Factors in Patient Responsiveness to Directional Preference-Matched Treatment of Neck Pain With or Without Upper Extremity Radiation

Purpose: Patient-related predictive factors in responsiveness to directional preference therapy for neck pain with or without upper extremity radiation (NP/R) have not been reported. A directional preference is any neck movement that, when performed repeatedly to end range, results in centralization and/or alleviation of NP/R. It was hypothesized that patient compliance with a prescribed, directional preference-matched home exercise program would improve positive responsiveness to NP/R treatment. Methods: Patient-related factors thought to affect responsiveness to care were collected retrospectively from charts and de-identified for patients with NP/R who underwent chiropractic treatment at a multispecialty spine clinic from January 2014 through June 2015. Responsiveness was measured by calculating the percentage change in Neck Bournemouth Questionnaire (NBQ) scores over treatment time. Multiple linear regression was used to identify factors associated with positive responsiveness. Results: Mean percentage change in patient NBQ score from initial intake to discharge was 50% (standard deviation: 32%). Of 104 patients meeting study inclusion criteria, 86 (83%) reported experiencing improvement after the first treatment session. Bivariate analysis of patient characteristics by compliance with directional preference-matched exercise indicated that compliant patients (n = 95, 91%) demonstrated significantly greater responsiveness to care than did noncompliant patients, at 55% versus 25% change in NBQ score, respectively (P = 0.0041). Four factors were statistically significant predictors of patient responsiveness to directional preference therapy for NP/R: patient compliance with directional preference-matched exercise (P = 0.0023), patient age (P = 0.0029), condition chronicity (P < 0.0001), and whether the patient reported improvement of symptoms following initial treatment session (P = 0.0003). Conclusions: The results of this study suggest that patient compliance with directional preference exercise is associated with patient responsiveness to conservative treatment of NP/R, as are age, chronicity and report of immediate symptom improvement

Identification and Functional Validation of the Novel Antimalarial Resistance Locus PF10_0355 in Plasmodium falciparum

The Plasmodium falciparum parasite's ability to adapt to environmental pressures, such as the human immune system and antimalarial drugs, makes malaria an enduring burden to public health. Understanding the genetic basis of these adaptations is critical to intervening successfully against malaria. To that end, we created a high-density genotyping array that assays over 17,000 single nucleotide polymorphisms (~1 SNP/kb), and applied it to 57 culture-adapted parasites from three continents. We characterized genome-wide genetic diversity within and between populations and identified numerous loci with signals of natural selection, suggesting their role in recent adaptation. In addition, we performed a genome-wide association study (GWAS), searching for loci correlated with resistance to thirteen antimalarials; we detected both known and novel resistance loci, including a new halofantrine resistance locus, PF10_0355. Through functional testing we demonstrated that PF10_0355 overexpression decreases sensitivity to halofantrine, mefloquine, and lumefantrine, but not to structurally unrelated antimalarials, and that increased gene copy number mediates resistance. Our GWAS and follow-on functional validation demonstrate the potential of genome-wide studies to elucidate functionally important loci in the malaria parasite genome.Bill & Melinda Gates FoundationEllison Medical FoundationExxon Mobil FoundationFogarty International CenterNational Institute of Allergy and Infectious Diseases (U.S.)Burroughs Wellcome FundDavid & Lucile Packard FoundationNational Science Foundation (U.S.). Graduate Research Fellowship Progra

The bactericidal effect of dendritic copper microparticles, contained in an alginate matrix, on Escherichia coli.

Although the bactericidal effect of copper has been known for centuries, there is a current resurgence of interest in the use of this element as an antimicrobial agent. During this study the use of dendritic copper microparticles embedded in an alginate matrix as a rapid method for the deactivation of Escherichia coli ATCC 11775 was investigated. The copper/alginate produced a decrease in the minimum inhibitory concentration from free copper powder dispersed in the media from 0.25 to 0.065 mg/ml. Beads loaded with 4% Cu deactivated 99.97% of bacteria after 90 minutes, compared to a 44.2% reduction in viability in the equivalent free copper powder treatment. There was no observed loss in the efficacy of this method with increasing bacterial loading up to 10(6) cells/ml, however only 88.2% of E. coli were deactivated after 90 minutes at a loading of 10(8) cells/ml. The efficacy of this method was highly dependent on the oxygen content of the media, with a 4.01% increase in viable bacteria observed under anoxic conditions compared to a >99% reduction in bacterial viability in oxygen tensions above 50% of saturation. Scanning electron micrographs (SEM) of the beads indicated that the dendritic copper particles sit as discrete clusters within a layered alginate matrix, and that the external surface of the beads has a scale-like appearance with dendritic copper particles extruding. E. coli cells visualised using SEM indicated a loss of cellular integrity upon Cu bead treatment with obvious visible blebbing. This study indicates the use of microscale dendritic particles of Cu embedded in an alginate matrix to effectively deactivate E. coli cells and opens the possibility of their application within effective water treatment processes, especially in high particulate waste streams where conventional methods, such as UV treatment or chlorination, are ineffective or inappropriate

Human cerebral malaria and Plasmodium falciparum genotypes in Malawi

<p>Abstract</p> <p>Background</p> <p>Cerebral malaria, a severe form of <it>Plasmodium falciparum </it>infection, is an important cause of mortality in sub-Saharan African children. A Taqman 24 Single Nucleotide Polymorphisms (SNP) molecular barcode assay was developed for use in laboratory parasites which estimates genotype number and identifies the predominant genotype.</p> <p>Methods</p> <p>The 24 SNP assay was used to determine predominant genotypes in blood and tissues from autopsy and clinical patients with cerebral malaria.</p> <p>Results</p> <p>Single genotypes were shared between the peripheral blood, the brain, and other tissues of cerebral malaria patients, while malaria-infected patients who died of non-malarial causes had mixed genetic signatures in tissues examined. Children with retinopathy-positive cerebral malaria had significantly less complex infections than those without retinopathy (OR = 3.7, 95% CI [1.51-9.10]).The complexity of infections significantly decreased over the malaria season in retinopathy-positive patients compared to retinopathy-negative patients.</p> <p>Conclusions</p> <p>Cerebral malaria patients harbour a single or small set of predominant parasites; patients with incidental parasitaemia sustain infections involving diverse genotypes. Limited diversity in the peripheral blood of cerebral malaria patients and correlation with tissues supports peripheral blood samples as appropriate for genome-wide association studies of parasite determinants of pathogenicity.</p

Human and mouse essentiality screens as a resource for disease gene discovery

The identification of causal variants in sequencing studies remains a considerable challenge that can be partially addressed by new gene-specific knowledge. Here, we integrate measures of how essential a gene is to supporting life, as inferred from viability and phenotyping screens performed on knockout mice by the International Mouse Phenotyping Consortium and essentiality screens carried out on human cell lines. We propose a cross-species gene classification across the Full Spectrum of Intolerance to Loss-of-function (FUSIL) and demonstrate that genes in five mutually exclusive FUSIL categories have differing biological properties. Most notably, Mendelian disease genes, particularly those associated with developmental disorders, are highly overrepresented among genes non-essential for cell survival but required for organism development. After screening developmental disorder cases from three independent disease sequencing consortia, we identify potentially pathogenic variants in genes not previously associated with rare diseases. We therefore propose FUSIL as an efficient approach for disease gene discovery. Discovery of causal variants for monogenic disorders has been facilitated by whole exome and genome sequencing, but does not provide a diagnosis for all patients. Here, the authors propose a Full Spectrum of Intolerance to Loss-of-Function (FUSIL) categorization that integrates gene essentiality information to aid disease gene discovery

Performance of non-invasive tests and histology for the prediction of clinical outcomes in patients with non-alcoholic fatty liver disease: an individual participant data meta-analysis

BackgroundHistologically assessed liver fibrosis stage has prognostic significance in patients with non-alcoholic fatty liver disease (NAFLD) and is accepted as a surrogate endpoint in clinical trials for non-cirrhotic NAFLD. Our aim was to compare the prognostic performance of non-invasive tests with liver histology in patients with NAFLD.MethodsThis was an individual participant data meta-analysis of the prognostic performance of histologically assessed fibrosis stage (F0–4), liver stiffness measured by vibration-controlled transient elastography (LSM-VCTE), fibrosis-4 index (FIB-4), and NAFLD fibrosis score (NFS) in patients with NAFLD. The literature was searched for a previously published systematic review on the diagnostic accuracy of imaging and simple non-invasive tests and updated to Jan 12, 2022 for this study. Studies were identified through PubMed/MEDLINE, EMBASE, and CENTRAL, and authors were contacted for individual participant data, including outcome data, with a minimum of 12 months of follow-up. The primary outcome was a composite endpoint of all-cause mortality, hepatocellular carcinoma, liver transplantation, or cirrhosis complications (ie, ascites, variceal bleeding, hepatic encephalopathy, or progression to a MELD score ≥15). We calculated aggregated survival curves for trichotomised groups and compared them using stratified log-rank tests (histology: F0–2 vs F3 vs F4; LSM: 2·67; NFS: 0·676), calculated areas under the time-dependent receiver operating characteristic curves (tAUC), and performed Cox proportional-hazards regression to adjust for confounding. This study was registered with PROSPERO, CRD42022312226.FindingsOf 65 eligible studies, we included data on 2518 patients with biopsy-proven NAFLD from 25 studies (1126 [44·7%] were female, median age was 54 years [IQR 44–63), and 1161 [46·1%] had type 2 diabetes). After a median follow-up of 57 months [IQR 33–91], the composite endpoint was observed in 145 (5·8%) patients. Stratified log-rank tests showed significant differences between the trichotomised patient groups (p<0·0001 for all comparisons). The tAUC at 5 years were 0·72 (95% CI 0·62–0·81) for histology, 0·76 (0·70–0·83) for LSM-VCTE, 0·74 (0·64–0·82) for FIB-4, and 0·70 (0·63–0·80) for NFS. All index tests were significant predictors of the primary outcome after adjustment for confounders in the Cox regression.InterpretationSimple non-invasive tests performed as well as histologically assessed fibrosis in predicting clinical outcomes in patients with NAFLD and could be considered as alternatives to liver biopsy in some cases

Factors in Patient Responsiveness to Directional Preference-Matched Treatment of Neck Pain With or Without Upper Extremity Radiation

Purpose Patient-related predictive factors in responsiveness to directional preference therapy for neck pain with or without upper extremity radiation (NP/R) have not been reported. A directional preference is any neck movement that, when performed repeatedly to end range, results in centralization and/or alleviation of NP/R. It was hypothesized that patient compliance with a prescribed, directional preference-matched home exercise program would improve positive responsiveness to NP/R treatment. Methods Patient-related factors thought to affect responsiveness to care were collected retrospectively from charts and de-identified for patients with NP/R who underwent chiropractic treatment at a multispecialty spine clinic from January 2014 through June 2015. Responsiveness was measured by calculating the percentage change in Neck Bournemouth Questionnaire (NBQ) scores over treatment time. Multiple linear regression was used to identify factors associated with positive responsiveness. Results Mean percentage change in patient NBQ score from initial intake to discharge was 50% (standard deviation: 32%). Of 104 patients meeting study inclusion criteria, 86 (83%) reported experiencing improvement after the first treatment session. Bivariate analysis of patient characteristics by compliance with directional preference-matched exercise indicated that compliant patients (n = 95, 91%) demonstrated significantly greater responsiveness to care than did noncompliant patients, at 55% versus 25% change in NBQ score, respectively (P = 0.0041). Four factors were statistically significant predictors of patient responsiveness to directional preference therapy for NP/R: patient compliance with directional preference-matched exercise (P = 0.0023), patient age (P = 0.0029), condition chronicity (P \u3c 0.0001), and whether the patient reported improvement of symptoms following initial treatment session (P = 0.0003). Conclusions The results of this study suggest that patient compliance with directional preference exercise is associated with patient responsiveness to conservative treatment of NP/R, as are age, chronicity and report of immediate symptom improvement

Factors in Patient Responsiveness to Directional Preference-Matched Treatment of Neck Pain With or Without Upper Extremity Radiation

Purpose: Patient-related predictive factors in responsiveness to directional preference therapy for neck pain with or without upper extremity radiation (NP/R) have not been reported. A directional preference is any neck movement that, when performed repeatedly to end range, results in centralization and/or alleviation of NP/R. It was hypothesized that patient compliance with a prescribed, directional preference-matched home exercise program would improve positive responsiveness to NP/R treatment. Methods: Patient-related factors thought to affect responsiveness to care were collected retrospectively from charts and de-identified for patients with NP/R who underwent chiropractic treatment at a multispecialty spine clinic from January 2014 through June 2015. Responsiveness was measured by calculating the percentage change in Neck Bournemouth Questionnaire (NBQ) scores over treatment time. Multiple linear regression was used to identify factors associated with positive responsiveness. Results: Mean percentage change in patient NBQ score from initial intake to discharge was 50% (standard deviation: 32%). Of 104 patients meeting study inclusion criteria, 86 (83%) reported experiencing improvement after the first treatment session. Bivariate analysis of patient characteristics by compliance with directional preference-matched exercise indicated that compliant patients (n = 95, 91%) demonstrated significantly greater responsiveness to care than did noncompliant patients, at 55% versus 25% change in NBQ score, respectively (P = 0.0041). Four factors were statistically significant predictors of patient responsiveness to directional preference therapy for NP/R: patient compliance with directional preference-matched exercise (P = 0.0023), patient age (P = 0.0029), condition chronicity (P < 0.0001), and whether the patient reported improvement of symptoms following initial treatment session (P = 0.0003). Conclusions: The results of this study suggest that patient compliance with directional preference exercise is associated with patient responsiveness to conservative treatment of NP/R, as are age, chronicity and report of immediate symptom improvement

A general SNP-based molecular barcode for <it>Plasmodium falciparum </it>identification and tracking

Abstract Background Single nucleotide polymorphism (SNP) genotyping provides the means to develop a practical, rapid, inexpensive assay that will uniquely identify any Plasmodium falciparum parasite using a small amount of DNA. Such an assay could be used to distinguish recrudescence from re-infection in drug trials, to monitor the frequency and distribution of specific parasites in a patient population undergoing drug treatment or vaccine challenge, or for tracking samples and determining purity of isolates in the laboratory during culture adaptation and sub-cloning, as well as routine passage. Methods A panel of twenty-four SNP markers has been identified that exhibit a high minor allele frequency (average MAF > 35%), for which robust TaqMan genotyping assays were constructed. All SNPs were identified through whole genome sequencing and MAF was estimated through Affymetrix array-based genotyping of a worldwide collection of parasites. These assays create a "molecular barcode" to uniquely identify a parasite genome. Results Using 24 such markers no two parasites known to be of independent origin have yet been found to have the same allele signature. The TaqMan genotyping assays can be performed on a variety of samples including cultured parasites, frozen whole blood, or whole blood spotted onto filter paper with a success rate > 99%. Less than 5 ng of parasite DNA is needed to complete a panel of 24 markers. The ability of this SNP panel to detect and identify parasites was compared to the standard molecular methods, MSP-1 and MSP-2 typing. Conclusion This work provides a facile field-deployable genotyping tool that can be used without special skills with standard lab equipment, and at reasonable cost that will unambiguously identify and track P. falciparum parasites both from patient samples and in the laboratory.</p