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A randomized controlled trial of dihydroartemisinin-piperaquine, artesunate-mefloquine and extended artemether-lumefantrine treatments for malaria in pregnancy on the Thailand-Myanmar border
Get PDFArtemisinin and artemisinin-based combination therapy (ACT) partner drug resistance in Plasmodium falciparum have spread across the Greater Mekong Subregion compromising antimalarial treatment. The current 3-day artemether-lumefantrine regimen has been associated with high treatment failure rates in pregnant women. Although ACTs are recommended for treating Plasmodium vivax malaria, no clinical trials in pregnancy have been reported.
Methods
Pregnant women with uncomplicated malaria on the Thailand-Myanmar border participated in an open-label randomized controlled trial comparing dihydroartemisinin-piperaquine (DP), artesunate-mefloquine (ASMQ) and a 4-day artemether-lumefantrine regimen (AL+). The primary endpoint for P. falciparum infections was the PCR-corrected cure rate and for P. vivax infections was recurrent parasitaemia, before delivery or day 63, whichever was longer, assessed by Kaplan-Meier estimate.
Results
Between February 2010 and August 2016, 511 pregnant women with malaria (353 P. vivax, 142 P. falciparum, 15 co-infections, 1 Plasmodium malariae) were randomized to either DP (n=170), ASMQ (n=169) or AL+ (n=172) treatments. Successful malaria elimination efforts in the region resulted in premature termination of the trial. The majority of women had recurrent malaria (mainly P. vivax relapses, which are not prevented by these treatments). Recurrence-free proportions (95% confidence interval [95% CI]) for vivax malaria were 20.6% (5.1–43.4) for DP (n=125), 46.0% (30.9–60.0) for ASMQ (n=117) and 28.7% (10.0–50.8) for AL+ (n=126). DP and ASMQ provided longer recurrence-free intervals. PCR-corrected cure rates (95% CI) for falciparum malaria were 93.7% (81.6–97.9) for DP (n=49), 79.6% (66.1–88.1) for AMSQ (n=55) and 87.5% (74.3–94.2) for AL+ (n=50). Overall 65% (85/130) of P. falciparum infections had Pfkelch13 propeller mutations which increased over time and recrudescence occurred almost exclusively in them; risk ratio 9.42 (95% CI 1.30–68.29). Among the women with falciparum malaria, 24.0% (95% CI 16.8–33.6) had P. vivax parasitaemia within 4 months. Nausea, vomiting, dizziness and sleep disturbance were more frequent with ASMQ. Miscarriage, small-for-gestational-age and preterm birth did not differ significantly among the treatment groups, including first trimester exposures (n=46).
Conclusions
DP was well tolerated and safe, and was the only drug providing satisfactory efficacy for P. falciparum-infected pregnant woman in this area of widespread artemisinin resistance. Vivax malaria recurrences are very common and warrant chloroquine prophylaxis after antimalarial treatment in this area
Risk of incident fractures in individuals hospitalised due to unexplained syncope and orthostatic hypotension
Get PDFBackground
Impaired orthostatic blood pressure response and syncope confer a high risk of falls and trauma. The relationship between a history of unexplained syncope and orthostatic hypotension (OH) with subsequent fractures, however, has not been thoroughly examined. In this study, we aimed to investigate the relationship between previous hospital admissions due to unexplained syncope and OH and incident fractures in a middle-aged population.
Methods
We analysed a large population-based prospective cohort of 30,399 middle-aged individuals (age, 57.5 ± 7.6; women, 60.2%). We included individuals hospitalised due to unexplained syncope or OH as the main diagnosis. Multivariable-adjusted Cox regression analysis was applied to assess the impact of unexplained syncope and OH hospitalisations on subsequent incident fractures.
Results
During a follow-up period of 17.8 + 6.5 years, 8201 (27%) subjects suffered incident fractures. The mean time from baseline and first admission for syncope (n = 493) or OH (n = 406) was 12.6 ± 4.2 years, and the mean age of the first hospitalisation was 74.6 ± 7.4 years. Individuals with incident fractures were older, more likely to be women, and had lower BMI, higher prevalence of prevalent fractures, and family history of fractures. Multivariable-adjusted Cox regression showed an increased risk of incident fractures following hospitalisations due to unexplained syncope (HR 1.20; 95% CI 1.02–1.40; p = 0.025) and OH (HR 1.42; 95% CI 1.21–1.66; p < 0.001) compared with unaffected individuals.
Conclusions
Individuals hospitalised due to unexplained syncope and orthostatic hypotension have an increased risk of subsequent fractures. Our findings suggest that such individuals should be clinically assessed for their syncope aetiology, with preventative measures aimed at fall and fracture risk assessment and management
Choice of HbA1c threshold for identifying individuals at high risk of type 2 diabetes and implications for diabetes prevention programmes: a cohort study
Get PDFType 2 diabetes (T2D) is common and increasing in prevalence. It is possible to prevent or delay T2D using lifestyle intervention programmes. Entry to these programmes is usually determined by a measure of glycaemia in the ‘intermediate’ range. This paper investigated the relationship between HbA1c and future diabetes risk and determined the impact of varying thresholds to identify those at high risk of developing T2D.
Methods
We studied 4227 participants without diabetes aged ≥ 40 years recruited to the Exeter 10,000 population cohort in South West England. HbA1c was measured at study recruitment with repeat HbA1c available as part of usual care. Absolute risk of developing diabetes within 5 years, defined by HbA1c ≥ 48 mmol/mol (6.5%), according to baseline HbA1c, was assessed by a flexible parametric survival model.
Results
The overall absolute 5-year risk (95% CI) of developing T2D in the cohort was 4.2% (3.6, 4.8%). This rose to 7.1% (6.1, 8.2%) in the 56% (n = 2358/4224) of participants classified ‘high-risk’ with HbA1c ≥ 39 mmol/mol (5.7%; ADA criteria). Under IEC criteria, HbA1c ≥ 42 mmol/mol (6.0%), 22% (n = 929/4277) of the cohort was classified high-risk with 5-year risk 14.9% (12.6, 17.2%). Those with the highest HbA1c values (44–47 mmol/mol [6.2–6.4%]) had much higher 5-year risk, 26.4% (22.0, 30.5%) compared with 2.1% (1.5, 2.6%) for 39–41 mmol/mol (5.7–5.9%) and 7.0% (5.4, 8.6%) for 42–43 mmol/mol (6.0–6.1%). Changing the entry criterion to prevention programmes from 39 to 42 mmol/mol (5.7–6.0%) reduced the proportion classified high-risk by 61%, and increased the positive predictive value (PPV) from 5.8 to 12.4% with negligible impact on the negative predictive value (NPV), 99.6% to 99.1%. Increasing the threshold further, to 44 mmol/mol (6.2%), reduced those classified high-risk by 59%, and markedly increased the PPV from 12.4 to 23.2% and had little impact on the NPV (99.1% to 98.5%).
Conclusions
A large proportion of people are identified as high-risk using current thresholds. Increasing the risk threshold markedly reduces the number of people that would be classified as high-risk and entered into prevention programmes, although this must be balanced against cases missed. Raising the entry threshold would allow limited intervention opportunities to be focused on those most likely to develop T2D
Bacterial vaginosis: drivers of recurrence and challenges and opportunities in partner treatment
Get PDFBacterial vaginosis (BV) is the most common vaginal dysbiosis to affect women globally, yet an unacceptably high proportion of women experience BV recurrence within 6 months of recommended antibiotic therapy. The low rate of sustained cure highlights our limited understanding of the pathogenesis of BV recurrence, which has been attributed to possible persistence and re-emergence of BV-associated bacteria (BVAB) or a BV-associated biofilm following antimicrobials and/or reinfection occurring from sexual partners.
There is a robust body of evidence to support the exchange of bacteria between partners during sexual activity, and while the hypothesis that women treated for BV are subsequently reinfected with BVAB following sex with an untreated sexual partner is not new, failure of past partner treatment trials has eroded confidence in this concept. If reinfection is a key driver of recurrence, current antimicrobial regimens directed to women alone are unlikely to achieve a high level of sustained cure, and the approach of partner treatment to reduce reinfection is justified. In this manuscript, we present the molecular and epidemiological evidence that underlies the hypothesis that BV is sexually transmitted, and summarise why research that continues to consider sexual partnerships is necessary. We also outline the significant barriers and challenges that we have identified while undertaking partner treatment studies, and we discuss the factors that impact on our ability to determine their effectiveness.
Ultimately, the pathogenesis of BV recurrence is likely to be multifaceted and not attributable to a single mechanism in all women. If we are to achieve sustained cure for women, it is likely that combined and individualised approaches to eradicate BVAB, support an optimal vaginal microbiome, and prevent reinfection from partners will be required
Exposure assessment in early life: it is about time for multi-omics approaches
Get PDFMulti-omics data, such as epigenomics, transcriptomics, proteomics, and metabolomics, are increasingly used to detect molecular responses to environmental exposures [1]. The integration of several omics layers can inform changes occurring in the structure, function, and dynamics of the body on a cellular level [2]. The correct identification of the effects of environmental exposures on the body is crucial in understanding disease development and progression [3]. Early life, i.e., pregnancy and childhood, is regarded as the most crucial periods of the developmental stages [4]. Environmental exposures in early life can have far reaching influences on the wellbeing and health of the individual [4]. Hence, the identification of these exposures and effects on the organism becomes critical.
Variability of omics biomarkers in epidemiological studies
Omics biomarkers can pose objective measures of exposure, as they might be able to depict “true” exposure in individuals, i.e., the average exposure over a month or year [5]. Exposure biomarkers measure the extrinsic variables individuals are exposed to, for example, diet, tobacco smoke, pesticides, and air pollution. However, the technical and biological variability of omics profiles needs to be assessed. Epidemiological studies predominantly rely on single measurements [6]; hence, the biological variability of omics profiles should be known to interpret changes and classify individuals correctly. High variability can lead to biased results, namely misclassification bias which leads to incorrect effect estimates [7]. Variability can be influenced by the circadian rhythm, season, or individual characteristics and can be categorized into within-individual variability and between-individual variability [5]. Thereby, between-individual variability is desired to be higher than within-individual variability, so the investigated changes are due to differences between the subjects. Another important source of variability that has to be considered in omics studies is the technical variability that is derived from the laboratory methods and procedures [5]. This becomes a crucial issue when measuring numerous compounds with omics technologies in a large set of samples as in epidemiological studies. Technical variability in omics data includes random measurement errors that reduce statistical power [5], but also systematic measurement errors, such as batch effects, that lead to biased results. Technical variability needs to be addressed, e.g., by running quality controls, standardized procedures, normalization of the data, replication of the analysis, statistical adjustment, and proper randomization of the samples according to the study design [8]
Punch Incision versus Elliptical Excision for Epidermal Inclusion Cysts: Systematic Review and Meta-Analysis
Get PDFPunch incision is an alternative to elliptical excision for treating epidermal inclusion cysts, but its efficacy has not been systematically reviewed. This study assessed the efficacy and safety of punch incision versus elliptical excision for epidermal inclusion cysts. Randomized controlled trials published through January 2021 that evaluated the performance of punch incision versus elliptical excision on epidermal inclusion cysts were identified through electronic databases and clinical registries. Version 2 of the Cochrane risk-of-bias tool for randomized trials tool was used. Review Manager software was used for the meta-analysis. Two trials (100 participants) were identified. The primary outcomes were recurrence rate (risk ratio, 2.40; 95% confidence interval [CI], 0.37–15.60 [favoring elliptical excision]), mean operative time (mean difference [MD], −5.28; 95% CI, −12.72 to 2.16 [favoring punch incision]), and mean postoperative wound length (MD, −11.67; 95% CI, −20.59 to −2.76 [favoring punch incision]). The evidence was low to moderate due to the small sample size and its considerable heterogeneity. The use of punch incision shortened the mean postoperative wound length and had comparable safety to that of elliptical excision
Video-Assisted Thoracic Surgery for Late Recurrence of Congenital Diaphragmatic Hernia
Get PDFongenital diaphragmatic hernia (CDH) is often diagnosed and treated in the perinatal period. Recurrence is a known complication that may very rarely occur years after the operation. We report here the case of a patient who had an operation for a CDH at birth that then recurred in adulthood. Given the risk of complications and the symptomatology of the patient, we decided to treat the patient surgically. We successfully performed a video-assisted thoracic surgery (VATS) procedure during which we reduced the hernia and closed the breach. Given the recurrent nature of the hernia, we decided to reinforce the repair with a mesh
Successful Treatment of Embolic Aortic Valve Endocarditis in a Patient Affected by COVID-19 Pneumonia
Get PDFThe COVID-19 pandemic has required reorganization of the cardiac surgery system in the Italian region of Lombardy during early 2020. As a consequence, the hub-and-spoke (H&S) model was introduced to manage emergent/urgent cardiac surgery cases. In this challenging scenario, in which thousands of people were affected by the novel coronavirus, we present the case of a successful treatment of a middle-aged patient affected by both COVID-19 pneumonia and subacute aortic endocarditis. Learning objective: How to treat endocarditis during the COVID-19 pandemi
Perioperative Complications after Parotidectomy Using a Standardized Grading Scale Classification System
Get PDFPerioperative complications after parotidectomy are poorly studied and have a potential impact on hospitalization stay. The Clavien–Dindo classification of postoperative complications used in visceral surgery allows a recording of all complications, including a grading scale related to the severity of complication. The cohort analyzed for perioperative complications is composed of 436 parotidectomies classified into three types, four groups, and three classes, depending on extent of parotid resection, inclusion of additional procedures, and pathology, respectively. Using the Clavien–Dindo classification, complications were reported in 77% of the interventions. In 438 complications, 430 (98.2%) were classified as minor (332 grade I and 98 grade II), and 8 (1.8%) were classified as major (grade III). Independent variables affecting the risk of perioperative complications were duration of surgery (odds ratio = 1.007, p-value = 0.029) and extent of parotidectomy (odds ratio = 4.043, p-value = 0.007). Total/subtotal parotidectomy was associated with an increased risk of grade II-III complications (odds ratio = 2.866 (95% CI: 1.307–6.283), p-value = 0.009). Median hospital stay increased moderately in patients with complications. Use of Clavien–Dindo classification shows that parotidectomy is followed by a higher rate of perioperative complications than usually reported. Almost all complications are minor and have limited consequence on hospital stay
Evaluation of an Algorithm for Testis-Sparing Surgery in Boys with Testicular Tumors: A Retrospective Cohort Study
Get PDFAim: This study reports surgical treatment and its outcome for boys with a testicular tumor, in order to analyze the considerations of testis-sparing surgery (TSS) and investigate whether, in retrospect, treatment was according to a recently developed algorithm. Methods: We retrospectively reviewed boys with testicular tumors who underwent surgical treatment between January 2000 and June 2020 at the Wilhelmina’s Children’s Hospital and the Princess Máxima Center for Pediatric Oncology, The Netherlands. Medical records were searched for clinical characteristics and outcome. Results: We identified 31 boys (median age = 5.5 years) with a testicular tumor, 26 germ cell tumors (GCTs), four sex cord-stromal tumors, and one gonadoblastoma. Seventeen boys (median age = 1.5 years) had malignant and 14 (median age = 3.6 years) had benign tumors. Four boys with benign GCTs were treated with TSS, 25 with radical inguinal orchiectomy (RIO), and 2 with scrotal orchiectomy. No recurrence or testicular atrophy was reported. All boys with benign testicular tumors were treated as suggested by the algorithm, except for one boy treated with RIO. Conclusion: Retrospective analysis of surgical treatment of prepubertal boys with benign testicular tumors showed that TSS appears to be safe, and should be considered based on clinicoradiological data, in line with our algorith