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Translational Vision Science &... Nov 2023This systematic review evaluates the safety and efficacy of ocular gene therapy using adeno-associated virus (AAV). (Meta-Analysis)
Meta-Analysis
PURPOSE
This systematic review evaluates the safety and efficacy of ocular gene therapy using adeno-associated virus (AAV).
METHODS
MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov were searched systematically for controlled or non-controlled interventional gene therapy studies using key words related to retinal diseases, gene therapy, and AAV vectors. The primary outcome measure was safety, based on ocular severe adverse events (SAEs). Secondary outcome measures evaluated efficacy of the therapy based on best corrected visual acuity (BCVA) and improvements in visual sensitivity and systemic involvement following ocular delivery. Pooling was done using a DerSimonian Laird random effects model. Risk of bias was assessed using the Cochrane Risk of Bias Tool, version 1.
RESULTS
Our search identified 3548 records. Of these, 80 publications met eligibility criteria, representing 28 registered clinical trials and 5 postmarket surveillance studies involving AAV gene therapy for Leber congenital amaurosis (LCA), choroideremia, Leber hereditary optic neuropathy (LHON), age-related macular degeneration (AMD), retinitis pigmentosa (RP), X-linked retinoschisis, and achromatopsia. Overall, AAV therapy vectors were associated with a cumulative incidence of at least one SAE of 8% (95% confidence intervals [CIs] of 5% to 12%). SAEs were often associated with the surgical procedure rather than the therapeutic vector itself. Poor or inconsistent reporting of adverse events (AEs) were a limitation for the meta-analysis. The proportion of patients with any improvement in BCVA and visual sensitivity was 41% (95% CIs of 31% to 51%) and 51% (95% CIs of 31% to 70%), respectively. Systemic immune involvement was associated with a cumulative incidence of 31% (95% CI = 21% to 42%).
CONCLUSIONS
AAV gene therapy vectors appear to be safe but the surgical procedure required to deliver them is associated with some risk. The large variability in efficacy can be attributed to the small number of patients treated, the heterogeneity of the population and the variability in dosage, volume, and follow-up.
TRANSLATIONAL RELEVANCE
This systematic review will help to inform and guide future clinical trials.
Topics: Humans; Retinal Degeneration; Dependovirus; Macular Degeneration; Retinitis Pigmentosa; Genetic Therapy
PubMed: 37982768
DOI: 10.1167/tvst.12.11.24 -
Vaccine Sep 2022National HPV vaccination coverage in Japan is less than one percent of the eligible population and cervical cancer incidence and mortality are increasing. This... (Meta-Analysis)
Meta-Analysis
BACKGROUND
National HPV vaccination coverage in Japan is less than one percent of the eligible population and cervical cancer incidence and mortality are increasing. This systematic review and meta-analysis aimed to provide a comprehensive estimate of HPV genotype prevalence for Japan.
METHODS
English and Japanese databases were searched to March 2021 for research reporting HPV genotypes in cytology and histology samples from Japanese women. Summary estimates were calculated by disease stage from cytology only assessment - Normal, ASCUS, LSIL, HSIL and from histological assessment - CIN1, CIN2, CIN3/AIS, ICC (ICC-SCC, and ICC-ADC), and other. A random-effects meta-analysis was used to calculate summary prevalence estimates of any-HPV, high-risk (HR) and low-risk (LR) vaccine types, and vaccine genotypes (bivalent, quadrivalent, or nonavalent). This study was registered with PROSPERO: CRD42018117596.
RESULTS
A total of 57759 women with normal cytology, 1766 ASCUS, 3764 LSIL, 2017 HSIL, 3130 CIN1, 1219 CIN2, 869 CIN3/AIS, and 4306 ICC (which included 1032 ICC-SCC, and 638 ICC-ADC) were tested for HPV. The summary estimate of any-HPV genotype in women with normal cytology was 15·6% (95% CI: 12·3-19·4) and in invasive cervical cancer (ICC) was 85·6% (80·7-89·8). The prevalence of HR-HPV was 86·0% (95% CI: 73·9-94·9) for cytological cases of HSIL, 76·9% (52·1-94·7) for histological cases of CIN3/AIS, and 75·7% (68·0-82·6) for ICC. In women with ICC, the summary prevalence of bivalent vaccine genotypes was 58·5% (95% CI: 52·1-64·9), for quadrivalent genotypes was 58·6% (52·2-64·9) and for nonavalent genotypes was 71·5% (64·9-77·6), and of ICC cases that were HPV positive over 90% of infections are nonavalent vaccine preventable. There was considerable heterogeneity in all HPV summary estimates and for ICC, this heterogeneity was not explained by variability in study design, sample type, HPV assay type, or HPV DNA detection method, although studies published in the 1990s had lower prevalence estimates of any-HPV and HR HPV genotypes.
INTERPRETATIONS
HPV prevalence is high among Japanese women. The nonavalent vaccine is likely to have the greatest impact on reducing cervical cancer incidence and mortality in Japan.
Topics: Age Distribution; Alphapapillomavirus; Atypical Squamous Cells of the Cervix; DNA; Female; Genotype; Humans; Japan; Papillomaviridae; Papillomavirus Infections; Prevalence; Uterine Cervical Neoplasms; Vaccines, Combined; Uterine Cervical Dysplasia
PubMed: 36085257
DOI: 10.1016/j.vaccine.2022.07.052 -
European Journal of Medical Research Feb 2022To determine the effect of polymorphisms and mutations in angiotensin-converting enzyme 2 (ACE2) and Type 2 transmembrane serine proteases (TMPRSS2) genes on...
OBJECTIVE
To determine the effect of polymorphisms and mutations in angiotensin-converting enzyme 2 (ACE2) and Type 2 transmembrane serine proteases (TMPRSS2) genes on susceptibility to corona virus disease 2019 (COVID-19) and patient prognosis.
INTRODUCTION
From December 2019 to the current time, an outbreak of epidemic of COVID-19, characterized by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has occurred around the world. It is now clear that SARS-CoV-2 binds to human ACE2 receptors, with expression of these receptors correlated with the rate of SARS-CoV-2 infection and mortality. Polymorphisms in individual patient factors, such as ACE2 and TMPRSS2 genes have been linked with an increase in negative outcomes, although evidence to affirm remains debatable.
METHODS
Here, we performed a systematic review, based on guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria, with the aim of assessing whether polymorphisms in ACE2 and TMPRSS2 genes affect the COVID-19 condition. We extensively searched PubMed, MEDLINE, Embase, the Cochrane Library, and Web of Science databases, for relevant articles and reports published in English between December 2019 and December 2021.
RESULTS
A total of 495 full-text articles were downloaded, of which 185 were excluded after preliminary examination as they were duplicates. Finally, 310 articles were evaluated, by reading their titles and abstracts, and 208 of them eliminated based on our selection criteria. Finally, 33 articles met our inclusion criteria and were included in the final assessment. Genetic data from 33,923 patients with COVID-19 drawn from the general population and deriving from over 160 regions and 50 countries, as well as approximately 560,000 samples from global-public genetic databases, were included in our analysis. Ultimately, we identified 10 SNPs and 21 mutations in the ACE2 gene, along with 13 SNPs and 12 variants in the TMPRSS2 gene, which may be associated with COVID-19.
CONCLUSIONS
ACE2 and TMPRSS2 play vital roles in the onset, development, and prognosis of SARS-CoV-2 infection, and have both been strongly associated with vulnerability, intensity, and the clinical result of COVID-19. Overall, these genetic factors may have potential for future development of personalized drugs and vaccines against COVID-19.
TRIAL REGISTRATION
CRD42021239400 in PROSPERO 2021.
Topics: Angiotensin-Converting Enzyme 2; COVID-19; Genetic Predisposition to Disease; Humans; Mutation; Polymorphism, Single Nucleotide; SARS-CoV-2; Serine Endopeptidases
PubMed: 35193695
DOI: 10.1186/s40001-022-00647-6 -
Animal : An International Journal of... Jun 2022Breeding objectives of livestock and other agricultural species are usually profit maximising. The selection emphasis placed on specific traits to achieve a breeding... (Review)
Review
Breeding objectives of livestock and other agricultural species are usually profit maximising. The selection emphasis placed on specific traits to achieve a breeding objective is often informed by the financial value of a trait to a farm system. However, there are alternative, and complementary approaches to defining both the breeding objective and the selection emphasis placed on traits that are included in associated selection tools. These are based on the preferences of stakeholders, which are often heterogeneous and include broader values and motivations than profit. In this regard, stated preference methods are useful when considering traits that have either no discernible market value or whose value is not fully transferred via the market. Such approaches can guide more appropriate breeding decisions that are amenable to changing societal values, for example with reduced negative environmental externalities. However, while stated preference methods offer promising conceptualisations of value in genetic improvement programmes, there is still a substantial knowledge gap in terms of the current state of research and a catalogue of publications to date. This paper reviews publications of stated preference approaches in the field of livestock breeding (and some relevant crop breeding examples), providing a knowledge base of published applications and promoting their continued development and implementation towards the formulation of appropriate breeding objectives and selection indices. A systematic review of 84 peer-reviewed publications and an aggregate ranking of traits for the most commonly studied subject (cattle) reveals uncertainty in preference estimates which may be driven by (i) a diverse set of non-standardised methodologies, (ii) common oversights in the selection, inclusion and description of traits, and (iii) inaccurate representations of the respondent population. We discuss key considerations to help overcome these limitations, including avoiding methodological confinement to a disciplinary silo and reducing complexity so that the values of broader respondent groups may be accounted for.
Topics: Animals; Cattle; Livestock; Phenotype
PubMed: 35588584
DOI: 10.1016/j.animal.2022.100535 -
Cancers Jan 2023Background: The association between Lynch syndrome (LS) and a higher risk of upper tract urothelial carcinoma is well established, but its effect on the risk of bladder... (Review)
Review
Background: The association between Lynch syndrome (LS) and a higher risk of upper tract urothelial carcinoma is well established, but its effect on the risk of bladder and kidney cancers remains controversial. This review aimed to compare the relative risk (RR) of bladder and kidney cancer in confirmed LS germline mutation carriers compared to the general population. Methods: Medline, Embase, Cochrane Central, and Google Scholar were searched on 14 July 2022 for studies published in English that reported on the rates of urological cancer in adults with confirmed LS germline mutation. The quality of included studies was assessed using Cochrane’s tool to evaluate risk of bias in cohort studies. Random effects meta-analysis estimated the pooled relative risk of bladder and kidney cancer in LS carriers compared to the general population. The quality of the overall evidence was evaluated using GRADE. Results: Of the 1839 records identified, 5 studies involving 7120 participants from 3 continents were included. Overall, LS carriers had a statistically significantly higher RR of developing bladder cancer (RR: 7.48, 95% CI: 3.70, 15.13) and kidney cancer (RR: 3.97, 95% CI: 1.23, 12.81) compared to unaffected participants (p < 0.01). The quality of the evidence was assessed as “low” due to the inclusion of cohort studies, the substantial heterogeneity, and moderate-to-high risk of bias. Conclusion: Lynch syndrome is associated with a significant increase in the relative risk of kidney and bladder cancer. Clinicians should adopt a lower threshold for germline mutation genetic testing in individuals who present with bladder cancer. Further studies evaluating the role and cost-effectiveness of novel urine-based laboratory tests are needed. High-quality studies in histologically proven renal cell carcinoma and their underlying germline mutations are necessary to strengthen the association with LS.
PubMed: 36672455
DOI: 10.3390/cancers15020506 -
BMC Medicine Jul 2023Studies of women of European ancestry have shown that the average familial relative risk for first-degree relatives of women with breast cancer is approximately twofold,... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Studies of women of European ancestry have shown that the average familial relative risk for first-degree relatives of women with breast cancer is approximately twofold, but little is known for Asian women. We aimed to provide evidence for the association between family history and breast cancer risk for Asian women by systematically reviewing published literature.
METHODS
Studies reporting the familial relative risk of breast cancer for Asian women were searched in three online databases and complemented by a manual search. Odds ratios (ORs) for the association between family history and breast cancer risk were pooled across all included studies and by subgroups in terms of the type of family history, age, menopausal status and geographical region.
RESULTS
The pooled OR for women who have a first-degree relative with breast cancer was 2.46 (95% confidence interval [CI]: 2.03, 2.97). There was no evidence that the familial risk differed by the type of affected relative (mother versus sisters), the woman's age (< 50 years versus ≥ 50 years), menopausal status (pre versus post) and geographical region (East and Southeast Asia versus other regions) (all P > 0.3). The pooled ORs for women of Asian ancestry with a family history in any relative were similar for those living in non-Asian countries (2.26, 95% CI: 1.42, 3.59) compared with those living in Asian countries (2.18, 95% CI: 1.85, 2.58).
CONCLUSIONS
Family history of breast cancer is associated with an approximately twofold relative risk of breast cancer for Asian women, which is of similar magnitude to that observed for women of European ancestry. This implies that similar familial factors are implicated in breast cancer risk between women of European and Asian ancestries. Genetic factors are likely to play a substantial role in explaining the breast cancer familial risk for Asian women, as similar risks were observed across different living environments and cultures.
Topics: Female; Humans; Middle Aged; Breast Neoplasms; Risk Factors; Genetic Predisposition to Disease; Asia; Mothers; Case-Control Studies
PubMed: 37400822
DOI: 10.1186/s12916-023-02950-3 -
Steroids Sep 2022Genetic susceptibility to dyslipidaemia remains incompletely understood. The liver X receptors (LXRs), members of the nuclear receptor superfamily of ligand dependent... (Meta-Analysis)
Meta-Analysis
Genetic susceptibility to dyslipidaemia remains incompletely understood. The liver X receptors (LXRs), members of the nuclear receptor superfamily of ligand dependent transcription factors, are homeostatic regulators of lipid metabolism. Multiple single nucleotide polymorphisms (SNPs)have been identified previously in the coding and regulatory regions of the LXRs. The aim of this systematic review and meta-analysis was to summarise associations between SNPs of LXRs (α and β isoforms) with blood lipid and lipoprotein traits. Five databases (PubMed, Ovid Embase, Scopus, Web of Science, and the Cochrane Library) were systematically searched for population-based studies that assessed associations between one or more blood lipid/lipoprotein traits and LXR SNPs. Of seventeen articles included in the qualitative synthesis, ten were eligible for meta-analysis. Nine LXRα SNPs and five LXRβ SNPs were identified, and the three most studied LXRα SNPs were quantitatively summarised. Carriers of the minor allele A of LXRα rs12221497 (-115G>A) had higher triglyceride levels than GG homozygotes (0.13 mmol/L; 95%CI: [0.03, 0.23], P = 0.01). Heterozygote carriers of LXRα rs2279238 (297C/T) had higher total cholesterol levels (0.12 mmol/L; (95%CI: [0.01, 0.23], P = 0.04) than either CC or TT homozygotes. For LXRα rs11039155 (-6G>A), no significant differences in blood levels of either triglyceride (P = 0.39) or HDL-C (P = 0.98) were detected between genotypes in meta-analyses. In addition, there were no strong associations for other SNPs of LXRα and LXRβ. This study provides the evidence of an association between LXRα, but not LXRβ, SNPs and blood-lipid traits. Systematic review registration: PROSPERO No. CRD42021246158.
Topics: Lipids; Lipoproteins; Liver X Receptors; Orphan Nuclear Receptors; Polymorphism, Single Nucleotide; Triglycerides
PubMed: 35679909
DOI: 10.1016/j.steroids.2022.109057 -
Hormone Research in Paediatrics 2023Congenital adrenal hyperplasia (CAH) is an autosomal recessive genetic disorder that causes defects in the adrenal cortex enzymes that impair the biosynthesis of... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Congenital adrenal hyperplasia (CAH) is an autosomal recessive genetic disorder that causes defects in the adrenal cortex enzymes that impair the biosynthesis of cortisol, aldosterone, or both. The most common type is the 21-hydroxylase enzyme deficiency in approximately 95% of cases resulting from CYP21A2 gene mutations or deletions.
OBJECTIVES
This study aimed to systematically review the national differences in CAH incidence and analyze the pooled results to determine disparities and whether ethnicity can predispose people to develop CAH.
METHODS
PubMed, Scopus, and LILACS were used to achieve results until June 22, 2018. Study eligibility criteria included availability of full-text; English, Spanish, or Portuguese languages; incidence or number of new cases; and number of live births or sample population. Only the classic CAH type (salt-wasting and simple-virilizing) was considered, and no distinction was made between the enzyme deficiency types.
RESULTS
This study summarizes the findings of 58 studies and 31 countries (from 1969 to 2017), in which the overall CAH incidence was 1:9,498 (95% confidence interval: 1:9,089, 1:9,945). Countries from the Eastern Mediterranean and Southeast Asia revealed the highest CAH incidence. The lowest incidence was reported in countries of the Western Pacific of Asia. No remarkable difference was observed in the Hispanics/Latino and White groups. However, they manifested a higher incidence of CAH than people identified as Black or of African descent. Published studies on CAH incidence in the sub-Saharan African region and parts of Europe were insufficient.
CONCLUSIONS
This study highlights the at-risk population for CAH and regions that need monitoring for CAH. The highest CAH incidence could be attributed to higher consanguinity, less genetic diversity, or other genetic causes since CAH is an inherited genetic disorder. Cultural practices in some places regarding consanguineous unions or geographic isolation may directly affect the incidence. Newborn screening for CAH may be unavailable in many developing countries, thereby affecting the actual CAH incidence. Therefore, healthcare workers should be trained to recognize CAH at an early stage to reduce its complications and mortality.
Topics: Infant, Newborn; Humans; Adrenal Hyperplasia, Congenital; Neonatal Screening; Adrenal Cortex; Mutation; Steroid 21-Hydroxylase
PubMed: 35973409
DOI: 10.1159/000526401 -
Clinical and Translational Medicine Jan 2023Approximately 10% of all bone fractures result in delayed fracture healing or non-union; thus, the identification of biomarkers and prognostic factors is of great... (Review)
Review
BACKGROUND
Approximately 10% of all bone fractures result in delayed fracture healing or non-union; thus, the identification of biomarkers and prognostic factors is of great clinical interest. MicroRNAs (miRNAs) are known to be involved in the regulation of the bone healing process and may serve as functional markers for fracture healing.
AIMS AND METHODS
This systematic review aimed to identify common miRNAs involved in fracture healing or non-union fractures using a qualitative approach. A systematic literature search was performed with the keywords 'miRNA and fracture healing' and 'miRNA and non-union fracture'. Any original article investigating miRNAs in fracture healing or non-union fractures was screened. Eventually, 82 studies were included in the qualitative analysis for 'miRNA and fracture healing', while 19 were selected for the 'miRNA and fracture non-union' category.
RESULTS AND CONCLUSIONS
Out of 151 miRNAs, miR-21, miR-140 and miR-214 were the most investigated miRNAs in fracture healing in general. miR-31-5p, miR-221 and miR-451-5p were identified to be regulated specifically in non-union fractures. Large heterogeneity was detected between studies investigating the role of miRNAs in fracture healing or non-union in terms of patient population, sample types and models used. Nonetheless, our approach identified some miRNAs with the potential to serve as biomarkers for non-union fractures, including miR-31-5p, miR-221 and miR-451-5p. We provide a discussion of involved pathways and suggest on alignment of future research in the field.
Topics: Humans; MicroRNAs; Prognosis; Fracture Healing; Fractures, Bone; Biomarkers
PubMed: 36629031
DOI: 10.1002/ctm2.1161 -
Orphanet Journal of Rare Diseases Apr 2021Recessive dystrophic epidermolysis bullosa (RDEB) is a genetic collagen disorder characterized by skin fragility leading to blistering, wounds, and scarring. There are... (Review)
Review
BACKGROUND/OBJECTIVE
Recessive dystrophic epidermolysis bullosa (RDEB) is a genetic collagen disorder characterized by skin fragility leading to blistering, wounds, and scarring. There are currently no approved curative therapies. The objective of this manuscript is to provide a comprehensive literature review of the disease burden caused by RDEB.
METHODS
A systematic literature review was conducted in MEDLINE and Embase in accordance with PRISMA guidelines. Observational and interventional studies on the economic, clinical, or humanistic burden of RDEB were included.
RESULTS
Sixty-five studies were included in the review. Patients had considerable wound burden, with 60% reporting wounds covering more than 30% of their body. Increases in pain and itch were seen with larger wound size. Chronic wounds were larger and more painful than recurrent wounds. Commonly reported symptoms and complications included lesions and blistering, anemia, nail dystrophy and loss, milia, infections, musculoskeletal contractures, strictures or stenoses, constipation, malnutrition/nutritional problems, pseudosyndactyly, ocular manifestations, and dental caries. Many patients underwent esophageal dilation (29-74%; median dilations, 2-6) and gastrostomy tube placement (8-58%). In the severely affected population, risk of squamous cell carcinoma (SCC) was 76% and mortality from SCC reached 84% by age 40. Patients with RDEB experienced worsened quality of life (QOL), decreased functioning and social activities, and increased pain and itch when compared to other EB subtypes, other skin diseases, and the general population. Families of patients reported experiencing high rates of burden including financial burden (50-54%) and negative impact on private life (79%). Direct medical costs were high, though reported in few studies; annual payer-borne total medical costs in Ireland were $84,534 and annual patient-borne medical costs in Korea were $7392. Estimated annual US costs for wound dressings ranged from $4000 to $245,000. Patients spent considerable time changing dressings: often daily (13-54% of patients) with up to three hours per change (15-40%).
CONCLUSION
Patients with RDEB and their families/caregivers experience significant economic, humanistic, and clinical burden. Further research is needed to better understand the costs of disease, how the burden of disease changes over the patient lifetime and to better characterize QOL impact, and how RDEB compares with other chronic, debilitating disorders.
Topics: Adult; Cost of Illness; Dental Caries; Epidermolysis Bullosa; Epidermolysis Bullosa Dystrophica; Humans; Quality of Life; Republic of Korea
PubMed: 33849616
DOI: 10.1186/s13023-021-01811-7