Aquaculture plays a key role in many emerging economies. Sources of fish for human consumption now exceed those from capture fisheries. However, the high cost of food to feed fish limits investment returns. Physiological inefficiencies in the way fish digest and assimilate nutrients and energy from food can be improved to lower the amount of feed required to farm fish whilst reducing waste and enhancing environmental sustainability. Being able to measure this ‘feed efficiency’ is crucial to develop strategies to improve it, yet we do not currently have a good means of doing this. With a focus on salmon, this research uses detailed physiological information involved in fish metabolic processes to better understand the mechanisms that can contribute towards better feed efficiency and growth, and at the same time enable development of models to accurately predict such measures. Our findings can be used to improve the efficiency of the salmon aquaculture industry and reduce the impact of farming practices on the environment.Oncorhynchus tshawytscha) and uncover the influential variables. Inter-omic relatedness between the different layers revealed several significant concordances, particularly between datasets originating from similar material/tissue and between blood indicators and some of the proteomic (liver), metabolomic (liver), and microbiomic layers. Single- and multi-layer random forest (RF) regression models showed that integration of all data layers provide greater FE prediction power than any single-layer model alone. Although FE was among the most challenging of the traits we attempted to predict, the mean accuracy of 40 different FE models in terms of root-mean square errors normalized to percentage was 30.4%, supporting RF as a feature selection tool and approach for complex trait prediction. Major contributions to the integrated FE models were derived from layers of proteomic and metabolomic data, with substantial influence also provided by the lipid composition layer. A correlation matrix of the top 27 variables in the models highlighted FE trait-associations with faecal bacteria (Serratia spp.), palmitic and nervonic acid moieties in whole body lipids, levels of free glycerol in muscle, and N-acetylglutamic acid content in liver. In summary, we identified subsets of molecular characteristics for the assessment of commercially relevant performance-based metrics in farmed Chinook salmon.Fish aquaculture is a rapidly expanding global industry, set to support growing demands for sources of marine protein. Enhancing feed efficiency (FE) in farmed fish is required to reduce production costs and improve sector sustainability. Recognising that organisms are complex systems whose emerging phenotypes are the product of multiple interacting molecular processes, systems-based approaches are expected to deliver new biological insights into FE and growth performance. Here, we establish 14 diverse layers of multi-omics and clinical covariates to assess their capacities to predict FE and associated performance traits in a fish model ( Meeting global demands for sources of sustainable food protein is one of our greatest challenges. Aquaculture is uniquely poised to help resolve this for future populations. Creation of a thriving and viable ‘blue economy’ will greatly expand resource availability, capacity, and opportunity. However, increased seafood production will need to be complemented by reductions in environmental impact and improvements in resource efficiency ,2. Fish Feed efficiency (FE) is the efficiency with which food is utilised by animals for productive purposes such as growth. Commonly expressed as the Feed Conversion Ratio (FCR), this measure is the ratio between feed intake and body weight gain over a particular period. FE is the inverse of FCR, with lower FCR values indicating higher (enhanced) FE; from herein the term FE is primarily used in discussion for simplicity. In salmonid aquaculture, feed typically comprises 50–60% of total production costs, and excess provisions through uneaten and/or poorly digested food can cause adverse environmental impact ,4. FE isOncorhynchus tshawytscha) that fish displaying higher FE also have higher capacities for protein, lipid, and energy retention, and lower minimal routine metabolic rates ) and palmitic acid (C16:0). Nervonic acid, a sphingomyelin-enriched long chain monounsaturated FA common in fish oils ,86, dispa et al.  recentlyOncorhynchus tshawytscha) model to predict a range of growth performance metrics, including FE. Our findings revealed the existence of strong concordance among covariate layers and demonstrated the unique contributions each layer provides towards trait prediction accuracies. FE-associations were made with some bacterial taxa, metabolites, and biochemical pathways, pointing towards key areas for subsequent hypothesis testing. Results further emphasise that FE is a highly complex trait; no single parameter we measured was able to reliably predict FE alone, but rather necessitated multiple variables for accurate prediction. Random Forest-based algorithms are useful for integrating multiple omics and clinical covariates and provide unique application for predicting growth and efficiency phenotypes in farmed Chinook salmon.Improving feed efficiency (FE) is a strategy to reduce production costs and improve sustainability in fish aquaculture. Measurement of individual FE in fish is logistically challenging, time-consuming, and costly. The identification of reliable predictors of FE could reduce phenotyping efforts. FE is governed by a myriad of intrinsic and environmental factors, which multi-omic analyses are anticipated to contribute greater mechanistic understanding. This study demonstrated the novel use of the Random Block algorithm to integrate a diverse set of multimodal covariates in a salmonid (


Structural changes occur in brain regions involved in cortico-basal ganglia networks in idiopathic blepharospasm (iBSP); whether these changes influence the function connectivity patterns of cortico-basal ganglia networks remains largely unknown. Therefore, we aimed to investigate the global integrative state and organization of functional connections of cortico-basal ganglia networks in patients with iBSP.Resting-state functional magnetic resonance imaging data and clinical measurements were acquired from 62 patients with iBSP, 62 patients with hemifacial spasm (HFS), and 62 healthy controls (HCs). Topological parameters and functional connections of cortico-basal ganglia networks were evaluated and compared among the three groups. Correlation analyses were performed to explore the relationship between topological parameters and clinical measurements in patients with iBSP.We found significantly increased global efficiency and decreased shortest path length and clustering coefficient of cortico-basal ganglia networks in patients with iBSP compared with HCs, however, such differences were not observed between patients with HFS and HCs. Further correlation analyses revealed that these parameters were significantly correlated with the severity of iBSP. At the regional level, the functional connectivity between the left orbitofrontal area and left primary somatosensory cortex and between the right anterior part of pallidum and right anterior part of dorsal anterior cingulate cortex was significantly decreased in patients with iBSP and HFS compared with HCs.Dysfunction of the cortico-basal ganglia networks occurs in patients with iBSP. The altered network metrics of cortico-basal ganglia networks might be served as quantitative markers for evaluation of the severity of iBSP. Idiopathic blepharospasm (iBSP) is a common sub-type of focal dystonia, which is characterized by bilateral intermittent or sustained spasms of the orbicularis oculi muscle, and commonly associated with psychiatric and cognitive co-morbidities that lead to heterogeneous clinical expressions . AlthougTraditionally, iBSP has been thought to be related to abnormalities in the basal ganglia . With thIn the present study, in accordance with the hypothesis that extensively altered functional connections exist in the large-scale cortico-basal ganglia networks in iBSP, we evaluated the global and local organization of functional connections using graph theoretical analysis of cortico-basal ganglia networks between patients with iBSP and healthy controls (HCs). A group of age-, gender-, and duration-matched patients with HFS was also recruited to determine whether these functional alterations in iBSP are derived from dystonic origin or excessive facial movements. Finally, correlation analyses were performed to explore relationships between topological parameters and clinical measurements  in patients with iBSP.Patients were recruited from an outpatient clinic of the First Affiliated Hospital of Sun Yat-sen University. They were diagnosed as adult-onset iBSP or HFS based on the standard criteria by two senior neurologists (G Liu and WX Zhang). The exclusion criteria for iBSP and HFS patients were the same with the following items: (i) aged less than 18 or more than 80; (ii) left handed; (iii) received botulinum toxin (BoNT) injections within 3 months before MRI scanning; (iv) had a family history of movement disorders; (v) reported evidence of stroke and traumatic brain injury, or any conditions which might be cause secondary blepharospasm; (vi) reported evidence of neurological diseases, such as Parkinson’s disease, Alzheimer’s disease, major depressive disorder, and epilepsy; (vii) had a history of exposure to previous neuroleptic medication; (viii) had any conditions that contradicted with cerebral MRI; (ix) show evidence of possible anxiety ; and (x) received oral medications for approximately 24 h before MRI scans. HCs were also recruited using the same exclusion criteria. This study was performed according to the Declaration of Helsinki and was approved by the Ethics Committee of the First Affiliated Hospital of Sun Yat-sen University [(2020)323]. Written informed consent was obtained from all subjects. Finally, 62 patients with iBSP, 62 with HFS , and 62 HCs were included in the current study.via face-to-face interviews before MRI scanning. The disease severity of patients was evaluated using the 0–4 scale Jankovic Rating Scale (JRS), which includes two subscales that measure severity  and frequency  of involuntary orbicularis oculi muscle contraction, respectively . Participants were instructed to keep their eyes closed and their heads motionless during scanning. An echo-planar imaging sequence with the following parameters was used: repetition time = 2,000 ms, echo time = 30 ms, flip angle = 90°, acquisition matrix = 64×64; voxel size = 3.4375 mm1  toolbox1 . The maiTo construct the cortico-basal ganglia networks for each participant, we used 91 MNI coordinates that were previously reported . The nodglob) that can indicate the efficiency of information transference across a network, clustering coefficients (Cp) that quantify the local inter-connectivity of a network, and the shortest path length (Lp) that can quantify the integration of a network, were calculated using a graph theoretical network analysis toolbox (GRETNA v2.0).2 Eglob and Lp are used to measure brain network integration, and Cp is employed to investigate brain network segregation. To avoid bias choice of a certain value, the complex network analyses were performed at a sparsity range from 0.1 to 0.5 with an interval of 0.05, and the area under curve (AUC) values under this range of sparsity were calculated for the statistical analyses  for regional indexes.Moreover, we also calculated the betweenness centrality and degree centrality as regional indexes for each region. To avoid bias choice of a certain value, the complex network analyses were performed at a sparsity range from 0.1 to 0.5 with an interval of 0.05, and the AUC values under this range of sparsity were calculated for the statistical analyses . The groP < 0.05.To reveal whether the changed global metrics and functional connections in the cortico-basal ganglia networks showed associations with clinical measurements in patients with iBSP, partial correlation analyses between changed indices and disease duration and JRS total scores were performed, using age and gender as covariates. The significance level was set at H test. Gender differences among the three groups and the number of patients receiving BoNT injections between patients with iBSP and HFS were compared using the Pearson 2χ test. Moreover, differences in the disease duration, JRS total scores, and duration of BoNT injections between patients with iBSP and HFS were assessed using the Mann–Whitney U test. A two-tailed P-value < 0.05 indicated statistical significance.We analyzed all the subjects’ demographics and clinical characteristics using SPSS 23.0 . Differences in the age among the iBSP, HFS, and HCs groups were identified using the non-parametric Kruskal–Wallis The clinical and demographic characteristics of the 62 patients with iBSP, 62 with HFS, and 62 HCs are presented in glob of the cortico-basal ganglia networks was significantly increased, whereas the Cp and Lp of the cortico-basal ganglia networks were significantly decreased in patients with iBSP compared to HCs  and left BA 2 (primary somatosensory cortex) and between the right anterior part of the pallidum (aPAL) and the right anterior part of BA 32  were significantly decreased in patients with iBSP and HFS compared to HCs , 4 afterNo significant differences of regional indexes were found among three groups after Bonferroni corrections.glob of the cortico-basal ganglia networks was positively correlated with JRS total scores, whereas Cp and Lp were negatively correlated with JRS total scores in patients with iBSP. Moreover, the Cp of the cortico-basal ganglia networks was positively correlated with disease duration in patients with iBSP  might suggest enhanced information transformation due to excessively optimized topological organization and global integration abilities in the cortico-basal ganglia networks in patients with iBSP. In addition, the existence of significant correlations between the severity of iBSP and graph theoretical metrics of the cortico-basal ganglia networks raises the possibility that abnormal topological organization in the cortico-basal ganglia networks is at least partly caused by excessive facial movements. Moreover, this possibility is further enhanced since these differences in Eglob, Cp, and Lp were not identified between iBSP and HFS groups. Thus, it is reasonable to speculate that facial hyperkinesia-related brain functional network changes in patients with iBSP might be attributed to the increase in facial activity and plastic changes in the brain white matter. This hypothesis is supported by a recent diffusion tensor imaging (DTI) study, which demonstrated that patients with iBSP exhibited increased network integration (significantly increased Eglob and decreased Cp and Lp) in the whole-brain white matter networks (Considering that Enetworks , but sucnetworks .glob and decreased Lp of the cortico-basal ganglia networks were positively and negatively correlated with severity in patients with iBSP, respectively. Current evidence obtained from fMRI studies suggests that the basal ganglia circuit is involved in the triggering of spasms, whereas the cerebello-thalamo-cortical network plays a key role in symptom severity in the iBSP (glob and decreased Lp in the whole-brain white matter networks with disease severity. They explained that the absence of infratentorial brain structures in the BNA-246 atlas they used may be responsible for it (glob and decreased Lp in the functional cortico-basal ganglia networks and disease severity are mainly attributed to changes in the cerebello-thalamo-cortical network remains unclear; further studies are needed to address this question.Interestingly, increased Ethe iBSP . Moreovethe iBSP . In addie for it . The keyWe also found that the functional connectivity between the left orbitofrontal area and left primary somatosensory cortex and between the aPAL and anterior part of the dorsal anterior cingulate cortex was significantly decreased in patients with iBSP and HFS compared to HCs. It has been shown that activation of the orbitofrontal area is involved in eye blinking . An fMRIThis study has the following limitations. First, global signal regression in rs-fMRI remains to be debated; we did not perform this step for image pre-processing since global mean signal regression can lead to spurious resting-state functional correlations and false inferences. Second, some patients with iBSP or HFS were treated with BoNT injections; at present, the effects of BoNT on functional connections between regions in the cortico-basal ganglia networks at rest remain unclear. This limitation should be considered in further studies. Third, given the prevalence of depression, obsessive/compulsive symptoms, and cognitive dysfunction in specific cognitive domains in patients with iBSP, the associations between the dysfunction of cortico-basal ganglia networks and aforementioned non-motor symptoms in patients with iBSP are worth exploring in a future study. Finally, we did not find any difference in regional indexes between iBSP and HFS, or any correlations between these regional indexes and clinical measurements in the iBSP or HFS after Bonferroni corrections. Therefore, it is hard to determine which region was special for iBSP or HFS based on our current results.glob and a short Lp in the cortico-basal ganglia networks in patients with iBSP. Moreover, these network metrics were significantly correlated with disease severity of iBSP and might serve as quantitative markers for the evaluation of clinical symptom severity of iBSP.In conclusion, we found a strong functional integration characterized by a high EThe original contributions presented in this study are included in the article/The studies involving human participants were reviewed and approved by the Ethics Committee of the First Affiliated Hospital of Sun Yat-sen University. The patients/participants provided their written informed consent to participate in this study.QC: data analysis and drafting the manuscript. HX and YLu: data acquisition and drafting the manuscript. LZ, YG, YLi, AW, and ZO: data acquisition. XF and XZ: data analysis. WZ, HW, and QH: revising the manuscript. KP: design and revising the manuscript. JX: design, data analysis, drafting, and revising the manuscript. GL: design, data acquisition, drafting, and revising the manuscript. All authors contributed to the article and approved the submitted version.


During the COVID-19 pandemic in Rwanda, Partners In Health Inshuti Mu Buzima collaborated with the Butaro Cancer Center of Excellence (BCCOE) to mitigate disruptions to cancer care by providing patients with free transportation to treatment sites and medication delivery at patients’ local health facilities. We assessed the relationship between facilitated access to care and self-reported wellbeing outcomes. This cross-sectional telephone survey included cancer patients enrolled at BCCOE in March 2020. We used linear regression to compare six dimensions of quality of life (EORTC QLQ-C30), depression (PHQ-9), anxiety (GAD-7), and financial toxicity (COST) among patients who did and did not receive facilitated access to care. We also assessed access to cancer care and whether patient wellbeing and its association with facilitated access to care differed by socioeconomic status. Of 214 respondents, 34.6% received facilitated access to care. Facilitated patients were more likely to have breast cancer and be on chemotherapy. Facilitation was significantly associated with more frequent in-person clinical encounters, improved perceived quality of cancer care, and reduced transportation-related barriers. Facilitated patients had significantly better global health status  and less financial toxicity . However, over half of patients reported missing or delaying appointment. Patient wellbeing was low overall and differed by patient socioeconomic status, with poor patients consistently showing worse outcomes. Socioeconomic status did not modify the association between facilitated access to care and wellbeing indicators. Further, facilitation did not lead to equitable wellbeing outcomes between richer and poorer patients. Facilitated access to care during COVID-19 pandemic was associated with some improvements in access to cancer care and patient wellbeing. However, cancer patients still experienced substantial disruptions to care and reported low overall levels of wellbeing, with socioeconomic disparities persisting despite facilitated access to care. Implementing more robust, equity-minded facilitation and better patient outreach programs during health emergencies may promote better care and strengthen patient care overall and effect better patients’ outcomes. COVID-19 drastically disrupted cancer care in high income countries. In an effort to efficiently use healthcare infrastructure during the peak waves of the COVID-19 pandemic, guidelines for cancer patient management recommended delay or cancelation of non-urgent cancer care services including referrals, surgery, drug treatment, follow-up, and screening . HoweverIn low- and middle-income countries (LMICs), where cancer care infrastructure was already constrained before the pandemic, the impact of COVID-19 on cancer care is expected to be even worse , 6, 7. CJust as the COVID-19 pandemic has increased disparities in access to cancer care between high- and low-income countries, within-country disparities in access to cancer care are also increasing , 17. In While many cancer care institutions have adapted interventions to mitigate care interruptions, many of these interventions were targeted at facility- or service delivery-levels and hence their evaluations did not measure the impact of such mitigation strategies on patient’s level , 22–24. ubudehe categories. The ubudehe system is a 4-tier socio-economic classification system used by the government to identify households that should benefit from social protection programs, where category one roughly corresponds to living in acute poverty and category two corresponds to living a substance lifestyle with no surplus income [Cancer care in Rwanda is mainly delivered at two cancer centers: the Butaro Cancer Center of Excellence (BCCOE), which was founded in 2012 and is located in the most rural district of Rwanda, and the Rwanda Cancer Center (RCC), which was founded in 2019 and is located in the capital city, Kigali. Currently, most cancer patients are managed at BCCOE whereas RCC primarily provides radiation therapy and chemotherapy for outpatients. Although BCCOE is largely government supported, since its founding it has also been supported by Partners in Health/ Inshuti Mu Buzima (PIH/IMB), the Rwandan branch of an international non-governmental organization that accompanies the Rwandan Ministry of Health in strengthening Rwanda’s health system. At BCCOE, medications, cost of treatment, transportation to cancer health facilities are substantially subsidized for poorer patients in the first and second s income . Patientnd, 2020 and was followed by an abrupt total lockdown until May 31st, 2020 with subsequent partial lockdowns. Although routine health care activities did not officially close during lockdowns, the cessation of other key services such as public transportation and household livelihood activities meaningfully disrupted access to and delivery of health care. During this time, Rwanda Ministry of Health (RMoH) collaborated with its key partners, including PIH/IMB, to promote continuity of cancer care services for patients in Rwanda and East Africa. These activities included a) expansion of free transportation to all cancer patients managed at BCCOE residing in Rwanda, where any patient who needed a consultation or infusion chemotherapy were eligible for round-trip transportation from their home to BCCOE regardless of their ubudehe category; and b) aerial or vehicle-based delivery of oral chemotherapy medication to local health centers of patients residing in remote areas. Over 40% of cancer patients managed at BCCOE received some sort of facilitated access to care from PIH/IMB during COVID-19 lockdowns in Rwanda. More details on the role of PIH/IMB in the decentralization of cancer care during COVID-19 lockdowns has been described elsewhere [The first case of COVID-19 was reported in Rwanda on March 22lsewhere .nd 2020, resided in Rwanda, had a telephone number recorded in the Electronic Medical Record (EMR), and were still alive at the time of data collection in August of 2021. We excluded patients under 18 years old, patients who initiated cancer treatment for the first time during the COVID-19 pandemic, patients without a confirmed diagnosis of cancer at the start of the pandemic, and patients who were confirmed dead by the time of data collection.We conducted a cross-sectional telephone survey among adult cancer patients who received cancer care at BCCOE and compared care provision, overall quality of life, mental health, and socioeconomic outcomes among patients who did and did not receive facilitated access to care during COVID-19 pandemic. Patients were eligible for inclusion if they were enrolled in cancer care at BCCOE by March 22We performed stratified simple random sampling to select study participants who did and did not receive facilitated access to care. Patients who received facilitated access to care were sampled from a list of beneficiaries, which was provided by the PIH/IMB’s oncology program that coordinated the support activities during the pandemic. Non-facilitated patients were drawn from EMR system managed at BCCOE. The non-supported were active cancer patients recorded in EMR whom we did not find on the oncology program list of those who have been supported during COVID-19 pandemic.We powered our study to detect a 10-point increase in quality of life using the European Organization for the Research and Treatment of Cancer Quality of Life (EORTC QLQ-C30) scale, which would correspond to effect size previously suggested as clinically meaningful if care needs of the newly diagnosed cancer patients are met . Assuminthand October 6th, 2021. The delay between the start of facilitation data collection reflects the fact that the primary goal of the program was to support clinical care, and the idea to conduct an evaluation occurred several months after facilitation began. Patients were recruited via phone calls and provided with information about the study. Those who were interested provided their voluntary informed verbal consent and set up an appointment for data collection. Data collectors confirmed that participants consented to the study before starting data collection. We made three phone-call attempts on three different days before a selected patient was considered to be non-responsive. For telephone numbers that were reachable but which were linked to patients who had died, we briefly interviewed the person who answered the call to ascertain the date of death and the cause of death. Data were collected via a 35-minute phone interview by research staff who were not cancer care providers. Data were stored on a password-protected REDCap database, a data management application first developed by Vanderbilt University and hosted on a Rwanda-based server [We conducted telephone-based data collection between September 6d server , 30.This study received approval from the Partners In Health/Inshuti Mu Buzima (PIH/IMB) Research Committee (IMBRC) and was conducted under an umbrella protocol for oncology research which was approved by the Rwandan National Ethics Committee (No. 804/RNEC/2021). Voluntary informed verbal consent was obtained from participants before phone-based data collection.To understand the relationship between receiving facilitated access to care and improved patient wellbeing, we developed a conceptual framework that considers four types of variables: baseline characteristics, receipt of facilitated access to care, cancer care provision, and patient wellbeing. Baseline characteristics included patients’ demographic and clinical characteristics. Although these characteristics were collected at the same time as outcome ascertainment, they reflected characteristics that are unlikely to change meaningfully over time and were therefore assumed to reflect patient status at the start of the pandemic. These characteristics could have impacted patients’ likelihood of receiving facilitated access to care during the pandemic as well as subsequent patient outcomes and were therefore considered to be potential confounders. Receiving facilitated access to care was our primary exposure of interest and was assumed to depend on patient characteristics. Cancer care provision outcomes were selected based on the literature and reflected changes in the provision of care following the start of the COVID-19 pandemic. These process outcomes were conceived as helping to explain the ways in which access to facilitated access to care could have improved patient wellbeing. Our primary outcome was patient wellbeing, which was measured according to various dimensions, including quality of life, mental health, and financial wellbeing. Because part of the goal of this intervention was to promote equitable access to health care for the most vulnerable patients, we also wanted to assess whether the association between receipt of facilitated access to care and patient wellbeing differed by patients’ baseline socioeconomic status. The relationship between these four types of variables is shown in ubudehe category. We reported on patient wealth using a simplified 15-item tool on household assets [We collected demographic characteristics including continuous age, gender, education, health insurance status, remoteness of residence classified as urban versus rural, and d assets . This wed assets  and can Respondents who were sampled from the PIH/IMB oncology program’s list of beneficiaries, which included both patients who received transport to treatment sites by PIH/IMB’s vehicles or receiving medication delivery between Mach 22, 2020 up to the time of data collection, were defined as having received facilitated access to care. Patients who were sampled from EMR system managed at BCCOE and not found on the list of beneficiaries were considered to belong to the non-facilitated group. Our primary analyses used this list-based status to define patient’s exposure status. However, to confirm this classification, during data collection we asked patients to self-report whether they actually received support from PIH/IMB to continue care during COVID-19 pandemic. In general, we believe the list-based status to be a more reliable way to classify whether or not patients received facilitated access to transportation because PIH/IMB provides many types of social support and it is possible that patients who self-reported receipt of support may be reporting on social support other than facilitated access to care during the COVID-19 pandemic. However, as a sensitivity analysis, we conducted two additional sets of analyses to explore the impact of discrepancies between self-reported facilitated access to care and lists-based status on our findings. The first set of sensitivity analysis considered self-reported receipt of facilitated access to care as the primary exposure and the second set of sensitivity analyses was restricted to patients whose list-based and self-reported exposures status were concordant.We assessed cancer care provision using self-reported data on whether patients missed or delayed appointments due to COVID-19-related circumstances during the pandemic, the number of in-person clinical visits since the start of the pandemic until the time of data collection (17 months); access to teleconsultation, defined as receiving a telephone or digital call from the patients’ usual oncology health provider to discuss their health during COVID-19 pandemic, perceived changes in the quality of cancer care before and during COVID-10 pandemic which was assessed using a 5-points Likert scale ranging from a much worse, a little worse, about the same, better, and much better; change of treatment plan defined as receiving a different treatment because the usual treatment was not available due to COVID-19 pandemic; care support in the household and barriers to care. Barriers to care experienced during COVID-19 pandemic assessed included financial barriers, family issues, lack of transportation, comorbidities, logistical issues to accessing transportation, worsened cancer disease, and COVID-19 infection. Logistical issues to accessing transportation included barriers to accessing transportation when transport means were available, which included difficulties of reaching pick-up points, affordability, missing transport or walking long distance to reach transport pick-up points. Perceived quality of cancer care during COVID-19 pandemic compared to pre-pandemic care was collapsed into three categories: worse, about the same and better.Quality of life was assessed using the European Organization for the Research and Treatment of Cancer Quality of Life (EORTC QOL-C30) questionnaire, a 30-item health-related quality of life (HRQL) tool which is widely used in cancer research [research . This toresearch . The perMental Health was assessed using the patient health questionnaire (PHQ-9), a 9-item questionnaire on depression symptoms over the past two weeks, and the general anxiety disorder questionnaire (GAD-7), a 7-item tool assessing symptoms of general anxiety over the past two weeks. Scores for the PHQ-9 range between 0 and 27 with high scores corresponding to more severe depression [pression , 36. Scopression .financial wellbeing, we used a validated COmprehensive Score for financial Toxicity (COST) questionnaire [To measure ionnaire . This 11ionnaire .For all outcomes,  we followed forward and backward translation procedure recommended by the EORTC translation group , to tranWe described baseline characteristics of study participants and cancer care provision outcomes using descriptive and summary statistics, including frequencies and percentages for categorical data and means and standard deviations for continuous outcome data. Variables were described for the overall population and separately by receipt of facilitated access to care. We used Fisher’s Exact tests, chi-square tests or t-tests to assess bivariate associations between receipt of facilitated access to care and patients’ baseline characteristics and process outcomes variables.For each of our four main outcome variables, we reported means and standard deviations for the overall study population and separately by receipt of facilitated access to care. We assessed for univariate associations using an independent t-test for continuous scores. For each outcome, we also conducted three linear regressions to assess the association between the continuous scores of the four main outcome variables and the receipt of facilitated access to care. For each outcome, we performed a crude analysis, a minimally adjusted analysis controlling for all baseline characteristics that were associated with receipt of facilitated access to care at a p≤0.20 level, and a fully adjusted analysis that adjusted for all baseline characteristics. We reported beta coefficients, 95% confidence intervals and p-values for each model.As a secondary analysis, we assessed associations between patients’ socioeconomic status and wellbeing as well as whether patients’ socioeconomic status modified the effect of facilitated access to care. We transformed each of the wellbeing scores to range from 0 (reflecting the worst possible wellbeing) to 100 (reflecting the best possible wellbeing), reversing the PHQ-9, GAD-7, and financial difficulties scale as needed and visualized the disparities in wellbeing by wealth quintiles using an equiplot. We identified dimensions of patient wellbeing that differed significantly by wealth quintiles by comparing a linear regression model with indicator variables for wealth category to an intercept-only model. Next, for each outcome we fitted a linear regression model that included an interaction term between wealth categories and receipt of facilitated access to care and adjusted for the remaining variables in the minimally adjusted model. We used parameters from the model to assess whether a significant association between facilitated access to care and patient wellbeing existed within each wealth category and whether this association was significantly different among wealth categories. We also plotted mean patient wellbeing scores with and without receipt of facilitated access to care by wealth category. Data analysis was performed in Stata/IC version 15.1..Of 343 patients contacted for participation in the study, 62% (n = 214) participated in the telephone survey. Non-response was mainly due to not reaching patients on the telephone  or death during the COVID-19 pandemic , with higher non-reachability among non-facilitated patients  compared to the facilitated patients  and equal prevalence of death during the pandemic in both groups (12% vs.12%). Of the 140 patients who were sampled from the EMR and therefore considered to be non-facilitated, 35.7% (n = 50) self-reported having received some types of assistance from PIH/IMB while 9.5% (n = 7) of those who were sampled from the list of beneficiaries receiving facilitated access to care self-reported not receiving any facilitation ubudehe category and 94.4% had membership in community-based health insurance  reported missing or delaying a scheduled clinical appointment, 26.6% did not have any in-person oncology encounters and only 9.8% reported any telemedicine consultations . About hCancer patients generally scored poorly on wellbeing indicators . The quaThese findings were consistent with the findings of our unadjusted regression models, where only global quality of life was significantly associated with facilitated access to care  . In the . Poor-middle patients consistently reported worse outcomes than richest patients for all wellbeing outcomes and reported worse outcomes than richer patients for all outcomes except cognitive functioning and financial difficulties. We did not observe evidence of wealth category modifying the association between facilitated access to care and wellbeing indicators; however, facilitation did not lead to equity between the richest and poorest groups and for many outcomes, especially physical functioning, role functioning, emotional functioning, depression, and anxiety, the disparities remain marked .When assessing patient wellbeing by wealth category, we observed statistically significant differences by wealth category on most wellbeing dimensions, including global quality of life, role functioning, emotional functioning, cognitive functioning, depression, anxiety, and financial toxicity Our study assessed the association between receipt of facilitated access to care during COVID-19 pandemic and patient wellbeing among cancer patients at Butaro Cancer Center of Excellence (BCCOE), Rwanda. During the pandemic, disruptions in accessing care at BCCOE were widespread, as evidenced by the 53% of respondents who missed or delayed a scheduled appointment and 26% who did not have any in-person contact with their oncology provider during the first 17 months of the COVID-19 pandemic. Despite the remote geographical location of BCCOE and challenges linked to providing cancer care in low income settings, the magnitude of these disruptions are comparable to what was reported in high income settings –42. FurtWhile facilitated access to care was associated with some improvements in quality of life and better financial wellbeing, respondents still exhibited generally low levels of patient wellbeing. Global quality of life scores (mean = 37.5) was lower than the scores reported among hospitalized cancer patients before COVID-19 pandemic in similar LMICs settings (mean = 49.5–54.6) , 28. SimAs has been frequently reported in both high- and low-income countries, our study found statistically significant disparities in patient wellbeing by socioeconomic status, with patients in poor wealth categories reporting worse wellbeing compared to the richest patients –53. WhilWhile providing all patients with facilitated access to care regardless of socioeconomic status was an appropriate mitigation strategy during COVID-19, poor overall patient wellbeing and disparities by socioeconomic status suggest a need for more robust, equity-minded interventions to promote the wellbeing of cancer patients at BCCOE even after the COVID-19 pandemic. Telemedicine has been one of strategies used to mitigate disruptions to cancer care and to maintain patient-provider interactions during COVID-19 lockdowns; however, in our study, fewer than 10% of patients reported ever having a telehealth session with their health provider during COVID-19 pandemic Improving the feasibility of telehealth would require improving recording and updating of patient’s contact information in electronic medical record (EMR) systems ; possiblnd and June 31st 2020 and subsequent small-scale lockdowns, while data collection took place in September 2021. Thus, it is possible that some beneficial effects of facilitation during the first national lockdown had dissipated by the time of data collection. Fourth, some misclassification of exposure to facilitated transport is likely as 26% of sampled patients contradicted their listed facilitation status; however, our sensitivity analysis that included only patients with concordant self-reported and listed exposure status showed results of a similar magnitude as our primary analysis, although the smaller sample size likely reduced our power to detect a significant effect. Furthermore, we would anticipate this misclassification to bias our results towards the null hypotheses of no association between receipt of facilitation and our outcomes of interest. Fifth, all data was self-reported and collected via telephone. Since the study was conducted by PIH/IMB, which is known to provide socioeconomic assistance to cancer patients, patients may have been motivated to over-emphasize hardships in effort to gain further assistance. Telephone surveys may be more vulnerable to mis-reporting than in-person surveys; however, given the increased risks of COVID-19 among cancer patients, we did not feel that in-person interviews would be ethical at the time of data collection. Sixth, while the EORTC QLQ-C30, PHQ-9, GAD-7, and COST-FACIT tools have been validated in similar settings including neighboring countries of Rwanda [The present study had several limitations. First, a large portion of patients who were sampled to participate were not reachable or had died. As evidenced by the fact that only a third of our respondents belonged in the bottom 60% of the national wealth distribution, it is likely that our telephone-based data collection excluded a large proportion of the poorest patients. Similarly, patients who were most economically vulnerable or who experienced the greatest disruptions in care may have been more likely to die prior to data collection. Collectively, we would expect these limitations to lead to a respondent population that is better off than the average cancer patient at BCCOE, resulting in an underestimation of poor patient outcomes. Second, we observed differential participation between the facilitated group and non-facilitated group, with the non-facilitated group being less likely to respond. If non-response were associated with worse patient well-being, we would expect this selection bias to underestimate the association between receipt of facilitated access to care and patient wellbeing. Third, facilitated access to care was mainly offered during COVID-19 lockdowns, including the national lockdown of between March 22f Rwanda , 61–64, Provision of facilitated transportations during COVID-19 pandemic was associated with more frequent in-person clinical encounter, better perceived care, greater global quality of life, and lower financial toxicity among patients receiving cancer care in rural Rwanda. However, cancer patients still reported disruptions to care and reported low overall levels of wellbeing, with socioeconomic disparities in patient wellbeing persisting despite the provision of facilitated transport to continue access to oncology care. Preemptively implementing stronger and equity-minded care facilitation and better patient outreach programs may promote better care, strengthen patient outcomes, and leave cancer centers better prepared to respond to future crises.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S1 Data(ZIP)Click here for additional data file.


An emerging application of nanotechnology in medicine currently being developed involves employing nanoparticles to deliver drugs, heat, light, or other substances to specific types of cells (such as cancer cells). As most biological molecules exist and function at the nanoscale, engineering and manipulating matter at the molecular level has many advantages in the field of medicine (nanomedicine). Although encouraging, it remains unclear how much of this will ultimately result in improved patient care. In surgical specialties, clinically relevant nanotechnology applications include the creation of surgical instruments, suture materials, imaging, targeted drug therapy, visualization methods, and wound healing techniques. Burn lesion and scar management is an essential nanotechnology application. Prevention, diagnosis, and treatment of numerous orthopedic conditions are crucial technological aspects for patients’ functional recovery. Orthopedic surgery is a specialty that deals with the diagnosis and treatment of musculoskeletal disorders. In recent years, the field of orthopedics has been revolutionized by the advent of nanotechnology. Using biomaterials comprised of nanoparticles and structures, it is possible to substantially enhance the efficacy of such interactions through nanoscale material modifications. This serves as the foundation for the majority of orthopedic nanotechnology applications. In orthopedic surgery, nanotechnology has been applied to improve surgical outcomes, enhance bone healing, and reduce complications associated with orthopedic procedures. This mini-review summarizes the present state of nanotechnology in orthopedic surgery, including its applications as well as possible future directions. Richard Feynman recognized the potential positive ramifications of nano concepts as early as 1959. Norio Taniguchi first used the word “nanotechnology” in 1974, and Eric Drexler’s writings helped popularize the concept . An emerOrthopaedics is an interesting area in which nanotechnology can be used because bone and its components, like Haversian systems, hydroxyapatite, and collagen fibrils are nano-compounds . In orthMore efficient antibiotic and chemotherapeutic medication delivery systems, 2) Implant and prosthesis surface preparations to increase osteointegration and decrease biofilm development, 3) Regulated medication eluting systems are being developed to address infections caused by implants, 4) Tissue engineering (TE) has been employed to build scaffolds for dealing with cartilage and bone abnormalities, and 5) Oncology-related applications for diagnostics are the major orthopedic applications of nanotechnology. Osteointegration failure is one of the primary concerns associated with the increased usage of uncemented complete arthroplasties of the joints. Even though joints of prosthetics are now treated for surface irregularity to enhance osseous ongrowth or ingrowth, the nanoscale, where cellular interactions occur, remains smooth. This promotes fibrous instead of bony ingrowth, resulting in premature failure . UtiliziOne of the leading reasons for early joint replacement failure and revision is periprosthetic joint infection. Several approaches, including antibiotic-loaded cement as well as other localized drug delivery systems, have been utilized with varying degrees of achievement. It has been demonstrated that the employment of titanium (Ti) nanotubes for nanophase silver or polypeptide nanofilm coatings on prosthetic surfaces regulated and sustained antibiotic release after the operation is efficient. It has been demonstrated that bacterial adhesion and colonization are diminished. Therefore, regulated antibiotic-eluting nanophasic prosthetic joints are a possible remedy for the catastrophic threat posed by periprosthetic joint infection .Nanotechnology has revolutionized therapeutics by enabling more precise drug delivery, which has proven notably advantageous in orthopedics. As mentioned previously, this is accomplished in part by combining medication delivery with nanosensors. Nanophase delivery methods, on the other hand, can be employed to deliver drugs without a sensor.Using nanotechnology and gold NPs, precise drug delivery has shown extremely promising outcomes. Animal research studies have demonstrated that gold has the potential to effectively deliver iontophoresis and is used to cure tendinopathy or a tendon illness and injury . It has For possible TJR uses, nanophase medication delivery is being examined. In a study conducted by Li et al., a nanofilm composed of a biodegradable polypeptide was employed to deliver cefazolin; the findings of this research investigation suggest that nanoscale medication delivery for TJR might help lower the infection risk while also increasing osteoblast recruitment and bone formation. . This syNanotechnology-based drug delivery is also applicable to tumor treatment, especially cancer of the bones. Osteosarcoma is a prevalent type of tumor, and the bone is a major site of cancer metastasis . CurrentRecently, nanotechnology for targeted drug therapy has incorporated tiny particles (such as silver) into materials with nanostructures . Using nNanotechnology’s orthopedic oncological applications have significant potential to enhance diagnosis, overcome medication resistance, decrease the toxicity of normal host cells, as well as more efficiently deliver medications to tumor cells . NPs areThe bone tumor can be eradicated using either local or systemic bifunctional biomaterials. The locally applied bifunctional scaffolds, which included hydrogels, nano/microparticle-containing scaffolds, and 3D-printed scaffolds, can be placed into the area of the bone defect for tumor photothermal treatment, promoting bone healing. When delivered systemically, nanoparticles target bone tissues for tumour therapy and prevent bone reabsorption by penetrating blood arteries .Therapy of segmental bone deformities caused by arthroplasty, and trauma-failed fixations presents a formidable obstacle. Present methods for treating these abnormalities with porous metals and auto/allografts have constraints, like restricted availability, risk of infection, and insufficient scaffolding abilities, which limits the degree of osteointegration. While the best scaffold for promoting osteointegration is controlled by the level of contact between the host tissues and the biomaterial, nanomaterials biomaterials are ideal because osteoblasts can colonize them . On the Biomaterials with nanostructures can offer structural support as well as appropriate pore size, as well as serve as a substrate for cell activity and movement. They can also send biological signals to control tissue transformation when laden with chemokines and growth factors, along with pharmacological assistance by providing peptide patterns that bind receptors and activate intracellular signaling cascades. Nanomaterials with these properties are regarded optimal for treating large bone deformities . After tMany naturally occurring and manmade nanostructured substances have been explored to cure bone deformities. Although natural biomaterials offer good biocompatibility, their handling properties, and structural support are substandard. In contrast, synthetic materials provide exceptional structural assistance but are not biocompatible. Synthetic biomaterials such as bioactive ceramics (hydroxyapatite (HA) and tricalcium phosphate (TCP) and derivatives), polymers including poly-glycolic acid (PGA) and poly-lactic acid (PLA), and a mixture of these known as composite matrices are currently favored as scaffolding substances for curing bone abnormalities because of their improved structural assistance. Surface therapy of these nanostructured biomaterials with growth factors, including bone sialoproteins (BSP) and bone morphogenic proteins (BMP), can enhance their capacity for effective osteointegration. Natural polymers such as gelatin and fibrin have also been utilized to treat bone deformities in non-load-bearing areas, for instance, cranial defects.Cartilage has a more complex structure, making it more difficult to treat cartilaginous defects with biological or synthesized scaffolds. Because of their greater biocompatibility, biodegradability, neovascularization, and cell infiltration , biologiAlthough most cartilage lesions may be repaired with less invasive surgery, the availability of parenteral scaffolds is crucial. Hydrogels are injectable nanomaterial polymeric networks made of collagen or gelatin that may solidify and acquire the appropriate defect form after insertion. When injected with chondrocytes, hydrogels have been demonstrated to form a cartilage-like extracellular matrix (ECM) with increasing technological advancement characteristics due to the continual accumulation of glycosaminoglycan-rich matrix.Using nanofibers to create chondrogenic or osteogenic scaffolds has demonstrated numerous benefits, including enhanced cell adhesion, propagation, and migration. The greatest concentration of type II collagen was seen in nanofiber scaffolds and improved absorption of human serum proteins, as well as considerable activation of cartilage-specific genes and proteins, including collagen II and IX. Numerous published investigations have demonstrated that tissue engineering for treating cartilage and osseous abnormalities is one of the most significant uses of nanotechnology and associated investigation in orthopedics .Although primary replacement surgery for joints has a high success rate, its durability is restricted. In arthroplasty, nanotechnology focuses on creating implanted materials able to function safely and efficiently while extending the typical lifetime of implants and preventing infection. By altering specific surface characteristics of the graft, a more beneficial interaction between the implant and native bone can be induced . NanotexAnother important application of nanotechnology in orthopedics is detection. In particular, nanotechnology has been applied to diagnose bone ailments like renal osteodystrophy, osteoporosis, and Paget’s disease . This isNumerous nanotechnology-based detection products are revolutionizing the orthopedics industry. In the case of osteoporosis, for instance, diagnostic techniques must provide accurate data detection in a fast, cost-effective, and non-invasive way. Prior to the development of strategies that make use of NPs, detection options were limited. However, new nanotechnology-based methods allow for the identification of osteoporosis using portable instruments. In particular, research has led to the development of a novel biochip that utilizes gold NPs to identify an osteoporosis-related protein . It has In addition, nanotechnology has been utilized in orthopedics to monitor orthopedic therapies and guide treatment plans . Some seDiagnostic instruments enable a physician to identify the origin of an illness and initiate therapy with greater precision and speed. Numerous instruments, devices, materials, and systems, including imaging and sensing techniques, are utilized to aid in the diagnostic process. Examples of diagnostic imaging advancements include Kutsuna and others’ non-invasive soft tissue imaging research, which has shown promise for the future.Using a nanosecond-pulsed laser and time-resolved laser-induced fluorescence spectroscopy (TR-LIFS), they were efficient in analyzing tissue-engineered cartilage. Utilizing peak fluorescein wavelengths, the researchers were ready to distinguish between two specimens representing variations in collagen replacements and cartilage tension loading . The ideBone’s ability to generate microcracks allows it to withstand greater stress before fracture . Recent Imaging also assists in distinguishing between conditions. Bone malignancies, such as osteosarcoma and chondrosarcoma, are distinguished using micro- and nano-CT 3D examination . Nano-CTPathogen detection that has colonized a surgical location or intraluminal maneuver is another crucial function of nanotechnology-enabled instruments. Under flow conditions, the Cady laboratory in the Division of Engineering and Nanoscale Science at the University at Albany has demonstrated potential in characterizing bacteriological biofilms.To quantify biofilm material properties, atomic force microscopy (AFM) and microfluidic flow platforms were utilized. Dr. Cady has also made advances in disease-detecting systems utilizing disposable DNA sensors, which have a wide variety of potential applications outside of the medical field . A previ. Self-illuminating quantum nanoparticles (NPs) with affixed R. reniformis luciferase (RLuc)   are of gRLuc was used by So et al., to stimulate the quantum dots through bioluminescence resonance energy transfer to circumvent this issue (BRET). BRET permits the nonradiative transfer of chemical energy from a light-emitting enzyme (RLuc) and its substrate to a fluorescent protein. Dots were infused with chemical substrate and RLuc and then injected into a rat model to create a self-contained imaging source. After examination, these quantum dot bioconjugates were shown to be capable of delivering significantly more sensitive deep tissue imaging with quantum dots .Some applications necessitate a greater spatial resolution is required to accurately identify diseased features, whereas the majority of orthopedic imaging applications focus on macroscale differentiation. Osteoporosis, the most prevalent deteriorating condition in the West, is first on the list because it necessitates comprehensive imaging to ascertain both the morphology and density of damaged bone. Currently, the resolving power of conventional computed tomography (CT) is just under 1 mm, which prevents the observation of microscopic features of the bone, including osteocyte lacunae and their connected canaliculi. Quantitative imaging is made possible via a revolutionary technique that utilize three-dimensional density investigations with submicron resolution using psychographic CT. Unlike conventional lenses, pty-chography is founded on refractive microscopy. It gathers micro-diffraction patterns generated when electromagnetic (EM) energy (X-ray in this instance) impacts the specimen using high-speed sensors. In addition to wave density, the data also incorporates the comparative phase of the EM wave. The capacity to quantitatively measure phase variations indicating sample density permits imaging of larger samples while lowering energy deposition compared to conventional high-resolution X-ray techniques .Magnetic resonance imaging (MRI) is an additional modality that nanotechnology will enhance. Mohanty et al.  reportedSykova and collaborators are capable of monitoring cellular migration employing T2-weighted MRI images by labeling bone marrow embryonic stem cells (ESCs) and mesenchymal stem cells (MSCs) with super paramagnetic iron oxide (SPIO) NPs . Using tin vivo strain measurements that deviate from normal limits. Metallic foil strain gauges are now available commercially, but their restricted sensitivity, enormous bulk, as well as in absence of long-term biocompatibility pose limitations. Existing strain gauges are being replaced by strain gauges enhanced by nanotechnology in every way  developed in cavities on a Ti surface is another method for detecting esistant . In addiesistant .in vivo sensors have limitations because they cannot be powered for extended durations. The Lajnef researcher group aims to overcome this restriction by employing piezo strain gauges with ultralow wattage (1 lW) capable of harvesting energy, thereby enabling the graft sensors to operate indefinitely. The prospect of wirelessly transferring this strain and development data to an external receiver through radio-frequency identification (RFID) and shortwave radio (Bluetooth) is also being investigated, so that the data may be employed efficiently in healthcare decision-making (Modern n-making .Nanotechnology is relatively new to orthopedic research, diagnostics, and treatment. However, in the short time that it has been studied and implemented, nanotechnology has revolutionized orthopedic treatment science and practice. Nanotechnology offers more precise, better bone growth, and theoretically safer methods of treating the human body, at least regarding infection rates and the need for reoperations. In addition to increasing research on nanotechnology’s current processes, benefits, and hazards, regulatory, manufacturing, and cost barriers should be investigated and addressed. Because of the nature and complexity of nanotechnology products, their production is challenging. The high price of these products can limit their accessibility, and the current regulatory processes can be lengthy, limiting the speed with which research can be implemented. Nanomaterials will be more accessible and their use in orthopedics will be promoted more effectively if these concerns are addressed.a. Personalized Medicine: Nanotechnology can be used to develop personalized treatments for musculoskeletal disorders. By tailoring treatment to individual patients, outcomes can be improved and complications can be reduced.b. Regenerative Medicine: Nanotechnology can be used to develop new strategies for tissue regeneration and repair. This could include the use of nanofibrous scaffolds and growth factors to promote the growth of new tissue.c. Biomimicry: Nanotechnology can be used to create materials that mimic the properties of natural bone tissue. This could lead to the development of more biocompatible implants with improved mechanical properties.d. Smart Implants: Nanotechnology can be used to develop implants that respond to their environment. This could include the use of sensors to monitor implant performance or the use of drug delivery systems that respond to changes in the body.Nanotechnology has the potential to revolutionize the field of orthopedic operation in the coming years. Future directions for research in this area include:Nanotechnology has the potential to revolutionize the field of orthopedic surgery by improving surgical outcomes, enhancing bone healing, and reducing complications associated with orthopedic procedures. Current applications of nanotechnology in orthopedic surgery include drug delivery, implants, tissue engineering, diagnostics, and infection control. Future directions for research in this area include personalized medicine, regenerative medicine, biomimicry, and smart implants. As the field of nanotechnology continues to evolve, it may play a significant role in diagnosing and treating musculoskeletal disorders.


Water, sanitation, and hygiene (WASH) improvements are promoted to reduce diarrhoea in low-income countries. However, trials from the past 5 years have found mixed effects of household-level and community-level WASH interventions on child health. Measuring pathogens and host-specific faecal markers in the environment can help investigate causal pathways between WASH and health by quantifying whether and by how much interventions reduce environmental exposure to enteric pathogens and faecal contamination from human and different animal sources. We aimed to assess the effects of WASH interventions on enteropathogens and microbial source tracking (MST) markers in environmental samples.We did a systematic review and individual participant data meta-analysis, which included searches from Jan 1, 2000, to Jan 5, 2023, from PubMed, Embase, CAB Direct Global Health, Agricultural and Environmental Science Database, Web of Science, and Scopus, of prospective studies with water, sanitation, or hygiene interventions and concurrent control group that measured pathogens or MST markers in environmental samples and measured child anthropometry, diarrhoea, or pathogen-specific infections. We used covariate-adjusted regression models with robust standard errors to estimate study-specific intervention effects and pooled effect estimates across studies using random-effects models.Few trials have measured the effect of sanitation interventions on pathogens and MST markers in the environment and they mostly focused on onsite sanitation. We extracted individual participant data on nine environmental assessments from five eligible trials. Environmental sampling included drinking water, hand rinses, soil, and flies. Interventions were consistently associated with reduced pathogen detection in the environment but effect estimates in most individual studies could not be distinguished from chance. Pooled across studies, we found a small reduction in the prevalence of any pathogen in any sample type . Interventions had no effect on the prevalence of MST markers from humans (pooled PR 1·00 [95% CI 0·88–1·13]) or animals (pooled PR 1·00 [95% CI 0·97–1·03]).The small effect of these sanitation interventions on pathogen detection and absence of effects on human or animal faecal markers are consistent with the small or null health effects previously reported in these trials. Our findings suggest that the basic sanitation interventions implemented in these studies did not contain human waste and did not adequately reduce exposure to enteropathogens in the environment.Bill and Melinda Gates Foundation and the UK Foreign and Commonwealth Development Office. Every year, diarrhoea kills an estimated 525 000 children younger than 5 years.6Evidence before this studyChildren in areas with poor drinking water, sanitation, and hygiene (WASH) conditions have increased diarrhoeal disease and reduced growth. Rigorous trials of WASH interventions from the past 5 years have shown mixed efficacy in reducing diarrhoeal disease in children and no improvements in child growth. Quantifying the effect of WASH improvements on enteric pathogens in environmental samples and on contamination originating from human versus animal sources might help elucidate if interventions successfully interrupt the causal pathway between poor WASH, environmental exposure to faecal pathogens, and child health. Most previous studies and meta-analyses on the effect of WASH interventions on faecal contamination in the environment have focused on faecal indicator bacteria (FIB). These studies have shown FIB reductions in water and on hands due to water treatment and handwashing, respectively, but no effects from sanitation. However, naturalised FIB can be present in the environment without faecal contamination, and poorly correlate with actual pathogen presence, affecting the interpretation of these findings. FIB also cannot distinguish between faecal contamination from humans and animals; this information can help identify whether the absence of health effects from sanitation interventions are due to zoonotic disease transmission from unsafely managed animal faeces. Applications of advanced analytic techniques to environmental sampling in low-income countries allow detection and enumeration of a range of enteropathogens, and faecal markers associated with specific hosts for microbial source tracking (MST). The evidence on WASH effects on pathogens and MST markers has not been previously synthesised. Therefore, we did a systematic review and individual participant data (IPD) meta-analysis of WASH intervention studies to assess if interventions reduced the prevalence and abundance of enteropathogens or MST markers in the domestic environment.Added value of this studyWe identified six eligible intervention studies that measured enteropathogens and MST markers in environmental samples and obtained data from five studies. Studies consistently indicated that the interventions were associated with reduced detection of pathogens, and some pathogens  showed large reductions, but most effect estimates in individual studies were null. The IPD meta-analysis approach allowed us to increase precision by pooling study-specific estimates to detect a small reduction in the prevalence of any type of pathogen in any type of sample. There was no overall intervention effect on the prevalence of human or animal MST markers. This study uses advanced methods to enumerate enteropathogens and host-specific faecal markers in a range of environmental samples, including understudied reservoirs such as soil. We provide the first synthesis of evidence of the effect of WASH interventions on these important targets to advance our understanding of the environmental mechanisms of interventions beyond the available evidence on effects on FIB.Implications of all the available evidenceThe environmental sampling in the studies in our review was mostly focused on onsite sanitation interventions that provided or promoted improved latrines with pits or septic tanks at the household or community level. The small reduction in pathogen prevalence in the environment, when pooled across all studies, might explain the small effect these interventions had on child health in the parent studies. Taken together, this evidence suggests that the sanitation interventions implemented in the studies in our review achieved a small reduction in faecal contamination in the environment. More comprehensive WASH interventions, such as safely managed water and sanitation, including safe disposal or treatment of excreta from both humans and animals, are potentially needed to reduce environmental contamination sufficiently to improve child health. We note that only a small number of intervention studies measured our targets of interest, and we identified no studies that assessed the effect of water treatment, hygiene, or safely managed or sewered sanitation interventions on pathogens and MST markers in the domestic environment, except for one study on a combined household water treatment and hygiene intervention in which data were not available for IPD analysis. Also, pathogen targets and analytic methods varied by study, reducing comparability. Future research would benefit from environmental sampling following implementation of a more diverse and comprehensive set of WASH interventions. Such studies should enumerate a common range of pathogen targets and use standardised laboratory methods for a given target and environmental matrix.Escherichia coli as a proxy for a wide range of enteropathogens, including bacteria, viruses, protozoa, and helminths. Sampling has primarily focused on drinking water  whereas other pathways, such as soil and surfaces, have received less attention.Escherichia coli in drinking water is correlated with increased risk of diarrhoea,14To date, WASH intervention studies measuring environmental contamination have mostly relied on faecal indicator bacteria (FIB), such as Applications of advanced molecular methods to environmental sampling in low-income settings can offer advantages over FIB measurements in characterising environmental contamination. These methods can directly detect a range of enteropathogens,We did a systematic review and individual participant data meta-analysis on the effects of WASH interventions on enteropathogens and MST markers in environmental samples. We searched PubMed, Embase, CAB Direct Global Health, Agricultural and Environmental Science Database, Web of Science, and Scopus . We inclFor each eligible study, we requested individual sample data from authors, and excluded studies in which data were not shared. Before sharing data, all personal identifiers such as GPS locations were removed, and indirect identifiers such as sampling dates were coarsened to a monthly resolution.We did not prespecify specific enteropathogens or markers as outcomes because each study measured a different set of targets. We used the pathogens and MST markers measured in the included studies to generate two composite measures as our primary outcomes: (1) detection of any pathogenic target or (2) any MST target, in any sample type collected during the same sampling round from the same compound, where a compound was defined by the original studies as a set of households with common courtyards, water sources, or latrines. Because many targets were infrequently detected in individual studies, composite outcomes allowed us to pool information from studies that focused on different targets and sample types, leveraging the IPD approach for increased statistical precision. We also analysed the prevalence of any pathogen and any MST marker separately for each sample type . Secondary outcomes included the prevalence of specific pathogen class , the prevalence of MST markers from specific host types , and the prevalence and abundance of individual enteropathogens and MST markers. We excluded general MST markers that are not host-specific from our analysis.10-transformed gene copies and negative binomial regressions to estimate ratios of soil-transmitted helminth (STH) egg counts. Because of repeated sampling or clustered designs in some studies, we used the Huber Sandwich Estimator to calculate robust standard errors using either the randomisation cluster or compound as the unit of independence.We compared outcomes between the intervention and control groups of each study. We estimated prevalence ratios (PRs) using modified Poisson regressions.Although estimated intervention effects from randomised trials should be unconfounded, covariate adjustment might increase statistical efficiency and improve exchangeability with matched cohorts and non-randomised trials.28vs wet), animal ownership  and pathogens (with vs without zoonotic transmission). The wet season for each study was defined as the 6 months of highest country-level average rainfall.Campylobacter jejuni, Campylobacter coli, Salmonella, Yersinia enterocolitica, Clostridioides difficile, Cryptosporidium, Giardia, and Ascaris.Ascaris as potentially zoonotic because Ascaris lumbricoides and Ascaris suum cross-infect humans and pigs, and the microscopy methods used in the studies in our review do not distinguish between them.E coli pathotypes , we classified Shiga toxin-producing E coli and enteropathogenic E coli  as zoonotic.We did subgroup analyses by season (dry https://github.com/amertens/wash-ipd). Our systematic review search strategy and statistical analysis plan were preregistered and are available on Open Science FrameworkWe also assessed heterogeneity by study-level characteristics, including setting, study design, intervention uptake and time between intervention onset, and environmental sampling. There was little heterogeneity in urbanicity within any individual study. Therefore, we pooled estimates separately for rural versus urban studies. We also separately pooled estimates from randomised versus quasi-experimental studies, studies with high versus low intervention uptake and studies with shorter (≤1 year) versus longer (>1 year) follow-up between intervention onset and sampling. We compared pooled estimates between strata with Wald tests. Analyses were done in R version 4.0.4. Analysis scripts are publicly available All studies assessed WASH intervention effects on diarrhoeal disease and growth in children younger than 5 years. Three studies were cluster-randomised controlled trials . MapSan was a controlled before-and-after study with control and intervention sites matched on compound size and time of enrolment. Gram Vikas was a matched cohort study in which control and intervention villages were matched on 12 preintervention WASH and socioeconomic characteristics. With the Newcastle-Ottawa scale, studies had low risk of bias due to blinded outcome assessments, with the Gram Vikas and MapSan studies having a lower rating due to higher loss to follow-up and lack of randomisation . WBB, WBAll sanitation interventions evaluated were onsite  technologies delivered at the household or community level. None of the interventions met the Sustainable Development Goal standard of safely managed sanitation because no intervention included excreta treatment or offsite removal, and they would be classified as basic sanitation . The WASH Benefits studies provided new or upgraded improved latrines for each household in enrolled compounds, child potties and sani-scoops for faeces removal. In the WBB trial, latrines were dual-pit latrines with a water seal, and in WBK plastic latrine slabs were used to improve existing latrines. MapSan provided pour-flush latrines draining to septic tanks, shared by multiple households. TSC promoted construction of a pour-flush latrine with a single pit and Y-joint for a second pit, subsidised post hoc by government funding. In the Gram Vikas study, a non-governmental organisation provided materials for the construction of pour-flush latrines in each household in selected villages and built community water tanks and piped distribution systems providing household connections. When every household in the village completed latrine construction, the water system was turned on for the whole village.Latrine access and use was higher in intervention households than control households in all studies. Definitions of latrine quality varied, including improved, clean, hygienic, or functional latrines, or latrines with a functional water seal, as observed by field staff. In four studies, 78–97% of intervention recipients had access to these types of facilities, compared with 18–45% of controls.Environmental samples were collected from 4 monthsE coli, Vibrio cholerae, Shigella, C jejuni, C coli, Salmonella, Yersinia, C difficile, rotavirus, norovirus, sapovirus, adenovirus, astrovirus, enterovirus, Cryptosporidium, Giardia, Entamoeba histolytica, A lumbricoides, and Trichuris trichiura (Methanobrevibacter smithii), animal , ruminant (BacR), and avian (GFD) faecal markers  of 496 for Interventions decreased the prevalence of any pathogen in any sample type in most individual studies but confidence intervals for PRs often crossed the null . Among iShigella (0·28 [0·10–0·78]) in any sample type in Capone and colleagues,Interventions reduced the prevalence of any bacterial pathogens in any sample type (pooled adjusted PR 0·92 [95% CI 0·85–0·99]) and the intervention effects were protective in all individual studies, although with varying precision . InterveOverall, intervention effects on MST markers were negligible, with no detected effects on both human markers (pooled adjusted PR 1·00 [95% CI 0·88–1·13]) and animal markers  per pair of hands  of 40 224 had abundances quantified, including STH egg countsof hands . The intof hands .Table 2MIntervention effects differed by season, but the direction of effects was inconsistent . Animal Our IPD analysis of five intervention studies, mostly focused on household-level and community-level onsite sanitation improvements, indicates a small overall reduction in pathogen prevalence in the environment associated with the interventions. Although the effects of interventions on pathogen prevalence within individual studies had variable precision, point estimates of intervention effects were consistently in the protective direction across studies when aggregated across pathogen and sample types, despite differences in setting, intervention design, and length of follow-up. In general, intervention effects were less consistent when disaggregated by pathogen and sample type, with confidence intervals overlapping with the null , but intThese findings add to a body of literature on the effectiveness of sanitation improvements in low-income countries in interrupting faecal-oral transmission. A previous systematic review found no effect of sanitation interventions on FIB in the environment.It is possible that current approaches to environmental sampling have affected the ability to detect intervention effects on pathogen presence in the environment. Faecal contamination in the domestic environment varies spatially and temporally,Our analysis had some strengths and limitations. The IPD meta-analysis allowed us to estimate intervention effects across studies with consistent statistical methodology, variable definitions, and covariate selection.V cholerae in stored water but not source water.V cholerae in drinking water, and including this study in our IPD analysis would have contributed an additional effect estimate in which the intervention reduced pathogen prevalence. However, the study was done in high-risk populations (household contacts of cholera patients) and is not directly comparable to the studies included in our analysis that focused on general paediatric populations. Additionally, although the studies tested a diverse set of sample types, including understudied pathogen reservoirs, such as soil, not all pathways were captured. For example, contaminated food has been identified as a dominant pathogen transmission pathway in previous research,Only a small number of studies met our inclusion criteria, limiting the generalisability of our findings. Three of the studies were from rural southeast Asia, with a defined monsoon season coinciding with peak diarrhoeal disease incidence, one from rural Kenya with two distinct rainy seasons, and one from drier and urban Maputo, Mozambique. This is consistent with previous WASH reviews indicating that Bangladesh, India, and Kenya are well represented in the published literature, and evidence from other settings is scarce.The basic sanitation interventions in our review resulted in a small reduction in the environmental presence of enteropathogens, consistent with the previously reported scarce health effects. Our results suggest that these sanitation interventions failed to contain human waste and thus prevent exposure to enteropathogens in these populations. More comprehensive approaches are needed to catalyse major health gains. Countries that have universal access to effective sanitation have seen remarkable improvements in health.amertens@berkeley.edu. The statistical analysis code is available at https://github.com/amertens/wash-ipd.The de-identified, aggregated individual participant data and data dictionary can be shared by request of investigators and after approval by the original trial data contributors. Data inquiries can be directed to Andrew Mertens at JER reports that a portion of her salary is supported by an unrestricted donation to The London School of Hygiene & Tropical Medicine from Reckitt; the salary support is wholly unrelated to her role in the preparation of this manuscript. TC has interest in publicly traded companies. All other authors declare no competing interests.


Imaging of pancreatic malignancies is challenging but has a major impact on the patients therapeutic approach and outcome. In particular with pancreatic ductal adenocarcinoma (PDAC), usually a hypovascularized tumor, conventional CT imaging can be prone to errors in determining tumor extent and presence of metastatic disease. Dual-layer spectral detector CT (SDCT) is an emerging technique for acquiring spectral information without the need for prospective patient selection or specific protocols, with a detector capable of differentiating high- and low-energy photons to acquire full spectral images. In this review, we present the diagnostic benefits and capabilities of modern SDCT imaging with a focus on PDAC. We highlight the most useful virtual reconstructions in oncologic imaging and their benefits in staging and assessment of resectability in PDAC, including the assessment of tumor extent, vascular infiltration, and metastatic disease. We present imaging examples on a latest-generation SDCT scanner. Pancreatic ductal adenocarcinoma (PDAC) is a prevalent malignant tumor with the seventh-largest cancer-related mortality worldwide . Five-yeWith spectral imaging, non-invasive information about the composition of specific materials is possible. This allows for selective quantification of elements such as iodine and calcium. To achieve this, the attenuation of at least two different predefined X-ray beam spectra must be acquired  instead of one whole integrated beam spectrum attenuation as used in conventional CT imaging. For spectral CT, this can be realized in several construction options of the scanner system, regarding either the X-ray source or the detector design. On the source side, dual-energy CT systems use two X-ray tubes with different tube currents , a single X-ray tube with kV switching, or a single tube with an additional filter to split the beam in two distinct spectra  . The newSDCT offers a solution where only one X-ray tube is necessary to generate full-spectrum images. It utilizes a detector consisting of two layers. The upper layer absorbs low-energy photons and is permeable for high-energy photons, while the layer beneath is sensitive for the remnant high-energy photons. This allows for the calculation of full-spectrum images in every examination  with excellent spatial and temporal resolution, while eliminating the need for additional tubes or specific protocols and parameter settings ,11. AcquAfter the scan, spectral information is used to calculate various digital reconstructions. The most investigated reconstructions so far are iodine density maps (IDM), virtual non-contrast imaging (VnC), virtual non-calcium imaging (VnCa) and virtual monoenergetic imaging (VMI). Of these VMI, IDM and VnC were shown to have the greatest diagnostic benefits in oncologic imaging . Table 1In virtual monochromatic imaging, post-processing algorithms create a virtual monochromatic X-ray beam usually in a range from 40 to 200 keV. With lower virtual monochromatic beam energies, the X-ray absorption of specific materials such as iodine is amplified by approaching the elements k-edge. The k-edge defines a specific X-ray energy in which a sudden increase in the X-ray absorption of a specific material is observed. The k-edge of iodine is 33.2 keV, thus lowering the virtual beam energy to values close to those that enhance iodine visualization and can provide better lesion-contrast ratios. This effect was shown to be useful in multiple oncologic settings. It helps in detecting and differentiating liver lesions ,17,18 anWith the addition of material decomposition algorithms, subtraction or highlighting of specific elements such as iodine or calcium is possible. With iodine being the major component of contrast media, iodine-based spectral reconstructions allow for direct visualization (or subtraction) of vascularization and perfusion in contrast-enhanced CT images . MultiplWith the above-mentioned material decomposition algorithms, virtual non-enhanced images can be generated by subtracting iodine from the enhanced CT image. The VNC image can replace true unenhanced images to reduce radiation or supplement an enhanced image protocol in case of incidental findings, where an unenhanced image is needed for further interpretation. It has shown equal sensitivity to true enhanced images in the detection of active hemorrhage  and coulUsing material decomposition algorithms to virtually subtract calcium has extensively been studied in orthopedic applications for the early detection of bone marrow edema in suspected trauma ,43,44. IIn most institutions, conventional CT is used as the standard preoperative imaging technique in patients with suspected pancreatic cancer. It allows for fast and comprehensive assessment of the disease extent and plays an important role in determining resectability.Usually, PDAC is a hypovascularized tumor, which can be detected as a hypoattenuating mass on multiphasic conventional CT. The current diagnostic algorithm consists of a multiphasic CT approach: The differentiation between the adjacent pancreatic tissue and the tumor, as well as peripancreatic arterial involvement can be best provided in a pancreatic parenchymal contrast phase , whereas venous involvement and metastases are characterized in the portal venous phase. The parenchymal phase allows the best differentiation; however, differences in contrast can sometimes be very subtle and tumor margins may appear ill defined on conventional CT images. Isoattenuating tumors are quite common with PDAC, with a prevalence of approximately 11%  and theyIodine density maps were identified to be also useful for clearer differentiating hypo- or hyper-vascularized lesions and may add supplemental information for the assessment of devascularization as a surrogate parameter for treatment response following chemotherapy as mentioned above ,24.A patient presenting with abdominal pain who received a single-phase protocol is shown in In pretreated PDAC following neoadjuvant chemotherapy, efficacy of conventional CT in staging and evaluation of resectability is severely impaired, with studies showing underestimation of therapy response by overestimation of tumor size and vascular conflicts, possibly leading to falsely excluding patients from curative treatment . More acOne of the most important factors in determining resectability is vascular involvement. The exact interpretation of tumor contact with the celiac trunk, the superior mesenteric artery, the common hepatic artery as well as the superior mesenteric vein and the portal vein is crucial for assessing the different categories of resectability, as stated in the NCCN criteria . DiffereTo be eligible for curative treatment absence of distant metastatic disease is mandatory. The detection of small hypovascularized liver metastases can be challenging in conventional CT imaging. A recent meta-analysis of 987 patients showed an overall pooled sensitivity for CT of 45% for detection of liver metastases . Though In In this review, we highlighted the benefits of SDCT imaging in the diagnosis, staging and assessment of pancreatic ductal adenocarcinoma. SDCT is an emerging technique for acquiring full spectral information without the need for prospective patient selection or specific protocols. Several virtual reconstructions are useful in PDAC imaging. VMI in the portal venous phase can help differentiate pancreatic malignancies, vascular involvement, and liver metastases by increasing contrast differences and can be especially useful in protocols where the pancreatic parenchymal phase is missing. Iodine density maps can also improve visualization of hypo- or hypervascularized lesions and might aid in evaluation of treatment response. There is still a lack of, or scarce, evidence concerning the potential of SDCT in evaluation of vascular invasion, therapy monitoring and differentiation of PDAC mimics, such as mass-forming pancreatitis, but the few existing studies suggest potential benefits that need to be investigated further.


Methods, Applications, and Protocols in Plant Science: Network Modeling-guided Understanding of Gene Regulation in Plants, the collection of research articles and reviews highlights recent progress in applying gene network or omics approaches to understanding gene expression changes necessary for significant agronomic traits. We believe that this broad snapshot would advance this inspiring field to the next level and provide opportunities for readers to spark new exciting ideas in their research.Like our daily lives with social network connections in various forms, molecular components  interact with each other to create biological networks, which allow complex organisms to timely coordinate appropriate biological responses. Surowiecki mentioned “the wisdom of crowds”, which refers to the phenomenon in which the collective knowledge of a community is greater than the knowledge of any individual. Similarly, if gene responses to internal or external stimuli could be investigated at “a network level” in plants, their function could be better understood and enabling for crop improvement. Network-enabled understanding of biological questions regarding a broad array of Research Topics including plant development, growth, and responses to environmental stress requires the ability to obtain genome-wide molecular measurements, which has been possible by the ever-increasing access to and decreasing costs of next-generation sequencing technology over the past decade. Thus, in the post-genomic era, gene network and omics approaches have been more powerful in the field of plant biology than ever before. In this Research Topic Gossypium hirsutum (Upland cotton) and G. barbadense (Sea-island cotton), have complex branching patterns mediated by complex gene regulatory networks. The review presented by Huang et al. takes a deep dive into the genetic basis underlying cotton plant architecture QTLs and the regulatory signaling pathways, the underlying molecular factors, and the evolutionary and bioengineering perspectives.Cotton is not only the most significant source of natural fiber worldwide but also a powerful model for understanding plant architecture. Two cultivated worldwide allotetraploid species, Jiang et al. present current advances in understanding the functional roles of OGs, focusing on the identification of OGs, gene expression modes and the association with significant biological traits. Possible future direction for functional studies of OGs is discussed.Gene homologs descend from a common evolutionary origin. Intriguingly, some genes have no sequence similarity with genes in other species. Those genes are referred to as orphan genes (OGs) and are ubiquitous in the genomes of sequenced organisms. In plants, OGs are associated with lineage-specific evolution, responses to environmental stress and metabolisms. Lancikova et al. report the identification of cytosine-5 DNA methyltransferase and demethylase genes in Amaranth (Amaranthus cruentus L.), and further, delineate their functional roles in response to heavy metal stress by exploring the gene expression profiles in different stress conditions and tissues. This finding may help us to characterize the molecular mechanism by which these epigenetic components regulate the dynamic gene expression changes under heavy metal stress in Amaranth and related crops.Climate change, whose frequency and severity are projected to increase, challenges plant growth, development, and crop productivity worldwide. To withstand these stressors, plants have evolved highly interconnected regulatory networks that coordinate proper cellular and metabolic responses. Epigenetic control is one of the elaborate mechanisms in these regulatory efforts. Brhane et al. characterize transcriptome profiles in response to aluminum toxicity in finger millet, which is a widely grown cereal in arid and semi-arid areas in Africa and Asia. Through a large-scale transcriptome assembly, this study presents high-quality genomics resources covering 198,546 unique genes, 3,553 single-copy SSR markers, and 119,073 SNP markers. The transcriptome profiling reveals hundreds of differentially expressed genes in genotypes tolerant to aluminum toxicity along with their annotated function. The genomic resources obtained in this study will serve as a fundamental resource for the research communities.Taken together, the Research Topic illustrates the potential derived from gene network and omics approaches in the field of plant biology. With these research articles and reviews, this Research Topic would provide new genomics resources and deep insights into the application of these approaches for crop improvement.DKK wrote the draft. MTS-B edited the text. All authors approve the submission.