Value-based pharmaceutical contracts (VBPCs) are performance-based reimbursement agreements between health care payers and pharmaceutical manufacturers in which the price, quantity, or nature of reimbursement is tied to value-based outcomes. As value-based payment models have permeated through much of the health care payment landscape via reimbursement to payers and providers, VBPCs offer opportunities for manufacturers to similarly engage in performance-based models.This article compares 2 VBPC schemes: “pay-for-failure” schemes, in which manufacturers offer rebates or discounts to payers for treatment failure, and “pay-for-success” schemes, in which manufacturers offer rebates or discounts to payers for treatment success. Each method has its own short-term and long-term trade-offs, and both lead to some degree of misaligned incentives between payers and manufacturers. These incentive differences have important downstream effects, influencing patient selection, provision of wraparound services, and nature of reimbursements. This analysis contrasts potential benefits and disadvantages for each of these approaches and offers potential solutions to address misalignment. For example, although pay-for-success models may be more aligned between payers and manufacturers, pay-for-failure contracts can be innovative and effective in controlling costs and/or improving outcomes. To illustrate, VBPCs aimed to reduce costs could incorporate total cost of care reduction as a value-based outcome.The authors encourage payers and manufacturers to consider a blended alternative where pay-for-failure and pay-for-success outcomes could be incorporated as VBPC outcomes. Since little is known about the effect of each scheme on outcomes, further research on VBPCs is necessary to fully understand how differing incentives ultimately affect clinical outcomes and costs. Furthermore, they can improve patient access to novel health care technologies. VBPCs have grown dramatically since 1997, with more than half of publicly disclosed VPBCs developed after 2015.4Value-based pharmaceutical contracts (VBPCs) are performance-based reimbursement agreements typically between health care payers and medical product manufacturers in which the price, quantity, or nature of reimbursement are tied to clinical, intermediate, or economic endpoints.These contracts, however, pose challenges. Factors affecting feasibility of VBPCs include meaningful outcome selection, transactional costs, administrative burden, limitations in data collection, agreement on contract details, determination of drug prices and associated rebates, and trust issues between payers and manufacturers. A particularly underreported challenge of VBPCs that does not exist in payer-provider value-based arrangements is the potential misalignment of incentives between payers and manufacturers. In payer-provider value-based payment models, where payers reimburse providers for better quality, incentives are more aligned towards complementary goals. When patient outcomes improve, providers directly benefit via value-based reimbursements, while payers benefit from decreased downstream utilization costs, as well as other desired outcomes such as patient satisfaction. Furthermore, providers and payers benefit from higher performance ratings on quality measures. With VBPCs, however, misalignment is introduced between short- and long-term incentives for payers and manufacturers.We illustrate such misalignment by examining 2 VBPC approaches: “pay-for-failure” and “pay-for-success” . Each me5 For example, Harvard Pilgrim has developed a VBPC for the Novartis heart failure drug sacubitril/valsartan (Entresto). If the heart failure-related hospitalization rate for sacubitril/valsartan users exceeds a predetermined threshold, Novartis pays Harvard Pilgrim an undisclosed amount as a discount.6 These traditional pay-for-failure contracts create misaligned incentives in 2 ways: (1) payers have opposing short-term and long-term incentives for drugs to perform well clinically, and (2) incentives vary between payers and manufacturers. In the short-term, payers receive rebates for unfavorable health outcomes in their enrollees , but this opposes the long-term benefit that payers achieve from their enrollees experiencing decreased heart failure-related hospitalizations as a result of sacubitril/valsartan use. On the other hand, manufacturers’ short- and long-term incentives are aligned: if their drug is effective, they pay fewer rebates to payers in the short term, and their respective drug can gain preferred formulary status and/or increased market share over time.Traditional pay-for-failure VBPC arrangements penalize manufacturers while rewarding payers via rebates when drugs perform poorly.7 In the latter example, those patients most likely to achieve benefit are also the population most likely to experience a fracture, and the manufacturer’s incentive would be to not seek them out. Payers engaged in pay-for-failure VBPCs for risedronate, on the other hand, do not have similar incentives to avoid use of risedronate in high-risk populations, since they receive rebates for adverse outcomes. This behavior may be in contrast with general strategies that payers might use to avoid risk among their enrollees independent of VBPCs, such as limiting specialist participation in provider networks or restricting member access to expensive drugs that treat rare or catastrophic conditions.As a result, pay-for-failure contracts incentivize manufacturers to behave differently than their traditional roles in 2 ways. First, pay-for-failure schemes ideally incentivize manufacturers to advocate for selecting patients likely to benefit from treatment . For instance, in the Health Alliance’s risedronate (Actonel) VBPC, the manufacturer reimburses the Health Alliance for health care costs resulting from fractures among risedronate users. From a patient selection perspective, this could be good or bad. If, in this case, the VBPC incentivizes the manufacturer to encourage patient selection focused on those who would be most likely to benefit from risedronate, that would be beneficial. However, the manufacturer might advocate for use of the drug in low-risk populations  or to avoid use in patients at highest risk for fracture.8An additional potential repercussion of pay-for-failure contracts is the manufacturer provision of wraparound services that promote medication adherence and care management around effective use of their medications. One such manufacturer-based wraparound program involved Abbvie’s anti-inflammatory disease-modifying medication adalimumab (Humira). In 2010, Abbvie began a patient support program to promote medication adherence, with a goal to improve clinical outcomes, diminish preventable health care utilization, and lower disease management costs. An industry-led publication reported that adalimumab users enrolled in a patient support program for ankylosing spondylitis had a 23% increased likelihood of controlled disease progression than adalimumab users who did not participate.Although manufacturer provision of wraparound services may benefit patients, there are issues of potential concern for payers. Wraparound services are traditionally a role led by providers, payers, and pharmacy benefit managers. Hence, there is a risk of unsynchronized duplicated care coordination efforts between payers and manufacturers when manufacturers provide patient support programs. Patients might be confused by the role of the manufacturer, and clinicians may not be aligned with the interventions provided. In addition, patients, payers, and providers may distrust manufacturers with a care coordination role, since this is a nontraditional purview for pharmaceutical companies. Specifically, there is concern that manufacturer provision of wraparound services may persuade patients to remain on high-cost drugs and hinder efforts to steer patients to lower-cost therapeutic alternatives, such as biosimilars or generics. Finally, it may be difficult for less established manufacturers to have resources to sustain these services.To better address the misalignment in traditional pay-for-failure VBPCs, an alternative pay-for-success approach has been implemented in which payers receive rebates for favorable rather than poor drug performance. In this alternative scheme, a manufacturer has differing short- and long-term incentives for its drug to be successful: When a drug successfully reaches positive outcome targets, its manufacturer is penalized in the short term by paying higher rebates to the payer. In the long term, manufacturers are rewarded when their drugs are successful by creating opportunities to increase their market share via formulary design strategies that optimize access to their drugs. Payer incentives, on the other hand, are aligned in pay-for-success contracts—in the short term, payers are rewarded for beneficial clinical outcomes through outcomes-based rebates, and in the long term, they may choose to promote drugs that demonstrate real-world effectiveness via VBPCs (long-term incentive is similar for pay-for-failure arrangements).In this scheme, payers are incentivized to optimize patients for success via wraparound programs that promote adherence and care management. Of note, similar to the mistrust that may occur when manufacturers provide wraparound services in pay-for-failure VBPCs, patients and providers may suspect that payer-based care management efforts may solely function to minimize short-term costs rather than optimize long-term clinical outcomes. In addition, this scheme also incentivizes payers, rather than manufacturers, to select patients likely to experience treatment success.9An example of a pay-for-success VBPC was implemented with Cigna and Merck for the diabetes medications sitagliptin (Januvia) and sitagliptin-metformin (Janumet). When sitagliptin and sitagliptin-metformin users experienced improvement in diabetes control as evidenced by reduction in A1c levels, and when medication adherence was demonstrated, discounts increased.The primary disadvantage of this alternative pay-for-success scheme is that manufacturers might be less incentivized in the short term to support wraparound programs and select patients who may succeed most, since better performance would result in higher rebates. This concern, however, is mitigated by the fact that wraparound services focused on those at risk in VBPCs may still be offered by providers, payers, and pharmacy benefits managers.10 The contract stipulates that the manufacturer provides additional reimbursements if TCOC is higher among empagliflozin users compared with other type 2 diabetes drugs.Incentive misalignment is inherent in pay-for-failure and pay-for-success VBPCs, and 1 scheme may be favored over the other depending on the disease, outcomes, and contract details. For many diseases, VBPCs that reward success may be philosophically desired over pay-for-failure schemes, since payers and manufacturers stand to benefit from the success of drugs. However, in some situations pay-for-failure VBPCs are innovative, and they should be considered if incentives are aligned for payers and patients. For instance, VBPCs that offer rebates to payers when total costs of care (TCOC), which include the cost of health services and medications, are higher than anticipated are a form of pay-for-failure VBPCs. However, TCOC-based contracts are particularly innovative , since for both payers and patients, lowered TCOC generally indicates better clinical outcomes. Furthermore, from the payer perspective, not receiving rebates would be preferred, since lowered TCOC would almost certainly offset any lost rebates from the VBPC that would have accrued had TCOC increased. For example, the UPMC Health Plan implemented a VBPC with Boehringer Ingelheim for the type 2 diabetes drug empagliflozin (Jardiance) that demonstrates how this metric can be used as a performance indicator for a VBPC.There is a dearth of literature assessing the effect of different types of VBPCs. In order to fully understand the effect of the different schemes on cost and clinical outcomes, these schemes must be studied further. Also, to rectify discordant pay-for-failure and pay-for-success concepts, we suggest further investigation into a “blended” approach to assess whether the drawbacks of both types of models could potentially be mitigated—payers and providers could consider multiple value-based outcomes in a VBPC, with some being pay-for-success and some being pay-for-failure. For instance, a VBPC for a diabetes drug could designate that payers receive rebates for improved diabetes control with A1c reduction (pay-for-success) and excess cardiovascular events (pay-for-failure). In this example, receiving rebates for A1c reduction encourages the payer to have a vested interest in the drug’s success in the short and long term but misaligns the manufacturer’s interests by creating an incentive for drugs to be less effective in the short term due to outcome-based reimbursements to the payer. By additionally incorporating cardiovascular events, the modified approach mitigates this misalignment by modifying the manufacturer’s short-term incentive to support the reduction of cardiovascular events. The effectiveness of such a contract would have to be tested to determine which incentives manifest.A limitation to our analysis of VBPC incentives (pay-for-success vs. pay-for-failure) is that we do not consider the magnitude of financial exposure of the manufacturer in these agreements. Because details of VBPCs are typically confidential, it is unknown whether there is truly enough “skin in the game” for manufacturers to be adversely incentivized in the examples previously mentioned. While we acknowledge this limitation, we posit that as VBPCs become increasingly viewed as a mechanism for improving the value of pharmaceuticals, careful consideration of the underlying philosophy of these contracts is important.There are various ways to develop incentive schemes linking patient outcomes to drug performance, but short-term and long-term incentives from the manufacturer and payer should be considered in contract development. A misalignment of incentives between the payer and manufacturer may lead to conflicting desires for a successful contract. VBPCs have had a difficult time gaining traction in the pharmaceutical space; in order to optimize the success of VBPCs, research is needed on the effect of different types of VBPC schemes on cost and clinical outcomes, and payers and manufacturers must be transparent about their incentives and work collaboratively to align them.


Closed incision negative pressure therapy (ciNPT) has been adopted into practices of diverse surgical specialties to help reduce postsurgical complication risks. There are two primary commercially available systems that deliver ciNPT through different mechanisms. The purpose of this meta-analysis is to compare the potential effects of two different ciNPT systems on clinical outcomes following hip and knee arthroplasty. A systematic literature search was conducted to identify hip and knee arthroplasty studies comparing the incidence of surgical site infections (SSIs) and surgical site complications (SSCs) versus standard of care (SOC) following the use of two different ciNPT systems. Four meta-analyses were performed by calculating risk ratios (RR) to assess the effect of (1) ciNPT with foam dressing (ciNPT-F) versus SOC and (2) ciNPT with multilayer absorbent dressing (ciNPT-MLA) versus SOC. Comprehensive Meta-Analysis Version 3.0  software was used to perform the analyses. Twelve studies comparing ciNPT-F to SOC and six studies comparing ciNPT-MLAto SOC were analyzed. SSI rates were reported in seven of 12 studies involving ciNPT-F. In those, ciNPT-F significantly reduced the incidence of SSI  = .190, .844; p = .016). Across four of six studies that reported SSI rates, there was no significant difference in SSI rates between ciNPT-MLAvs SOC . SSC rates were evaluated in eight of 12 ciNPT-F studies that reported SSC rates. This meta-analysis of the eight ciNPT-F studies showed significantly reduced SSC rates with ciNPT-F vs SOC . For ciNPT-MLA, five of six studies reported SSC rates. In those, there was no significant difference in SSC rates between ciNPT-MLA vs SOC . These meta-analyses results showed a significant reduction in SSI and SSC rates in the ciNPT-F group vs SOC and no difference in SSI and SSC rates in the ciNPT-MLA group vs SOC. The reasons for these observed differences were not evaluated as part of this study. Future controlled clinical studies comparing outcomes between different ciNPT systems over closed orthopedic incisions would help to validate these study results. Surgical site infections (SSIs) or other complications following total joint arthroplasty can result in significant morbidity for the patient and an enormous burden on the healthcare system. One study estimated that on average, SSI cases following primary knee replacement surgery cost eight times more than noninfected controls during the two-year follow-up period . StandarAppropriate surgical wound and incision management during postoperative care are important to prevent complications, including SSI and wound dehiscence. Particularly for patients at higher risk of postoperative wound complications, wound dressings can play a critical role in closed incisions. The use of closed incision negative pressure therapy (ciNPT) to postoperatively manage the closed surgical incision has been expanding, as evidenced by a growing body of literature describing its use in numerous fields of surgery. Applying ciNPT over closed incisions acts as a barrier against external contamination while removing excess fluid that may contain infectious materials. Depending on construction, it can decrease lateral tension and mechanically offload the incision by approximating the wound edges . A reducHowever, the results and reported endpoints, as well as the type of ciNPT system used, are mixed across published orthopedic studies evaluating ciNPT -9. ThereLiterature searchesTwo systematic literature searches were conducted to identify published studies that compared the effect of ciNPT vs standard of care (SOC) over closed incisions after hip or knee arthroplasty (KA). Public/Publisher MEDLINE (PubMed), Excerpta Medica dataBASE (EMBASE), and internal library QUOSA database were searched to identify relevant ciNPT-F studies, and EMBASE and Medical Literature Analysis and Retrieval System Online (MEDLINE) databases were used to identify relevant ciNPT-MLA studies published between January 2005 and July 2021. The QUOSA database was not used for the ciNPT-MLA literature search because it is an internal database; MEDLINE and EMBASE were selected to cover the best global ciNPT-MLA evidence.◊ Single Use Negative Pressure Wound Therapy System ) over closed incisions versus SOC following primary or revision knee or HA. Exclusion criteria included meta-analysis, preclinical studies, veterinary studies, pediatric patient population, non-comparative studies, or the use of non-ciNPT devices. There were no restrictions on the inclusion or exclusion criteria with respect to patient or surgical risk factors for complications or follow-up time. Studies were excluded if the ciNPT treatment arm included a mixture of ciNPT types/brands or if SSI/SSC rates were not reported by type/brand, as were studies that described the use of ciNPT with products other than the two devices.Inclusion criteria consisted of published abstracts or manuscripts written in English that compared the effects of one of two manufacturer’s ciNPT systems  or PICOTitles and abstracts of publications identified in the databases were logged. After removing all duplicates, titles and abstracts of each paper were read to assess eligibility. The remaining publications were read to ensure all inclusion criteria and no exclusion criteria were met. References from identified publications were also reviewed for relevant studies that fit the inclusion criteria.Data collectionOne reviewer completed data extraction from all eligible studies and a second reviewer validated the findings. Disagreements were resolved by discussion between the two reviewers or by the addition of a third reviewer. The following data were extracted from each study: funding source, bias assessments, study design, publication status, study date range, number of study sites, study location, surgical procedures, high-risk enrollment criteria (if applicable), study objectives, control type, number of treatment days, follow-up period, number of patients/incisions, number of patients/incisions analyzed, and definition of SSC. Patient outcomes data such as number of SSCs, SSIs, dehiscence, seromas, hematomas, skin necrosis, readmissions, reoperations, deaths, amputations, type of SSI, and length of stay were extracted.Risk of bias assessmentTo assess the randomized controlled trial (RCT) risk of bias, the Cochrane Collaboration’s tool, designating “low”, “high”, or “unclear” risk, was used. Each RCT study included in the meta-analysis was assessed for selection bias based on a randomization process and allocation concealment. Performance bias results were based on a blinded assessment of outcomes and attrition bias was assessed by “lost to follow up” and incomplete datasets. Reporting bias was determined by comparing reported results to endpoints defined in the protocol. The impact of studies with a high risk of bias was assessed related to their overall impact on results using the “one-study-removed” procedure; no assumptions were made to fill in missing data. Data were used in the analyses as reported.Statistical analysisPrimary grouping for analysis was based on the type of ciNPT device used. The endpoints evaluated were SSI rates and the reported composite SSC rates and were based on the availability of reported SSI and SSC endpoints. Further endpoint evaluations were not feasible due to the limited number of studies regarding ciNPT use post total knee or hip arthroplasty (HA).To assess the effect of ciNPT versus SOC on dichotomous variables, weighted risk ratios (RR) were calculated to pool study and control groups in each publication for analysis. Treatment effects were combined, and a random effects model was used to assess the mean effect of (1) ciNPT-F versus SOC and (2) ciNPT-MLA versus SOC for all endpoints evaluated due to the assumed variability in study populations and procedures.2 statistic was used to help assess heterogeneity. Fixed effects models were used for sensitivity analyses. Comprehensive Meta-Analysis Version 3.0  software was used to perform the analyses.Random effects models were used regardless of the heterogeneity assessments. Forest plots of the risk ratios were generated with all studies. The ISearch resultsThe ciNPT-F-related search yielded 610 citations after duplicates were eliminated. After removing studies that did not meet inclusion criteria, 84 papers were identified for further evaluation. Of these, 12 were specific to ciNPT-F application over KA and/or HA incisions  plus one added by reference search resulted in six ciNPT-MLA papers for analysis Figure .These 18 studies were included in the four meta-analyses. All studies with SSI and SSC incidence data were included in the related outcome assessments. Study characteristics and definitions of SOC for each of the studies are summarized in Table Four of the ciNPT-F studies were RCTs, two were prospective studies, and six were retrospective studies. Of the ciNPT-MLA studies, four were RCTs, one was prospective, and one was retrospective. The ciNPT-F vs SOC studies comprised 956 patients in the ciNPT-F cohort and 1,534 in the SOC cohort, and the ciNPT-MLA vs SOC studies comprised 487 in the ciNPT-MLA cohort and 622 in the SOC cohort. ciNPT-F studies took place primarily in the US (n=9), plus Germany (n=2), and Australia (n=1). Only one of the ciNPT-MLA studies took place in the US with the rest being from Italy (n=1), Australia (n=1), Brazil (n=1), and the UK (n=2).Arthroplasty procedures varied across the ciNPT-F studies and comprised primary TKA and/or THA, revision TKA and/or THA, unicompartmental knee arthroplasty (UKA), patellofemoral arthroplasty (UniPat), and hemiarthroplasty for femoral neck fractures. The ciNPT-MLA studies comprised revision and primary hip and KA patients.OutcomesIn the studies evaluating SSC, investigators reported overall SSC rates where SSC was defined as a composite endpoint that included multiple types of complications. The meaning of SSC was defined individually in each study. Types of SSCs included the following: SSI, suture granuloma, focal swelling/bullae, suture reaction/stitch abscess, skin necrosis, blistering, non-healing wound, post-operative antibiotics, edema/swelling, hyperemia, periprosthetic joint infection, seroma, hematoma, dehiscence, cellulitis, prolonged drainage and return to the operating room.Meta-analyses results are listed in Table Individual study results with the combined summary result are presented in forest plots for SSI rates in Figure Seven ciNPT-F studies reported SSI rates and were included in the meta-analysis. The weighted RR was 0.401  = .190, .844; p = .016) indicating a significant difference in SSI rates in favor of ciNPT-F. Four ciNPT-MLA studies reported SSI rates and were included in the meta-analysis. The weighted RR was 0.580  indicating no difference between ciNPT-MLA and SOC with respect to SSI rates.Eight of 12 ciNPT-F studies reported total SSC rates, and across the eight studies, the weighted RR was 0.332 . This indicates a significant difference in favor of ciNPT-F versus SOC. Five of six ciNPT-MLA studies reported SSC rates and the weighted RR was 0.798 , indicating no significant difference in SSC rates between ciNPT-MLA and SOC. For all SSI and SSC rate analyses, the results from the fixed effects model were consistent with the results of the random effects models.Of all studies analyzed for bias, only the Karlakki (2016) ciNPT-MLA RCT presented a high risk of bias. For all other types of bias analyzed, all other studies had a “low” or “unclear” risk of bias.While there was low heterogeneity in the ciNPT-F studies that reported SSI or SSC rates , there was higher heterogeneity across ciNPT-MLA studies, especially among those reporting SSC (I2 = 72.013). The heterogeneity could be due to the variation in study outcomes between the studies. All ciNPT-F studies reported a lower SSC rate versus SOC, with six of the eight studies reporting a significantly lower SSC rate. Hence, the low heterogeneity in ciNPT-F studies related to SSC outcomes.DiscussionPreventing SSI and other complications remains a significant ongoing concern for orthopedic surgeons due to cost and the growing numbers and complexities of patients seeking a joint replacement. In developed countries, between 2009 and 2019, the average number of hip replacements increased by 22% and the number of knee replacements by 35% , and hipTo date, this is the largest meta-analysis comparing clinical outcomes between two different ciNPT products in orthopedic surgery. The findings support our hypothesis of increased SSC and SSI reduction with ciNPT-F. The results also complement outcomes of a recently published meta-analysis by Elhage and colleagues (2022)  that demOf the seven ciNPT-F studies in this meta-analysis, five studies (Higuera-Rueda (2021), Cooper (2016), Curley (2018), Tyagi (2019), and Tyagi (2020)) reported a follow-up time in line with the CDC-recommended 90-day surveillance period for determining infections as specified for hip and knee prostheses. Follow-up time was 60 days for Redfern (2017) and 84 days for Newman (2017). One of four of the ciNPT-MLA studies (Helito 2020) followed the CDC-recommended ≥ 90-day surveillance period to determine SSI and the reported follow-up period for the other three studies ranged from 35 to 42 days. The greater variation in postoperative follow-up times among the ciNPT-MLA studies is aligned with the finding of greater heterogeneity across ciNPT-MLA studies, weakening the data quality compared to the ciNPT-F studies, with respect to the SSI endpoint. Overall, the results from ciNPT-F studies suggested greater reliability due in part to more consistent adherence to a 90-day follow-up period.Performance bias results were based on a blinded assessment of outcomes, which was unreported in all but the Karlakki (2016) study and therefore did not yield any strong conclusions. The high risk for reporting bias in the Karlakki (2016) study was a result of the number of analyzed surgeries (102 in the study group and 107 in the control group) being lower than the number of enrolled surgeries (n = 110) for each group. The Karlakki study was included in both SSI and SSC assessments. One-study-removed analysis indicated that this study did not change the overall results, but it did contribute to a positive trend for the ciNPT-MLA group when included.The Higuera-Rueda (2021) RCT is the highest-quality study included in the ciNPT-F analysis. It is a well-designed multi-site ciNPT-F study that showed that the primary endpoint of investigator-assessed 90-day occurrence of SSC was significantly lower in the ciNPT-F group versus the control group , demonstrating outcomes that are aligned with the results of this meta-analysis. Although a comparison of individual SSC types  between both cohorts in the Higuera-Rueda study did not show a statistically significant reduction within the ciNPT-F cohort, there was a positive trend for SSI reduction which contributed to overall lower rates of 90-day SSC in the meta-analysis.The findings from this meta-analysis have reinforced our institution’s practice of using ciNPT-F to manage closed incisions in high-risk total joint arthroplasty patients, with the goal of reducing their risk of SSC and SSI. Our current approach is to use ciNPT-F in most revision arthroplasty patients and, as described by Anatone (2018), a minority of primary arthroplasty patients who carry multiple risk factors for SSC or SSI.Still, several limitations may impact the results of this study, including the difference in population size between the ciNPT-F vs SOC group  and the ciNPT-MLA vs SOC group . In addition, the rate of revision total joint arthroplasty (TJA) is underrepresented in ciNPT-MLA studies compared to ciNPT-F studies. Different definitions of SSC and SSI across studies could also have affected the accuracy of the results. Also, the wide variance between the types of SSCs  as well as surgical procedure variances could limit the results. Results could be further limited by differences in study design, target populations, administrative methodology, and timing of outcome measurements. The available data were insufficient to conduct subgroup analysis of different types of SSCs, except SSIs. Clinical studies are recommended to determine the comparative outcomes between different ciNPT systems over closed incisions following TJA.We performed four meta-analyses to compare SSI and SSC rates with the use of ciNPT-F versus SOC or ciNPT-MLA versus SOC over closed incisions following HA and KA. The meta-analyses demonstrated a statistically significant reduction in the incidence of SSIs and SSCs in the ciNPT-F versus SOC group, but no significant difference in SSI or SSC rates in the ciNPT-MLA group compared to the SOC group.This is the first set of meta-analyses comparing the outcomes of two different types of ciNPT systems versus SOC in managing closed incisions following HA and KA. Results suggest there could be differences in SSC rates between types of ciNPT used, but considerably more study is needed to validate these outcomes.


Zr), meta-analysed and then re-converted to correlation coefficients. Egger’s regression presented no significant risk of bias. Vertical jump performance was not significantly affected by asymmetry , whereas COD and sprint both presented significant weak associations . The results demonstrate that inter-limb asymmetries seem to present a negative impact to COD and sprint performance but not vertical jump performance. Practitioners should consider implementing monitoring strategies to identify, monitor and possibly address inter-limb asymmetries, specifically for performance tests underpinned by unilateral movements such as COD and sprint performance.Inter-limb asymmetry refers to an imbalance in performance between the left and right limbs. Discrepancies throughout asymmetry research does not allow practitioners to confidently understand the effect of inter-limb asymmetries on athletic performance. Therefore, this review summarized the current literature using a meta-analytic approach, conforming to the Preferred Reporting Items for Systematic Review and Meta-Analyses guidelines to identify the association between inter-limb asymmetry and athletic performance. A literature search using PubMed, Web of Science and SPORTDiscus databases yielded 11-studies assessing the effect of inter-limb asymmetries, measured via unilateral jump performance, on bilateral jump, change of direction (COD) and sprint performance in adult sports players. The quality of evidence was assessed via a modified Downs and Black checklist and in compliance with the Grading of Recommendations Assessment Development and Evaluation. Correlation coefficients were transformed via Fishers z ( Asso12–0.75) , and the12–0.75) –28. ThusWhether inter-limb asymmetries translate to an effect on athletic performance remains unclear, with studies supporting , 9, 21, Despite the potential impact of asymmetries, there remains discrepancies in asymmetry research highlighting the lack of clarity for practitioners to understand the true effects of asymmetry on performance and the necessity for further research. Thus, the aim of this study was to systematically review and meta-analyse the available studies on the effect of inter-limb asymmetries on jump, COD, and sprint performance in sporting cohorts. A meta-analysis was conducted to summarise and statistically quantify the data from individual studies, to increase the statistical power of the study .This review conformed to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) 2020 guidelines . The folLiterature was screened in line with the inclusion-exclusion criteria below. Population, Comparator, Outcome and Study design was used to establish the parameters of which this review was conducted in accordance with PICOS.Studies included within the review used participants that were healthy men and women who were: aged 18–35 years; participated in a sport involving jumping, COD and/or sprinting, free from any injury or disability, and had not undergone surgery that may cause inter-limb asymmetry. No restrictions were given for training age or level.Studies that were included compared the associations between inter-limb asymmetry and jump, COD, and/or sprint performance between participants. All studies quantified asymmetry within the lower limbs via UCMJ, UDJ and/or unilateral squat jump (USJ) height, as these provide implications into asymmetrical physical qualities such as the stretch shortening cycle that underpin athletic performance and remain accessible and inexpensive .The primary outcome was to test the effect of inter-limb asymmetry on athletic performance. For the purpose of this review, athletic performance was defined as an individual’s jump, COD and sprint performance. All data were categorized into three individual performance measures; bilateral jumping (countermovement jump (CMJ), drop jump (DJ) and/or squat jump (SJ)), COD (no limit on the number of cuts/turns), and sprint performance.No specific study design was needed to be included within this review. Studies were considered for inclusion if they were: published in full, in a peer-reviewed journal; written in English or had a previously accessible translation to be retrieved; and had the primary or secondary aim to assess the effect of lower, inter-limb asymmetries on athletic performance. Dissertations, abstracts, and conference papers were excluded.A systematic literature search was conducted electronically by KTF, identifying all relevant articles using PubMed, Web of Science, and SPORTDiscus, from inception of the database until 22/03/2023. Search terms included keywords from relevant literature  and usedOnce duplicates were removed, two independent reviewers (KTF and LTP) conducted a two-stage screening process in line with the pre-determined inclusion-exclusion criteria , using tStudy quality was assessed independently by KTF and reviewed by LTP. Priori-study quality was determined via the Downs and Black  checklisData were extracted by KTF using a pre-piloted form, reviewed by LTP, to ensure all relevant study characteristics were extracted. If relevant data was limited, the authors were contacted and given six-weeks to respond and provide the appropriate material. If this information was not provided, the study was excluded from the meta-analysis. All raw data retrieved from the included studies and used for meta-analysis is available in the -1 compared to seconds; therefore, the correlation was reversed to fit the same correlation trendline for meta-analysis. Effect sizes were calculated using Fishers z (Zr) transformation where Zr and its standard error (SEz) were used for meta-analysis [Zr, was assumed to be random, hence the Hedges and Colleges random-effects method was employed. Heterogeneity was assessed via the I2 and Q-statistic where an I2 statistic output > 50% was considered a problematic amount of variability, in accordance with the Cochrane Handbook for Systematic Reviews of Interventions [P < 0.05. The exact overall effect size and its 95% confidence intervals (95% CI) were identified and reported. Eggers regression test of funnel plot asymmetry was employed to assess small study bias (publication bias). The overall estimate effect sizes, expressed as Zr, were re-converted to a correlation coefficient providing the relationship between lower, inter-limb asymmetries and athletic performance. The magnitude of estimate effect was determined in line with Cohens d thresholds, whereby an effect size was categorised as trivial (< 0.2), small (0.2–0.5), moderate (0.5–0.8) and large (> 0.8) [r-value) was considered very weak (≤ 0.19), weak (0.2–0.39), moderate (0.4–0.59), strong (0.6–0.79) or very strong (≥ 0.8).All data were extracted to an excel spreadsheet . All included studies employed observational designs, providing correlation coefficients. Data extracted across different performance measures or as different tests to assess the same performance measure  within the same study was included as its own entity and underwent the same statistical process. One study assessed COD and sprint performance via m.sanalysis , 45. Theventions . Forest  (> 0.8) . The str (> 0.8) , where tThe literature search and selection are presented in n = 11) was conducted via a modified Downs and Black [An assessment of quality for all included studies , of which 20-transformed effect sizes were provided, investigated the effect of inter-limb asymmetry on bilateral jump performance  although the Q-statistic was significant (P = 0.005). The overall estimate effect was insignificant .Seven studies (formance . The quan = 187), of which 37-transformed effect sizes were provided, investigated the effect of inter-limb asymmetry on COD performance . The overall estimate effect was significant, though the magnitude was small .Eight studies (formance . The quan = 211), of which 54-transformed effect sizes were provided, investigated the effect of inter-limb asymmetry on COD performance . The overall estimate effect was statistically significant though the magnitude was small .Nine studies  presented moderate quality and only two studies showed indirectness. However, emphasis is given on the inclusion of observational studies, thus the interpretation of these results should be done with caution.The lack of association between asymmetry and jump performance, aligns with previous research , 29–32, d = -0.96 to -1.40). However, the significant findings presented by Bishop et al. [Change of direction and sprint performance both had significant weak relationships with inter-limb asymmetry, indicating negative impacts to performance in the presence of asymmetry. These movements are more complex than jumping and, in addition to technique, rely heavily on reactive strength ability , the strp et al.  proposedp et al. , where jAs previously stated, COD ability incorporates independent use of each limb. This unilateral independence may explain why COD tasks are able to detect asymmetry, thus have previously been employed as an approach to quantify asymmetry between the left and right limbs, further rationalising the results of this review, that inter-limb asymmetries negatively associate with COD performance . HoweverDue to limited literature, sex and competition levels were pooled. As physiological- and sport-specific performance differs between men and women , and betConsidering the implications that the ability to change direction and sprint have on sporting-performance and talent identification, this review suggests that inter-limb symmetry might provide small beneficial effects to an individual’s athletic performance. This could inform athletes and practitioners on the potential importance of asymmetry monitoring, specifically for performance tests underpinned by unilateral movements, such as COD and sprint performance. This small association found could have been due to the small asymmetries identified within the included studies therefore futures research should investigate populations where larger asymmetry dysfunctions are present. It is important for practitioners to comprehend the specific needs of each individual athlete and the magnitude of the individual’s asymmetry. Additionally, to achieve this, practitioners could regularly assess and monitor asymmetries to provide an insight into their athlete’s movement proficiencies and dysfunctions.To conclude, the plausible effects of inter-limb asymmetries on athletic performance has recently been at the forefront of strength and conditioning research recently, however, an axiom conclusion has yet to be reached. Therefore, this study is the first systematic review with a meta-analysis to assess the association between inter-limb asymmetry and athletic performance. The data suggests that inter-limb asymmetries, quantified via unilateral jump performance, negatively impact COD and sprint, but not jump performance, in sporting cohorts.S1 Appendix(CSV)Click here for additional data file.S2 Appendix(CSV)Click here for additional data file.S3 Appendix(CSV)Click here for additional data file.S4 Appendix(DOCX)Click here for additional data file.S5 Appendix(DOCX)Click here for additional data file.


Para-aortic lymph node metastasis associated with colorectal cancer is a very rare occurrence, but at the same time an important predictor of survival. Despite its importance, there is still no gold standard management strategy, particularly for lymph nodes detected during follow-up, after resection of the primary tumour. Therefore, this review was undertaken to examine the evidence available on the surgical and non-surgical management of metachronous para-aortic lymph node metastasis (m-PALNM) in colorectal cancer treatment.This is a systematic review using the patient, intervention, comparison, outcome and study strategy. The literature search was undertaken using Cochrane, MEDLINE, EMBASE and PubMed databases with the following MeSH terms: lymph node excision, para-aortic lymph node, metastasis, metachronous and colorectal neoplasms.Five original papers met the study criteria including 188 patients in total . Surgical resection of the m-PALND was the management of choice in 64% of patients. Reporting styles on survival outcomes were heterogeneous. However, patients undergoing surgical management for m-PALNM had longer disease-free survival and overall survival rates.There is significant paucity in the evidence available on the management of m-PALNM. However, the evidence reported by this review suggests that surgical management should be considered whenever possible, with the aim of prolonging survival. Future randomised trials are needed in order to provide further high-level evidence on m-PALNM management. Para-aortic lymph node metastasis (PALNM) associated with colorectal cancer (CRC), unlike liver and lung metastasis, is a rare occurrence with incidence rates reported as < 2% . DespiteThere is still no clearly defined gold standard management strategy for PALNM. A significant contributing factor to this dilemma is the variation in definition of PALNM. According to the Japanese Society for Cancer of the Colon and Rectum PALNM is classified as regional or stage III disease , 3. On tPALNM may occur synchronously or metachronously, with synchronous PALNM (s-PALNM) resulting in more advanced disease at diagnosis, and poorer patient survival outcomes, when compared with metachronous PALNM (m-PALNM) . The lacResection of synchronous and metachronous CRC-associated hepatic or pulmonary metastases is now widely practised after significant evidence of improved survival and morbidity outcomes has been presented , 9. HoweEligibility criteria were determined using the population, intervention, comparison, outcome and study design (PICOS) strategy . The relPapers containing non-published series, papers not providing original data, papers not written in English, case series, case reports and expert opinions (levels IV and V evidence) were excluded. Other exclusion criteria were: editorials, letters, non-human studies, cadaveric studies and articles in which PALNM occurred concurrently with distant metastases.A literature search using Cochrane, MEDLINE, EMBASE and PubMed databases was conducted independently by one reviewer (OO) using MeSH terms: lymph node excision, para-aortic lymph node, metastasis, metachronous and colorectal neoplasms (“Appendix Para-aortic lymph nodes (PALNs) were defined as lymph nodes surrounding the abdominal aorta and inferior vena cava, which were located in the area from the uppermost part of the origin of the celiac trunk to the lower margin of the aortic bifurcation .Data were extracted on the following categories: study type, participant demographics, diagnostic modalities utilised, resection margins, primary tumour locations, tumour histology, additional therapeutic modalities utilised, surgery-related morbidity and mortality, overall survival, disease or recurrence-free survival/ interval, recurrence rates and recurrence sites.The risk of bias assessment was performed using the National Heart, Lung and Blood Institute’s (NIH) Quality Assessment Tool . The tooData were extracted to populate a pre-defined series of tables addressing the clinical characteristics described above.The protocol was reviewed by the research and development department of Central Manchester University Hospitals NHS Foundation Trust who stated that as there is no direct clinical contact, and therefore further ethics committee review was not required.The search strategy provided a total of 1897 results, which were critically reviewed for eligibility of inclusion , radiotherapy (RT) or a combination of both. CT and RT use was variable amongst the studies Table . CT regip = 0.049) and 42.5 vs 18.7 months  respectively [p = 0.603) and 77 vs 62 months  respectively.[23]Shibata et al. reported 2-year and 5-year OS rates for resected vs non-resected groups of 60% vs 20% and 15% vs 0% respectively [Reporting styles on survival characteristics were heterogeneous. Patients undergoing surgical management for m-PALNM had longer disease-free survival (DFS) and overall survival (OS) rates. Three of the studies compared survival between surgical and non-surgical cohorts. Table  Min et aectively . Kim et ectively . Time toThe NIH’s quality assessment tool for observational cohort and cross-sectional studies was utilised to assess the internal and external validity of the included studies. The overall quality was good for two studies and fair for the remaining three Table . All stu. described an increased survival rate amongst patients having radical paraaortic lymph node resection at the time of primary resection compared to those having targeted lymphadenectomy [Managing metachronous para-aortic lymph node metastases (m-PALNM) requires understanding of their prognostic significance, weighing up the risk of repeat resection and complications of surgery with overall survival, and comparing surgical management with systemic therapy. As isolated metachronous PALNM is a relatively rare pathology, there is no established treatment strategy. Synchronous resection of the primary tumour (s-PALNM) seems to be less controversial , 26–28. At the time of submission of this article, there were two very recently published review articles. Chen et al. reviewed both synchronous PALNM (s-PALNM) and m-PALNM articles . Their mThis present review is not free from limitations. The number of studies extracted from the literature search is rather small, and the overall study period ranges between 1988 and 2014. Treatment strategies have changed for both operative and non-operative management of metastatic colorectal cancer within this period. Surgical strategies for managing metastases from CRC have been more aggressive during the past two decades, and chemotherapy guidelines have changed not only in terms of timing and duration of treatment but also in terms of the recommended regimens, especially after the broad utilisation of biological agents . SecondlDespite the above limitations it is worth highlighting that resection of m-PALMN is reported to be a safe operation despite the fact that patients with recurrent disease undergo a second surgical procedure in a relatively short period after their colectomy. According to older reports, surgical resection for m-PALNM was thought to carry a high risk of complications , but thiMost importantly, this systematic review has demonstrated a significantly improved overall survival in patients undergoing surgical resection for m-PALNM compared to non-operative strategies. This is supported by three out of the five included studies, which compared survival outcomes between surgical and non-surgical management. Clear resection margins were reported in 88% of the cases, which is in keeping with the overall survival benefit observed after surgical management of m-PALNM.In conclusion, the available evidence, as reported by this systematic review, suggests that surgical management of m-PALNM should be considered a safe procedure aiming to prolong survival. Based on the so far reported outcomes, a future randomised trial would be a safe and ethical step forward to provide more evidence in this field, ideally in a multicentre setting due to the low incidence of m-PALNM. In the era of multimodality treatment for metastatic colorectal cancer, surgical management of isolated metachronous lymph node metastases definitely represents a considerable option in carefully selected patients.


Risk prediction rules are important to establish appropriate treatment and management strategy for patients with different risk classification of pulmonary embolism (PE). Neutrophils are considered to be related to PE as an essential marker of inflammation. However, few studies have reported the association between neutrophil levels and risk classification of acute PE (APE). The aim of this study was to investigate the role of neutrophil levels upon admission in the assessment of risk classification of APE.n = 233) and intermediate- and high-risk (n = 60) APE.A total of 299 consecutive APE patients and 90 patients without APE confirmed by computed tomographic pulmonary angiography were retrospectively screened. APE patients were stratified into two subgroups according to clinical guidelines: low- (P < 0.001). In multivariable logistic regression analysis, neutrophil levels were significantly and independently associated with intermediate- and high-risk APE . Neutrophil levels were positively correlated with the pulmonary embolism severity index score , high sensitive C-reactive protein, D-dimer and pulmonary artery obstruction index (PAOI), in the overall population of APE patients. Receiver-operating characteristic curve analysis revealed that neutrophils had a better diagnostic value for intermediate- and high-risk APE  compared to PAOI (AUC = 0.719) and D-dimer (AUC = 0.645).The neutrophil levels in intermediate- and high-risk APE patients were significantly higher compared to low-risk APE or non-APE patients (High neutrophil levels upon admission were significantly and independently associated with intermediate- and high-risk APE, which could be regarded as an indicator of inflammation and thrombosis in APE simultaneously. The potent diagnostic role of neutrophil levels and their competitive advantage over PAOI and D-dimer for the assessment of APE risk classification are suggested.The online version contains supplementary material available at 10.1186/s12959-023-00471-w. Pulmonary embolism (PE) is one of the manifestations of venous thromboembolism (VTE) together with deep vein thrombosis (DVT) . PE is cIn recent years, PE has been found to be accompanied by inflammation. Neutrophils are an essential indicator of inflammation that has been reported to be associated with PE. Elevated neutrophil and neutrophil–lymphocyte ratio (NLR) levels have been observed in patients with PE , 11. OurWe hypothesized that neutrophil levels strongly correlate with PE risk classification. Therefore, the present study sought to investigate the ability of neutrophil levels upon admission in determining the risk stratification of APE in comparison to other inflammatory and thrombotic markers of APE.We retrospectively screened 455 consecutive patients who were admitted to Fuwai Hospital  and underwent CTPA on admission prior to any therapy measures between October 2014 and November 2019. A total of 299 patients diagnosed with APE and 90 patients without APE were included in this study. The exclusion criteria were as follows: age of < 18 years; no available laboratory or clinical data; active infection; acute myocardial infarction; autoimmune diseases; inflammatory rheumatic disease; hematological diseases; severe renal or liver disease; other systemic inflammatory diseases; and trauma or recent surgery. Patients who received immune suppressant treatment, had a recent blood transfusion, or used anti-inflammatory drugs were also excluded in consideration of the potential effect on the level of total and differential leukocyte counts. The diagnostic criteria and risk stratification standard for APE were in accordance with the European Society of Cardiology (ESC) guidelines [CTPA was conducted for every subject to determine PE burden . Scans were carried out using a 64-row spiral CT . A total of 100 mL of contrast medium (Omnipaque-300) was injected into the elbow vein at a flow rate of 4 mL/s. Lungs were scanned from the base to the apex in the caudocephalic direction with the tube voltage of 120 kV during an inspiratory breath hold. The presence of thrombus and the thrombus burden were interpreted by two experienced radiologists specifically trained in thoracic imaging who were blinded to the echocardiographic and biochemical results. Imaging data were evaluated according to the Fleischner Society’s Glossary of Terms . The preVenous blood samples were drawn by strictly following a standard procedure at baseline before CTPA and prior to any therapy measures and then sent to the Laboratory Medicine Center of Fuwai Hospital for immediate testing. Routine blood tests including total and differential leukocyte counts, platelet (PLT) and hemoglobin (HGB) levels, and red cell distribution width (RDW) were performed using Sysmex XN 2000 automated hematology analyzer . Serum total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), high-sensitivity C-reactive protein (hsCRP), creatinine (CREA), aspartate transaminase (AST), and alanine transaminase (ALT) were assayed using Olympus AU-5400 biochemistry auto-analyzer . Plasma NT-proBNP was measured using a dedicated kit . D-dimer was detected using STA R Max automated coagulation analyzer . The NLR and PLR values were calculated according to neutrophil, platelet, and lymphocyte counts. The left ventricular ejection fraction (LVEF) and right ventricular diameter were determined according to the biplane Simpson rule via echocardiography.25-75) if the data had a skewed distribution. All data were analyzed using independent-samples t-test, one-way ANOVA, or the Mann–Whitney U-test, as appropriate. Categorical variables were expressed as number, n  and assessed by chi-square or Fisher’s exact tests. Bivariate correlation analysis was performed with Pearson or Spearman’s correlation analysis. Multivariate logistic regression analysis was performed to identify the independent association between the risk factors and intermediate- and high-risk APE. Receiver-operating characteristic (ROC) curves were used to evaluate the predictive value of variables for APE patients with intermediate and high risk. Youden’s index was calculated as sensitivity + specificity-1 to determine the optimal cut-off value. A double-sided P-value of < 0.05 was considered to be statistically significant.Statistical data analysis was performed using SPSS version 21.0 . The results were presented as mean ± standard deviation (SD) for continuous variables if the data were normally distributed or as median and interquartile range  and intermediate- and high-risk (n = 66) groups according to the ESC guidelines[P = 0.010). The prevalence of diabetes, hyperlipidemia, and coronary artery disease in the APE group was significantly lower than that in the non-APE group. However, there were no significant differences in the prevalence of the three diseases mentioned above between the two risk class APE groups. In the patients with intermediate- and high-risk APE, alcoholic drinkers accounted for a greater proportion than in low-risk APE patients . Higher heart beat levels, right ventricular diameter (RV), RV/LV, and PAOI (P < 0.001) and lower levels of systolic blood pressure  were also observed. When analyzing medications, the use of statin, aspirin, angiotensin II receptor blockers/angiotensin-converting enzyme inhibitors (ARB/ACEI), β-blocker, calcium antagonists, and diuretics did not exhibit significant differences between the two APE groups. However, non-APE patients used these drugs (except diuretics) more frequently compared to APE patients.The study population included 389 patients undergoing CTPA . Among the 389 patients, 299 patients were diagnosed with APE and 90 patients were included in the non-APE group confirmed by CTPA. APE patients were divided into low-risk (P < 0.001). The levels of neutrophils and other inflammatory and thrombotic markers according to clinical diagnosis and risk stratification are shown in Fig. According to the biochemical and hematological analysis results, significant increases in TC, LDL-C, NT-proBNP, and D-dimer levels were found in the APE group, especially in the intermediate- and high-risk APE patients. The inflammatory biomarkers, including white blood cells (WBC), neutrophils, monocytes, NLR, and hsCRP, were notably increased in patients with intermediate- and high-risk APE compared to low-risk APE or non-APE patients P < 0.00. The levP < 0.001). Furthermore, percentages of low-risk and intermediate- and high-risk APE patients in the whole APE cohort were calculated. As shown in Fig. P < 0.001). Patients with low-risk APE were more likely to be in tertile 1 and 2 groups (P < 0.001).In view of the predominant increase in neutrophil levels in the APE group, especially in the intermediate- and high-risk compared to low-risk APE group, the role of neutrophils in indicating APE risk classification became a noteworthy focus of the study. To investigate the association between neutrophils and APE risk classification further, APE patients were stratified into three subgroups according to neutrophil tertiles. Demographic and clinical characteristics of APE patients according to neutrophil tertiles are reported in Table P = 0.044), 1.239 , and 5.440 , respectively, whereas hsCRP and D-dimer were not significantly independent.Given the differences in neutrophil levels based on the APE risk stratification, three regression models were subsequently established to determine if the neutrophil level upon admission is a significant predictor for intermediate- and high-risk APE Table . As a rer = 0.357, P < 0.001), yet weakly correlated with RV/LV , in the overall population of APE patients , and thrombotic markers including D-dimer  and PAOI . It was also positively correlated with NT-proBNP , which has been suggested to be a laboratory APE biomarker in the guidelines. Despite that, hsCRP, D-dimer, PAOI and NT-proBNP were also significantly correlated with the PESI score, while neutrophil levels had the strongest correlation with the PESI score. Notably, there was a relatively stronger correlation between NT-proBNP and RV/LV  compared to the other clinical and hematologic biomarkers.Pulmonary embolism severity index (PESI) score, RV/LV and NT-proBNP have been recommended to be associated with APE risk classification. The correlation analysis of clinical and hematologic parameters including neutrophils, with those parameters associated with APE risk classification, was performed. Neutrophil levels were positively correlated with the PESI score (ts Table . FurtherP < 0.001). The optimal cut-off value for the admission neutrophil level to distinguish intermediate- and high-risk from low-risk APE was 6.0 × 109 cells/L. The AUC values for PAOI and D-dimer for intermediate- and high-risk APE were 0.719  and 0.645 , respectively.ROC curve analysis was performed to evaluate the diagnostic value of neutrophil level for intermediate- and high-risk APE Fig. . The diaPrior works have documented the role of neutrophils in inflammation –23 and tThe present study clarified that the admission neutrophil levels were significantly higher in APE patients than in non-APE patients, which was confirmed by CTPA. In recent years, the function of inflammation in VTE in addition to acute coronary syndrome has become a topic of investigation . The preImportantly, neutrophil levels in the present study exhibited an ascending trend in intermediate- and high-risk APE after risk stratification. In addition, a promising diagnostic performance of neutrophils was identified with increasing AUC, sensitivity, and specificity compared to PAOI and D-dimer. The markedly positive correlation between neutrophils and PAOI or D-dimer levels suggested a potential role for neutrophil levels in venous thrombogenic activity. D-dimer testing, which reflects the level of secondary fibrinolysis and detects the presence of venous thrombus, was used extensively in conjunction with clinical decision rules , 28. PAOIn addition to laboratory biomarkers and imaging indicators, a positive correlation between neutrophil levels and PESI score, a clinical parameter, was also observed. It can thus be implied that the neutrophil level simultaneously reflects the inflammation and thrombosis levels, thus presenting a promising diagnostic parameter for intermediate- and high-risk APE. In contrast, D-dimer and PAOI only indicate thrombosis, which lack information regarding the level of inflammation. D-dimer testing has a high negative predictive value in which a normal D-dimer level renders acute PE or DVT unlikely. However, D-dimer risk stratification ability is low, which was also observed in the present study. Accordingly, the association between PAOI and APE risk classification remains controversial. The present study adopted the Qanadli score to calculate the value of PAOI, concluding that PAOI is associated with APE risk classification, which is consistent with Mahmoud M. Higazi1 et al. results . In contNeutrophil level testing can be regarded as a cheap and widely available indicator of inflammation and thrombosis. The present study provides diagnostic implications for intermediate- and high-risk APE in order to better understand the function role of neutrophils in APE. This introduces a new insight into the clinical diagnosis of APE risk classification and addresses the important role of neutrophil level changes in the progression of APE. The internal mechanisms of elevated neutrophil levels and inflammatory response in APE patients need to be further explored. Overall, the presence of this association should not be ignored by the clinicians during objective APE risk stratification and therapy management for APE patients with different risk stratification. Furthermore, many times patients who come in with hemodynamic shock (or who develop it in the ICU) and are suspected of having a massive PE are not stable enough to go to the CT scanner for a CT angiogram. The clinician is then faced with making a risk: benefit decision of using systemic lytic therapy with tPA based on clinical suspicion for massive PE. Based on our study, it would be worth attempting to generate a predictive calculator for likelihood of a PE being present that accounts for neutrophil levels to improve clinical diagnosis in the absence of CT scans, which would be explored in the future study.This study has several limitations. First, this was a cross-sectional single-center study, which cannot provide prognostic information. Second, because neutrophil levels could be affected by active infections, autoimmune/rheumatologic diseases, hematologic diseases, and other systemic inflammatory disorders. To avoid the effect on it, we excluded patients with these diseases. Therefore, the conclusion drawn by this study could be applicable to those patients without these diseases, which might be the limitation of applicable population. Given the lack of specificity of neutrophil levels, which are often elevated in response to any physiologic stress (including moderate and brief exercise), a repeat study similar to this but including all patient populations may render the finding non-useful. For the same reason, many of the groups of patients who would be high risk for developing a PE were excluded in the first place. Thus, intermediate- and high-risk patients were combined into one group. Further studies in a larger population and a more detailed grouping are needed to verify these findings, for example whether neutrophils can distinguish high-risk from intermediate-risk APE. Third, we used the upper limit of D-dimer to describe out of range values due to the limitation of clinical assay. The data of D-dimer had a skewed distribution and Mann–Whitney U-test was used to analyze the difference of D-dimer levels among groups. Therefore, there was no impact on this result. We have also made sensitivity analysis to evaluate the impact on the other statistical analysis, in which patients with D-dimer > 20 ng/mL were excluded. Some important results were shown in Supplementary materials. It could be found that there was no obvious impact on P values, so the impact of D-dimer could be ignored. In addition, the study findings cannot be extrapolated to other ethnic groups. Therefore, the association between elevated neutrophil level and APE risk classification in other populations should be studied in the future.In summary, a high neutrophil level upon admission is significantly and independently associated with intermediate- and high-risk APE, which could be regarded as an indicator of inflammation and thrombosis in APE simultaneously. The potent diagnostic role of neutrophil level upon admission and its competitive advantage over PAOI and D-dimer for the assessment of APE risk classification, suggesting that it could be applied in clinics, including as part of a decision making pathway with regards to who gets a CTPA study or not and for QI analysis.Additional file1:Table S1. Regression analysis of clinical and hematologic parameters for prediction of intermediate- and high-risk APEa. Table S2. Correlation analysis of D-dimer with PESI score, RV/LV and NT-proBNP in APE patients. Table S3. Receiver operating characteristic (ROC) curve data for admission D-dimer and neutrophils for intermediate- and high-risk APE in the whole APE patient cohort.


The Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) is among the largest U.S. social safety net programs. Although strong evidence exists regarding the benefits of WIC, take-up  has steadily declined in the past decade. This study addresses gaps in our knowledge regarding predictors of WIC take-up during this time.Data were drawn from the 1998–2017 waves of the National Health Interview Study (NHIS), a serial cross-sectional study of the U.S. population. The analytic sample included 23,645 children and 10,297 women eligible for WIC based on self-reported demographic characteristics. To investigate predictors of WIC take-up, we regressed self-reported WIC receipt on a range of individual-level predictors  and state- level predictors  using multivariable logistic regression. In secondary analyses, results were additionally stratified by race/ethnicity, time period, and age (for children).For both women and children, older maternal age and higher educational attainment were associated with decreased take-up of WIC. Associations differed by race/ethnicity, time period, and state characteristics including caseload of other social programs .Our study identifies groups that are less likely to take up WIC benefits for which they are eligible, thereby contributing important evidence to inform programs and policies to increase WIC participation among groups with lower take-up. As WIC evolves past the COVID-19 pandemic, special attention will be needed to ensure that resources to encourage and support the participation of racially and economically marginalized individuals are equitably distributed.The online version contains supplementary material available at 10.1007/s10995-023-03728-y. What is already known on this subject? Among women and children eligible for the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC), take-up of services has been steadily declining since 2009.What this study adds: In this national, longitudinal study, we found differences in take-up by individual-level characteristics  and state-level characteristics . Given the increased needs for social support programs following the COVID-19 pandemic and our findings of disparate take-up of WIC benefits, special attention is needed to ensure that program accessibility is equitable.The online version contains supplementary material available at 10.1007/s10995-023-03728-y. The quality of perinatal and early childhood nutrition has consequences for lifelong chronic disease risk among women and children  is one of the largest U.S. safety net programs, and was established in the early 1970s to improve the health of low-income families. WIC provides food benefits, health education, and screenings/referrals for low-income pregnant and postpartum women and infants and children up to age 5. WIC serves approximately half of all infants, one fourth of all pregnant/postpartum women and one fourth of children aged 1–4 in the United States ; 1997–2018 NHIS; Data, Questionnaires and Related Documentation, Data were compiled from the 1998–2017 waves of the National Health Interview Survey (NHIS), a serial cross-sectional annual household survey representative of the U.S. population   age (5 categories ranging from under 25 to 40 or older), marital status (vs. not), educational attainment , employment status (employed in the past week vs. not); child age ; family size; inflation-adjusted household income; nativity (any immigrant in household vs. none); census region of residence ; and race/ethnicity. The latter was categorized into non-Hispanic White, non-Hispanic Black, Hispanic, and other, since other subgroups contained fewer observations that might result in unstable estimates. This variable was constructed based on two questions in the NHIS, which separately assessed Hispanic origin and race. Because the generosity of state programs such as Medicaid may be a good indicator of how well the state supports other safety programs like WIC, we included several state-level variables in this study. State-level characteristics were drawn from online governmental databases and the University of Kentucky Poverty Research Center  .Approximately half of likely WIC-eligible children (44.3%) and women 39.1%) reported receiving WIC Below is the link to the electronic supplementary material.


In addition to auxiological, clinical and metabolic features measurements of growth hormone (GH) and insulin-like growth factor I (IGF-I) complement our tools in diagnosis and follow-up of GH-related disorders. While comparably robust during the pre-analytical phase, measurement and interpretation of concentrations of both hormones can be challenging due to analytical issues and biological confounders. Assay methods differ in terms of antibody specificity, interference from binding proteins, reference preparations and sensitivity. GH assays have different specificity towards different GH-isoforms  and interference from the GH antagonist Pegvisomant. The efficacy to prevent binding protein interference is most important in IGF-I assays. Methodological differences between assays require that reference intervals and diagnostic cut-offs are assay-specific. Among biological variables, pubertal development and age are most relevant for IGF-I, making detailed reference intervals mandatory for interpretation. GH has pulsatile secretion and short half-life. Its concentration is modified by acute factors such as stress, exercise and sleep, but also by intake of oral estrogens and anthropometric factors (e.g. BMI). Other GH dependent biomarkers such as free IGF-I, IGF binding protein 3 (IGFBP 3) and acid labile subunit (ALS) have been proposed. Their concentrations largely mirror the information obtained through measurement of IGF-I, but their measurement can be helpful in particular situations. In this review, we describe the evolution of analytical methods to measure biomarkers of GH action, the impact of the methodological changes on laboratory results and the need to include biological variables in their interpretation. Arch Endocrinol Metab. 2019;63(6):618-29 In all growth hormone (GH) related disorders – GH deficiency (GHD), GH insensitivity and GH excess – GH and insulin-like growth factor-I (IGF-I) are the most important biomarkers used for diagnosis and during follow-up. Other parameters, such as insulin-like growth factor binding protein 3 (IGFBP 3) and acid labile subunit (ALS), can be useful in particular situations, but overall their diagnostic relevance is limited   , 2 . AlThroughout the last decades, GH and IGF-I assays evolved. Generally, assays have become more sensitive and specific. Nevertheless, significant differences in the results obtained from measurements by different laboratories or with assays from different manufacturers still are common   . In addThis review focusses on the analytical and interpretative aspects related to GH and IGF-I concentrations. We also describe less frequently used GH-related biomarkers. Suitability of specific stimulation and suppression tests and the respective diagnostic cut-offs have been extensively discussed elsewhere, and are not the primary focus of this article   - 8 .GH is a polypeptide hormone and a cytokine of the growth factor superfamily. GH is mainly expressed in somatotropic cells of the pituitary gland. It is secreted into the blood stream and mediates its effects via dimerized GH receptors in many tissues. GH in circulation consists of a variety of different isoforms, fragments and molecular complexes (homo- and hetero-dimers and oligomers)   . With oTo measure GH concentrations for clinical routine purposes, assays from different commercially sources as well as some in-house methods are being used. Most of the assays still recognize a broader spectrum of GH isoforms or have unknown isoform specificity. However, some of today’s routine assays have already incorporated recent recommendations and specifically detect the 22kDa isoform only   , 11 . Ath  for signal generation and amplification. Since the biotin intake in users of dietary supplements can lead to significant amounts of free biotin in blood samples, this can interfere with signal generation in the immunoassays. Depending on assay design, measured hormone concentrations become falsely high or falsely low. In sandwich type immunoassays, which are routinely used for GH (and IGF-I) measurements, biotin can lead to falsely low concentrations. Physicians should be aware of this potential source of interference when seeing implausibly low results for GH (and IGF-I) and ask their patients about recent use of nutritional supplements. An efficient and easy measure to overcome the biotin interference is stopping biotin intake 24 hours before drawing the blood sample.Another situation where interpretation of GH concentrations can be problematic is in pregnant females: Physiologically, the syncytiotrophoblast of the placenta takes a lead in secreting a variant of GH, named GH-V. In turn, pituitary GH secretion is suppressed through the increase in IGF-I, induced by high tonic GH-V secretion. Depending on the antibody used in the local GH assay, cross-reactivity can lead to falsely high GH concentrations. If there is a need to asses GH secretory status during pregnancy, it is mandatory to use an assay without cross-reactivity with GH-V   . NotablFinally, in patients who are treated with the GH antagonist pegvisomant, GH concentrations, as measured by most commercially available assays, are unreliable. Depending on the binding site of the antibody, pegvisomant can lead to falsely high or falsely low GH concentrations. Based on published information, there is only one commercially available GH assay that does not cross-react with pegvisomant and therefore can be used to investigate GH secretory status in the respective patients on treatment   .The 20kDa GH isoform does not play a role in routine diagnostics, and there is no assay to measure 20kD GH which is commercially available. However, assays specific for 20kD GH have been established in research labs. Some groups have reported that the 20/22kDa ratio is elevated in patients with acromegaly. Furthermore, it has been shown that 20kD GH decreases after injection of recombinant 22kD GH, making a 20kD GH assay potentially useful in doping analyses   , 31 .Some of the effects of GH are direct effects, but the majority is mediated via IGF-I. IGF-I is a smaller polypeptide hormone (molecular weight 7.66 kD) that shares structural similarities with insulin. It is synthesized in many tissues but mainly in the liver. Binding of GH to the pre-dimerized GH receptor induces a conformational change which triggers intracellular signaling and, subsequently, IGF-I synthesis and release   . In conWhile rather stable during shorter time-periods, IGF-I exhibits a strong age-related secretion pattern: Concentrations decline immediately after birth, but start to increase after the first year of life   . The peth ( The first radioimmunoassays for IGF-I (somatomedin-C) were developed in the 1970th   . Similath   . The math   , 39 . Ath     4 ).  . th .They must be established based on transparently described, well-characterized large cohorts representing the “normal” background population, and include an appropriate number of subjects of all age groups and from both sexes.th and 97.5th percentile) have to be reported in mass units, and an approach to convert IGF-I concentrations to standard deviation scores (SDS) or z scores must be provided.The lower and upper limit of normal , parametric method or the LMS approach   - 52 .th percentile) is significantly higher in both sexes, and the IGF-I peak occurs earlier in girls, if evaluated according to Tanner stages rather than chronological age  and proposed IGFBP-3 as a superior maker in that age group   . This oIGF-I assays used in clinical routine measure total IGF-I, which in most cases is reasonable to assess the GH-IGF-I axis. Only in specific clinical conditions where concentrations of binding protein concentrations can be significantly altered , total IGF-I might no longer be the most reliable biomarker   . In sucIGFBP 3 is the most abundant IGF binding protein and – since its synthesis is also stimulated by GH - is used itself as a biomarker of integrated GH secretion   . The agAs mentioned above, some advantage has been demonstrated especially in in young children (<3 years), where IGFBP 3 correlates well with integrated GH secretion, and seems more sensitive than IGF-I in the diagnosis of GHD   , 73 . TALS is another protein which is synthesized in a GH-dependent manner in the liver, and which in circulation becomes part of the ternary complex with high affinity for the binary IGF-I/IGFBP 3 complex     Figur . It hasAlpha soluble klotho is mainly expressed in the kidney and the choroid plexus, but to a lesser extend also in the pituitary gland   . It hasApproximately half of the circulating GH is bound to GHBP, which resembles the extracellular domain of the GHR   . In casMeasurements of different biomarkers have been proposed for the diagnosis of diseases related to the GH-IGF-I axis, as well as for monitoring of therapy. Currently, IGF-I is considered the most important and reliable surrogate parameter reflecting GH secretory status, and its measurement is recommended in the guidelines for acromegaly and GHD. Measurement of integrated, stimulated or suppressed GH is used as the most important confirmatory parameter. Measuring GH and IGF-I in blood samples is not without pitfalls, and laboratories are requested to only use methods which have been proven to adhere to recent guidelines. Calibration, removal of binding protein interference, long-term stability of assay performance and quality of method-specific reference intervals or cut-offs are critical aspects of GH and IGF-I assay quality. Obviously, meaningful interpretation of data is also possible only when the biological variability and a wide variety of potential confounders of both parameters are taken into account. Determination of other parameters such as IGFBP-3, ALS, alpha soluble klotho and GHBP have not been shown to add significant information in the majority of cases. However, their measurement might be useful in certain age groups, in diagnostically ambiguous cases or in the diagnostic workup of rare genetic diseases.


PMIndoor that addresses these two challenges. We use multiple loss functions to constrain the depth estimation for non-textured regions. We introduce a pose rectified network that only estimates the rotation transformation between two adjacent frames of images for the camera pose problem, and improves the pose estimation results with the pose rectified network loss. We also incorporate a multi-head self-attention module in the depth estimation network to enhance the model’s accuracy. Extensive experiments are conducted on the benchmark indoor dataset NYU Depth V2, demonstrating that our method achieves excellent performance and is better than previous state-of-the-art methods.Self-supervised monocular depth estimation, which has attained remarkable progress for outdoor scenes in recent years, often faces greater challenges for indoor scenes. These challenges comprise: (i) non-textured regions: indoor scenes often contain large areas of non-textured regions, such as ceilings, walls, floors, etc., which render the widely adopted photometric loss as ambiguous for self-supervised learning; (ii) camera pose: the sensor is mounted on a moving vehicle in outdoor scenes, whereas it is handheld and moves freely in indoor scenes, which results in complex motions that pose challenges for indoor depth estimation. In this paper, we propose a novel self-supervised indoor depth estimation framework- Through the visual system, humans acquire information about the external world and can perceive and judge the surrounding environment accurately. Computer vision technology, which aims to enable computers to have the ability to perceive the external environment like humans, has become a significant topic in the current field of computer research. Depth estimation is a very important problem in the field of computer vision, and it has a wide range of applications, such as intelligent robots , 3D recoIn recent years, some indoor depth estimation methods have also emerged. Zhou et al.  proposedPMIndoor, a self-supervised monocular depth estimation framework, as shown in 2net [PMIndoor outperforms many previous state-of-the-art methods.In this paper, we propose  in 2net , which u in 2net : Manhatt in 2net , the aut in 2net , and theWe propose a new pose rectified network (PRN) to solve the camera pose problem, while also using the pose rectified network loss to remove the rotational motion between adjacent frames.We use multiple loss functions, such as patch-based multi-view photometric consistency loss, Manhattan normal loss, and Co-planar loss, to solve the problem of non-textured regions.We add multi-head self-attention (MHSA) modules to the depth estimation network to improve the expression and generalization of the model.PMIndoor outperforms many existing state-of-the-art methods.The experimental results on the indoor benchmark dataset NYUv2  demonstrOur contributions can be summarized as follows:PMIndoor proposed in this paper. We first provide an overview of our framework. Then, we explain three core components: depth estimation network, pose rectified network, and multiple loss functions, in detail.In this section, we introduce the self-supervised monocular depth estimation framework The self-supervised monocular depth estimation framework for indoor scenes designed in this paper is shown in Q), key (K), and value (V), and are fed into the MHSA module for training, as illustrated in The depth estimation network used in this paper is based on the U-Net architecture, a typical encoder–decoder network. The basic structure follows Monodepth2 , and skiWe also follow the same practice as Monodepth2  regardinThis paper introduces the pose rectified network (PRN), which aims to eliminate the rotational motion between consecutive frames and improve the model accuracy for the camera pose problem. The SC_Depthv2  mathematThe pose rectified network (PRN) has a similar structure to the pose estimation network, a simple encoder–decoder network, employed in SC_Depthv2 , but we We adopt multiple loss functions ,20,22,242Net [N is set to 3. Then, based on this, the improved photometric consistency loss function isOur loss function is based on the photometric consistency loss, a general loss function of self-supervised learning, which uses reprojection to calculate the reprojection error. However, unlike the common loss function in self-supervised learning, we adopt a new image patch-based photometric consistency loss function proposed in P2Net . This meIndoor scenes often contain large non-textured regions, which pose a significant challenge for depth estimation. These regions can lead to photometric consistency loss problems and ineffective mismatching. To address this issue, we incorporate the Manhattan normal loss and Co-planar loss proposed in Structdepth . The Manuctdepth  for planuctdepth  to segmeAccording to the theory and method in SC_Depthv2 , which wSimilar to the general unsupervised depth estimation methods, we use the edge-aware smoothness loss function proposed in  to ensurTherefore, we can obtain the final loss function form by combining the following loss functions: image patch-based photometric consistency loss, Manhattan normal loss, Co-planar loss, PRN loss, and edge-aware smoothness loss. Different loss functions are used to deal with different problems, as described in the previous sections. Image patch-based photometric consistency loss, Manhattan normal loss, and Co-planar loss are used to handle the non-textured regions problem, and PRN loss is used to handle the camera pose problem. The final loss function can be written as follows: uctdepth  and SC_Ductdepth , and the2Net [We use P2Net  without 2Net , which i2Net  optimize2Net , i.e., ted model . We empled model , which sWe use the NYUv2  dataset,We use two types of evaluation metrics for depth estimation: error and accuracy metrics. The error metrics consist of the root mean squared error (RMSE), mean log10 error (Log10), and absolute relative error (AbsRel). The accuracy metric is the accuracy under the threshold  and the multi-head self-attention (MHSA) module. First, we perform experiments without using the PRN and MHSA module as a baseline. For all the experiments, we use all the proposed loss functions except for the PRN loss. The results are presented in To assess the effectiveness of the proposed PRN loss and the impacts of Manhattan normal loss and Co-planar loss, we perform ablation experiments using the same network architecture, namely adding the PRN and MHSA module to the original network framework. The results are shown in Depth estimation is the process of recovering the depth information of a three-dimensional scene from a single or multiple two-dimensional images. It is an essential component for many applications such as autonomous driving, augmented reality, three-dimensional reconstruction, etc. These applications often demand real-time performance, which requires depth estimation models to be able to produce accurate depth maps with high efficiency. In order to assess the real-time performance of our proposed model, we perform a frame rate (FPS) test and compare it with several other state-of-the-art depth estimation methods. The test results are presented in As shown in the table, our model attains a remarkable frame rate of 55.2 FPS, which makes it feasible for real-world applications. In contrast, the Monodepth2  method lPMIndoor, which mainly consists of three modules: (a) Pose Rectified Network (PRN): we introduce a Pose Rectified Network (PRN) before the pose estimation network to remove the rotational motion between adjacent frames, which can obtain more accurate pose estimation results and solve the camera pose problem. (b) Multiple Loss Functions: we employ multiple loss functions  to simultaneously address the camera pose problem and non-textured regions. (c) Multi-Head Self-Attention Module: the Multi-Head Self-Attention Module (MHSA) can enable the model to focus on multiple key regions at the same time, enhancing the ability of capturing features at different positions and scales in the image, and improving the expressive and generalization ability of the model. We incorporate the Multi-Head Self-Attention Module (MHSA) into the depth estimation network to improve the accuracy of the model. Experimental evaluations demonstrate the superior performance of our method.In this work, we propose a novel indoor depth estimation framework