Treatment of fecal impaction in children using combined polyethylene glycol and sodium picosulphate.

BACKGROUND AND AIM: Polyethylene glycol (PEG) is the gold standard for fecal disimpaction in constipation. A regimen of PEG combined with the stimulant laxative sodium picosulphate (SPS) produced fecal disimpaction in chronically constipated children in the community, but it is unknown if it is effective for more severe constipation. To determine the stool output and effect of a combined PEG and SPS regimen on fecaloma in children with severe constipation and impaction. METHODS: Children with symptoms for a duration of ≥2 years, a palpable fecaloma, and enlarged rectum on X-ray (rectal: pelvic ratio > 0.6) were recruited from a tertiary hospital. Daily diaries recorded laxative dose, stool frequency, volume, and consistency (Bristol stool scale, BSS). Abdominal X-rays were taken on day 1 and day 8, and stool loading was assessed using the Leech score. Laxative doses were based on the child's age. The dose of PEG with electrolytes taken was 2-8 sachets (14.7 g/sachet) on days 1-2, reducing to 2-6 sachets on day 3. The SPS dose was 15-20 drops on days 2-3. RESULTS: Eighty-nine children (4-18 years) produced a large volume of soft stool (median/inter-quartile-range: 2.2/1.6-3.1 L) over 7 days. Stool volume on X-rays decreased significantly in the colon (P < 0.001). Fecalomas resolved in 40 of 89 children, while 49 needed a second high dose. Rectal:pelvic ratios did not change. CONCLUSIONS: A combined high dose of PEG and SPS on days 1 and 2 was effective in removing the fecaloma in half of the children. Administering high doses for a longer period should be tested to provide outpatient disimpaction for severe fecalomas. Rectums remained flaccid after emptying.

Sponsor-Imposed Publication Restrictions Disclosed on ClinicalTrials.gov.

We investigated whether sponsor-imposed publication restrictions for ClinicalTrials.gov trials were reasonable, based on consistency with Good Publication Practice 2 (GPP2). ClinicalTrials.gov trial record data were electronically imported (October 7, 2012) and screened for eligibility (phase 2-4, interventional, recruitment closed, results available, first received for registration after November 10, 2009, any sponsor type, investigators not sponsor employees). Two authors categorized restrictions information as consistent or not consistent with GPP2, resolving discrepancies by consensus. Of the eligible trials (388/484, n = 81,768 participants), 80.7% (313/388) had restrictions disclosed, and 92.5% (311/388) were industry-sponsored. Significantly more trials had restrictions that were consistent with GPP2 than not (74.1% [232/313], n = 55,280 participants vs. 25.9% [81/313], n = 19,677 participants; P < .001). Reasons for inconsistency were insufficient, unclear, or ambiguous information (48.1%, 39/81), sponsor-required approval for publication (35.8%, 29/81), sponsor-required text changes (8.6%, 7/81), and outright bans (7.4%, 6/81). Follow-up of trials with insufficient information and a contact email (response rate, 46.9% [15/32]) revealed 2 additional bans. A total of 776 participants had consented to trials that had publication bans. Many, but not all, sponsor-imposed publication restrictions disclosed on ClinicalTrials.gov may be considered reasonable. Sponsors should ensure restrictions are appropriately disclosed. Volunteers should be alerted to any restrictions before consenting to participate in a clinical trial.

Publication misconduct and plagiarism retractions: a systematic, retrospective study.

OBJECTIVES: To investigate whether plagiarism is more prevalent in publications retracted from the medical literature when first authors are affiliated with lower-income countries versus higher-income countries. Secondary objectives included investigating other factors associated with plagiarism (e.g., national language of the first author's country affiliation, publication type, journal ranking). DESIGN: Systematic, controlled, retrospective, bibliometric study. DATA SOURCE: Retracted publications dataset in MEDLINE (search filters: English, human, January 1966-February 2008). DATA SELECTION: Retracted misconduct publications were classified according to the first author's country affiliation, country income level, and country national language, publication type, and ranking of the publishing journal. Standardised definitions and data collection tools were used; data were analysed (odds ratio [OR], 95% confidence limits [CL], chi-squared tests) by an independent academic statistician. RESULTS: Of the 213 retracted misconduct publications, 41.8% (89/213) were retracted for plagiarism, 52.1% (111/213) for falsification/fabrication, 2.3% (5/213) for author disputes, 2.3% (5/213) for ethical issues, and 1.4% (3/213) for unknown reasons. The OR (95% CL) of plagiarism retractions (other misconduct retractions as reference) were higher (P < 0.001) for first authors affiliated with lower-income versus higher-income countries (15.4 [4.5, 52.9]) and with non-English versus English national language countries (3.2 [1.8, 5.7]), for non-original research versus original research publications (8.4 [3.3, 21.3]), for case reports and series versus other original research types (4.2 [1.4, 13.0]), and for publications in low-ranked versus high-ranked journals (4.9 [2.4, 9.9]). Up until 2012, there were significantly (P < 0.007) fewer 'serial offenders' (first authors with >1 retraction) with publications retracted for plagiarism (11.5%, 9/78) than other types of misconduct (28.9%, 24/83). CONCLUSIONS: This is the first study to demonstrate that publications retracted for plagiarism are significantly associated with first authors affiliated with lower-income countries. These findings have implications for developing appropriate evidence-based strategies and allocation of resources to help mitigate plagiarism misconduct.

Lack of involvement of medical writers and the pharmaceutical industry in publications retracted for misconduct: a systematic, controlled, retrospective study.

OBJECTIVES: The primary objective of this study was to quantify how many publications retracted because of misconduct involved declared medical writers (i.e., not ghostwriters) or declared pharmaceutical industry support. The secondary objective was to investigate factors associated with misconduct retractions. DESIGN: A systematic, controlled, retrospective, bibliometric study. DATA SOURCE: Retracted publications dataset in the MEDLINE database. DATA SELECTION: PubMed was searched (Limits: English, human, January 1966 - February 2008) to identify publications retracted because of misconduct. Publications retracted because of mistake served as the control group. Standardized definitions and data collection tools were used, and data were analyzed by an independent academic statistician. RESULTS: Of the 463 retracted publications retrieved, 213 (46%) were retracted because of misconduct. Publications retracted because of misconduct rarely involved declared medical writers (3/213; 1.4%) or declared pharmaceutical industry support (8/213; 3.8%); no misconduct retractions involved both declared medical writers and the industry. Retraction because of misconduct, rather than mistake, was significantly associated with: absence of declared medical writers (odds ratio: 0.16; 95% confidence interval: 0.05-0.57); absence of declared industry involvement (0.25; 0.11-0.58); single authorship (2.04; 1.01-4.12); first author having at least one other retraction (2.05; 1.35-3.11); and first author affiliated with a low/middle income country (2.34; 1.18-4.63). The main limitations of this study were restricting the search to English-language and human research articles. CONCLUSIONS: Publications retracted because of misconduct rarely involved declared medical writers or declared pharmaceutical industry support. Increased attention should focus on factors that are associated with misconduct retractions.

Phase 2 gene therapy trial of an anti-HIV ribozyme in autologous CD34+ cells.

Gene transfer has potential as a once-only treatment that reduces viral load, preserves the immune system and avoids lifetime highly active antiretroviral therapy. This study, which is to our knowledge the first randomized, double-blind, placebo-controlled, phase 2 cell-delivered gene transfer clinical trial, was conducted in 74 HIV-1-infected adults who received a tat-vpr-specific anti-HIV ribozyme (OZ1) or placebo delivered in autologous CD34+ hematopoietic progenitor cells. There were no OZ1-related adverse events. There was no statistically significant difference in viral load between the OZ1 and placebo group at the primary end point (average at weeks 47 and 48), but time-weighted areas under the curve from weeks 40-48 and 40-100 were significantly lower in the OZ1 group. Throughout the 100 weeks, CD4+ lymphocyte counts were higher in the OZ1 group. This study indicates that cell-delivered gene transfer is safe and biologically active in individuals with HIV and can be developed as a conventional therapeutic product.

Long-term survival and concomitant gene expression of ribozyme-transduced CD4+ T-lymphocytes in HIV-infected patients.

BACKGROUND: An anti-HIV-1 tat ribozyme, termed Rz2, has been shown to inhibit HIV-1 infection/replication and to decrease HIV-1-induced pathogenicity in T-lymphocyte cell lines and normal peripheral blood T-lymphocytes. We report here the results of a phase I gene transfer clinical trial using Rz2. METHODS: Apheresis was used to obtain a peripheral blood cell population from each of four HIV-negative donors. After enrichment for CD4+ T-lymphocytes, ex vivo expansion and genetic manipulation (approximately equal aliquots of the cells were transduced with the ribozyme-containing (RRz2) and the control (LNL6) retroviral vector), these cells were infused into the corresponding HIV-1-positive twin recipient. Marking was assessed over an initial 24-week period and in total over an approximate 4-year period. RESULTS: The gene transfer procedure was shown to be safe, and technically feasible. Both RRz2- and LNL6-gene-containing peripheral blood mononuclear cells (PBMC) were detected at all time points examined to 4 years. There was concomitant gene construct expression in the absence of the need for ex vivo peripheral blood cell stimulation and there was no evidence of immune elimination of the neoR T-lymphocytes nor of silencing of the Moloney murine leukemia virus long terminal repeat. CONCLUSIONS: The proof of principle results reported here demonstrate safety and feasibility of this type of gene transfer approach. While not specifically tested, T-lymphocytes containing an anti-HIV gene construct may impact on HIV-1 viral load and CD4+ T-lymphocyte count, potentially representing a new therapeutic modality for HIV-1 infection.

Anti-human immunodeficiency virus hematopoietic progenitor cell-delivered ribozyme in a phase I study: myeloid and lymphoid reconstitution in human immunodeficiency virus type-1-infected patients.

A phase I gene transfer clinical study was undertaken to examine the ability to introduce a potential anti-human immunodeficiency virus (HIV) gene therapeutic into hematopoietic progenitor cells (HPC), thereby contributing to multilineage engraftment. The potential therapeutic effect of genetically modifying HPC with protective genes in HIV-infected adults depends in part on the presence of adult thymic activity and myeloid capacity in the setting of HIV replication. Herein we report the presence and expression of a retroviral vector encoding an anti-HIV-1 ribozyme in mature hematopoietic cells of different lineages, and de novo T-lymphocyte development ensuing from genetically engineered CD34(+) HPC. Sustained output of vector-containing mature myeloid and T-lymphoid cells was detected even in patients with multidrug-resistant infection. In addition, the study showed that the degree of persistence of gene-containing cells was dependent on transduced HPC dose. These novel findings support the concept of gene therapy as a modality to effect immune reconstitution with cells engineered to inhibit HIV replication and this report represents the first demonstration of long-term maintenance of a potential therapeutic transgene in HIV disease.