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Abstract Background Intensive deployment of insecticide based malaria vector control tools resulted in the rapid evolution of phenotypes resistant to these chemicals. Understanding this process at the genomic level is important for the deployment of successful vector control interventions. Therefore, longitudinal sampling followed by whole genome sequencing (WGS) is necessary to understand how these evolutionary processes evolve over time. This study investigated the change in genetic structure and the evolution of the insecticide resistance variants in natural populations of Anopheles gambiae over time and space from 2012 to 2017 in Burkina Faso. Methods New genomic data have been generated from An. gambiae mosquitoes collected from three villages in the western part of Burkina Faso between 2012 and 2017. The samples were whole-genome sequenced and the data used in the An. gambiae 1000 genomes (Ag1000G) project as part of the Vector Observatory. Genomic data were analysed using the analysis pipeline previously designed by the Ag1000G project. Results The results showed similar and consistent nucleotide diversity and negative Tajima’s D between An. gambiae sensu stricto (s.s.) and Anopheles coluzzii. Principal component analysis (PCA) and the fixation index (F ST ) showed a clear genetic structure in the An. gambiae sensu lato (s.l.) species. Genome-wide F ST and H12 scans identified genomic regions under divergent selection that may have implications in the adaptation to ecological changes. Novel voltage-gated sodium channel pyrethroid resistance target-site alleles (V402L, I1527T) were identified at increasing frequencies alongside the established alleles (Vgsc-L995F, Vgsc-L995S and N1570Y) within the An. gambiae s.l. populations. Organophosphate metabolic resistance markers were also identified, at increasing frequencies, within the An. gambiae s.s. populations from 2012 to 2017, including the SNP Ace1-G280S and its associated duplication. Variants simultaneously identified in the same vector populations raise concerns about the long-term efficacy of new generation bed nets and the recently organophosphate pirimiphos-methyl indoor residual spraying in Burkina Faso. Conclusion These findings highlighted the benefit of genomic surveillance of malaria vectors for the detection of new insecticide resistance variants, the monitoring of the existing resistance variants, and also to get insights into the evolutionary processes driving insecticide resistance.

Abstract The source of malaria vector populations that re-establish at the beginning of the rainy season is still unclear yet knowledge of mosquito behaviour is required to effectively institute control measures. Alternative hypotheses like aestivation, local refugia, migration between neighbouring sites, and long-distance migration (LDM) are stipulated to support mosquito persistence. This work assessed the malaria vector persistence dynamics and examined various studies done on vector survival via these hypotheses; aestivation, local refugia, local or long-distance migration across sub-Saharan Africa, explored a range of methods used, ecological parameters and highlighted the knowledge trends and gaps. The results about a particular persistence mechanism that supports the re-establishment of Anopheles gambiae, Anopheles coluzzii or Anopheles arabiensis in sub-Saharan Africa were not conclusive given that each method used had its limitations. For example, the Mark-Release-Recapture (MRR) method whose challenge is a low recapture rate that affects its accuracy, and the use of time series analysis through field collections whose challenge is the uncertainty about whether not finding mosquitoes during the dry season is a weakness of the conventional sampling methods used or because of hidden shelters. This, therefore, calls for further investigations emphasizing the use of ecological experiments under controlled conditions in the laboratory or semi-field, and genetic approaches, as they are known to complement each other. This review, therefore, unveils and assesses the uncertainties that influence the different malaria vector persistence mechanisms and provides recommendations for future studies.

Abstract Background Residual dried blood spots (rDBS) from newborn screening programmes represent a valuable resource for medical research, from basic sciences, through clinical to public health. In Hong Kong, there is no legislation for biobanking. Parents’ view on the retention and use of residual newborn blood samples could be cultural-specific and is important to consider for biobanking of rDBS. Objective To study the views and concerns on long-term storage and secondary use of rDBS from newborn screening programmes among Hong Kong Chinese parents. Methods A mixed-method approach was used to study the views and concerns on long-term storage and secondary use of rDBS from newborn screening programmes among Hong Kong Chinese parents of children 0–3 years or expecting parents through focus groups (8 groups; 33 participants) and a survey (n = 1012, 85% mothers) designed with insights obtained from the focus groups. We used framework analysis to summarise the themes as supportive factors, concerns and critical arguments for retention and secondary use of rDBS from focus group discussion. We used multiple logistic regression to assess factors associated with support for retention and secondary use of rDBS in the survey. Results Both in focus groups and survey, majority of parents were not aware of the potential secondary use of rDBS. Overall secondary use of rDBS in medical research was well accepted by a large proportion of Hong Kong parents, even if all potential future research could not be specified in a broad consent. However parents were concerned about potential risks of biobanking rDBS including leaking of data and mis-use of genetic information. Parents wanted to be asked for permission before rDBS are stored and mainly did not accept an “opt-out” approach. The survey showed that parents born in mainland China, compared to Hong Kong born parents, had lower awareness of newborn screening but higher support in biobanking rDBS. Higher education was associated with support in rDBS biobanking only among fathers. Conclusion Long-term storage and secondary use of rDBS from newborn screening for biomedical research and a broad consent for biobanking of rDBS are generally acceptable to Hong Kong parents given their autonomy is respected and their privacy is protected, highlighting the importance of an accountable governance and a transparent access policy for rDBS biobanks.

Abstract Background It is unclear whether genetic variants identified from single nucleotide polymorphisms (SNPs) strongly associated with coronary heart disease (CHD) in genome-wide association studies (GWAS), or a genetic risk score (GRS) derived from them, can help stratify risk of recurrent events in patients with CHD. Methods Study subjects were enrolled at the close-out of the LIPID randomised controlled trial of pravastatin vs placebo. Entry to the trial had required a history of acute coronary syndrome 3–36 months previously, and patients were in the trial for a mean of 36 months. Patients who consented to a blood sample were genotyped with a custom designed array chip with SNPs chosen from known CHD-associated loci identified in previous GWAS. We evaluated outcomes in these patients over the following 10 years. Results Over the 10-year follow-up of the cohort of 4932 patients, 1558 deaths, 898 cardiovascular deaths, 727 CHD deaths and 375 cancer deaths occurred. There were no significant associations between individual SNPs and outcomes before or after adjustment for confounding variables and for multiple testing. A previously validated 27 SNP GRS derived from SNPs with the strongest associations with CHD also did not show any independent association with recurrent major cardiovascular events. Conclusions Genetic variants based on individual single nucleotide polymorphisms strongly associated with coronary heart disease in genome wide association studies or an abbreviated genetic risk score derived from them did not help risk profiling in this well-characterised cohort with 10-year follow-up. Other approaches will be needed to incorporate genetic profiling into clinically relevant stratification of long-term risk of recurrent events in CHD patients.

Respiratory viruses such as influenza do not typically cause viremia; however, SARS-CoV-2 has been detected in the blood of COVID-19 patients with mild and severe symptoms. Detection of SARS-CoV-2 in blood raises questions about its role in pathogenesis as well as transfusion safety concerns. Blood donor reports of symptoms or a diagnosis of COVID-19 after donation (post-donation information, PDI) preceded or coincided with increased general population COVID-19 mortality. Plasma samples from 2,250 blood donors who reported possible COVID-19–related PDI were tested for the presence of SARS-CoV-2 RNA. Detection of RNAemia peaked at 9%–15% of PDI donors in late 2020 to early 2021 and fell to approximately 4% after implementation of widespread vaccination in the population. RNAemic donors were 1.2- to 1.4-fold more likely to report cough or shortness of breath and 1.8-fold more likely to report change in taste or smell compared with infected donors without detectable RNAemia. No infectious virus was detected in plasma from RNAemic donors; inoculation of permissive cell lines produced less than 0.7–7 plaque-forming units (PFU)/mL and in susceptible mice less than 100 PFU/mL in RNA-positive plasma based on limits of detection in these models. These findings suggest that blood transfusions are highly unlikely to transmit SARS-CoV-2 infection.

Abstract Background Measures of linkage disequilibrium (LD) play a key role in a wide range of applications from disease association to demographic history estimation. The true population LD cannot be measured directly and instead can only be inferred from genetic samples, which are unavoidably subject to measurement error. Previous studies of r 2 (a measure of LD), such as the bias due to finite sample size and its variance, were based on the special case that the true population-wise LD is zero. These results generally do not hold for non-zero rtrue2 $$ {r}_{true}^2 $$ values, which are more common in real genetic data. Results This work generalises the estimation of r 2 to all levels of LD, and for both phased and unphased data. First, we provide new formulae for the effect of finite sample size on the observed r 2 values. Second, we find a new empirical formula for the variance of the observed r 2, equals to 2E[r 2](1 − E[r 2])/n, where n is the diploid sample size. Third, we propose a new routine, Constrained ML, a likelihood-based method to directly estimate haplotype frequencies and r 2 from diploid genotypes under Hardy-Weinberg Equilibrium. While serving the same purpose as the pre-existing Expectation-Maximisation algorithm, the new routine can have better convergence and is simpler to use. A new likelihood-ratio test is also introduced to test for the absence of a particular haplotype. Extensive simulations are run to support these findings. Conclusion Most inferences on LD will benefit from our new findings, from point and interval estimation to hypothesis testing. Genetic analyses utilising r 2 information will become more accurate as a result.

CRISPR-based homing gene drives can be designed to disrupt essential genes whilst biasing their own inheritance, leading to suppression of mosquito populations in the laboratory. This class of gene drives relies on CRISPR-Cas9 cleavage of a target sequence and copying ('homing') therein of the gene drive element from the homologous chromosome. However, target site mutations that are resistant to cleavage yet maintain the function of the essential gene are expected to be strongly selected for. Targeting functionally constrained regions where mutations are not easily tolerated should lower the probability of resistance. Evolutionary conservation at the sequence level is often a reliable indicator of functional constraint, though the actual level of underlying constraint between one conserved sequence and another can vary widely. Here we generated a novel adult lethal gene drive (ALGD) in the malaria vector Anopheles gambiae, targeting an ultra-conserved target site in a haplosufficient essential gene (AGAP029113) required during mosquito development, which fulfils many of the criteria for the target of a population suppression gene drive. We then designed a selection regime to experimentally assess the likelihood of generation and subsequent selection of gene drive resistant mutations at its target site. We simulated, in a caged population, a scenario where the gene drive was approaching fixation, where selection for resistance is expected to be strongest. Continuous sampling of the target locus revealed that a single, restorative, in-frame nucleotide substitution was selected. Our findings show that ultra-conservation alone need not be predictive of a site that is refractory to target site resistance. Our strategy to evaluate resistance in vivo could help to validate candidate gene drive targets for their resilience to resistance and help to improve predictions of the invasion dynamics of gene drives in field populations.

Abstract Background Compassion has been identified as important for therapeutic relationships in clinical medicine however there have been few empirical studies looking at how compassion is expressed different contexts. The purpose of this study was to explore how context impacts perceptions and expressions of compassion in the intensive care unit and in palliative care. Methods This was an inductive qualitative study that employed sensitizing concepts from activity theory, realist inquiry, phenomenology and autoethnography. Clinicians working in intensive care units and palliative care services wrote guided field notes on their observations and experiences of how suffering and compassion were expressed in these settings. Data were analyzed using constructivist grounded theory. Results Fifty-eight field notes were generated, along with transcripts from three focus groups. Clinicians conceptualized, observed, and expressed compassion in different ways within different contexts. Patterns of compassion identified were relational, dispositional, activity-focused, and situational. A pattern language of compassion in healthcare was developed based on these findings. Conclusions Recognizing compassion as shifting patterns of diverse attitudes, behaviours, and relationships raises numerous questions as to how compassion can be developed, supported and recognized in different clinical settings.

Background and objectives: This retrospective study analysed a case series of subjects with citrin deficiency, and aims to present the molecular and clinical characterization of this disease in the Hong Kong Chinese population for the first time. Patients and Methods: Data from medical records of eighteen patients with citrin deficiency (years 2006–2015) were retrieved. Demographic data, biochemical parameters, radiological results, genetic testing results, management, and clinical outcome were collected and analysed. Results: Eighteen patients with diagnosis of citrin deficiency were recruited. All 18 patients carried at least one common pathogenic variant c.852_855delTATG in SLC25A13. Prolonged jaundice (neonatal intrahepatic cholestasis caused by citrin deficiency, NICCD) was the most common presenting symptom, in conjunction with elevated plasma citrulline, threonine, alkaline phosphatase, and alpha-fetoprotein levels. The abnormal biochemical parameters including liver derangement returned to normal range in most of the cases by 6 months of age after the introduction of a lactose-free formula. There were a few cases with atypical presentations. Two subjects did not present with NICCD, and were subsequently diagnosed later in life after their siblings presented with symptoms of citrin deficiency at one month of age and subsequently received a molecular diagnosis. One patient with citrin deficiency also exhibited multiple liver hemangioendotheliomas, which subsided gradually after introduction of a lactose-free formula. Only one patient from this cohort was offered expanded metabolic screening at birth. She was not ascertained by conducted newborn screening and was diagnosed upon presentation with cholestatic jaundice by 1 month of age. Conclusion: This is the first report of the clinical and molecular characterization of a large cohort of patients with citrin deficiency in Hong Kong. The presentation of this cohort of patients expands the clinical phenotypic spectrum of NICCD. Benign liver tumors such as hemangioendotheliomas may be associated with citrin deficiency in addition to the well-known association with hepatocellular carcinoma. Citrin deficiency may manifest in later infancy period with an NICCD-like phenotype. Furthermore, this condition is not always ascertained by expanded newborn metabolic screening testing. Keywords: Citrin deficiency, NICCD, FTTDCD, CTLN2, Hemangioendothelioma

Extraction of vegetation canopy structure parameters is of great significance for researching global ecosystem and environment. Focused on the effective synergy between active and passive sensors, we carried out some ground-based observations about different vegetation on different terrains. In different experimental sites, a light detection and ranging (LiDAR) data and an imaging spectrum data of typical vegetation were collected from different directions and angles. Meanwhile, a variety of canopy structure parameters, including plant height, crown breadth, leaf area index, etc, were measured. The whole observed results form a comprehensive ground synchronous data set corresponding to flight data and provide data support for development and validation of synergic retrieval methods of vegetation canopy structure parameters. Our specific experimental objectives and design are introduced, including the selection of sampling plots, arrangement of observation stations, acquisition of active and passive data, and measurement of auxiliary data. The processing and practical applications of those obtained synchronous data are also discussed. Finally, our experimental experience is summarized and it is a valuable reference for remote sensing researchers.

Natural source Super Low Frequency(SLF) electromagnetic prospecting methods have become an increasingly promising way in the resource detection. The capacity estimation of the reservoirs is of great importance to evaluate their exploitation potency. In this paper, we built a signal-estimate model for SLF electromagnetic signal and processed the monitored data with adaptive filter. The non-normal distribution test showed that the distribution of the signal was obviously different from Gaussian probability distribution, and Class B instantaneous amplitude probability model can well describe the statistical properties of SLF electromagnetic data. The Class B model parameter estimation is very complicated because its kernel function is confluent hypergeometric function. The parameters of the model were estimated based on property spectral function using Least Square Gradient Method(LSGM). The simulation of this estimation method was carried out, and the results of simulation demonstrated that the LGSM estimation method can reflect important information of the Class B signal model, of which the Gaussian component was considered to be the systematic noise and random noise, and the Intermediate Event Component was considered to be the background ground and human activity noise. Then the observation data was processed using adaptive noise cancellation filter. With the noise components subtracted out adaptively, the remaining part is the signal of interest, i.e., the anomaly information. It was considered to be relevant to the reservoir position of the coalbed methane stratum.

The rise in global warming triggered by climate change and increased slush and burn activities particularly in Indonesia has been a major concern for deteriorating air pollution in Borneo regions in last two decades. Brunei Darussalam is facing increasing fire risk particularly during the dry season (February to April) of the year. The study is an effort to focus on the recent rise of fire events in Brunei Darussalam as fires can tremendously downgrade the quality of the country’s well-known forestry; affect the economy and most importantly, health of the people. Geographical Information System (GIS) have been widely used by researchers to study fire risk assessment. The ArcGIS software is used for Optimized Hot Spot Analysis, Inversed Distance Weighted (IDW), and Kriging to compare and analyse the data and prepare a map for identifications of hotspot areas. High temperatures due to the El Nino phenomenon and low precipitation contribute greatly to the forest fire outbreaks. Results show that the Brunei-Muara district is mostly affected compared to Tutong and Belait districts. From the hotspots identified, the percentages of forest areas affected are 53%, 64%, 25% in Brunei-Muara, Tutong and Belait districts respectively.

Background: Whether low-dose azathioprine (AZA) is effective in maintaining remission in patients with steroid-dependent ulcerative colitis (UC) remains unclear. We assessed the efficacy and safety of low-dose AZA in a Chinese population with UC. Methods: We identified steroid-dependent UC patients in clinical remission on AZA maintenance therapy from a territory-wide IBD Registry. Standard- and low-dose AZA were defined as at least 2 mg/kg/day and less than 2 mg/kg/day, respectively. Relapse rates were analyzed by Kaplan–Meier analysis and compared using log-rank test. Results: Among 1226 UC patients, 128 (53% male, median duration on AZA 44 months) were included. Median maintenance AZA dose was 1.3 mg/kg/day. 97.7% of the patients were on concomitant oral 5-aminosalicylic acid. Cumulative relapse-free rates in patients on standard-dose and low-dose AZA were 71.2%, 52.8% and 45.2%, and 71.8%, 55.3% and 46.2% at 12, 24 and 36 months, respectively ( p = 0.871). Relapse rate within 12 months was higher in patients who withdrew compared with those who maintained on AZA (52.6% versus 29.4%; p = 0.045). Mean corpuscular volume increased after AZA therapy in both of the low-dose [median (interquartile range, IQR): 88.2 (81.4–92.2) versus 95.1 (90.1–100.9) fl, p < 0.001] and standard-dose subgroups [median (IQR) 86.8 (76.9–89.9) versus 94.7 (85.9–99.7) fl, p < 0.001]. Leukopenia occurred in 21.1% of the patients. Patients on standard dose had a higher risk for leukopenia than those on low-dose AZA [odds ratio (OR) 3.9, 95% CI 1.9–8.2, p < 0.001]. Conclusions: In the Chinese population, low-dose AZA is effective for maintaining remission in steroid-dependent UC patients. Standard-dose AZA was associated with more than threefold increased risk of leukopenia.

Adeno-associated virus (AAV) has become one of the most promising vectors in gene transfer in the last 10 years with successful translation to clinical trials in humans and even market approval for a first gene therapy product in Europe. Administration to humans, however, revealed that adaptive immune responses against the vector capsid can present an obstacle to sustained transgene expression due to the activation and expansion of capsid-specific T cells. The limited number of peripheral blood mononuclear cells (PBMCs) obtained from samples within clinical trials allows for little more than monitoring of T-cell responses. We were able to identify immunodominant major histocompatibility complex (MHC) class I epitopes for common human leukocyte antigen (HLA) types by using spleens isolated from subjects undergoing splenectomy for non-malignant indications as a source of large numbers of lymphocytes and restimulating them with single AAV capsid peptides in vitro. Further experiments confirmed that these epitopes are naturally processed and functionally relevant. The design of more effective and less immunogenic AAV vectors, and precise immune monitoring of vector-infused subjects, are facilitated by these findings.