2 level was 817.75 pg/mL and 448.03 pg/mL in the CC and letrozole groups, respectively, on the day of hCG administration. The mean endometrial thickness on the day of hCG administration was 9.03 mm and 10.37 mm in the CC and letrozole groups, respectively. The mean D21 serum P was 13.09 ng/mL and 19.09 ng/mL in the CC and letrozole groups, respectively. Thirteen patients from the letrozole group (40.63%) and six patients from the CC group (18.75%) became pregnant. CONCLUSION(S): Letrozole has better ovulation and PR in comparison to CC in patients with PCOS.