The fragility of statistically significant findings in randomised controlled anaesthesiology trials: systematic review of the medical literature

The fragility index (FI), the number of events the statistical significance a result depends on, and the number of patients lost to follow-up are important parameters for interpreting randomised clinical trial results. We evaluated these two parameters in randomised controlled trials in anaesthesiology. For this, we performed a systematic search of the medical literature, seeking articles reporting on anaesthesiology trials with a statistically significant difference in the primary outcome and published in the top five general medicine journals, or the top 15 anaesthesiology journals. We restricted the analysis to trials reporting clinically important primary outcome measures. The search identified 139 articles, 35 published in general medicine journals and 104 in anaesthesiology journals. The median (inter-quartile range) sample size was 150 (70–300) patients. The FI was 4 (2–17) and 3 (2–7), and the number of patients lost to follow-up was 0 (0–18) and 0 (0–6) patients in trials published in general medicine and anaesthesiology journals, respectively. The number of patients lost to follow-up exceeded the FI in 41 and 27% in trials in general medicine journals and anaesthesiology journals, respectively. The FI positively correlated with sample size and number of primary outcome events, and negatively correlated with the reported P-values. The results of this systematic review suggest that statistically significant differences in randomised controlled anaesthesiology trials are regularly fragile, implying that the primary outcome status of patients lost to follow-up could possibly have changed the reported effect.     

Effects of perfluorohexane vapor in the treatment of experimental lung injury

RationaleWe investigated the effects of vaporized perfluorohexane (PFH) on pulmonary vascular tone, pulmonary vascular resistance and peak inspiratory pressure as well as lipid mediator formation in the treatment of calcium ionophore induced lung injury in a model of the isolated perfused and ventilated rabbit lungs.MethodsLung injury was induced in isolated perfused and ventilated rabbit lungs by calcium ionophore A23187. Lungs were treated with either 4.5 vol.% (4.5 vol.% PFH; n = 6) or 18 vol.% (18 vol.% PFH; n = 6) PFH. Six lungs remained untreated (Control). In addition 5 lungs (PFH-sham) remained uninjured receiving 18 vol.% PFH only. Mean pulmonary artery pressure (mPAP), peak inspiratory pressure (P_max), and lung weight (weight) were monitored for 120 min. Experiments were terminated before when the increase in lung weight exceeded 40 g. Perfusate samples were taken at regular intervals for analysis of TXB₂, 6-keto-PGF₁ and LTB₄.ResultsControls reached the study end point significantly earlier than both PFH groups. Significant differences were found for a weight gain of 10 g and 20 g between the control and the 4.5 vol.% PFH and the 18 vol.% PFH. Differences in mPAP were more pronounced in the 4.5 vol.% PFH. However increases in P_max were more marked in 4.5 vol.% PFH. TXA₂-, PGI₂-, and LTB₄-levels were significantly lower in PFH groups. Uninjured lungs remained unaffected by the presence of 18 vol.% PFH.ConclusionInflammatory lung injury was attenuated by the treatment with 4.5 vol.% PFH and 18 vol.% PFH vapor in the isolated perfused rabbit lung. Therapeutic effects were more pronounced with a concentration of 4.5 vol.% PFH.     

Amplified transmission of HIV-1: comparison of HIV-1 concentrations in semen and blood during acute and chronic infection

OBJECTIVES: This study was conducted to compare viral dynamics in blood and semen between subjects with antibody negative, acute HIV-1 infection and other subjects with later stages of infection. DESIGN: A prospective cohort study was embedded within a cross-sectional study of HIV screening in a Lilongwe, Malawi STD clinic. METHODS: Blood samples from HIV antibody negative or indeterminate volunteers were used to detect HIV RNA in plasma using a pooling strategy. Blood and seminal plasma HIV-1 RNA concentrations were measured over 16 weeks. RESULTS: Sixteen men with acute HIV infection and 25 men with chronic HIV infection were studied. Blood viral load in subjects with acute HIV infection was highest about 17 days after infection (mean +/- SE, 6.9 +/- 0.5 log10 copies/ml), while semen viral load peaked about 30 days after infection (4.5 +/- 0.4 log10 copies/ml). Semen viral load declined by 1.7 log10 to a nadir by week 10 of HIV infection. Semen and blood viral loads were more stable in chronically infected subjects over 16 weeks. Higher semen levels of HIV RNA were noted in subjects with low CD4 cell counts. CONCLUSIONS: These results provide a biological explanation for reported increases in HIV transmission during the very early (acute) and late stages of infection. Recognizing temporal differences in HIV shedding in the genital tract is important in the development of effective HIV prevention strategies.     

Rapid, real-time detection of acute HIV infection in patients in Africa

BACKGROUND: We conducted a prospective study to evaluate methods of detecting clients with sexually transmitted diseases (STDs) who were acutely coinfected with human immunodeficiency virus (HIV) in Lilongwe, Malawi. METHODS: After informed consent was obtained, all clients with acute STDs were offered voluntary HIV counseling and testing by 2 rapid antibody tests. Samples from rapid test-negative or -discordant subjects were pooled (50 : 5 : 1) and tested for HIV RNA. Western blots were performed on all rapid test-discordant specimens with detectable HIV RNA. A subset of specimens received p24 antigen testing with standard and/or ultrasensitive methods. Patients with possible acute HIV infection were followed to confirm seroconversion. RESULTS: A total of 1450 clients (34% female and 66% male) agreed to testing, of whom 588 (40.55%) had established HIV infection and 21 (1.45%) had acute infection. Discordant rapid antibody tests identified 7 of 21 (33.3% sensitivity), standard p24 antigen identified 12 of 16 (75% sensitivity), and ultrasensitive p24 antigen identified 15 of 17 (88% sensitivity) acute cases. By definition, the sensitivity of the RNA assay was 100%. CONCLUSIONS: Real-time pooled RNA testing for the detection of acute HIV infection is feasible in resource-limited settings. However, parallel rapid testing and p24 antigen testing are technologically simpler and together may detect approximately 90% of acute cases.     

Effect of periodontal treatment on oral anticoagulation in patients with heart disease.

In recent decades, there have been several studies on the correlation between periodontal disease (PD) and cardiovascular disease, but the influence of PD on the effect of oral anticoagulant drugs has not been reported. OBJECTIVE: To assess the influence of PD on oral anticoagulation in patients with heart disease. METHODS: Dental treatment for patients of the Anticoagulation Clinic of the Instituto Nacional de Cardiologia Laranjeiras (INCL), receiving warfarin as a prophylactic treatment for thromboembolic events, was performed without suspending the drug and according to the INCL's "Protocol of dental treatment for patients with acquired coagulopathy". A therapeutic anticoagulation level was maintained and was assessed using the international normalized ratio (INR) on the of the patient's visit. The patient was thus protected against thromboembolic events and could undergo dental treatment, even oral surgery. Our study comprised 40 patients who underwent prospective oral assessment and were divided into two groups: Group I--20 patients with PD; and Group II--20 patients without PD. Dental treatment was performed in the two groups as follows: PD control in Group I and treatment of dental caries in Group II. The INR of the patients was assessed before each dental consultation, to guarantee hemostasis during the procedures and to monitor the anticoagulation level obtained. INR prior to the dental intervention was then compared with that after the intervention in both groups. An INR increase of > or =50% was considered significant. RESULTS: In Group I, all patients showed an increase in INR after the dental treatment, which was significant in 15 (75%). In Group II, only 8 patients had increased INR, which was significant in 5 (25%) (p = 0.002). Considering the oral health of the two groups,. the extent of tissue injury in the oral cavity was not significant compared to the INR increase; however, comparison between the two groups showed significant INR increase mainly in patients with PD (p = 0.002). CONCLUSION: This study showed that dental treatment in patients with any type of PD significantly increases INR.     

In vitro and in vivo studies of the trypanocidal activity of a diarylthiophene diamidine against Trypanosoma cruzi

Aromatic diamidines are DNA minor groove-binding ligands that display excellent antimicrobial activity against fungi, bacteria, and protozoa. Due to the currently unsatisfactory chemotherapy for Chagas’ disease and in view of our previous reports regarding the effect of diamidines and analogues against both in vitro and in vivo Trypanosoma cruzi infection, this study evaluated the effects of a diarylthiophene diamidine (DB1362) against both amastigotes and bloodstream trypomastigotes of T. cruzi, the etiological agent of Chagas’ disease. The data show the potent in vitro activity of DB1362 against both parasite forms that are relevant for mammalian infection at doses which do not exhibit cytotoxicity. Ultrastructural analysis and flow cytometry studies show striking alterations in the nuclei and mitochondria of the bloodstream parasites. In vivo studies were performed at two different drug concentrations (25 and 50 mg/kg/day) using a 2-day or a 10-day regimen. The best results were obtained when acutely infected mice were treated with two doses at the lower concentration, resulting in 100% survival, compared to the infected and untreated mice. Although it did not display higher efficacy than benznidazole, DB1362 reduced both cardiac parasitism and inflammation, and in addition, it protected against the cardiac alterations (determined by measurements) common in T. cruzi infection. These results support further investigation of diamidines and related compounds as potential agents against Chagas’ disease.     

Malignancy-related 67kDa laminin receptor in adenoid cystic carcinoma. Effect on migration and beta-catenin expression

Adenoid cystic carcinoma is a malignant salivary gland neoplasm with recurrence and metastasis. We studied the expression of a malignancy-related non-integrin laminin receptor, the 67LR, in this neoplasm. Immunohistochemistry showed 67LR in adenoid cystic carcinoma. This receptor binds a sequence of laminin β1 chain, the YIGSR peptide. We studied the effect of 67LR and YIGSR in cells (CAC2) from adenoid cystic carcinoma. Three-dimensional cultures of cells embedded into either laminin-111 gel (controls) or YIGSR-enriched laminin-111 (treated) were prepared and studied by light microscopy. CAC2 cells treated with YIGSR appeared fibroblast-like, while control cells were epithelioid. Blockage of 67LR by antibody abolished YIGSR effect in three-dimensional cultures. We analysed the relevance of 67LR and YIGSR on β-catenin expression in CAC2 cells. Immunofluorescence and immunoblot showed that YIGSR decreased β-catenin, while blockage of 67LR restored the presence of this molecule. The 67LR and YIGSR induced fibroblast-like morphology in CAC2 cells, with disruption of cell–cell contacts and decrease of β-catenin. These features resemble epithelial–mesenchymal transition (EMT). EMT also increases cell migration. In monolayer assays YIGSR increased migration of CAC2 cells. We conclude that 67LR and YIGSR are involved in epithelial–mesenchymal transition, modulation of β-catenin expression, and migratory activity of CAC2 cells.     

Strategies to improve antiretroviral therapy (ART) initiation and early engagement among men in sub-Saharan Africa: A scoping review of interventions in the era of universal treatment

Objectives

Men in sub-Saharan Africa (SSA) have lower rates of antiretroviral therapy (ART) initiation and higher rates of early default than women. Little is known about effective interventions to improve men's outcomes. We conducted a scoping review of interventions aimed to increase ART initiation and/or early retention among men in SSA since universal treatment policies were implemented.

Methods

Three databases, HIV conference databases and grey literature were searched for studies published between January 2016 to May 2021 that reported on initiation and/or early retention among men. Eligibility criteria included: participants in SSA, data collected after universal treatment policies were implemented (2016–2021), quantitative data on ART initiation and/or early retention for males, general male population (not exclusively focused on key populations), intervention study (report outcomes for at least one non-standard service delivery strategy), and written in English.

Results

Of the 4351 sources retrieved, 15 (reporting on 16 interventions) met inclusion criteria. Of the 16 interventions, only two (2/16, 13%) exclusively focused on men. Five (5/16, 31%) were randomised control trials (RCT), one (1/16, 6%) was a retrospective cohort study, and 10 (10/16, 63%) did not have comparison groups. Thirteen (13/16, 81%) interventions measured ART initiation and six (6/16, 37%) measured early retention. Outcome definitions and time frames varied greatly, with seven (7/16, 44%) not specifying time frames at all. Five types of interventions were represented: optimising ART services at health facilities, community-based ART services, outreach support (such as reminders and facility escort), counselling and/or peer support, and conditional incentives. Across all intervention types, ART initiation rates ranged from 27% to 97% and early retention from 47% to 95%.

Conclusions

Despite years of data of men's suboptimal ART outcomes, there is little high-quality evidence on interventions to increase men's ART initiation or early retention in SSA. Additional randomised or quasi-experimental studies are urgently needed.     

Serum levels of brain-derived neurotrophic factor in schizophrenia on a hypocaloric diet

Dietary factors influence BDNF in animal studies, but there is no comparable data in clinical populations. We examined the effect of a dietary intervention on BDNF serum levels in 67 DSM-IV schizophrenic outpatients (51 males and 16 females). Two groups were assessed in a cross-sectional study: one on a hypocaloric diet (HD) and the other not on a hypocaloric diet. Weight, height and BMI data were collected concurrently with 5-ml blood sampling of each subject. BDNF levels were measured with a sandwich-ELISA. The blood sample was obtained a minimum of one month after the exposure to dietary intervention. Serum BDNF levels were significantly higher in patients on the HD (p=0.023). Additional research examining the interaction among patterns of nutritional food behavior and underlying physiopathology may result in insights upon which evidence-based decisions regarding dietary interventions can be made in people identified with major psychiatric disorders, such as schizophrenia.     

Benefits of the use of the CO<Subscript>2</Subscript> laser in orthodontics

Esthetics is an important factor for patients seeking orthodontic treatment, and not always is the orthodontist able to make adjustments on the gingival contour, and this aspect is neglected. Many orthodontists are familiar with the name laser. However, there is a lack of information regarding their application on the orthodontic practice. There are several options for the use of CO₂ lasers on surgical procedures of interest to orthodontists, especially on soft tissues. There is no evidence that the use of the CO₂ laser has any side effect or contraindication on surgical procedures. This paper reports a series of surgical procedures carried out on orthodontic patients. It is concluded that the carbon dioxide laser not only allows surgeons to enhance current surgical options for treatment but also have contributed to the evolution of a variety of new procedures that are now commonplace in oral surgery, and its use shows several benefits for the orthodontic patient.