Diet and physical activity based interventions in pregnancy: Study-level and Individual Participant Data (IPD) meta-analyses

PhDEvidence synthesis is considered a corner stone of modern health care and clinical practice. Systematic reviews of randomised trials, when undertaken with meta-analysis provide summary estimates on the effectiveness of interventions. However, the findings of meta-analysis are often limited by the selective reporting of primary studies, and the variations in population, intervention and outcomes. Furthermore, difficulties in disentangling the study and individual level associations in meta-analysis make them susceptible to ecological fallacy, and may lead to incorrect conclusions. Meta-analysis using Individual Participant Data (IPD) has the potential to overcome many of the above limitations, by using raw trial data. Access to IPD minimises problems from incomplete or incorrect reporting of trial outcomes, by verifying reported results, and by standardising the definition of outcomes where possible. Importantly, this allows detecting any variation in the effects of interventions according to characteristics of the participants. Amalgamated individual datasets assembled to address the effectiveness question, can be further used to explore secondary objectives such as the relationship between surrogate and clinical outcomes. This maximises the use of available clinical data, and addresses the problem of research waste. In this thesis, I evaluated the effects of diet and physical activity based interventions in pregnancy on maternal and offspring outcomes using both study-level and IPD meta-analyses, and assessed the differential effects of interventions on outcomes according to mother’s BMI pre or in early pregnancy. I reviewed the variation in outcomes reported in this field, and developed composite outcomes for IPD meta-analysis. I also evaluated the relationship between weight gain in pregnancy and clinical outcomes in pregnancy using the IPD meta-analysis methodology. Aims The aim of this thesis was to evaluate the effects of diet and physical activity based interventions in pregnancy on clinical outcomes using standard and advance methods of evidence synthesis; assess the variation in outcomes and their clinical importance in a trial with those interventions and examine the relationship between gestational weight gain and important clinical outcomes. Methods Delphi methodology, systematic reviews of literature, and meta-analyses using study-level and individual participant data of randomised controlled trials (RCTs). Results Composite outcomes Developed composite outcomes comprise of four maternal (gestational diabetes, hypertensive disorders in pregnancy, preterm birth, caesarean section) and four offspring outcomes (stillbirth, small for gestational age, large for gestational age, and admission to neonatal intensive care unit). The components to assess maternal composite outcome were available in two-thirds (66.7%, 24/36) and for offspring composite in half (50%, 18/36) of the studies in the IPD meta-analysis. The effect of interventions was not statistically significant neither on the maternal nor on the offspring composite – Odds Ratio (OR) 0.90 (95% CI 0.79, 1.03) and OR 0.94 (95% CI 0.83, 1.08), respectively. The direction of the pooled effect was consistent between the composite and its components for the maternal composite and variable for the offspring outcomes. 6 Effects of diet and physical activity based interventions The IPD meta-analysis of 36 RCTs (>12 500 women) showed a significant effect of diet and physical activity based interventions in pregnancy in reducing gestational weight gain (Mean Difference -0.70 kg, 95% CI -0.92, -0.48) and chance of caesarean section delivery (OR 0.91, 95% CI 0.83, 0.99) in comparison to routine antenatal care. There was no effect of the interventions on any of the offspring complications. Incorporation of outcome data unavailable on study-level returned more modest magnitude of the summary estimates in comparison to effects obtained using study-level data of trials that shared IPD. The addition of study-level data from non-IPD trials changed the magnitude and the statistical significance of the summary effects on GDM – from OR 0.89 with only IPD (95% CI 0.72, 1.10; 27 studies, 9 427 women) to OR 0.76 (95% CI 0.65, 0.89; 59 studies, 16 885 women). It has also changed the funnel plot structure in the meta-analysis for gestational weight gain (Egger’s test p = 0.04 with only IPD to p= 0.61). The IPD meta-analysis shows that the effects of diet and physical activity based interventions on the maternal and the offspring outcomes did not differ by women’s BMI status. While the study-level meta-regression indicated that the interventions might reduce gestational weight gain stronger for the obese women – coefficient -0.22 (95% CI -0.33, -0.11) for each 10% change in the proportion of women in the obese class. Outcomes in trials with diet and physical activity based interventions 66 primary publications from trials with diet and physical activity based interventions in pregnancy reported 142 outcomes. Half of those outcomes appeared in the publications once (72/142). ‘Critically important’ outcomes are reported less often in comparison to ‘non-critical’ ones (15.5%, 22/142 vs 68.3%, 97/142). The overall quality of outcome reporting varied between trials with the least frequently provided information on the methods to improve the quality of outcome measures (33.3%, 22/66 publications). 7 Gestational weight gain and pregnancy outcomes IPD from 4 429 pregnant women randomised to the control arms of RCTs with diet and physical activity based interventions were available for the analysis. Women who most often exceeded the IOM recommendation belonged to the overweight (51.5%, 641/ 1 245 women) and the obese groups (44.5%, 695/ 1 562 women) while women with normal BMI most often gained below the recommended amounts (40%, 649/1 622 women). Each kilogram of gestational weight gain within the IOM ranges was not link with a change in the chances of preterm birth, caesarean section, or birth of LGA and SGA infant. Not achieving of the recommended weight was associated with the decreasing chance of giving birth to LGA infant with each kilogram below the lower limit among the obese women (OR 0.80, 95% CI 0.65, 0.99). Each kilogram of weight gain above the upper limit was associated with an increase in the chance of caesarean section (adjusted 1.04, 95% CI 1.01, 1.08) and delivering LGA infant (adjusted 1.08, 95% CI 1.05, 1.12) regardless on women’s BMI status. Conclusions Diet and physical activity based interventions in pregnancy moderately reduced gestational weight gain and decrease the odds of caesarean delivery. Overall, IPD meta-analysis improved the robustness of the evidence synthesis of RCTs with diet and physical activity based interventions. However, more attention is needed for the data-related issues in IPD meta-analysis as the purported benefits of the method are not always practically realised. The use of the composite outcomes was hampered by the variable availability of important clinical outcomes. The introduction of minimal core outcome set would facilitate the comparison of the wide range of the evaluated interventions and improve implementation of the composite outcomes. Gestational weight gain was found to be associated with the odds of delivering LGA infant and caesarean section. Future research should aim to collect and report a minimal set of outcomes, and ensure better reporting of study conduct and its findings.World Health Organization National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme (grant no. 12/01/50

Treatment of newly diagnosed glioblastoma in the elderly

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To determine the most effective and best‐tolerated approaches for the treatment of elderly people with newly diagnosed glioblastoma. To summarise current evidence for the incremental resource use, utilities, costs and cost‐effectiveness associated with the different management strategies for newly diagnosed glioblastoma among adults aged over 70 years

Association of antenatal diet and physical activity–based interventions with gestational weight gain and pregnancy outcomes : a systematic review and meta-analysis

Importance: Excessive gestational weight gain (GWG) is common and associated with adverse pregnancy outcomes. Antenatal lifestyle interventions limit GWG; yet benefits of different intervention types and specific maternal and neonatal outcomes are unclear. Objective: To evaluate the association of different types of diet and physical activity–based antenatal lifestyle interventions with GWG and maternal and neonatal outcomes. Data Sources: A 2-stage systematic literature search of MEDLINE, Embase, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Cochrane Central Register of Controlled Trials, and Health Technology Assessment Database was conducted from February 1, 2017, to May 31, 2020. Search results from the present study were integrated with those from a previous systematic review from 1990 to February 2017. Study Selection: Randomized trials reporting GWG and maternal and neonatal outcomes. Data Extraction and Synthesis: Data were extracted for random-effects meta-analyses to calculate the summary effect estimates and 95% CIs. Main Outcomes and Measures: Outcomes were clinically prioritized, with mean GWG as the primary outcome. Secondary outcomes included gestational diabetes, hypertensive disorders of pregnancy, cesarean section, preterm delivery, large or small for gestational age neonates, neonatal intensive care unit admission, or fetal death. Results: A total of 117 randomized clinical trials of antenatal lifestyle interventions (involving 34 546 women) were included. Overall lifestyle intervention was associated with reduced GWG (−1.15 kg; 95% CI, −1.40 to −0.91), risk of gestational diabetes (odds ratio [OR], 0.79; 95% CI, 0.70-0.89), and total adverse maternal outcomes (OR, 0.89; 95% CI, 0.84-0.94) vs routine care. Compared with routine care, diet was associated with less GWG (−2.63 kg; 95% CI, −3.87 to −1.40) than physical activity (−1.04 kg; 95% CI, −1.33 to −0.74) or mixed interventions (eg, unstructured lifestyle support, written information with weight monitoring, or behavioral support alone) (−0.74 kg; 95% CI, −1.06 to −0.43). Diet was associated with reduced risk of gestational diabetes (OR, 0.61; 95% CI, 0.45-0.82), preterm delivery (OR, 0.43; 95% CI, 0.22-0.84), large for gestational age neonate (OR, 0.19; 95% CI, 0.08-0.47), neonatal intensive care admission (OR, 0.68; 95% CI, 0.48-0.95), and total adverse maternal (OR, 0.75; 95% CI, 0.61-0.92) and neonatal outcomes (OR, 0.44; 95% CI, 0.26-0.72). Physical activity was associated with reduced GWG and reduced risk of gestational diabetes (OR, 0.60; 95% CI, 0.47-0.75), hypertensive disorders (OR, 0.66; 95% CI, 0.48-0.90), cesarean section (OR, 0.85; 95% CI, 0.75-0.95), and total adverse maternal outcomes (OR, 0.78; 95% CI, 0.71-0.86). Diet with physical activity was associated with reduced GWG (−1.35 kg; 95% CI, −1.95 to −0.75) and reduced risk of gestational diabetes (OR, 0.72; 95% CI, 0.54-0.96) and total adverse maternal outcomes (OR, 0.81; 95% CI, 0.69-0.95). Mixed interventions were associated with reduced GWG only. Conclusions and Relevance: This systematic review and meta-analysis found level 1 evidence that antenatal structured diet and physical activity–based lifestyle interventions were associated with reduced GWG and lower risk of adverse maternal and neonatal outcomes. The findings support the implementation of such interventions in routine antenatal care and policy around the world

Treatment for radiographically active, sputum culture-negative pulmonary tuberculosis: a systematic review and meta-analysis

Background: People with radiographic evidence for pulmonary tuberculosis (TB), but negative sputum cultures, have increased risk of developing culture-positive TB. Recent expansion of X-ray screening is leading to increased identification of this group. We set out to synthesise the evidence for treatment to prevent progression to culture-positive disease. Methods: We conducted a systematic review and meta-analysis. We searched for prospective trials evaluating the efficacy of TB regimens against placebo, observation, or alternative regimens, for the treatment of adults and children with radiographic evidence of TB but culture-negative respiratory samples. Databases were searched up to 18 Oct 2022. Study quality was assessed using ROB 2·0 and ROBINS-I. The primary outcome was progression to culture-positive TB. Meta-analysis with a random effects model was conducted to estimate pooled efficacy. This study was registered with PROSPERO (CRD42021248486). Findings: We included 13 trials (32,568 individuals) conducted between 1955 and 2018. Radiographic and bacteriological criteria for inclusion varied. 19·1% to 57·9% of participants with active x-ray changes and no treatment progressed to culture-positive disease. Progression was reduced with any treatment (6 studies, risk ratio [RR] 0·27, 95%CI 0·13–0·56), although multi-drug TB treatment (RR 0·11, 95%CI 0·05–0·23) was significantly more effective than isoniazid treatment (RR 0·63, 95%CI 0·35–1·13) (p = 0·0002). Interpretation: Multi-drug regimens were associated with significantly reduced risk of progression to TB disease for individuals with radiographically apparent, but culture-negative TB. However, most studies were old, conducted prior to the HIV epidemic and with outdated regimens. New clinical trials are required to identify the optimal treatment approach

Intercommunal associations and rules of their governance

Tematem pracy są związki międzygminne i zasady ich funkcjonowania. Jest to najbardziej zaawansowana forma współpracy jednostek samorządu terytorialnego z którą powiązany jest szereg problemów prawnych. W pracy poruszane zostały kwestie podstaw działalności związków, procesu ich tworzenia i likwidacji oraz zasad przystępowania i występowania ze związków. Część pracy dotyczy działalności związków szczególnie trybu działania oraz wspólnego wykonywania zadań w ramach związku. Przedstawione zostały również aspekty związane z nadzorem nad działalnością związków oraz organami funkcjonującymi w strukturze związku . Ukazana została także problematyka istoty współdziałania jednostek samorządu terytorialnego.The dissertation focuses on intercommunal associations and rules of their governance. It is the most advanced form of cooperation among regional government units with which many legal problems are connected. The paper describes the basis of associations' operations and the process of their formation and closure, as well as rules of participation and withdrawing from them. Part of the paper concerns mode of action of such addictions and sharing common responsibilities. Moreover, the diploma thesis gives an information on supervision over such associations and their bodies. The dissertation also addresses the issue of cooperation among regional government units

Effectiveness of treatment options for tubal ectopic pregnancy: A systematic review and network meta-analysis

BACKGROUND: Tubal ectopic pregnancy (TEP) is a common gynaecological emergency. Several medical and surgical treatment options exist, but it is not clear which is the safest and most effective treatment. OBJECTIVES: To compare the effectiveness of expectant, medical and surgical treatment options for TEP using a systematic review and network meta-analysis. SEARCH STRATEGY: MEDLINE, EMBASE, and CENTRAL from inception till September 2022. SELECTION CRITERIA: Randomised trials that evaluated any treatment option for woman with a TEP. DATA COLLECTION AND ANALYSIS: We performed pairwise and network meta-analyses using a random effect model. We assessed the studies' risk of bias, heterogeneity and network inconsistency. We reported primarily on TEP resolution and treatment failure using relative risk (RR) and 95% confidence-intervals (CI). MAIN RESULTS: We included 31 randomised trials evaluating ten treatments (n = 2938 women). Direct meta-analysis showed no significant benefit for using methotrexate compared to expectant management for TEP resolution. Network meta-analysis showed similar effect-size for most conservative treatment options compared to expectant management for TEP resolution (glucose intra-sac instillation vs. expectant RR 0.84, 95% CI 0.63-1.12; methotrexate intra-sac instillation vs. expectant RR 0.91, 95% CI 0.75-1.10; multi-dose methotrexate vs. expectant RR 1.00, 95% CI 0.88-1.15; prostaglandin intra-sac instillation vs. expectant RR 0.75, 95% CI 0.53-1.07; salpingotomy vs. expectant RR 0.99, 95% CI 0.84-1.16; single dose methotrexate vs. expectant RR 0.97, 95% CI 0.85-1.10; single dose methotrexate + mifepristone vs. expectant RR 1.09, 95% CI 0.89-1.33). All treatment options showed a higher risk of failure compared to salpingectomy. CONCLUSIONS: There is insufficient evidence to support the use of any medical treatment option for TEP over expectant management

Angiogenesis inhibitors for the treatment of epithelial ovarian cancer

Background: Many women, and other females, with epithelial ovarian cancer (EOC) develop resistance to conventional chemotherapy drugs. Drugs that inhibit angiogenesis (development of new blood vessels), essential for tumour growth, control cancer growth by denying blood supply to tumour nodules. Objectives: To compare the effectiveness and toxicities of angiogenesis inhibitors for treatment of epithelial ovarian cancer (EOC). Search methods: We identified randomised controlled trials (RCTs) by searching CENTRAL, MEDLINE and Embase (from 1990 to 30 September 2022). We searched clinical trials registers and contacted investigators of completed and ongoing trials for further information. Selection criteria: RCTs comparing angiogenesis inhibitors with standard chemotherapy, other types of anti‐cancer treatment, other angiogenesis inhibitors with or without other treatments, or placebo/no treatment in a maintenance setting, in women with EOC.  Data collection and analysis: We used standard methodological procedures expected by Cochrane. Our outcomes were overall survival (OS), progression‐free survival (PFS), quality of life (QoL), adverse events (grade 3 and above) and hypertension (grade 2 and above). Main results: We identified 50 studies (14,836 participants) for inclusion (including five studies from the previous version of this review): 13 solely in females with newly‐diagnosed EOC and 37 in females with recurrent EOC (nine studies in platinum‐sensitive EOC; 19 in platinum‐resistant EOC; nine with studies with mixed or unclear platinum sensitivity). The main results are presented below.  Newly‐diagnosed EOCBevacizumab, a monoclonal antibody that binds vascular endothelial growth factor (VEGF), given with chemotherapy and continued as maintenance, likely results in little to no difference in OS compared to chemotherapy alone (hazard ratio (HR) 0.97, 95% confidence interval (CI) 0.88 to 1.07; 2 studies, 2776 participants; moderate‐certainty evidence). Evidence is very uncertain for PFS (HR 0.82, 95% CI 0.64 to 1.05; 2 studies, 2746 participants; very low‐certainty evidence), although the combination results in a slight reduction in global QoL (mean difference (MD) ‐6.4, 95% CI ‐8.86 to ‐3.94; 1 study, 890 participants; high‐certainty evidence). The combination likely increases any adverse event (grade ≥ 3) (risk ratio (RR) 1.16, 95% CI 1.07 to 1.26; 1 study, 1485 participants; moderate‐certainty evidence) and may result in a large increase in hypertension (grade ≥ 2) (RR 4.27, 95% CI 3.25 to 5.60; 2 studies, 2707 participants; low‐certainty evidence). Tyrosine kinase inhibitors (TKIs) to block VEGF receptors (VEGF‐R), given with chemotherapy and continued as maintenance, likely result in little to no difference in OS (HR 0.99, 95% CI 0.84 to 1.17; 2 studies, 1451 participants; moderate‐certainty evidence) and likely increase PFS slightly (HR 0.88, 95% CI 0.77 to 1.00; 2 studies, 2466 participants; moderate‐certainty evidence). The combination likely reduces QoL slightly (MD ‐1.86, 95% CI ‐3.46 to ‐0.26; 1 study, 1340 participants; moderate‐certainty evidence), but it increases any adverse event (grade ≥ 3) slightly (RR 1.31, 95% CI 1.11 to 1.55; 1 study, 188 participants; moderate‐certainty evidence) and may result in a large increase in hypertension (grade ≥ 3) (RR 6.49, 95% CI 2.02 to 20.87; 1 study, 1352 participants; low‐certainty evidence).  Recurrent EOC (platinum‐sensitive)Moderate‐certainty evidence from three studies (with 1564 participants) indicates that bevacizumab with chemotherapy, and continued as maintenance, likely results in little to no difference in OS (HR 0.90, 95% CI 0.79 to 1.02), but likely improves PFS (HR 0.56, 95% CI 0.50 to 0.63) compared to chemotherapy alone. The combination may result in little to no difference in QoL (MD 0.8, 95% CI ‐2.11 to 3.71; 1 study, 486 participants; low‐certainty evidence), but it increases the rate of any adverse event (grade ≥ 3) slightly (RR 1.11, 1.07 to 1.16; 3 studies, 1538 participants; high‐certainty evidence). Hypertension (grade ≥ 3) was more common in arms with bevacizumab (RR 5.82, 95% CI 3.84 to 8.83; 3 studies, 1538 participants).  TKIs with chemotherapy may result in little to no difference in OS (HR 0.86, 95% CI 0.67 to 1.11; 1 study, 282 participants; low‐certainty evidence), likely increase PFS (HR 0.56, 95% CI 0.44 to 0.72; 1 study, 282 participants; moderate‐certainty evidence), and may have little to no effect on QoL (MD 6.1, 95% CI ‐0.96 to 13.16; 1 study, 146 participants; low‐certainty evidence). Hypertension (grade ≥ 3) was more common with TKIs (RR 3.32, 95% CI 1.21 to 9.10). Recurrent EOC (platinum‐resistant)Bevacizumab with chemotherapy and continued as maintenance increases OS (HR 0.73, 95% CI 0.61 to 0.88; 5 studies, 778 participants; high‐certainty evidence) and likely results in a large increase in PFS (HR 0.49, 95% CI 0.42 to 0.58; 5 studies, 778 participants; moderate‐certainty evidence). The combination may result in a large increase in hypertension (grade ≥ 2) (RR 3.11, 95% CI 1.83 to 5.27; 2 studies, 436 participants; low‐certainty evidence). The rate of bowel fistula/perforation (grade ≥ 2) may be slightly higher with bevacizumab (RR 6.89, 95% CI 0.86 to 55.09; 2 studies, 436 participants). Evidence from eight studies suggest TKIs with chemotherapy likely result in little to no difference in OS (HR 0.85, 95% CI 0.68 to 1.08; 940 participants; moderate‐certainty evidence), with low‐certainty evidence that it may increase PFS (HR 0.70, 95% CI 0.55 to 0.89; 940 participants), and may result in little to no meaningful difference in QoL (MD ranged from ‐0.19 at 6 weeks to ‐3.40 at 4 months). The combination increases any adverse event (grade ≥ 3) slightly (RR 1.23, 95% CI 1.02 to 1.49; 3 studies, 402 participants; high‐certainty evidence). The effect on bowel fistula/perforation rates is uncertain (RR 2.74, 95% CI 0.77 to 9.75; 5 studies, 557 participants; very low‐certainty evidence). Authors' conclusions Bevacizumab likely improves both OS and PFS in platinum‐resistant relapsed EOC. In platinum‐sensitive relapsed disease, bevacizumab and TKIs probably improve PFS, but may or may not improve OS. The results for TKIs in platinum‐resistant relapsed EOC are similar. The effects on OS or PFS in newly‐diagnosed EOC are less certain, with a decrease in QoL and increase in adverse events. Overall adverse events and QoL data were more variably reported than were PFS data. There appears to be a role for anti‐angiogenesis treatment, but given the additional treatment burden and economic costs of maintenance treatments, benefits and risks of anti‐angiogenesis treatments should be carefully considered.

PRISMA flow diagram outlining study selection in the systematic review on nutritional manipulation in the prevention of gestational diabetes.

<p>PRISMA flow diagram outlining study selection in the systematic review on nutritional manipulation in the prevention of gestational diabetes.</p