To assess if SARS-CoV-2 (COVID-19) systemic disease can be determined by available nucleoprotein assays, we compared the performance of three commercial SARS-CoV-2 nucleoprotein (N) assays in plasma. ...A total of 272 plasma samples collected in the period November-December 2021 were analyzed by the methods Simoa SARS CoV-2 N Protein Advantage Kit Quanterix Simoa, Solsten SARS-CoV-2 Antigen enzyme immunosorbent assay (ELISA) Solsten ELISA, and Elecsys SARS-CoV-2 Antigen electrochemiluminescence immunoassay Elecsys ECLIA. Additionally, a dilution series of inactivated virus culture was analyzed by the three assays. The SARS CoV-2 PCR-status was not known for the patients. Linear correlation in the pairwise correlation between assays as well as linearity of dilution series of inactivated virus culture was estimated by Spearman score. Sensitivity and specificity were estimated by pairwise comparison. The three assays showed poor agreement on patient samples with regards to concentration. Performance on virus culture was excellent but with different level of detection (LOD). Positive vs negative results show comparable sensitivity and specificity of Quanterix Simoa and Solsten ELISA, with a higher LOD in Elecsys ECLIA and thus lower sensitivity and high specificity. N by all tested assays can be used as a marker for systemic COVID-19 disease.
Pay for performance (P4P) schemes provide financial incentives to health workers or facilities based on the achievement of pre-specified performance targets and have been widely implemented in health ...systems across low and middle-income countries (LMICs). The growing evidence base on P4P highlights that (i) there is substantial variation in the effect of P4P schemes on outcomes and (ii) there appears to be heterogeneity in incentive design. Even though scheme design is likely a key determinant of scheme effectiveness, we currently lack systematic evidence on how P4P schemes are designed in LMICs.
We develop a typology to classify the design of P4P schemes in LMICs, which highlights different design features that are a priori likely to affect the behaviour of incentivised actors. We then use results from a systematic literature review to classify and describe the design of P4P schemes that have been evaluated in LMICs. To capture academic publications, Medline, Embase, and EconLit databases were searched. To include relevant grey literature, Google Scholar, Emerald Insight, and websites of the World Bank, WHO, Cordaid, Norad, DfID, USAID and PEPFAR were searched.
We identify 41 different P4P schemes implemented in 29 LMICs. We find that there is substantial heterogeneity in the design of P4P schemes in LMICs and pinpoint precisely how scheme design varies across settings. Our results also highlight that incentive design is not adequately being reported on in the literature - with many studies failing to report key design features.
We encourage authors to make a greater effort to report information on P4P scheme design in the future and suggest using the typology laid out in this paper as a starting point.
Celotno besedilo
Dostopno za:
CEKLJ, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Pay for performance (P4P) programmes are popular health system-focused interventions aiming to improve health outcomes in low-and middle-income countries (LMICs). This realist review aims to ...understand how, why and under what circumstance P4P works in LMICs.We systematically searched peer-reviewed and grey literature databases, and examined the mechanisms underpinning P4P effects on: utilisation of services, patient satisfaction, provider productivity and broader health system, and contextual factors moderating these. This evidence was then used to construct a causal loop diagram.We included 112 records (19 grey literature; 93 peer-reviewed articles) assessing P4P schemes in 36 countries. Although we found mixed evidence of P4P's effects on identified outcomes, common pathways to improved outcomes include: community outreach; adherence to clinical guidelines, patient-provider interactions, patient trust, facility improvements, access to drugs and equipment, facility autonomy, and lower user fees. Contextual factors shaping the system response to P4P include: degree of facility autonomy, efficiency of banking, role of user charges in financing public services; staffing levels; staff training and motivation, quality of facility infrastructure and community social norms. Programme design features supporting or impeding health system effects of P4P included: scope of incentivised indicators, fairness and reach of incentives, timely payments and a supportive, robust verification system that does not overburden staff. Facility bonuses are a key element of P4P, but rely on provider autonomy for maximum effect. If health system inputs are vastly underperforming pre-P4P, they are unlikely to improve only due to P4P. This is the first realist review describing how and why P4P initiatives work (or fail) in different LMIC contexts by exploring the underlying mechanisms and contextual and programme design moderators. Future studies should systematically examine health system pathways to outcomes for P4P and other health system strengthening initiatives, and offer more understanding of how programme design shapes mechanisms and effects.
•Pay for performance (P4P) is a popular approach to improve health in LMICs.•This is the first realist review assessing how and why P4P works in LMICs.•Key Key mechanisms through which P4P can work were not obviously linked to the financial incentive component of P4P.•We report scheme design features supporting or impeding P4P's health system effects.•If health systems are weak pre-P4P, they are unlikely to improve only due to P4P.
Abstract
Although pay-for-performance (P4P) schemes have been implemented across low- and middle-income countries (LMICs), little is known about their distributional consequences. A key concern is ...that financial bonuses are primarily captured by providers who are already better able to perform (for example, those in wealthier areas), P4P could exacerbate existing inequalities within the health system. We examine inequalities in the distribution of pay-outs in Zimbabwe’s national P4P scheme (2014–2016) using quantitative data on bonus payments and facility characteristics and findings from a thematic policy review and 28 semi-structured interviews with stakeholders at all system levels. We found that in Zimbabwe, facilities with better baseline access to guidelines, more staff, higher consultation volumes and wealthier and less remote target populations earned significantly higher P4P bonuses throughout the programme. For instance, facilities that were 1 SD above the mean in terms of access to guidelines, earned 90 USD more per quarter than those that were 1 SD below the mean. Differences in bonus pay-outs for facilities that were 1 SD above and below the mean in terms of the number of staff and consultation volumes are even more pronounced at 348 USD and 445 USD per quarter. Similarly, facilities with villages in the poorest wealth quintile in their vicinity earned less than all others—and 752 USD less per quarter than those serving villages in the richest quintile. Qualitative data confirm these findings. Respondents identified facility baseline structural quality, leadership, catchment population size and remoteness as affecting performance in the scheme. Unequal distribution of P4P pay-outs was identified as having negative consequences on staff retention, absenteeism and motivation. Based on our findings and previous work, we provide some guidance to policymakers on how to design more equitable P4P schemes.
Healthcare databases can be a valuable source of epidemiological research regarding postoperative venous thromboembolism (VTE), ie, deep vein thrombosis (DVT) and pulmonary embolism (PE), following ...orthopedic procedures, but only if the diagnoses are valid. We examined the validity of VTE diagnosis codes in the Danish National Patient Registry (DNPR) by calculating their positive predictive value (PPV) and negative predictive value (NPV) versus actual medical records.
We identified patients who had undergone lower limb surgery during the period 2009-2019 at a hospital in the North Denmark Region. Of these, 420 patients had at least one VTE diagnosis registered in the DNPR within 180 days after lower limb surgery. Each patient with a VTE diagnosis was matched with two patients on age and sex, as well as type, location and period of surgery. The entire medical record and diagnostic imaging were reviewed to confirm VTE diagnosis.
The overall PPVs was 85.2% (95% CI: 81.5-88.5%) for first time VTE diagnosis following lower limb surgery, 82.6% (95% CI: 77.5-82.8%) for DVT, and 90.3% (95% CI: 84.3-94.6%) for PE. We found improvement in PPV during the study period when stratifying for three periods of the whole period. There were no significant differences when stratifying for sex, age, or surgery site. All negative predictive values were higher than 99%. A total of 113 additional VTE diagnoses were registered among 88 VTE patients during follow-up. Only four of the suspected recurrent VTEs were confirmed to be true recurrent VTEs.
The VTE diagnosis codes in the DNPR after lower limb orthopedic surgery were highly valid against the actual medical records, and we observed better PPV over recent years.
Glioblastoma (GBM) remains uniformly lethal, and despite a large accumulation of immune cells in the microenvironment, there is limited antitumor immune response. To overcome these challenges, a ...comprehensive understanding of GBM systemic immune response during disease progression is required. Here, we integrated multiparameter flow cytometry and mass cytometry TOF (CyTOF) analysis of patient blood to determine changes in the immune system among tumor types and over disease progression. Utilizing flow cytometry analysis in a cohort of 259 patients ranging from benign to malignant primary and metastatic brain tumors, we found that GBM patients had a significant elevation in myeloid-derived suppressor cells (MDSCs) in peripheral blood but not immunosuppressive Tregs. In GBM patient tissue, we found that increased MDSC levels in recurrent GBM portended poor prognosis. CyTOF analysis of peripheral blood from newly diagnosed GBM patients revealed that reduced MDSCs over time were accompanied by a concomitant increase in DCs. GBM patients with extended survival also had reduced MDSCs, similar to the levels of low-grade glioma (LGG) patients. Our findings provide a rationale for developing strategies to target MDSCs, which are elevated in GBM patients and predict poor prognosis.
In the modern world with climate changes and increasing pollution, different types of stress are becoming an increasing challenge. Hence, the identification of reliable biomarkers of stress and ...accessible sensors to measure such biomarkers are attracting increasing attention. In the current study, we demonstrate that the activity, but not the expression, of the ubiquitous enzyme topoisomerase 1 (TOP1), as measured in crude cell extracts by the REEAD sensor system, is markedly reduced in response to thermal stress in both fruit flies (Drosophila melanogaster) and cultivated human cells. This effect was observed in response to both mild-to-moderate long-term heat stress and more severe short-term heat stress in D. melanogaster. In cultivated HeLa cells a reduced TOP1 activity was observed in response to both cold and heat stress. The reduced TOP1 activity appeared dependent on one or more cellular pathways since the activity of purified TOP1 was unaffected by the utilized stress temperatures. We demonstrate successful quantitative measurement of TOP1 activity using an easily accessible chemiluminescence readout for REEAD pointing towards a sensor system suitable for point-of-care assessment of stress responses based on TOP1 as a biomarker.
We have investigated the function of human topoisomerase 1 (TOP1) in regulation of G-quadruplex (G4) formation in the Pu27 region of the MYC P1 promoter. Pu27 is among the best characterized G4 ...forming sequences in the human genome and it is well known that promoter activity is inhibited upon G4 formation in this region. We found that TOP1 downregulation stimulated transcription from a promoter with wildtype Pu27 but not if the G4 motif in Pu27 was interrupted by mutation(s). The effect was not specific to the MYC promoter and similar results were obtained for the G4 forming promoter element WT21. The other major DNA topoisomerases with relaxation activity, topoisomerases 2α and β, on the other hand, did not affect G4 dependent promoter activity. The cellular studies were supported by in vitro investigations demonstrating a high affinity of TOP1 for wildtype Pu27 but not for mutant sequences unable to form G4. Moreover, TOP1 was able to induce G4 formation in Pu27 inserted in double stranded plasmid DNA in vitro. This is the first time TOP1 has been demonstrated capable of inducing G4 formation in double stranded DNA and of influencing G4 formation in cells.
Quality of life is often reduced in patients with sleep-wake disorders. Insomnia is commonly treated with benzodiazepines, despite their well-known side effects. Pellotine (1), a Lophophora alkaloid, ...has been reported to have short-acting sleep-inducing properties in humans. In this study, we set out to evaluate various in vitro and in vivo properties of 1. We demonstrate that 1 undergoes slow metabolism; e.g. in mouse liver microsomes 65% remained, and in human liver microsomes virtually no metabolism was observed after 4 h. In mouse liver microsomes, two phase I metabolites were identified: 7-desmethylpellotine and pellotine-N-oxide. In mice, the two diastereomers of pellotine-O-glucuronide were additionally identified as phase II metabolites. Furthermore, we demonstrated by DESI-MSI that 1 readily enters the central nervous system of rodents. Furthermore, radioligand-displacement assays showed that 1 is selective for the serotonergic system and in particular the serotonin (5-HT)1D, 5-HT6, and 5-HT7 receptors, where it binds with affinities in the nanomolar range (117, 170, and 394 nM, respectively). Additionally, 1 was functionally characterized at 5-HT6 and 5-HT7, where it was found to be an agonist at the former (EC50 = 94 nM, E max = 32%) and an inverse agonist at the latter (EC50 = 291 nM, E max = −98.6). Finally, we demonstrated that 1 dose-dependently decreases locomotion in mice, inhibits REM sleep, and promotes sleep fragmentation. Thus, we suggest that pellotine itself, and not an active metabolite, is responsible for the hypnotic effects and that these effects are possibly mediated through modulation of serotonergic receptors.
Many marine infaunal animals form organic tube and burrow linings. The role of these materials in organic matter cycling and preservation in sediments is largely unknown. In the case examined here, ...the infaunal sea anemone, Ceriantheopsis americanus, (a common component of bottom
communities along the east coast of North America) forms a leathery, fibrous tube lining 2-3 mm thick, ∼1 cm in diameter, and typically extending 20-30 cm into deposits. Tube fibers (∼2 mm long, 2-5 μm thick) formed from discharged specialized nematocyst cells,
ptychocysts, are composed of a silk-like protein copolymer, cerianthin. Tubes incubated under oxic and anoxic conditions over a period of 122 days demonstrate that initial rates of whole tube decay are 10-100 times slower than usually found for fresh planktonic debris and aquatic macrophytes
despite a relatively low molar C:N ratio of ∼5.1. First order decomposition rate constants in oxic water, anoxic water and anoxic sediment are ∼0.76, ∼0.41 and ∼0.22 yr-1 for particulate tube carbon and ∼0.2, ∼0.1 and ∼0.1 yr-1
for particulate nitrogen, respectively (20°C). There are no obvious (under SEM) morphological changes in tube fibers during initial tube decomposition, implying slower long term rates. Although slow, tube decomposition stimulates bacterial activity in sediments from below ∼10 cm depth
where any organic matter present is even more refractory than the tubes themselves. In central Long Island Sound muds, tubes apparenlly account for a minimum of ∼0.6-1.8% and 2.8-8.4% of the steady state C and N detrital pools in the upper 10-30 cm of the sediment. C.
americanus tube production apparently accounts for ∼9% of the average particulate carbon and ∼12% of the nitrogen fluxes to the benthos. Tube construction by infaunal benthos may thus represent an important pathway for refractory compound formation and organic matter preservation.
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