ObjectiveAlthough COVID-19 is primarily a respiratory illness, there is mounting evidence suggesting that the GI tract is involved in this disease. We investigated whether the gut microbiome is ...linked to disease severity in patients with COVID-19, and whether perturbations in microbiome composition, if any, resolve with clearance of the SARS-CoV-2 virus.MethodsIn this two-hospital cohort study, we obtained blood, stool and patient records from 100 patients with laboratory-confirmed SARS-CoV-2 infection. Serial stool samples were collected from 27 of the 100 patients up to 30 days after clearance of SARS-CoV-2. Gut microbiome compositions were characterised by shotgun sequencing total DNA extracted from stools. Concentrations of inflammatory cytokines and blood markers were measured from plasma.ResultsGut microbiome composition was significantly altered in patients with COVID-19 compared with non-COVID-19 individuals irrespective of whether patients had received medication (p<0.01). Several gut commensals with known immunomodulatory potential such as Faecalibacterium prausnitzii, Eubacterium rectale and bifidobacteria were underrepresented in patients and remained low in samples collected up to 30 days after disease resolution. Moreover, this perturbed composition exhibited stratification with disease severity concordant with elevated concentrations of inflammatory cytokines and blood markers such as C reactive protein, lactate dehydrogenase, aspartate aminotransferase and gamma-glutamyl transferase.ConclusionAssociations between gut microbiota composition, levels of cytokines and inflammatory markers in patients with COVID-19 suggest that the gut microbiome is involved in the magnitude of COVID-19 severity possibly via modulating host immune responses. Furthermore, the gut microbiota dysbiosis after disease resolution could contribute to persistent symptoms, highlighting a need to understand how gut microorganisms are involved in inflammation and COVID-19.
Large structural variants (SVs) in the human genome are difficult to detect and study by conventional sequencing technologies. With long-range genome analysis platforms, such as optical mapping, one ...can identify large SVs (>2 kb) across the genome in one experiment. Analyzing optical genome maps of 154 individuals from the 26 populations sequenced in the 1000 Genomes Project, we find that phylogenetic population patterns of large SVs are similar to those of single nucleotide variations in 86% of the human genome, while ~2% of the genome has high structural complexity. We are able to characterize SVs in many intractable regions of the genome, including segmental duplications and subtelomeric, pericentromeric, and acrocentric areas. In addition, we discover ~60 Mb of non-redundant genome content missing in the reference genome sequence assembly. Our results highlight the need for a comprehensive set of alternate haplotypes from different populations to represent SV patterns in the genome.
Three hundred million people living with rare diseases worldwide are disproportionately deprived of in-time diagnosis and treatment compared with other patients. This review provides an overview of ...global policies that optimize development, licensing, pricing, and reimbursement of orphan drugs.
Pharmaceutical legislation and policies related to access and regulation of orphan drugs were examined from 194 World Health Organization member countries and 6 areas. Orphan drug policies (ODPs) were identified through internet search, emails to national pharmacovigilance centers, and systematic academic literature search. Texts from selected publications were extracted for content analysis.
One hundred seventy-two drug regulation documents and 77 academic publications from 162 countries/areas were included. Ninety-two of 200 countries/areas (46.0%) had documentation on ODPs. Thirty-four subthemes from content analysis were categorized into 6 policy themes, namely, orphan drug designation, marketing authorization, safety and efficacy requirements, price regulation, incentives that encourage market availability, and incentives that encourage research and development. Countries/areas with ODPs were statistically wealthier (gross national income per capita = $10 875 vs $3950, P < .001). Country/area income was also positively correlated with the scope of the respective ODP (correlation coefficient = 0.57, P < .001).
Globally, the number of countries with an ODP has grown rapidly since 2013. Nevertheless, disparities in geographical distribution and income levels affect the establishment of ODPs. Furthermore, identified policy gaps in price regulation, incentives that encourage market availability, and incentives that encourage research and development should be addressed to improve access to available and affordable orphan drugs.
•Before undertaking this study, we searched academic databases for all English systematic reviews on global orphan drug policies published before July 2019. We identified 1 review on orphan drug policies published in 2015 and 2 reviews on laws and national strategies for rare diseases from selected countries that were published in 2017 and 2018, respectively. These 3 reviews uncovered a plethora of governmental efforts that facilitate the availability of and access to orphan drugs, with critical differences in scope and approaches among countries.•Vast areas worldwide were omitted from previous reviews, such as Africa, India, Latin America, and Russia. No studies attempted an overview of orphan drug policies in all countries with both governmental and academic evidence. The current global landscape of orphan drug policy (ODP) remains unclear. By systematically reviewing pharmaceutical policies and academic literature from 200 countries/areas, our study presents the most comprehensive review on global ODP to date.•Of the 200 countries or areas examined, 92 had ODPs alongside a notable increase in ODP establishment in non-high-income countries/areas over the last decade. Our findings highlight disparities in ODP establishment and scope in countries/areas with different income levels. This allows respective stakeholders to reference orphan drug regulatory standards of countries/areas with similar political realities while informing policy formulation and advocacy direction for treatment access of patients with rare diseases.
Summary
We report reference‐quality genome assemblies and annotations for two accessions of soybean (Glycine max) and for one accession of Glycine soja, the closest wild relative of G. max. The ...G. max assemblies provided are for widely used US cultivars: the northern line Williams 82 (Wm82) and the southern line Lee. The Wm82 assembly improves the prior published assembly, and the Lee and G. soja assemblies are new for these accessions. Comparisons among the three accessions show generally high structural conservation, but nucleotide difference of 1.7 single‐nucleotide polymorphisms (snps) per kb between Wm82 and Lee, and 4.7 snps per kb between these lines and G. soja. snp distributions and comparisons with genotypes of the Lee and Wm82 parents highlight patterns of introgression and haplotype structure. Comparisons against the US germplasm collection show placement of the sequenced accessions relative to global soybean diversity. Analysis of a pan‐gene collection shows generally high conservation, with variation occurring primarily in genomically clustered gene families. We found approximately 40–42 inversions per chromosome between either Lee or Wm82v4 and G. soja, and approximately 32 inversions per chromosome between Wm82 and Lee. We also investigated five domestication loci. For each locus, we found two different alleles with functional differences between G. soja and the two domesticated accessions. The genome assemblies for multiple cultivated accessions and for the closest wild ancestor of soybean provides a valuable set of resources for identifying causal variants that underlie traits for the domestication and improvement of soybean, serving as a basis for future research and crop improvement efforts for this important crop species.
Significance Statement
Accurate shared genome assemblies provide a framework and coordinate system for collaborative research, and provide essential genomic information, including genes, non‐coding regions and information on evolutionary histories. Here, we report high‐quality genome assemblies for two important soybean cultivars, including major improvements to the most widely used reference assembly, and also for a close wild relative of soybean.
Aims
To utilize transgenic GMR‐Aβ42 Drosophila melanogaster as a model to evaluate potential Alzheimer’s disease (AD)‐reversal effects via the administration of lactic acid bacteria (LAB) strains, ...and associations of LAB with changes in gut microbiota profiles.
Methods and Results
Wild‐type flies (Oregon‐R) were crossed with glass multimer reporter‐GAL4 (GMR‐GAL4) to produce GMR‐OreR (Control), while UAS‐Aβ42 (#33769) were crossed with GMR‐GAL4 to produce transgenic Drosophila line that expressed Aβ42 (GMR‐Aβ42). Feed containing seven different LAB strains (Lactobacillus paracasei 0291, Lactobacillus helveticus 1515, Lactobacillus reuteri 30242, L. reuteri 8513d, Lactobacillus fermentum 8312, Lactobacillus casei Y, Lactobacillus sakei Probio65) were given to GMR‐Aβ42 respectively, while feed without LAB strains were given to control and transgenic GMR‐Aβ42.nf Drosophila lines. The morphology of the eyes was viewed with scanning electron microscopy (SEM). The changes in gut microbiota profiles associated with LAB were analysed using 16s high throughput sequencing. Malformation of eye structures in transgenic GMR‐Aβ42 Drosophila were reversed upon the administration of LAB strains, with more prevalent effects from L. sakei Probio65 and L. paracasei 0291. The GMR‐Aβ42.nf group showed dominance of Wolbachia in the gut, a genus that was almost absent in the normal control group (P < 0·05). The administration of L. sakei Probio65 and L. paracasei 0291 reduced the abundance of Wolbachia accompanied by increased abundance of Stenotrophomonas and Acetobacter (P < 0·05), resembling the microbial profile of the control group.
Conclusions
Lactobacillus sakei Probio65 and Lactobacillus paracasei 0291 have more prominent effects in reversing malformed eye of transgenic GMR‐Aβ42 Drosophila, and reducing the abundance of Wolbachia accompanied by an increased abundance of Stenotrophomonas and Acetobacter.
Significance and Impact of the Study
Potentials of LAB to prevent and/or alleviate the onset and pathogenesis of neurodegenerative diseases such as AD, supporting brain health strategies along the gut–brain axis.
Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects gastrointestinal tissues, little is known about the roles of gut commensal microbes in susceptibility to and severity of ...infection. We investigated changes in fecal microbiomes of patients with SARS-CoV-2 infection during hospitalization and associations with severity and fecal shedding of virus.
We performed shotgun metagenomic sequencing analyses of fecal samples from 15 patients with Coronavirus Disease 2019 (COVID-19) in Hong Kong, from February 5 through March 17, 2020. Fecal samples were collected 2 or 3 times per week from time of hospitalization until discharge; disease was categorized as mild (no radiographic evidence of pneumonia), moderate (pneumonia was present), severe (respiratory rate ≥30/min, or oxygen saturation ≤93% when breathing ambient air), or critical (respiratory failure requiring mechanical ventilation, shock, or organ failure requiring intensive care). We compared microbiome data with those from 6 subjects with community-acquired pneumonia and 15 healthy individuals (controls). We assessed gut microbiome profiles in association with disease severity and changes in fecal shedding of SARS-CoV-2.
Patients with COVID-19 had significant alterations in fecal microbiomes compared with controls, characterized by enrichment of opportunistic pathogens and depletion of beneficial commensals, at time of hospitalization and at all timepoints during hospitalization. Depleted symbionts and gut dysbiosis persisted even after clearance of SARS-CoV-2 (determined from throat swabs) and resolution of respiratory symptoms. The baseline abundance of Coprobacillus, Clostridium ramosum, and Clostridium hathewayi correlated with COVID-19 severity; there was an inverse correlation between abundance of Faecalibacterium prausnitzii (an anti-inflammatory bacterium) and disease severity. Over the course of hospitalization, Bacteroides dorei, Bacteroides thetaiotaomicron, Bacteroides massiliensis, and Bacteroides ovatus, which downregulate expression of angiotensin-converting enzyme 2 (ACE2) in murine gut, correlated inversely with SARS-CoV-2 load in fecal samples from patients.
In a pilot study of 15 patients with COVID-19, we found persistent alterations in the fecal microbiome during the time of hospitalization, compared with controls. Fecal microbiota alterations were associated with fecal levels of SARS-CoV-2 and COVID-19 severity. Strategies to alter the intestinal microbiota might reduce disease severity.
Display omitted
Aims
The aim of this study was to investigate the effects of lactobacilli strains in preventing the recurrences of vaginal candidiasis (VC) in 78 pregnant women with VC (lactobacilli, n = 39; ...placebo, n = 39) and the potential benefits on quality of life.
Methods and Results
The lactobacilli putative probiotic (SynForU‐HerCare; two capsules/day of 9·5 log CFU per capsule) or placebo was administered for 8‐weeks in a randomized, double‐blind, placebo‐controlled study. Subjects were assessed for vaginal and gut health conditions at baseline, week‐4 and week‐8 via questionnaires. The vulvovaginal symptom questionnaire not only covered aspects pertaining to vulvovaginal symptoms but also the quality of life impacts such as emotional, social and sexual. The administration of lactobacilli reduced symptoms of irritation (P = 0·023) and discharge (P = 0·011) starting week‐4 and continued after week‐8 (P < 0·05), accompanied by reduced symptoms for burning after week‐8 (P = 0·046) as compared to the placebo. Patients consuming lactobacilli also showed reduced concern about symptoms after week‐4 (P = 0·010) and continued after week‐8 (P = 0·001), accompanied by reduced impairment of daily activities attributed to vulvovaginal symptoms (P = 0·012) and continued after week‐8 (P = 0·026). Insignificant differences were observed for sexual impacts between treatment groups. The administration of lactobacilli also reduced recurrences of both emotional and social stress as compared to the placebo at both week‐4 and week‐8 (P < 0·05). Patients consuming lactobacilli showed higher defecation times per week at week‐4 (P = 0·010) and week‐8 (P = 0·001) as compared to the placebo group, indicating the potential to reduce risks of pregnancy‐induced constipation.
Conclusions
Lactobacilli probiotics are beneficial towards pregnant women, especially in reducing vulvovaginal symptoms and recurrences of VC, accompanied by improved emotional and social distress attributed to VC.
Significance and Impact of the Study
The study demonstrated the preventive and modulatory roles of lactobacilli strains against VC in pregnant women. Taken altogether, our present data illustrated that lactobacilli probiotics are beneficial towards pregnant women, especially in reducing vulvovaginal symptoms and recurrences of VC, accompanied by improved emotional and social distress attributed to VC, thus could be a potential strategy for the maintenance of vaginal health during pregnancy.
In this paper, we have implemented a large-scale agent-based model to study the outbreak of coronavirus infectious diseases (COVID-19) in Singapore, taking into account complex human interaction ...pattern. In particular, the concept of multiplex network is utilized to differentiate between social interactions that happen in households and workplaces. In addition, weak interactions among crowds, transient interactions within social gatherings, and dense human contact between foreign workers in dormitories are also taken into consideration. Such a categorization in terms of a multiplex of social network connections together with the Susceptible-Exposed-Infectious-Removed (SEIR) epidemic model have enabled a more precise study of the feasibility and efficacy of control measures such as social distancing, work from home, and lockdown, at different moments and stages of the pandemics. Using this model, we study an epidemic outbreak that occurs within densely populated residential areas in Singapore. Our simulations show that residents in densely populated areas could be infected easily, even though they constitute a very small fraction of the whole population. Once infection begins in these areas, disease spreading is uncontrollable if appropriate control measures are not implemented.
Research comparing sex differences in the effects of antipsychotic medications on acute ischemic heart disease (IHD) is limited and the findings ambiguous. This study aimed to investigate these ...associations within a primary care setting.
Hong Kong public general outpatient electronic records of patients aged 45+ during 2007-2010 were extracted, with the last consultation date as the baseline for a 4-year follow-up period to observe acute IHD hospitalizations (2011-2014). Antipsychotic use was defined as any prescription over the previous 12 months from a list of 16 antipsychotics, while acute IHD was defined by ICD-9: 410.00-411.89. Both sex-specific and sex-combined (both sexes) mixed-effects Cox models (random intercept across 74 clinics) were implemented to examine the association and test the interaction between antipsychotics and sex.
Among 1,043,236 included patients, 17,780 (1.7%) were prescribed antipsychotics, and 8342 (0.8%) developed IHD. In sex-specific analyses, antipsychotic prescription was associated with a 32% increased hazard rate of acute IHD among women (95% CI 1.05-1.67) but not among men. A likelihood ratio test comparing sex-combined models with and without the interaction between antipsychotic use and sex suggested significant interaction (χ
= 4.72, P = 0.030). The association between antipsychotic use and IHD among women attenuated and became non-significant when haloperidol was omitted from the operationalization of antipsychotic use (HR = 1.23, 95% CI 0.95-1.60).
Our results suggest that antipsychotic prescription is moderately associated with an increased risk of acute IHD among women in primary care and this relationship may be explained by specific antipsychotics. Further research should observe and capture the potential intermediary mechanisms and the dose-response relationship of this association to provide more rigorous evidence to establish causality and inform clinical practices.
Summary
Guidelines for doctors managing osteoporosis in the Asia-Pacific region vary widely. We compared 18 guidelines for similarities and differences in five key areas. We then used a structured ...consensus process to develop clinical standards of care for the diagnosis and management of osteoporosis and for improving the quality of care.
Purpose
Minimum clinical standards for assessment and management of osteoporosis are needed in the Asia-Pacific (AP) region to inform clinical practice guidelines (CPGs) and to improve osteoporosis care. We present the framework of these clinical standards and describe its development.
Methods
We conducted a structured comparative analysis of existing CPGs in the AP region using a “5IQ” model (identification, investigation, information, intervention, integration, and quality). One-hundred data elements were extracted from each guideline. We then employed a four-round Delphi consensus process to structure the framework, identify key components of guidance, and develop clinical care standards.
Results
Eighteen guidelines were included. The 5IQ analysis demonstrated marked heterogeneity, notably in guidance on risk factors, the use of biochemical markers, self-care information for patients, indications for osteoporosis treatment, use of fracture risk assessment tools, and protocols for monitoring treatment. There was minimal guidance on long-term management plans or on strategies and systems for clinical quality improvement. Twenty-nine APCO members participated in the Delphi process, resulting in consensus on 16 clinical standards, with levels of attainment defined for those on identification and investigation of fragility fractures, vertebral fracture assessment, and inclusion of quality metrics in guidelines.
Conclusion
The 5IQ analysis confirmed previous anecdotal observations of marked heterogeneity of osteoporosis clinical guidelines in the AP region. The Framework provides practical, clear, and feasible recommendations for osteoporosis care and can be adapted for use in other such vastly diverse regions. Implementation of the standards is expected to significantly lessen the global burden of osteoporosis.
PDF
