DATABASES REVIEWED: Medline via PubMed, Embase, Web of Science, Cochrane Central Register of Controlled Trials, and Google Scholar for studies published from inception to March 1, 2023.
METHODS: Studies of 15- to 60-year-old patients undergoing microscopic/endoscopic myringoplasty using underlay/overlay technique with reported postoperative mean hearing gain and graft uptake were included. Studies requiring simultaneous surgical procedures, reporting patients with comorbidities and with non-English full text articles were excluded. Articles were independently screened by two researchers with data extracted according to a predetermined proforma in Microsoft Excel. Cochrane risk-of-bias assessment was used for risk of bias evaluation of randomized studies and Risk of Bias in Nonrandomized Studies of Interventions for nonrandomized studies. Similar studies were pooled for meta-analysis using the inverse variance random effects model to calculate the mean difference and corresponding 95% confidence interval (CI) for mean hearing gain and DerSimonian and Laird random effects model for graft uptake.
RESULTS: Thirty-three studies comprising 2,373 patients met the inclusion/exclusion criteria, seven were pooled for meta-analysis. Included articles showed inactive OM patients have higher average postoperative mean hearing gain of 10.84 dB and graft uptake of 88.7% compared to active OM patients (9.15 dB and 84.2%). Meta-analysis of mean hearing gain (MD, -0.76 dB; 95% CI, -2.11 to 0.60; p = 0.27, moderate certainty) and graft uptake (OD, 0.61; 95% CI, 0.34-1.09; p = 0.10, moderate certainty) have an overall p value >0.05.
CONCLUSION: There were no statistically significant differences in postoperative mean hearing gain and graft uptake between active and inactive OM patients undergoing tympanoplasty. Hence, tympanoplasty procedures should not be postponed solely because of patients' preoperative ear discharge status.
METHODS: The GBD 2021 risk factor analysis used data from 54 561 total distinct sources to produce epidemiological estimates for 88 risk factors and their associated health outcomes for a total of 631 risk-outcome pairs. Pairs were included on the basis of data-driven determination of a risk-outcome association. Age-sex-location-year-specific estimates were generated at global, regional, and national levels. Our approach followed the comparative risk assessment framework predicated on a causal web of hierarchically organised, potentially combinative, modifiable risks. Relative risks (RRs) of a given outcome occurring as a function of risk factor exposure were estimated separately for each risk-outcome pair, and summary exposure values (SEVs), representing risk-weighted exposure prevalence, and theoretical minimum risk exposure levels (TMRELs) were estimated for each risk factor. These estimates were used to calculate the population attributable fraction (PAF; ie, the proportional change in health risk that would occur if exposure to a risk factor were reduced to the TMREL). The product of PAFs and disease burden associated with a given outcome, measured in disability-adjusted life-years (DALYs), yielded measures of attributable burden (ie, the proportion of total disease burden attributable to a particular risk factor or combination of risk factors). Adjustments for mediation were applied to account for relationships involving risk factors that act indirectly on outcomes via intermediate risks. Attributable burden estimates were stratified by Socio-demographic Index (SDI) quintile and presented as counts, age-standardised rates, and rankings. To complement estimates of RR and attributable burden, newly developed burden of proof risk function (BPRF) methods were applied to yield supplementary, conservative interpretations of risk-outcome associations based on the consistency of underlying evidence, accounting for unexplained heterogeneity between input data from different studies. Estimates reported represent the mean value across 500 draws from the estimate's distribution, with 95% uncertainty intervals (UIs) calculated as the 2·5th and 97·5th percentile values across the draws.
FINDINGS: Among the specific risk factors analysed for this study, particulate matter air pollution was the leading contributor to the global disease burden in 2021, contributing 8·0% (95% UI 6·7-9·4) of total DALYs, followed by high systolic blood pressure (SBP; 7·8% [6·4-9·2]), smoking (5·7% [4·7-6·8]), low birthweight and short gestation (5·6% [4·8-6·3]), and high fasting plasma glucose (FPG; 5·4% [4·8-6·0]). For younger demographics (ie, those aged 0-4 years and 5-14 years), risks such as low birthweight and short gestation and unsafe water, sanitation, and handwashing (WaSH) were among the leading risk factors, while for older age groups, metabolic risks such as high SBP, high body-mass index (BMI), high FPG, and high LDL cholesterol had a greater impact. From 2000 to 2021, there was an observable shift in global health challenges, marked by a decline in the number of all-age DALYs broadly attributable to behavioural risks (decrease of 20·7% [13·9-27·7]) and environmental and occupational risks (decrease of 22·0% [15·5-28·8]), coupled with a 49·4% (42·3-56·9) increase in DALYs attributable to metabolic risks, all reflecting ageing populations and changing lifestyles on a global scale. Age-standardised global DALY rates attributable to high BMI and high FPG rose considerably (15·7% [9·9-21·7] for high BMI and 7·9% [3·3-12·9] for high FPG) over this period, with exposure to these risks increasing annually at rates of 1·8% (1·6-1·9) for high BMI and 1·3% (1·1-1·5) for high FPG. By contrast, the global risk-attributable burden and exposure to many other risk factors declined, notably for risks such as child growth failure and unsafe water source, with age-standardised attributable DALYs decreasing by 71·5% (64·4-78·8) for child growth failure and 66·3% (60·2-72·0) for unsafe water source. We separated risk factors into three groups according to trajectory over time: those with a decreasing attributable burden, due largely to declining risk exposure (eg, diet high in trans-fat and household air pollution) but also to proportionally smaller child and youth populations (eg, child and maternal malnutrition); those for which the burden increased moderately in spite of declining risk exposure, due largely to population ageing (eg, smoking); and those for which the burden increased considerably due to both increasing risk exposure and population ageing (eg, ambient particulate matter air pollution, high BMI, high FPG, and high SBP).
INTERPRETATION: Substantial progress has been made in reducing the global disease burden attributable to a range of risk factors, particularly those related to maternal and child health, WaSH, and household air pollution. Maintaining efforts to minimise the impact of these risk factors, especially in low SDI locations, is necessary to sustain progress. Successes in moderating the smoking-related burden by reducing risk exposure highlight the need to advance policies that reduce exposure to other leading risk factors such as ambient particulate matter air pollution and high SBP. Troubling increases in high FPG, high BMI, and other risk factors related to obesity and metabolic syndrome indicate an urgent need to identify and implement interventions.
FUNDING: Bill & Melinda Gates Foundation.
OBJECTIVES: To evaluate the benefits and harms of gene therapy in people with hepatocellular carcinoma, irrespective of sex, administered dose, and type of formulation.
SEARCH METHODS: We identified randomised clinical trials through electronic searches in The Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, LILACS, Science Citation Index Expanded, and Conference Proceedings Citation Index-Science. We searched five online clinical trial registries to identify unpublished or ongoing trials. We checked reference lists of the retrieved studies for further trials. The date of last search was 20 January 2023.
SELECTION CRITERIA: We aimed to include randomised clinical trials assessing any type of gene therapy in people diagnosed with hepatocellular carcinoma, irrespective of year, language of publication, format, or outcomes reported.
DATA COLLECTION AND ANALYSIS: We followed Cochrane methodology and used Review Manager to prepare the review. The primary outcomes were all-cause mortality/overall survival (whatever data were provided), serious adverse events during treatment, and health-related quality of life. The secondary outcomes were proportion of people with disease progression, adverse events considered non-serious, and proportion of people without improvement in liver function tests. We assessed risk of bias of the included trials using RoB 2 and the certainty of evidence using GRADE. We presented the results of time-to-event outcomes as hazard ratios (HR), dichotomous outcomes as risk ratios (RR), and continuous outcomes as mean difference (MD) with their 95% confidence intervals (CI). Our primary analyses were based on intention-to-treat and outcome data at the longest follow-up.
MAIN RESULTS: We included six randomised clinical trials with 364 participants. The participants had unresectable (i.e. advanced inoperable) hepatocellular carcinoma. We found no trials assessing the effects of gene therapy in people with operable hepatocellular carcinoma. Four trials were conducted in China, one in several countries (from North America, Asia, and Europe), and one in Egypt. The number of participants in the six trials ranged from 10 to 129 (median 47), median age was 55.2 years, and the mean proportion of males was 72.7%. The follow-up duration ranged from six months to five years. As the trials compared different types of gene therapy and had different controls, we could not perform meta-analyses. Five of the six trials administered co-interventions equally to the experimental and control groups. All trials assessed one or more outcomes of interest in this review. The certainty of evidence was very low in five of the six comparisons and low in the double-dose gene therapy comparison. Below, we reported the results of the primary outcomes only. Pexastimogene devacirepvec (Pexa-Vec) plus best supportive care versus best supportive care alone There is uncertainty about whether there may be little to no difference between the effect of Pexa-Vec plus best supportive care compared with best supportive care alone on overall survival (HR 1.19, 95% CI 0.78 to 1.82; 1 trial (censored observation at 20-month follow-up), 129 participants; very low-certainty evidence) and on serious adverse events (RR 1.42, 95% CI 0.60 to 3.33; 1 trial at 20 months after treatment, 129 participants; very low-certainty evidence). The trial reported quality of life narratively as "assessment of quality of life and time to symptomatic progression was confounded by the high patient dropout rate." Adenovirus-thymidine kinase with ganciclovir (ADV-TK/GCV) plus liver transplantation versus liver transplantation alone There is uncertainty about whether ADV-TK/GCV plus liver transplantation may benefit all-cause mortality at the two-year follow-up (RR 0.39, 95% CI 0.20 to 0.76; 1 trial, 45 participants; very low-certainty evidence). The trial did not report serious adverse events other than mortality or quality of life. Double-dose ADV-TK/GCV plus liver transplantation versus liver transplantation alone There is uncertainty about whether double-dose ADV-TK/GCV plus liver transplantation versus liver transplantation may benefit all-cause mortality at five-year follow-up (RR 0.40, 95% CI 0.22 to 0.73; 1 trial, 86 participants; low-certainty evidence). The trial did not report serious adverse events other than mortality or quality of life. Recombinant human adenovirus-p53 with hydroxycamptothecin (rAd-p53/HCT) versus hydroxycamptothecin alone There is uncertainty about whether there may be little to no difference between the effect of rAd-p53/HCT versus hydroxycamptothecin alone on the overall survival at 12-month follow-up (RR 3.06, 95% CI 0.16 to 60.47; 1 trial, 48 participants; very low-certainty evidence). The trial did not report serious adverse events or quality of life. rAd-p53/5-Fu (5-fluorouracil) plus transarterial chemoembolisation versus transarterial chemoembolisation alone The trial included 46 participants. We had insufficient data to assess overall survival. The trial did not report serious adverse events or quality of life. E1B-deleted (dl1520) adenovirus versus percutaneous ethanol injection The trial included 10 participants. It did not report data on overall survival, serious adverse events, or health-related quality of life. One trial did not provide any information on sponsorship; one trial received a national research grant, one trial by the Pedersen foundation, and three were industry-funded trials. We found five ongoing randomised clinical trials.
AUTHORS' CONCLUSIONS: The evidence is very uncertain about the effects of gene therapy on the studied outcomes because of high risk of bias and imprecision of outcome results. The trials were underpowered and lacked trial data on clinically important outcomes. There was only one trial per comparison, and we could not perform meta-analyses. Therefore, we do not know if gene therapy may reduce, increase, or have little to no effect on all-cause mortality or overall survival, or serious adverse events in adults with unresectable hepatocellular carcinoma. The impact of gene therapy on adverse events needs to be investigated further. Evidence on the effect of gene therapy on health-related quality of life is lacking.
METHODS: The translation and cross-cultural adaptation process adhered to international guidelines. The Malay-AQoL-6D underwent content and face validity assessments via expert review, and pretesting among healthy individuals and patients with chronic conditions. Subsequent psychometric validation utilised clinico-sociodemographic data and paired AQoL-6D and EQ-5D-5L data from a health-related quality-of-life (HRQoL) survey involving Malay-speaking patients with HF, which encompassed assessments of Malay-AQoL-6D acceptability, internal consistency and test-retest reliability, as well as its construct, concurrent, convergent and divergent, and known-group validity.
RESULTS: The Malay-AQoL-6D was deemed acceptable among clinicians and local patients, achieving a 90.8% completion rate among 314 patients surveyed. The instrument demonstrated strong content validity (item-level content validity index [CVI]: 0.83-1.00, average CVI: 0.98), internal consistency (Cronbach's alpha: 0.72-0.89; MacDonald's omega: 0.82-0.90, excluding the Senses dimension), and test-retest reliability (average intraclass correlation coefficients: 0.79-0.95). Confirmatory factor analysis confirmed the instrument's two-level, six-factor structure (Satorra-Bentler [SB]-scaled χ2(df: 164): 283.67, p-value
METHODS: A 42-item survey questionnaire was developed and validated with a total of 443 patients. The perceived importance of information provided and level of patient satisfaction were assessed with a 5-point Likert scale in 10 domains (Diagnosis, Surgery, Radiotherapy, Systemic therapy, Clinical trials, Pain management, Treatment monitoring, Psychosocial support, Sexual care and fertility issues, and Financial support). A Spearman's rank correlation test was applied to determine the correlation between response in both item and domain categories for perceived importance and satisfaction.
RESULTS: Overall, patients were more satisfied with information related to cancer diagnosis, treatment and surgery but less satisfied with information pertaining to sexual aspects of care and family planning, psycho-social support and financial support. The majority of patients were satisfied with the level of treatment-related information received but preferred the information to be delivered in more easily comprehendible formats. Sexual aspects of care and family planning, psychosocial support and treatment monitoring post-discharge were perceived as important but seldom addressed by health care professionals due to lack of professional counsellors, social workers and clinical nurse specialists. Many patients face financial toxicity following a cancer diagnosis, particularly when diagnosed with advanced cancer requiring complex multi-modality treatment.
CONCLUSION: Cancer patients in Sarawak have various unmet information needs. Written information and educational videos in local indigenous languages may be more suitable for Sarawak's multi-ethnic population. Sexual aspects of care and family planning are challenging but essential topics to discuss, in particular due to the high prevalence of breast and cervical cancer amongst young women of reproductive age in Sarawak. Financial assessment and information on support services offered by government and non-government organisations should be provided to eligible patients. A holistic needs assessment of each patient at time of diagnosis and support through their cancer journey requires a multi-disciplinary team of medical, nursing and allied health professionals including clinical nurse specialists, pharmacists, counsellors, physiotherapists, occupational therapists, speech and language therapists, dieticians and social workers.
MATERIALS AND METHODS: All patients who had 3D-ABUS between January 2014 and January 2022 for screening were included in this retrospective study. The images were reported by 1 of 6 breast radiologists based on the Breast Imaging Reporting and Data Systems (BI-RADS). The 3D-ABUS was reviewed together with the digital breast tomosynthesis (DBT). Recall rate, biopsy rate, positive predictive value (PPV) and cancer detection yield were calculated.
RESULTS: In total, 3616 studies were performed in 1555 women (breast density C/D 95.5% (n = 3455/3616), breast density A/B 4.0% (n = 144/3616), density unknown (0.5% (n = 17/3616)). A total of 259 lesions were detected on 3D-ABUS (87.6% (n = 227/259) masses and 12.4% (n = 32/259) architectural distortions). The recall rate was 5.2% (n = 188/3616) (CI 4.5-6.0%) with only 36.7% (n = 69/188) cases recalled to another date. Moreover, recall declined over time. There were 3.4% (n = 123/3616) biopsies performed, with 52.8% (n = 65/123) biopsies due to an abnormality detected in 3D-ABUS alone. Ten of 65 lesions were malignant, resulting in a positive predictive value (PPV) of 15.4% (n = 10/65) (CI 7.6-26.5%)). The cancer detection yield of 3D-ABUS is 2.77 per 1000 screening tests (CI 1.30-5.1).
CONCLUSION: The cancer detection yield of 3D-ABUS in a real clinical screening setting is comparable to the results reported in previous prospective studies, with lower recall and biopsy rates. 3D-ABUS also may be an alternative for screening when mammography is not possible or declined.
CLINICAL RELEVANCE STATEMENT: 3D automated breast ultrasound screening performance in a clinical setting is comparable to previous prospective studies, with better recall and biopsy rates.
KEY POINTS: • 3D automated breast ultrasound is a reliable and reproducible tool that provides a three-dimensional representation of the breast and allows image visualisation in axial, coronal and sagittal. • The diagnostic performance of 3D automated breast ultrasound in a real clinical setting is comparable to its performance in previously published prospective studies, with improved recall and biopsy rates. • 3D automated breast ultrasound is a useful adjunct to mammography in dense breasts and may be an alternative for screening when mammography is not possible or declined.
METHODS: Eligibility criteria are those diagnosed with T2DM, aged between 18 and 65 years, with HbA1c between 8 and 15% and on insulin therapy for 1 year. Patients were randomly allocated to receive either the USM-IAM-based counselling or the standard counselling (SC) at baseline and the second visit. Patients were instructed to adjust insulin doses based on blood glucose levels. Outcomes were changes in adherence score, FBS and HbA1c levels from baseline to 3 months and baseline to sixth month.
RESULTS: Ninety patients were randomised to each group. The baseline sociodemographic and clinical characteristics were homogenous among groups. Ninety patients were analysed for each group. Adherence score changes between baseline to 3 months were - 8.30 (- 11.47, - 5.14) in USM-IAM-based counselling group (USM-IAM) and - 7.64 (- 10.89, - 4.40) in standard counselling group (SCG), between baseline to sixth month were - 10.21 (- 13.40, - 7.03) in USM-IAM and - 10.79 (- 14.64, - 6.97) in SCG. FBS changes between baseline to 3 months were 1.374 (0.25, 2.50) in USM-IAM and 0.438 (- 0.66, 1.54) in SCG, and between baseline to sixth month were 1.713 (0.473, 2.95) in USM-IAM and 0.998 (- 0.02, 2.01) in SCG. HbA1c changes between baseline to 3 months were 1.374 (0.25, 2.50) in USM-IAM and 0.547 (0.12, 0.98) in SCG, and between baseline to sixth month were 1.03 (0.65, 1.41) in USM-IAM and 0.617 (0.20, 1.03) in SCG. Between-subjects effects for all outcomes were not statistically significant.
CONCLUSION: Both groups had significant improvements in adherence score and HbA1c with time, with higher improvement in patients receiving the USM-IAM. FBS reductions were significant in the intervention group but not in the control group.
TRIAL REGISTRATION: This study protocol is registered with Clicaltrials.gov with ID NCT05125185 dated 17th November 2021.
METHODS: We conducted a two-round modified Delphi survey among local and international communication experts, and also recipients of medicines risk communication in Malaysia. We developed a list of 37 strategies based on the findings of our previous studies. In Round 1, participants were asked to rate the priority for each strategy using a 5-point Likert scale and suggest additional strategies via free-text comments. Strategies scoring a mean of ≥ 3.75 were included in Round 2. We defined consensus for the final list of strategies a priori as > 75% agreement. Data were analysed using descriptive statistics and thematic analysis.
RESULTS: Our final Delphi panel (n = 39, 93% response rate) comprised medicines communication experts from nine countries and Malaysian healthcare professionals. Following Round 1, we dropped 14 strategies and added 11 strategies proposed by panellists. In the second round, 21 strategies achieved consensus. The priority areas identified were to improve the format and content of risk communication, increase the use of technology, and increase collaboration with various stakeholders. Priority ratings for the strategy "to offer incentives to pharmaceutical companies which maintain effective communication systems" were significantly higher among recipients compared to communicators [χ2(1, N = 39) = 10.1; p = 0.039] and among local versus international panellists [χ2(1, N = 39) = 14.3; p = 0.007].
CONCLUSIONS: Our study identified 21 priority strategies, which were used to develop a strategic plan for enhancing medicines risk communication. This plan is potentially adaptable to all countries with developing pharmacovigilance systems. The difference in views between communicators and recipients, as well as local and international panellists, highlights the importance of involving multiple stakeholders in research.