Chronic lymphocytic leukaemia (CLL) is a malignancy of clonally expanded antigen-switched, neoplastic, mature B cells. CLL is characterised by a variable degree of immunosuppression and secondary hypogammaglobulinemia. B-cell depleting therapies have historically been deployed with a proportion of patients becoming resistant to multiple lines of treatment with an associated worsening of immunosuppression and heightened infection risk. Advances in molecular diagnostics and the development of new therapies targeting Bruton’s tyrosine kinase and B-cell lymphoma-2 have resulted in novel insights into the cellular mechanisms associated with an increased infection risk and T-cell escape from the complex tumour environment found in CLL. Generally, immunoglobulin replacement therapy with polyvalent human immunoglobulin G (IgG) is indicated in patients with recurrent severe bacterial infections and low IgG levels, but there is no consensus on the threshold IgG level for initiation of such therapy. A proportion of CLL patients have residual IgG production, with preserved quality of the immunoglobulin molecules, and therefore a definition of ‘IgG quality’ may allow for lower dosing or less frequent treatment with immunoglobulin therapy in such patients. Immunoglobulin therapy can restore innate immunity and in conjunction with CLL targeted therapies may allow T-cell antigen priming, restore T-cell function thereby providing an escape from tumour-associated autoimmunity and the development of an immune-mediated anti-tumour effect. This review aims to discuss the mechanisms by which CLL-targeted therapy may exert a synergistic therapeutic effect with immunoglobulin replacement therapy both in terms of reducing tumour bulk and restoration of immune function. Chronic lymphocytic leukaemia (CLL) is the most common form of leukaemia in the Western World, with around 4700 new cases diagnosed each year in the United Kingdom . CurrentThe inherent disease-related immune dysfunction along with secondary hypogammaglobulinemia, decreased cell-mediated immunity (T-cell dysfunction), and immunosuppression related to B-cell directed therapies are the major causes of the increased susceptibility to infection in CLL. Finally, although the mechanism of CLL-associated hypogammaglobulinemia is largely unknown, factors such as T-cell dysfunction and the abnormal cytokine environment  may affect immunoglobulin production .Current guidelines recommend immunoglobulin replacement therapy (IgRT) to reduce the risk of bacterial infections and hospitalization in patients with recurrent severe infections and low immunoglobulin G (IgG) levels . In addiin-vitro studies showing an associated decrease in the survival of CLL cells  along with effects on invariant-natural killer T-cells (iNKT) and alterations in serum IL-2 and TNF-α , 8. WhetLL cells . AlthougIt is a general characteristic of malignancies that the cancer cell manipulates the immune system to the advantage of the tumour, and CLL is no different in this respect.9/L B-cells in the circulation. Progression of MBL to CLL is characterized by continuous clonal evolution with the acquisition of high-risk genetic driver mutations that may lead to symptomatic disease  characterized by the co-expression of CLL-like surface markers  with less than 5 x 10 disease .IGHV 4-34, 3-23, 1-69 as well the expression of highly stereotypic BCRs (IGHV) genes indicative of pre-germinal centre CD5+ B-cells, mutations in TP53, Ataxia-Telangestasia Mutated (ATM), DDX3X, NOTCH1, spicing factor 3b subunit 1 (SF3B1) genes are all associated with high-risk disease. In contrast, deletions of chromosome 13q and highly mutated IGHV genes  are associated with a favourable prognosis . Such a reduction in immunoglobulins is present in up to a third of persons with CLL at diagnosis, and a further third develop hypogammaglobulinemia as the disease progresses, or because of administered therapy . Of notevs 7.4 years)  . Of noteIGHV mutation status or Rai stage  or del(11q22.3)  . It is e11q22.3) . In addiIt is generally agreed that persons with CLL with significant hypogammaglobulinemia characterized by an IgG of less than 4g/L, in the presence of recurrent or severe bacterial infection despite antibiotic prophylaxis, are candidates for long-term IgRT . IgRT isWhilst prophylaxis with IgRT was effective in an early study of patients with recurrent severe infections and a serum IgG<3g/L, a crossover study found that restoration of serum IgG levels did not parallel a decrease in the number of severe infectious episodes , 41. ThiA systematic review and meta-analysis of randomised-controlled trials of immunoglobulin prophylaxis concluded that although IgRT use in lymphoproliferative disorders and plasma cell dyscrasias does not provide a survival benefit such therapy does prevent major infections with decreased numbers of infections . HoweverDuring the past decade, the utilisation of BTKi for CLL treatment has grown rapidly, radically changing the treatment landscape of this disease. Both innate and adaptive immunity may be impacted by BTKi treatment. Ibrutinib, the first-in-class BTKi, induces a partial restoration of normal B-cell numbers and humoral immunity during the first two years of therapy. Improvements in serum IgA in BTKi-treated persons were inversely correlated with the infection rate. Acalabrutinib is a newer, more selective BTKi; however, the effect of this agent on humoral and cellular immunity is similar to that observed with ibrutinib and translates into a partial humoral immune reconstitution with a decreased risk of infection, although a degree of immunodeficiency likely persists.These data pertaining to BTKi-induced immune reconstitution suggests that a reassessment of immunoprophylaxis with IgRT is needed in the era of targeted agents with regards to the timing of discontinuation of IgRT after immune reconstitution is achieved. Studies of infection and immune reconstitution in BTKi-treated persons should also employ uniform definitions of infection severity, and patient-reported outcomes.IGHV genes, adverse cytogenetic features or a complex karyotype), or the presence of exhausted T-cell phenotype. Some of these are in-vitro findings and require specialised laboratories so therefore may not be routinely available. Prospective studies comparing an earlier versus delayed IgRT usage should clarify the optimal timing of the initiation of IgRT therapy in CLL.The prevailing paradigm underpinning current guidelines of IgRT usage in CLL is that such an approach should be deployed in those patients with reduced serum IgG levels and one major infection. However, the first major infectious episode could be fatal, especially in certain patients. This implies that a pre-emptive treatment could be offered to selected patients. In It has been shown that scIgRT is safe, efficacious, and well tolerated when compared to intravenous IgRT (ivIgRT), providing patients with primary or secondary immunodeficiency disorders with an alternative route of Ig administration , 50. SomAlthough limited to few retrospective analyses, the results of efficacy and safety analyses suggest that scIgRT should be preferred in clinical practice for persons with CLL and symptomatic hypogammaglobulinaemia.The financial cost of IgRT is significant due to high procurement costs and indefinite usage. Unnecessary and indiscriminate use of IgRT could result in product shortages, adverse outcomes and higher healthcare costs. Keegan and colleagues reported on the demand, supply, and patterns of utilisation of IgRT in CLL in Australia and revealed a sustained increased usage of 5.5% per annum but with significant regional variation across geographical areas .Numerous other studies have demonstrated that scIgRT compared to ivIgRT results in reduced resource use and is therefore more cost effective. A study comparing the cost-effectiveness of scIgRT and ivIgRT suggests that significant cost savings could be made with a subcutaneous formulation as opposed to an intravenous preparation . A CanadAnother approach to maximise cost-effectiveness is to de-escalate or withdraw IgRT when this approach is no longer necessary. Current guidelines do not provide clear advice with respect to the timing and indications for safe IgRT discontinuation. Therefore, in the absence of evidence-based recommendations for IgRT discontinuation clinical expertise and medical judgment should guide decision making. A reasonable approach could be a gradual IgRT discontinuation at one-year in patients with history of underlying disease in remission, a normal IgG trough level and evidence of immune reconstitution if CLL-directed therapy has been deployed. Following discontinuation, the criteria for the recommencement of IgRT should be the same as those for the primary indication.There is a need therefore to develop a clinical trial wherein the efficacy, safety of IgRT replacement is compared with less costly prophylactic oral antibiotics in persons with CLL with secondary hypogammaglobulinemia.IgRT is administered at distinct dosage in two different clinical contexts:- immunodeficient patients are treated with replacement doses of immunoglobulin, typically 0.2-0.4g/kilogram every 3 to 4 weeks whilst patients with autoimmune and inflammatory diseases are administered with very high doses of IgRT such as 0.5-2g/kilogram often over a single, or several days . In CLL,in vitro by BCR ligation  preparation which includes all immunoglobulin isotypes, versus standard preparations which contained only IgG, on leukemic and T-cells obtained from CLL patients (in-vitro cultures decreased venetoclax-induced T-cell apoptosis, this did not affect CLL-cell apoptosis in response to this drug. This may indicate an intrinsic CLL-cell resistance to apoptosis in the presence of IgRT and is perhaps supportive role of BTKi therapy as opposed to BCL-2 inhibition in CLL patients treated with IgRT.Spaner et al. showed that scIgRT preparations have the ability to impair BCR signalling, activation, and cytokine secretion by CLL-cells when stimulated ligation . This Igpatients . This stColado et al. also showed that the proliferation of T-cells from persons with CLL in response to TCR-stimulation or IL-15 was differentially affected by two different immunoglobulin preparations . There wIn conclusion, in the era of targeted therapy, IgRT should be offered to CLL patients as suggested by current guidelines . HoweverProspective studies to assess the cost-effectiveness of IgRT and the impact on quality of life for persons with CLL are required. Furthermore, long-term IgRT for persons with CLL may not be necessary therefore a systematic approach to IgRT discontinuation is needed. Expert opinion suggests that IgRT could be discontinued after six months without an infection in the presence of evidence of immune reconstitution.Finally, the successful navigation of the complex TME in CLL and the development of an understanding of the disease- and treatment-related immunosuppression is a significant challenge, but the development of BTKi has permitted fascinating insights into immune escape mechanisms present in CLL patients. We suggest that a mechanism of immunomodulation with a combination of B-cell-directed therapies and polyclonal immunoglobulin in high-risk CLL is possible and worthy of future investigation. Such combined modality immunomodulation could represent a novel therapeutic approach for CLL treatment.SK conceived the idea and wrote the main body of the paper. DA and SM directed, reviewed, and revised the manuscript. All authors contributed to the article and approved the submitted version.


With increasing knowledge of immunologic factors and with the advent of potent immunosuppressive agents, the last several decades have seen significantly improved kidney allograft survival. However, despite overall improved short to medium-term allograft survival, long-term allograft outcomes remain unsatisfactory. A large body of literature implicates acute and chronic rejection as independent risk factors for graft loss. In this article, we review measures taken at various stages in the kidney transplant process to minimize the risk of rejection. In the pre-transplant phase, it is imperative to minimize the risk of sensitization, aim for better HLA matching including eplet matching and use desensitization in carefully selected high-risk patients. The peri-transplant phase involves strategies to minimize cold ischemia times, individualize induction immunosuppression and make all efforts for better HLA matching. In the post-transplant phase, the focus should move towards individualizing maintenance immunosuppression and using innovative strategies to increase compliance. Acute rejection episodes are risk factors for significant graft injury and development of chronic rejection thus one should strive for early detection and aggressive treatment. Monitoring for DSA development, especially in high-risk populations, should be made part of transplant follow-up protocols. A host of new biomarkers are now commercially available, and these should be used for early detection of rejection, immunosuppression modulation, prevention of unnecessary biopsies and monitoring response to rejection treatment. There is a strong push needed for the development of new drugs, especially for the management of chronic or resistant rejections, to prolong graft survival. Prevention of rejection is key for the longevity of kidney allografts. This requires a multipronged approach and significant effort on the part of the recipients and transplant centers. Our understanding of the role of the immune system in allograft survival has evolved immensely since the first human-to-human kidney transplant in 1933 which failed promptly due to acute rejection . HoweverA large body of literature implicates acute rejection as an independent risk factor for graft loss ,7,8,9,10The human leukocyte antigen (HLA) system is a complex set of highly polymorphic antigens that are responsible for immune activation by antigen presentation and recognition of ‘self’ and ‘non-self’. Although >25,000 HLA alleles have been identified, only 60 to 70 of the most frequently occurring alleles are considered when determining compatibility for organ transplantation . Mismatcp = 0.019) [The benefit of better HLA matching in reducing acute rejection risk has been repeatedly demonstrated. Compared to a 0 HLA mismatch, any increase in total burden of HLA mismatches at the HLA-A, B, DR loci is associated with an incremental rate of rejection  and over= 0.019)  to prediFor deceased donor organ recipients, while the degree of HLA mismatch is not modifiable, this information can certainly guide induction immunosuppression therapy (discussed later), as well as allow the individualization of maintenance immunosuppression to minimize kidney transplant rejection. However, in the scenario of a living donation where there are multiple potential donors, the donor with the lowest antigen mismatch load may be selected preferentially. Transplant centers are increasingly enrolling HLA compatible living donor pairs in the kidney-paired donation program. A multi-center study demonstrated that 26.9% of otherwise compatible pairs enrolled in such a program and more than half successfully received an equivalent or better match . Severalp < 0.001) and increase the risk for graft failure  [Approximately 20% of the kidney transplant recipient pool is ‘sensitized’, which refers to the presence of antibodies against commonly found HLA antigens that may be donor-specific and may render the donor and recipient HLA-incompatible. Common reasons for HLA antibody development include prior blood transfusions, multiple pregnancies and prior organ transplantation . Presenc = 0.01) .However, in the case of highly sensitized patients (cPRA > 98%) that have a potential living donor or have been waiting for a deceased donor transplant for a long time, some centers opt for desensitization to improve the likelihood of transplantation and to reduce the risk of rejection across HLA-incompatibility. This entails identifying certain low-level DSAs (>3000 MFI) that may result in a positive flow cross match that are aggressively removed prior to transplantation via pheresis or immunoadsorption followed by targeted B and T-cell therapy to prevent further DSA formation.p < 0.001). As such, desensitization can be a valuable tool to minimize rejection in highly sensitized individuals receiving HLA-incompatible transplants.Different combinations of therapies with varying amounts of success have been studied. IVIG therapy by itself has shown little promise  but IVIGA wide variety of desensitization protocols have been employed by transplant centers depending on center-specific practices. Ranging from monthly IVIG for a total of 2 g/kg  to more p = 0.760). A French study looked at tocilizumab (IL-6 inhibitor) in comparison to standard therapy (apheresis and Rituximab) and found no difference in reduction of pre-transplant MFIs between the groups [Some studies have explored the use of novel agents for desensitization. Marks et al. examined the use of eculizumab versus standard of care (plasmapheresis +/− IVIG) and found no significant difference in treatment failure between the two groups at 9 weeks post transplantation , and improved graft survival at 3 years  but no difference in rate of acute rejection was identified [A prolonged cold ischemia time of >24 h versus <12 h has been demonstrated to increase the rate of acute transplant rejection with relative risk of 1.13  in first-time transplant recipients and relative risk of up to 1.66  in retransplant candidates. This effect was not noted in recipients >60 years of age . Strategentified . Most trInduction immunosuppression is provided at the time of transplantation to minimize the risk of hyperacute and acute rejection. There are two categories of agents available: lymphocyte-depleting such as alemtuzumab (anti-CD52 antibody) and anti-thymocyte globulin (multi-cellular inhibition) and non-depleting such as basiliximab (IL-2 receptor antagonist) .p = 0.002) [p = 0.02) and of acute rejection that required treatment with antibodies  [Previous studies looking at induction vs. no induction agent demonstrated an overall reduction in deceased donor graft failure with lymphocyte-depleting agents  with red= 0.002) . It is n= 0.002) . Compare= 0.005) . Howeverp = 0.13), 1-year graft survival rate , 1-year patient survival rate  or 1-year infection rate [p = 0.02).In most studies comparing alemtuzumab to ATG, there was no significant difference in biopsy-proven acute rejection or allograft survival ,47,48 beion rate . HoweverAnother meta-analysis that compared efficacy and safety of induction agents found that alemtuzumab  and rATG  exhibited lower incidence of biopsy-proven acute rejection than basiliximab without a difference in graft survival. This came at the cost of a higher infection rate with ATG . In conclusion, use of ATG for induction is beneficial for individuals identified as having high risk immunologic profiles to minimize the risk of acute rejection. While comparison studies do not demonstrate convincing evidence of improved allograft survival using ATG vs. basiliximab, lack of long-term follow-up remains a limitation. In addition, use of ATG in high-risk individuals minimizes the cumulative burden of immunosuppression for treatment of acute rejection episodes. Infectious risk is an important factor that weighs into this decision due to greater infection rates with ATG use.Key points of peri-transplant measuresMinimizing cold ischemia times and optimizing kidney perfusion are associated with a decreased risk of rejection.Induction immunosuppression should be individualized based on risk factors for rejection as highlighted and the risks of infections and malignancy in the long run.We will now take a more detailed look into the post-transplant measures to reduce the risk of rejection in the kidney allograft.The post-transplant phase is critical in the prevention of both acute and chronic rejection of the kidney allograft. This can be divided into the immediate post-operative period, in which maintenance immunosuppression is introduced into a recipient’s arsenal to prevent rejection and is a critical transition period where tolerability, therapeutic drug levels and early compliance is established. This is followed by the chronic post-transplant phase where compliance is cemented and a fine balance between immunosuppression and infection is maintained.Conventional maintenance regimens consist of a combination of immunosuppressive agents that differ by mechanism of action and side effect profiles . This stThe most common strategy is triple drug therapy with a combination of calcineurin inhibitor (CNI), antimetabolite (mycophenolic acid or azathioprine) and steroids. The use of non-CNI based regimens including co-stimulation blockers (Belatacept) and mTOR inhibitors (sirolimus or everolimus) is around 10%.Serial discoveries and improvements in the drugs employed for maintenance immunosuppression have played a key role in the dramatic decrease in rates of acute rejection to <10% within the first year after transplant . With exThis section will be sub-divided into the prevention of cell mediated and antibody mediated rejections.T-cell proliferation and signaling pathwaysPathophysiology of rejection in kidney transplantation.The key cellular mediator of rejection is the T-lymphocyte. Most immunosuppressive agents work by disrupting the keys pathways of T-cell activation. Signal 1 is initiated by the interaction of the T-cell receptor (TCR) on the T-cell with the Major Histocompatibility Complex (MHC) molecule on the Antigen Presenting Cell (APC) via the CD3 complex. Co-stimulation or Signal 2 constitutes the interaction of CD80 and CD86(B7) on the surface of APC and CD28 on T-cells. Both Signal 1 and 2 are essential to activate three signal transduction pathways: the calcium-calcineurin pathway, the RAS-mitogen activated protein (MAP) kinase pathway and the nuclear factor-kb pathway . These pCNIs are considered the backbone of maintenance immunosuppression and are used by a vast majority of transplant centers in the United States  CyclospoAntimetabolites are an integral part of maintenance immunosuppression regimens. The most used agents are Mycophenolic acid (MPA) and azathioprine. These agents inhibit nucleotide synthesis which limits T and B-lymphocyte proliferation. MPA was approved by the FDA for the prevention of rejection in 1995. This was based on the Tricontinental Study  which showed a significantly lower risk of acute rejection in kidney transplant recipients on MPA compared to Azathioprine . A meta-Although tacrolimus remains the main component of maintenance immunosuppression, it is associated with significant toxicities and thus may not be usable in all patients. In such situations, CNI free regimens have been established. Belatacept is a first in class co-stimulation blocker which interacts with Signal 2 and thus selectively blocks T-cell activation. It was approved by FDA in 2011 based on two landmark trials which compared Belatacept with cyclosporine for maintenance immunosuppression both in standard and extended criteria kidneys. Although the rate of acute rejection was higher in the Belatacept cohorts, however, this did not have an impact on long term patient and graft survival ,60. SubsCorticosteroids remain an integral part of most immunosuppressive regimens. They inhibit production of activating cytokines and downregulate the expression of activating molecules on the surface of T-lymphocytes. However, recent trends have seen an increase in steroid free regimens to minimize long term side effects .Antibody-mediated rejection (AMR) is a significant complication following kidney transplantation that contributes toward both short- and long-term injury in approximately 1% to 10% of kidney transplant recipients . CertainMaintenance of immunosuppression remains a key element in this approach. Therapeutic tacrolimus levels are associated with reduced production of de novo DSA . CNI minAnother aspect of this multipronged strategy involves monitoring for the development of DSA. Currently there are no standard guidelines for this approach, and individual centers create their own protocols based on multiple factors including patient variables, HLA lab and logistical support and cost. It is debatable if lab monitoring for alloantibodies is needed in all transplant patients, but it seems justified in immunologically high-risk patients, desensitized recipients, patients with a suspicion for rejection and during treatment of an AMR to recognize allograft injury early and prevent its translation into chronic rejection .Non-compliance is a major risk factor for rejection and has been associated with premature graft loss ,74. It eCurrent therapies in Kidney Transplant Rejection.Patients at risk for denovo DSA formation have preceding cellular rejections with more intense inflammation within the microvasculature and if not treated early and aggressively, it is postulated that peritubular capillaritis can lead to increased HLA expression in the microcirculation, thereby increasing the risk of allo-recognition by the recipient B-cell compartment. Moreover, when cellular rejection coincides with DSA and antibody-mediated microvascular injury, it may accelerate the time to graft dysfunction and graft loss . This unA multitude of novel biomarkers have been developed to assess allograft health and predict rejection before changes in GFR take place and to predict long term graft outcomes. Only a few are currently available in clinic practice. A potential early indicator for the injury and loss of allograft is donor derived cell free DNA circulating in the blood of transplanted patients. This is measured as a percent of recipient circulating DNA and increase in this fraction is a sensitive marker of allograft injury . Three aGiven the significant improvements in acute cellular rejection rates over time , there hDaratumumab is a monoclonal antibody against CD38 which has shown promising results in decreasing anti-HLA antibodies in AMR ,87 and hBelimumab is a humanized, monoclonal, anti B-lymphocyte stimulator (BLyS) IgG1 antibody that prevents B-cell survival and differentiation into plasma cells. In a RCT with 28 kidney transplant recipients, there was no significant difference in the risk of major infections compared to standard immunosuppression but the IL-10/IL6 ratio of the B-cell distribution was skewed towards a regulatory profile and activated memory B-cells and plasmablasts were significantly reduced  This likImlifidase, an IgG degrading enzyme of Streptococcus pyogenes (IdeS), cleaves human IgG at a specific amino acid sequence within the hinge region producing Fc and F(ab)s fragments effectively blocking complement dependent cytotoxicity and antibody dependent cellular cytotoxicity . It was Berinert and Cinryze are plasma C1-esterase inhibitors that have been tested in two pilot studies and have shown a functional improvement in AMR ,93. MoreA more detailed discussion on these agents is covered in a subsequent article of the series.Key points of the post-transplant measuresMaintenance immunosuppression is a key part of preventing acute and chronic rejection and should be individualized and offer different mechanisms and less side effects.Strategies should be devised to increase long-term compliance.Acute rejections should be treated aggressively to decrease risk of chronic rejection.Novel biomarkers should be utilized in a judicious manner.Emerging therapies offer promise but need more studies.Kidney transplantation is considered the best modality to manage ESRD. It has not only shown improved outcomes, both in terms of mortality and quality of life as compared to dialysis, but multiple studies have shown its cost-effectiveness and economic advantages over dialysis ,95. WhilPrevention of rejection is key for the longevity of kidney allografts. This can be achieved at various stages in the lifetime of the graft and requires a multipronged approach and significant effort on the part of the recipients and transplant centers . We reco


Anomalous origin of the right coronary artery (RCA) is a rare congenital cardiovascular anomaly that can pose significant diagnostic challenges during cardiac evaluation. We present a case of a 54-year-old male patient with chest pain and a syncopal episode and subsequently diagnosed with non-ST-elevated myocardial infarction (NSTEMI). Coronary angiography revealed an anomalous origin of the RCA, making it difficult to precisely locate the artery's point of origin with selective contrast injection. During coronary angiography, the use of aortic root non-selective angiographic contrast injection aided in localizing the RCA ostium.Our case highlights the clinical significance of aortic contrast injection as a valuable and safe adjunctive technique in cases of anomalous coronary artery origins. Early detection and precise localization of such anomalies are essential for effective treatment planning and improved patient outcomes. Further studies may help validate the utility of aortic contrast injection in similar cases, thereby enhancing diagnostic accuracy and patient care in the management of anomalous coronary artery ostium. Anomalous coronary artery origin is a rare but clinically significant congenital anomaly that involves the abnormal origin or course of one or more coronary arteries from the aorta or other non-standard locations. These anomalies affect approximately one percent of the general population  While maIn this case report, we present a compelling clinical encounter of a patient diagnosed with a non-ST-segment elevated myocardial infarction (NSTEMI) and who was subsequently found to have an anomalous origin of the right coronary artery (RCA) on cardiac catheterization. The significance of this anomaly lies not only in its rarity but also in the potentially life-threatening consequences it poses and the technical challenges it can pose during angiography.By elucidating the clinical presentation, diagnostic workup, and subsequent management of this patient, we seek to contribute valuable insights to the medical community. Our objective is to enhance awareness of anomalous coronary artery origins among healthcare professionals and the potential role of non-selective angiographic contrast injection in detecting such an anomaly.A 48-year-old gentleman with a past medical history of hypertension and non-compliance with his medication regimen presented via ambulance with a 12-hour history of chest pain. The pain was described as substernal, radiating to the left shoulder, and 10/10 in intensity. The patient also had associated diaphoresis, and a five-minute loss of consciousness was reported. He was given sublingual nitroglycerin and 324mg aspirin in the field with improvement in his pain. On arrival at the hospital, his blood pressure was 159/105, and his heart rate was 89. He was given a loading dose of ticagrelor and started on nitroglycerin infusion for suspected Acute Coronary syndrome. He was admitted to the Coronary Care unit.Initial ECG was indicative of an infero-posterolateral NSTEMI with Q waves in the inferior leads and V2 and tall R in V2 Figure . InitialThe RCA was engaged using a 6 French Amplatz Right 1 diagnostic catheter Figure  and therThe patient was diagnosed with triple vessel disease. The electrophysiology service was consulted due to his loss of consciousness on presentation, and this was attributed to a vasovagal episode secondary to the NSTEMI. The patient was discharged on dual antiplatelet therapy, high-intensity statin therapy and Goal-directed medical therapy for Heart failure with mid-range Ejection fraction 9 HFmrEF. At the clinic follow-up one-month post-discharge, he was chest pain-free and was maintaining good compliance with his goal-directed medical therapy.Anomalous origin of the RCA is a rare congenital abnormality characterized by an aberrant ostium location, deviating from the typical anatomical course. One study reported a prevalence for an anomalous RCA origin of approximately 1% in a large series of coronary anomalies involving over 126,000 patients undergoing coronary arteriography ,5.The high take-off origin of the RCA has been defined as an RCA origin that is 5-10mm above the sinotubular junction. It has been described in approximately 0.019%-0.17% of autopsy studies . The casThe utility of aortic root non-selective contrast injection in cases of anomalous coronary arteries has been recognized in the literature. Aortic root non-selective contrast injection can be particularly useful in localizing anomalous coronary artery origins and differentiating them from other structures in the vicinity of the Ostia. A single-center study utilized this approach when the selective engagement of the RCA proved difficult during a study on coronary interventions in cases of anomalous RCA origin . In the This clinical case demonstrates the finding of an anomalous high take-off RCA origin in a gentleman who presented with NSTEMI. The case also demonstrates the potential utility of aortic root non-selective contrast injection in identifying the ostium of the vessel in such cases.Anomalous coronary artery origin, a rare congenital anomaly involving aberrant positioning or course of one or more coronary arteries, has been recognized as an important clinical entity with potential life-threatening implications. In this case report, we present a case of a patient who presented as an NSTEMI and was found to have a high take-off RCA ostium during coronary angiography. This case report highlights the potential role of the use of a non-selective Aortic root contrast injection for identifying a rare anomalous high take-off RCA ostium in cases where the coronary artery ostium proves challenging to locate and engage.


Endoscopic ultrasound guided gastrojejunostomy (EUS-GJ) with lumen apposing metal stents has recently emerged as a viable option, as an alternative to surgical gastrojejunostomy and endoscopic enteral stenting, for managing gastric outlet obstruction (GOO). We aim to perform a retrospective analysis of the efficacy, safety and outcomes of EUS-GJ performed at three tertiary institutions in the United Kingdom.Consecutive patients who underwent EUS-GJ between August 2018 and March 2021 were identified from a prospectively maintained database. Data were obtained from interrogation of electronic health records.p < 0.01). Adverse events occurred in 2/25 patients (8%), both due to stent maldeployment necessitating endoscopic closure of the gastric defect with clips. Long-term follow-up data were available for 21 of 23 patients and the re-intervention rate was 4.8% (1/21) over a median follow-up period of 162 (range 5–474) days.Twenty five patients  with a median age of 63 years old (range 29–80) were included for analysis. 88% (22/25) of patients had GOO due to underlying malignant disease. All patients were deemed surgically inoperable or at high surgical risk. Both technical and clinical success were achieved in 92% (23/25) of patients. There was an improvement in the mean Gastric Outlet Obstruction Scoring System scores following a technically successful EUS-GJ (2.52 vs 0.68, EUS-GJ in carefully selected patients is an effective and safe procedure when performed by experienced endoscopists.The online version contains supplementary material available at 10.1007/s00464-022-09692-y. Gastric outlet obstruction (GOO) is a condition secondary to mechanical obstruction and is characterised by post-prandial abdominal pain, abdominal distension, nausea and vomiting. These symptoms usually result in nutritional compromise and detriment to a patient’s quality of life (QOL). GOO can be caused by both benign and malignant pathologies, with a preponderance for malignancies , 2. If pThe decision to pursue one option over the other should take into account factors such as the patient’s life expectancy, fitness for surgery, anticipated duration of post-procedural recovery and relative likelihood of success of either modality. Meta-analyses have demonstrated both ES and S-GJ to be clinically effective in treating GOO but ES is associated with increased re-intervention rates, largely due to tumour ingrowth through the stent thus compromising its patency. Currently, S-GJ is considered in patients with good performance status and life expectancy greater than 3 months although this decision has to factor in the recovery process, post-operative morbidity and potential adverse events –7.Endoscopic ultrasound guided gastrojejunostomy (EUS-GJ) with a lumen apposing metal stent (LAMS) has recently emerged as an alternative to ES and S-GJ in the management of GOO. EUS-GJ combines the minimally invasive nature of ES with the creation of a conduit between the stomach and the jejunum away from the primary tumour site, in similar fashion to a S-GJ, thus preventing compromise of the stent patency by tumour ingrowth, if performed in patients with malignant GOO . Meta-anWe conducted a multi-centre, retrospective review of all consecutive patients who underwent EUS-GJ between August 2018 and March 2021 across three tertiary institutions in the United Kingdom: Leeds Teaching Hospitals NHS Trust (LTHT), University Hospital Southampton NHS Foundation Trust and University College London Hospitals NHS Foundation Trust. Data on demographics, baseline patient characteristics, procedural information and post-procedural events were obtained from each institution’s electronic records database. The study was registered as a service evaluation project and approved by the information governance board at LTHT and was carried out in accordance with the Helsinki Declaration.All patients were deemed not suitable for S-GJ on the basis of poor fitness for surgery and/or surgical technical factors such as an unfavourable anatomy. Suitability for EUS-GJ was made following discussion in a formal multi-disciplinary team setting or close liaison between oncology, surgical and endoscopic teams.LAMS are fully covered stents, made of nitinol material, which are configured in a dumbbell shaped design with two flanges on either end providing lumen to lumen apposition when fully deployed. This unique design allows the LAMS to safely function as a conduit as the apposition capability of the flanges provide traction between two lumens to bring them together and the fully covered component of the stent prevents any leakage within the stent or around the tract. The addition of an electrocautery enhanced delivery system through which the LAMS can be deployed has simplified what used to be a multi-step procedure requiring exchanges of different endoscopic accessories. The first mainstream role of LAMS was in endoscopic drainage of pancreatic fluid collections (PFC) but LAMS are increasingly used in EUS guided biliary drainage (EUS-BD) and the creation of internal digestive anastomoses, particularly EUS-GJ . The HotIdentification of a jejunal loop under EUS guidance. In some instances, this was assisted by endoscopic insertion of an oroduodenal/orojejunal catheter downstream of the level of obstruction and infusion of a mixture of contrast, distilled water and methylene blue dye via an irrigation pump, thus distending the jejunum and improving visibility on EUS and x-ray screening. On occasion, the endoscopist may choose to confirm the presence of a jejunal loop (rather than colon) by transgastric puncture using a 22G fine needle aspiration (FNA) needle and aspiration of methylene blue stained jejunal contents.(i)Freehand approach: Direct puncture through the gastric wall and into the jejunum with the cautery enhanced tip of the LAMS delivery system(ii)Wire-guided approach: Puncture of the jejunum with a 19G FNA needle, passage of a guidewire through the needle into the jejunum and loading the LAMS delivery system over the guidewire and puncture through the gastric wall and into the jejunum with the cautery enhanced tip of the LAMS delivery systemDeployment of the LAMS to create a gastrojejunostomy was performed either via the freehand or wire-guided approach:Following deployment of the flange of the LAMS on the gastric side, an endoscopic view of methylene blue stained solution refluxing back into the stomach through the lumen of the LAMS and/or injection of contrast through the LAMS from the stomach into the jejunum confirms successful creation of a gastrojejunostomy.At one institution (LTHT), endoscopic balloon dilatation through the lumen of the LAMS was routinely performed with a balloon diameter of 18 mm–20 mm in increments of 1 mm. This practice was abandoned following displacement of the LAMS during balloon dilatation.The procedures were performed by five senior interventional endoscopists with prior extensive experience with EUS and the use of LAMS in the management of PFC and EUS-BD. All procedures were performed with the patient under general anaesthesia with endotracheal intubation. Prophylactic antibiotics were given in accordance with individual institution’s policy. In this study, the EUS-GJ procedure was carried out via the following method:Technical success was defined as the successful creation of a gastrojejunostomy with the LAMS. Clinical success was defined as an improvement of oral enteral intake and increased tolerance of a higher consistency diet when compared to baseline, utilising a validated scale of dietary consistencies , known as the gastric outlet obstruction scoring system (GOOSS) . Patientp-value of less than 0.05. Statistical analyses were performed with IBM SPSS Statistics version 26.0 .Mean values are expressed with standard deviation values and median values with range values. Comparison of GOOSS pre and post-procedure was performed with the Wilcoxon signed-rank test. Statistical significance was determined at a Twenty five patients 15 males) with a median age of 63 (range 29–80) years old were included for analysis. Demographics and baseline characteristics of the patients are summarised in Table 5 males wKey outcomes are summarised in Table In a third patient, a successfully placed LAMS was displaced following endoscopic balloon dilatation through the lumen of the LAMS. The gastric defect was closed with endoscopic clips and duodenal stent placed instead.p < 0.01).Clinical success was achieved in all 23 patients who had a technically successful procedure. All patients who had required supplementary feeding were successfully weaned off them. The median time from LAMS deployment to cessation of supplementary feeding was 5 days (IQR 4–7 days). There was a significant improvement of mean GOOSS . Only one patient required re-intervention. This was in a patient who developed recurrent GOO symptoms and underwent endoscopic re-intervention 63 days after the initial EUS-GJ. At the time of repeat endoscopy, there was preferential passage of the endoscope and contrast through the lumen of the LAMS into the afferent limb of the jejunum due to the angle of the LAMS. This was successfully rectified by placement of a long colonic stent into the direction of the efferent limb and fixated to the LAMS with endoscopic clips. The patient resumed oral intake and no further re-intervention was required.Traditionally, the two main modalities for treatment of GOO were endoscopic ES or a S-GJ via either an open or laparoscopic approach. The recent innovations in therapeutic endoscopy continue to push the boundaries of the limits of minimally invasive options for patients. The potential of EUS in the internal creation of digestive anastomoses and the advent of new technology, such as the LAMS in this case, have led to the possibility of EUS-GJ, which is now being increasingly recognised as a viable option in the treatment of GOO.In this multi-centre, retrospective series, we demonstrated EUS-GJ to be an effective and safe treatment option for patients with GOO. Prior to the intervention, all of the patients exhibited significant nutritional compromise, consequentially rendering them to be suboptimal physiologically for a S-GJ. Prior to consideration for an EUS-GJ, a multi-disciplinary approach involving the endoscopist, surgeon, nutritionist and oncologist (if applicable) is essential to determine the most appropriate modality of treatment for a patient with GOO.One important advantage of EUS-GJ over its counterparts is its applicability in patients with altered post-surgical anatomy of the alimentary tract. Perez-Miranda et al., reported the successful completion of EUS-GJ in seven patients with previous surgeries  as part of a larger retrospective comparison of EUS-GJ and S-GJ . EUS-GJ There are several reports in the literature evaluating EUS-GJ against ES and S-GJ. Chandan, et al. conducted a meta-analysis of 659 patients in five retrospective studies comparing outcomes of EUS-GJ and ES. They demonstrated comparable technical success (EUS-GJ 95.2% vs ES 96.9%), clinical success (EUS-GJ 93.3% vs ES 85.6%), although ES was more likely to be associated with higher re-intervention rates (EUS-GJ 4% vs ES 23.6%) . Howeverp = 0.11) and clinical success  were observed in both groups. However, EUS-GJ may be more cost beneficial with the financial analysis demonstrating EUS-GJ to be a third the cost of a laparoscopic S-GJ.Bronswijk, et al. conducted a propensity score-matched comparator, multi-centre, retrospective study between EUS-GJ and laparoscopic S-GJ demonstrating similar technical and clinical success rates, although patients who underwent EUS-GJ resumed oral intake quicker, had a shorter length of stay and encountered less adverse events . Perez-MAlthough EUS-GJ is increasingly adopted, its place in the algorithm of management of GOO alongside the more established ES and S-GJ modalities remains unclear. ES remains an effective, safe procedure which can be performed in most secondary care institutions. The need for re-intervention following ES tends to be predicted by an anticipated longer life expectancy of the patient. Although re-intervention is usually straight forward, the need for repeated procedures, symptom recurrence affecting QOL and interruptions in oncological treatment have to be considered. A life expectancy threshold of 3 months has been suggested as a cut-off for considering EUS-GJ or S-GJ over ES . In the The long-term impact and any potential safety issues of a LAMS remaining in-situ remains unclear. In this series, no adverse events relating to a successfully placed LAMS were encountered over the follow-up period (range 5–474 days). Delayed or late safety events following placement of LAMS for drainage of pancreatic fluid collections have been well documented, particularly with regards to bleeding . In the EUS-GJ remains an advanced endoscopic technique which is usually only performed in tertiary institutions. There is a substantial learning curve even for endoscopists with extensive experience in diagnostic and therapeutic endoscopy . In the There are multiple varieties of the technique of performing a EUS-GJ  and a deThere are several limitations to our study. Firstly, this was a retrospective series and therefore subject to inherent pitfalls of it’s design. Secondly, as patients were identified from multiple institutions without pre-defined enrolment criteria, there would be differences in patient selection for the procedure. Thirdly, the lack of a control group precluded direct comparison of outcomes although all consecutive patients were included for analysis, which may mitigate a degree of selection bias. Lastly, all procedures were performed by experienced endoscopists at tertiary institutions therefore the results may not be generalisable.In conclusion, EUS-GJ appears to be an effective and safe procedure when performed by experienced endoscopists. Prospective studies in the form of randomised, controlled trials are needed to evaluate the performance of EUS-GJ against its counterparts.Supplementary file1 (MP4 184116 KB) Video 1 depicts key components of EUS-GJBelow is the link to the electronic supplementary material.


Angiotensin-converting enzyme (ACE) is canonically known for its role in the renin-angiotensin system (RAS) where its conversion of angiotensin I (Ang I) to the bioactive peptide angiotensin II (Ang II) helps to regulate blood pressure, electrolyte, and volume homeostasis. Further studies on ACE have shown that its enzymatic activity is relatively non-specific and functions outside of the RAS axis. Of the multiple systems it has been implicated in, ACE has been found to play an important role in the development and modulation of hematopoiesis and the immune system, both through the RAS and independently of the RAS axis. Angiotensin-converting enzyme (ACE) is a type-I cell surface zinc metallopeptidase with two functional catalytic domains towards the N- and C-terminal and is a crucial component of the renin-angiotensin system (RAS). ACE is responsible for conversion of angiotensin I (Ang I) to the bioactive peptide angiotensin II (Ang II) . AngioteACE has been shown to be involved in the development of hematopoiesis in humans. ACE expression in embryonic body cells is linked with hematopoietic potential, even more so than other markers such as CD34 . ACE is + hematopoietic stem cells. ACE knock-out mice shows decreased segmented neutrophils but increase in progenitor cell types, suggesting issues with terminal granulopoiesis  (Ang 1-7), another component of the RAS system produced through breakdown of Ang I or Ang II, has also been shown to cause pan-lineage proliferation which accelerated hematopoietic recovery in mice after irradiation . Ang 1-7ACE can additionally exert influence over myelopoiesis through its non-RAS related enzymatic function. ACE is capable of degrading substance P and thereby can regulate its level within the bone marrow . While tAcetyl-Ser-Asp-Lys-Pro (Ac-SDKP) is another substrate degraded by ACE. Studies looking at both ACE knock-out and ACE inhibitors have shown that decreased ACE activity significantly increased the serum and bone marrow levels of Ac-SDKP . Ac-SDKP0 to G1 transition, delaying hematopoiesis which has radioprotective effects and is at least partially modulated through the inhibition of the RAS and increased AcSDKP concentration. Longer inhibition, on the scale of weeks after radiation exposure and initiation of ACE inhibitors, leads to increased progenitor proliferation compared to untreated controls  challenge, ACE knocked-out mice had lower bacterial resistance as indicated by larger skin lesions and higher bacterial burden. Conversely, a line of mice which had overexpression of ACE in neutrophils (NeuAce mice) showed enhanced bacterial resistance. An explanation for these differences is that ACE expression is directly correlated to neutrophil production of reactive oxygen species (ROS)  . Interes+ T-cells. Studies looking at mice with independently knocked out N- and C-domains of ACE in myeloid cells revealed that this tumor resistance could be attributed to the ACE C-domain, which seemed to induce macrophages to assume an M1 phenotype  class I peptides. Studies have shown that knocking out or inhibiting ACE in mice significantly altered the repertoire of MHC class I peptides, suggesting that the non-specific peptidase activity of ACE functions in trimming peptides for display and might explain why there is impaired T-cell stimulation with decreased ACE activity .An important mediator of ACE is through its influence over cellular ATP. Recent studies have shown that ACE C-domain catalytic expression is associated with upregulation of numerous proteins, including electron transport chain proteins NDUFB8, ATP5A, and ATP5β and has been associated with an increase in ATP production. This increase in ATP has subsequently been linked to increase in phagocytosis and superoxide production, providing a mechanism for the functional maturation of these myeloid cells. ATP-upregulation in this context is counteracted by use of ACE-inhibitor but not angiotensin II AT1 receptor antagonists, likewise suggesting that this change is mediated outside of the RAS axis .Despite its near universal expression in lymphocytes, ACE’s effect in lymphocytes has not been extensively studied . Beyond ACE is an exceptionally important enzyme for its role in mediating homeostasis and blood pressure; however, as more studies are performed, ACE has become deeply implicated in the immune response due to regulation of myelopoiesis and immune cell functional maturation. ACE accomplishes this both through its role in the RAS as well as its independent peptidase functions. Although there are complex and multifactorial interactions with ACE and the immune system, understanding of the mechanisms and extent of ACE’s influence has yet to be fully explored.


Pilot studies to detect newborns with Duchenne Muscular Dystrophy (DMD) by newborn bloodspot screening (NBS) have been conducted under the New York State Newborn Screening Program (NYS) and are currently in progress as part of the Early Check Program at Research Triangle Institute (RTI) International. The Newborn Screening Quality Assurance Program (NSQAP) at the U.S. Centers for Disease Control and Prevention (CDC) produced a set of seven prototype dried blood spot (DBS) reference materials spiked with varying levels of creatine kinase MM isoform (CK-MM). These DBS were evaluated over a 3-week period by CDC, NYS, and RTI, all using the same CK-MM isoform-specific fluoroimmunoassay. Results from each laboratory were highly correlated with the relative proportion of CK-MM added to each of the six spiked pools. Based on reference ranges established by NYS and RTI for their pilot studies, these contrived DBS collectively spanned the CK-MM ranges found in typical newborns and the elevated ranges associated with DMD. This set allows quality assessment over the wide range of fluctuating CK-MM levels in typical and DMD-affected newborns. For each pool, a card printed with 15 outlined circles was manually spotted with 100 uL per circle of the same pool. The cards were allowed to dry overnight under ambient conditions and then packaged in low-permeability ziplock bags  containing desiccant packs . Complete sets including one card each of Pools A through G were sent overnight at ambient temperature to NYS and RTI, and one set was retained at CDC. The packaged cards were stored at −20 °C between analyses. For analysis, bagged cards were removed from the freezer and allowed to reach room temperature before removal from the desiccated bag.Each of the three laboratories conducted weekly runs over the same three-week period. In every run, three 3.2 mm punches were taken from each DBS card, generating 27 measurements over the three weeks for each of the seven pools. CK-MM concentrations in these punches were measured using the GSP Neonatal Creatine Kinase-MM kit  with the GSP high-throughput analyzer as per the manufacturer’s instructions. The GSP instrument software was configured to output extrapolated results above the default upper reporting limit. Results were exported into spreadsheets by each laboratory and compiled at CDC, where they were graphed and analyzed for descriptive statistics using spreadsheet functions . The kitA total of 189 measured CK-MM results (63 from each laboratory) were collected over the three-week period . The resThe mean values and variances for each pool were comparable among all three laboratories . The difThe 27 CK-MM results from each pool were evaluated based on both the multiple cutoffs used by NYS depending on post-natal age , and on Renewed interest in population-based NBS for DMD is the result of technical advances in screening , the rapThis report is the first multi-laboratory evaluation of the isoform-specific immunometric method of measuring CK-MM designed for NBS. Since it is limited to the use of contrived DBS, collaboration with NBS laboratories which were screening newborns in pilot studies was essential for evaluating the clinical relevance of the CK-MM levels included in the prototype DBS-QC set. The validity of the CK-MM distributions from the NYS and RTI studies is underscored by the similarity of their cutoff values for typical newborns , and by their mutual agreement with the provisional cutoff value (2040 ng/mL) provided in the CK-MM assay product insert  instructions for use, version 1).For NBS programs to establish and sustain DMD screening, laboratories will need reliable access to external QC materials to validate assays, conduct stability studies , ensure In this study, the measured CK-MM values in Pools B–D encompassed the expected levels for typical newborns 24 to 72 h old, while CK-MM values in Pools F and G were in an elevated range. Results from an earlier multi-national evaluation of the same assay reported that CK-MM levels in the ranges commensurate with Pools F and G were found only in Duchenne-affected newborns . OverallNew York State used multiple cutoffs based on both newborn age and whether the elevation was Borderline (B), requiring re-test of a new specimen, or sufficiently elevated to require immediate Referral (R) for second-tier genetic testing and genetic counseling. RTI used a preliminary provisional cutoff and a subsequent refined cutoff for all newborns less than 72 h old. The other programs used a single cutoff for their follow-up actions, as described in their respective references. The Newborn Population column includes the age range of newborns at specimen collection as reported in each reference.The amount of CK-MM used to spike Pool G was calculated to result in a concentration of 5000 ng/mL, based on the specific activity provided in the product insert. No information regarding CK-MM content measured immunometrically was provided, and no independent standard for accuracy of CK-MM measurements is currently available. The content of CK-MM measured immunometrically could also vary with respect to the method used to extract and purify the enzyme. These factors could potentially account for the 35% difference between the expected and measured CK-MM levels in Pool G. In the future, a workgroup formed by an authoritative standards agency may be able to establish a primary reference material to serve as a common calibrator.Pre-analytical sources of variability are especially important with DBS specimens. The lack of homogeneous blood distribution throughout the spot, variations in the punched samples that are analyzed, and dissimilar accessibility of analytical reagents to the entire blood sample contained in the punch can all contribute to variability in the final result that is not related to the chemical analysis per se. Because the contrived DBS in this study were made from non-clotting blood applied uniformly using volumetric techniques, these issues are generally less problematic than they can be with heelstick samples collected from newborns. To ensure consistency, DBS materials distributed by NSQAP for use as external QC are assessed for homogeneity and stability using standard operating procedures approved under an accredited quality management system.Based on the reference ranges established by the NYS and RTI DMD pilot studies as well as other recent published studies ,11,12,13


Objective. Digital breast tomosynthesis (DBT) is a quasi-three-dimensional breast imaging modality that improves breast cancer screening and diagnosis because it reduces fibroglandular tissue overlap compared with 2D mammography. However, DBT suffers from noise and blur problems that can lower the detectability of subtle signs of cancers such as microcalcifications (MCs). Our goal is to improve the image quality of DBT in terms of image noise and MC conspicuity. Approach. We proposed a model-based deep convolutional neural network (deep CNN or DCNN) regularized reconstruction (MDR) for DBT. It combined a model-based iterative reconstruction (MBIR) method that models the detector blur and correlated noise of the DBT system and the learning-based DCNN denoiser using the regularization-by-denoising framework. To facilitate the task-based image quality assessment, we also proposed two DCNN tools for image evaluation: a noise estimator (CNN-NE) trained to estimate the root-mean-square (RMS) noise of the images, and an MC classifier (CNN-MC) as a DCNN model observer to evaluate the detectability of clustered MCs in human subject DBTs. Main results. We demonstrated the efficacies of CNN-NE and CNN-MC on a set of physical phantom DBTs. The MDR method achieved low RMS noise and the highest detection area under the receiver operating characteristic curve (AUC) rankings evaluated by CNN-NE and CNN-MC among the reconstruction methods studied on an independent test set of human subject DBTs. Significance. The CNN-NE and CNN-MC may serve as a cost-effective surrogate for human observers to provide task-specific metrics for image quality comparisons. The proposed reconstruction method shows the promise of combining physics-based MBIR and learning-based DCNNs for DBT image reconstruction, which may potentially lead to lower dose and higher sensitivity and specificity for MC detection in breast cancer screening and diagnosis. RED defines a regularizer based on a general image filter or denoiser :et alA variety of optimization algorithms exist for inverse problems with 2.2.2.2.1.d’) focus only on the visibility of the target objects. The MC classifier was implemented as a DCNN with trainable weights, and therefore called CNN-MC. It took an image region of interest (ROI) or patch as input. The training set included MC patches as positives with label of 1 and MC-free background patches as negatives with label of 0. The training loss was the binary cross entropy (BCE) loss, which has been shown to give the maximum likelihood estimation of the DCNN weights from the training data  while other measures such as the detectability index (We trained the CNN-MC for each image condition and tested it accordingly. The area under the receiver operating characteristic (ROC) curve (AUC) of the test set scores was used as an MC detectability measure. If the underlying image condition enhanced the MCs effectively, the CNN-MC should learn the MC features more accurately during training and have better classification ability between image patches with and without MCs during testing, resulting in a higher AUC metric. Any MC-like artifacts in the background patches would degrade the classification performance of CNN-MC and reduce the AUC. We studied the use of CNN-MC to rank the relative performances of different DBT reconstruction and denoising methods.et alet alThere are variations in the CNN-MC observer modeling. DCNN classifiers with different network structures learn image features differently. Even for the same network structure, the randomness in DCNN training such as kernel initialization or data batching can lead to different local minima. These are akin to the interobserver and intraobserver variabilities of human observers. To account for these variations, we investigated the VGG-Net  to quantify the root-mean-square (RMS) noise level of its input image patch. We designed their network structures to be the same as those for CNN-MC table , except 2.2.3.et alet alFor training CNN-NE and CNN-MC, we adopted the training technique of transfer learning  package  targets and the DBTs with the remaining 10 exposure levels as the training low dose (LD) inputs. To ensure that DNGAN covered a wide range of DBT noise levels due to variations in patient sizes and other factors in clinical settings, we trained a suite of DNGAN denoisers, each of which can handle a certain range of image noise levels. To do so, we calculated the average RMS noise for each DBT volume using the method described in section 2.3.3.et alWe randomly extracted 128 × 128 pixel patches within the breast regions from all the 70 virtual phantom DBTs and 11 exposure levels to form the CNN-NE training set. This gave a total of 256 194 patches. The low-frequency background was removed from the patches to reduce the nonuniformity caused by heterogeneous breast structures . The system acquired 21 PVs in 60° scan angle and 3° increments with a 29 kVp Rh/Rh x-ray beam. The distances between source and isocenter and between isocenter and detector were 640 mm and 20 mm, respectively. The breast support was at the same height as the isocenter. For our reconstructions, we used the central 9 PVs in 24° angle so that the scan geometry was similar to that of the GE commercial Pristina DBT system. The radiation doses at 9 PVs were similar to those of the Pristina system. A Mammography Quality Standards Act (MQSA) approved radiologist marked the biopsied MCs with 3D bounding boxes in the reconstructed DBT images based on all available clinical information.2.3.5.We split the human subject DBTs by case into three disjoint sets for training, validation and testing. The training set consisted of 64 cases, or 127 DBT views . The validation set consisted of 52 cases, or 104 DBT views. The remaining 122 cases with 246 views  were sequestered as independent test set. For each data set, positive patches of size 128 × 128 × 3 pixels containing clustered MCs were extracted inside the radiologist’s 3D boxes on a regular grid with centers separated by 128 pixels in the two directions along a slice and separated by 1 slice with offset centers along the depth direction. An MC cluster therefore might be extracted multiple times in part or in whole but spatially shifted in each patch, which served as augmented samples to reduce the imbalance between the two classes. Non-overlapping negative patches of the same size were randomly extracted outside the 3D boxes in the structured breast background. For the CNN-MC, we obtained 751 positive and 19 079 negative patches for the training set, 709 positive and 1955 negative patches for the validation set, and 2289 positive and 6176 negative patches for the test set. For each patch, we removed the low-frequency background and took maximum intensity projection (MIP) over the three slices to emphasize the MCs, if any. Figure 2.3.6.et alet al  training, we set the number of epochs to 600 (300) and the mini-batch size to 2048 (512). The Adam optimizer was set with an initial learning rate of 2.5.et alet alet alet al , indicating that CNN-NE can accurately estimate the RMS noise of an input patch. Similar correlations were observed for other reconstructions (not shown). While CNN-NE was trained using VICTRE images from 3 iterations of SART, it was applicable to other reconstructions and human subject images at deployment because it was designed to assess the RMS variations in noisy pixels without relying on the specific image conditions.As an example, we deployed one of the five CNN-NE models with VGG-Net backbone trained with different random initializations to the CNN-NE validation set from 2 iterations of SART images. Figure et al . The three terms could be turned on or off separately to create 6 partial models. To turn off Figure 3.4.We compared eight image conditions in this section: (a) SART iteration 2; (b) SART iteration 3; (c) SART iteration 3 with post-reconstruction DNGAN denoising; (d) RED without DBCN modeling, equivalent to ‘Figure 3.5.The GEN2 DBT system used for acquiring the human subject DBTs was developed as a prototype for research purposes, so it lacked a built-in reconstruction method. To compare the proposed MDR with gold standard reconstruction, we reconstructed a human subject DBT case acquired with the commercial GE Pristina DBT system. Figure The darkening of breast periphery as seen in the MDR reconstructed image in figure 4.DBCN and DNGAN represent two distinct approaches for enhancing the subtle signals in DBT. The DBCN method approximates the deblurring and noise decorrelation by the inverse of the detector point spread filter and the prewhitening filter. Both operations boost the high frequency signals, which inevitably amplify high frequency noise at the same time. DBCN therefore is incorporated with an EP regularizer to control the noise. DNGAN emphasizes the signals by smoothing the surrounding backgrounds like a regularizer. It also increases the contrast of the signals to some extent, but sometimes falsely enhances the high frequency structures and creates MC-like artifacts. We explored combining the two methods to take advantage of both. We implemented the newly proposed MDR method in an efficient way so that it could reconstruct the full-sized 3D DBT images at full resolution. Quantitative results using our newly developed DCNN image quality measures on the independent test set of human subject DBTs revealed that MDR achieved the highest AUC rankings for MC detectability and low noise among the reconstruction and denoising approaches studied. This study shows the promise of combining the physics-based MBIR and the learning-based DCNNs for reconstruction.d’ where the target signal is trained to be fitted with channelized functions or mathematically defined. Moreover, the CNN-MC can include the assessment of image background with and without MC-like false enhancement , indicating the effectiveness of quadratic fitting for background removal. While using noise-free images may be the ideal approach for accurate RMS calculations, its real-world impact is limited due to the linearity and small differences. More importantly, having the noise-free images is a special case and they are typically unavailable for actual scanned images. Therefore, we employed the fitting method in our work due to its practicality in general scenarios in case others would want to adopt the method for their applications.The RMS noise calculation introduced in section et al (et al (A suboptimal CNN-MC model observer is preferred for evaluating the effectiveness of image processing techniques since image processing is not expected to improve the performance of an ideal observer. Zhang et al  showed tl (et al . Since tet alet alet alWe did not analyze the convergence property of MDR in this study. Due to the limited-angle nature of the DBT scan and the fact that radiologists are accustomed to the tissue texture appearance of the 2D projection mammograms, we usually do early stopping on the DBT reconstruction so that the soft tissue structured backgrounds are not overly enhanced. The truncation artifact correction Lu et al during rThere are limitations in the current study. First, the DNGAN denoisers were trained on the SART images but were directly applied to the intermediate images of MDR. This introduced a noise mismatch between the denoiser and the images to be denoised. The fact that the DNGAN works well in MDR indicates the flexibility of the application, but it also leaves room for improvement by fine-tuning the DNGAN denoisers at every MDR iteration, which will tradeoff computational efficiency, however. Second, the number of MC clusters in our data set is limited. A larger CNN-MC training set may further improve the generalizability of the CNN-MC model observer and reduce the AUC variations among the different DCNN models or between training and deployment to unseen cases. Third, although MDR achieved the highest MC detectability ranking and low noise, post DBCN reconstruction with DNGAN denoising was also among the top three rankings. Post-reconstruction denoising is the only practical approach if the raw PVs are not available for user-designed reconstruction. It will be of interest to evaluate the effectiveness of DNGAN denoising for the DBT images reconstructed by the various commercial DBT systems when large human subject data sets with subtle MCs from these systems become available. Fourth, the proposed DCNN image evaluation approach only focused on image noise and MC detectability. The evaluations of mass and tissue textures still relied on visual judgment. It will be useful if DCNN models can be developed to assess the quality of these important image features as well in the future. Finally, we do not address the time efficiency of MBIR as it falls outside the primary scope of this paper. We encourage future research to tackle this issue, which may complement and enhance the utility of the proposed method.5.We proposed MDR by combining DBCN modeling and DNGAN denoising using the RED framework for DBT reconstruction. To facilitate the task-based image quality assessment, we also proposed two DCNN tools. The CNN-NE was trained to estimate the RMS noise of the DBT images. The CNN-MC was trained to be a model observer to evaluate the detectability of clustered MCs. The efficacies of DNGAN, CNN-NE and CNN-MC were demonstrated using physical phantom DBTs and human subject DBTs. We investigated the impacts of the MDR regularization parameters and the cost function terms. MDR reduced image noise and improved MC detectability on an independent test set of human subject DBTs. The proposed CNN-NE and CNN-MC evaluation method can serve as a surrogate for human observers to provide task-specific metrics and rank the imaging systems in a cost-effective way. The proposed reconstruction method may potentially lead to lower dose and higher sensitivity and specificity for MC detection in breast cancer screening and diagnosis.


Inhibitors of monoamine oxidase B (MAO-B) and catechol-O-methyltransferase (COMT) are major strategies to reduce levodopa degradation and thus to increase and prolong its effect in striatal dopaminergic neurotransmission in Parkinson’s disease patients. While selegiline/rasagiline and tolcapone/entacapone have been available on the market for more than one decade, safinamide and opicapone have been approved in 2015 and 2016, respectively. Meanwhile, comprehensive data from several post-authorization studies have described the use and specific characteristics of the individual substances in clinical practice under real-life conditions. Here, we summarize current knowledge on both medication classes, with a focus on the added clinical value in Parkinson’s disease. Furthermore, we outline practical considerations in the treatment of motor fluctuations and provide an outlook on ongoing studies with MAO-B and COMT inhibitors. Parkinson’s disease (PD) is the second most common neurodegenerative disorder, coined by progressive motor and non-motor symptoms affecting multiple aspects of health-related quality of life  inhibitors and catechol-O-methyltransferase (COMT) inhibitors. As new substances were recently approved for the latter classes, the present review article summarizes existing knowledge on MAO-B and COMT inhibitors, with a focus on existing knowledge from pivotal trials as well as post-approval evidence. Dopamine may be degraded by both MAO and COMT Webster . The proMonoamine oxidase B (MAO-B) is an enzyme located at the outer mitochondrial membrane which catalyzes the oxidation of arylalkylamine neurotransmitters, and is the main degradation pathway of dopamine into 3,4-dihydroxyphenylacetic acid within striatal glial cells  as well as on its motor and ADL subscales , daily OFF time (– 0.4 h both for 50 mg and 100 mg safinamide), UPDRS part III , and CGI-C . COMT is expressed in all peripheral tissues and in the central nervous system (CNS) while the peripheral component is critical for the CNS bioavailability of levodopa. Peripheral COMT not only reduces levodopa concentrations, but its product 3-OMD also competes with levodopa in terms of blood–brain barrier transport and CNS dopamine uptake, and thus worsens motor function  is expected to be sufficient  or levodopa/carbidopa/entacapone (LECIG) are approved invasive therapeutic options for the treatment of motor fluctuations that cannot be adequately controlled by non-invasive drug therapy. Although the actual goal of intestinal infusion therapy is the discontinuation of other dopaminergic drugs, the labels of both infusion combinations specifically allow concomitant use of MAO-B inhibitors, as well as COMT inhibitors for levodopa/carbidopa. In PD patients with high levels of intestinal levodopa infusion rates, addition of MAO-B or COMT inhibitors may help avoid the need of multiple changes of infusion cassettes per day. Moreover, pyridoxine levels are frequently reduced when levels of daily levodopa administration are high  showed positive effects not only on daily OFF time, but also on aspects of quality of life as measured with the PDQ-39 scale  as well as motor scales , but did not alter laser-evoked potentials as a surrogate marker of central processing of nociceptive inputs  four weeks after baseline  (Costa et al. With the availability of the latest generation of MAO-B and COMT inhibitors, their pharmacokinetics of a once daily application and their tolerability pose the question whether they can be used at earlier timepoints, before motor fluctuations emerge (Jenner et al. In the ADOPTION study, initiation of opicapone directly upon the emergence of early motor fluctuations will be tested versus placebo (Ferreira et al. It is established that high doses of oral levodopa favor the occurrence of motor fluctuations in the long-term (Tran et al. Inhibitors of MAO-B and COMT have become a highly valuable component in the therapy of PD patients when motor fluctuations cannot be adequately controlled by adjusting levodopa dosing. Reduction of OFF time, increase in ON time as well as reduction of daily levodopa doses have been demonstrated for all substances, and additionally, positive effects on non-motor symptoms are emerging. Safinamide and opicapone currently represent the latest generations of both classes, and their efficacy and safety profiles have now been well characterized in the pivotal studies as well as a variety of subsequent phase 4 studies.


Simulation-based training is a practical medical education tool to develop health professionals’ knowledge and experience in a low risk, realistic clinical setting. It trains clinicians to recognise and manage rare and complex clinical scenarios without compromising patient safety. Despite an evidence base demonstrating simulation to be an effective medical education tool, it is not commonly used in postgraduate psychiatry training as it is in other medical specialties.This project outlines the development and effectiveness of a hybrid-virtual simulation-based workshop designed to improve patient care by improving clinical skills of non-consultant hospital doctors (NCHDs) in detecting and managing rare and complex psychiatric emergencies.Three clinical vignettes based on near-miss clinical scenarios in psychiatry were developed by a multidisciplinary team of doctors and nurses in psychiatry, and experts in simulation-based medical education. The workshop, ‘SafePsych’ was delivered in a simulation laboratory, while being captured on camera and broadcasted via Zoom video-conferencing platform to observers. Debriefing followed each clinical scenario. Participants completed pre- and post-workshop questionnaires to evaluate clinical knowledge of the scenarios in the training programme.The workshop was attended by consultants (n=12), NCHDs in psychiatry and emergency medicine (n=19), and psychiatric nurses (n=5). In the psychiatry NCHD group, test scores significantly improved following the workshop (p<0.001). There were significant improvements in the test scores with a mean difference of 2.56 . Feedback from participants and observers was positive, with constructive appraisals to improve the virtual element of the workshop.Simulation-based training is effective in teaching high risk, rare complex psychiatric cases to psychiatry NCHDs. Further exploration of the learning needs of nursing staff is required. Future workshop delivery is feasible in the COVID-19 environment and beyond, using a virtual element to meet social distancing requirements while enhancing the reach of the training.None Declared


A global plan has been set to end human deaths from dog-mediated rabies by 2030 ("Zero-by-30"), but whether it could be achieved in some countries, such as China, remains unclear. Although elimination strategies through post-exposure prophylaxis (PEP) use, dog vaccination, and patient risk assessments with integrated bite case management (IBCM) were proposed to be cost-effective, evidence is still lacking in China. We aim to evaluate the future burdens of dog-mediated human rabies deaths in the next decade and provide quantitative evidence on the cost-effectiveness of different rabies-control strategies in China.Based on data from China's national human rabies surveillance system, we used decision-analytic modelling to estimate dog-mediated human rabies death trends in China till 2035. We simulated and compared the expected consequences and costs of different combination strategies of the status quo, improved access to PEP, mass dog vaccination, and use of IBCM.The predicted human rabies deaths in 2030 in China will be 308 (95%UI: 214–411) and remain stable in the next decade under the status quo. The strategy of improved PEP access alone could only decrease deaths to 212 (95%UI: 147–284) in 2028, remaining unchanged till 2035. In contrast, scaling up dog vaccination to coverage of 70% could eliminate rabies deaths by 2033 and prevent approximately 3,265  extra deaths compared to the status quo during 2024–2035. Moreover, with the addition of IBCM, the "One Health" approach through mass dog vaccination could avoid unnecessary PEP use and substantially reduce total cost from 12.53 (95%UI: 11.71–13.34) to 8.73 (95%UI: 8.09–9.85) billion US dollars. Even if increasing the total costs of IBCM from 100 thousand to 652.10 million US dollars during 2024–2035, the combined strategy of mass dog vaccination and use of IBCM will still dominate, suggesting the robustness of our results.The combined strategy of mass dog vaccination and IBCM requires collaboration between health and livestock/veterinary sectors, and it could eliminate Chinese rabies deaths as early as 2033, with more deaths averted and less cost, indicating that adding IBCM could reduce unnecessary use of PEP and make the "One Health" rabies-control strategy most cost-effective.The online version contains supplementary material available at 10.1186/s12916-023-02821-x. As a nearly always fatal but entirely vaccine-preventable viral disease, dog-transmitted human rabies remains a critical but neglected threat to global health in some countries, especially for children . For exaThe WHO rabies modelling consortium has developed epidemiological and economic models to predict rabies deaths and investigate the effectiveness of enhancing post-exposure prophylaxis (PEP) access in 67 rabies-endemic countries during 2020–2035 [Unlike other Western or Gavi-eligible nations , China hOn the other hand, dog vaccination coverage in China remains inadequate from the "One Health" approach perspective , 11. As Taken togehter, evidence on the effectiveness and cost-effectiveness of comprehensive strategies of improved PEP access for humans, mass dog vaccination, and collaboration between the health and livestock/veterinary sectors through the use of IBCM in the context of the "One Health" approach is lacking in China. We used the updated data from China's national human rabies surveillance system and similar decision-analytic modelling methods as the WHO rabies modelling consortium in the Strategies to inTerrupt RAbies Transmission for the Elimination Goal by 2030 In China (STRATEGIC) study. Specific aims include: (1) to estimate whether the global rabies plan of "Zero-by-30" could be achieved in China under the status quo; (2) if not, to predict the time when the Chinese elimination goal will be accomplished; and (3) to find out the most cost-effective strategy for the purpose in China.As described in the statistical analysis plan , and calculated costs by direct medical expenses only. The incremental cost-effectiveness ratio (ICER) was reported in terms of cost per death prevented, converting all prices to US dollars in 2020. Based on China's per-capita gross domestic product (GDP) of 10,410 US dollars in 2020, if the ICER is less than three times per-capita GDP, the strategy is considered "cost-effective". All scenarios were simulated with a discount rate of 3%, and the time horizon was set from 2024 to 2035.The parameters were divided into three groups based on their role in being bitten by dogs, seeking medical care, and the resulting health outcomes for patients. These categories include parameters related to rabies exposure, healthcare activities, and DALYs and costs. Parameters related to rabies exposure were used to determine the number of people bitten by rabid or healthy dogs. Those related to health care activities were used to calculate the number of human deaths due to dog-borne rabies and medical services used. The parameters related to DALYs and costs were used to calculate the DALYs and estimate the unit cost . The parameter values (including the probability distributions of each probability function) are presented in Additional file The probabilities and numbers bitten by dogs were calculated as follows:In the above formulas, of China . The numThe parameter mentclass2pt{minim Formula .The probability of a patient being bitten by healthy dogs is represented by the parameter  Formula . This vaentclass1pt{minimaHuman deaths caused by dog-mediated rabies were calculated as follows:We used the probabilities of seeking medical care (te=0.99) , and theConsistent with the WHO Rabies Modelling Consortium study , we estiPinfect); and (4) probability of preventing rabies by complete or incomplete PEP treatment (Pprevent) in the one-way sensitivity analyses.We performed probabilistic sensitivity analyses (PSA) to examine the robustness of our results. By drawing 1,000 sets of model parameter values from their distributions, we constructed the results' 95% uncertainty interval (UI). We also separately considered the uncertainty of the following parameters: (1) incidence of rabid dog bites per person annually (the rabid bite incidence); (2) incidence of non-rabid dog bites per person annually (the non-rabid bite incidence); (3) probability of developing rabies with exposure , the annual deaths will decrease from 305 95%UI: 212–407) in 2023 to 212 (95%UI: 147–284) in 2028 and then remain unchanged till 2035  million human-used PEP vaccines will be required during 2024–2035 under the status quo, approximately 25.38 million vials annually, which already exceeds the signed vials in 2020 in China Table . FurtherFrom the cost-effectiveness perspective, the ICERs of the strategies of improving PEP access only (scenario 2) or mass dog vaccination alone (scenario 3a) are 337,771 or 962,920 US dollars per death prevented, respectively, compared with the status quo , the deaths in Hunan  continue to decline, while the trends in Shandong (East China) remain almost unchanged. Scaling up dog vaccination could also facilitate the elimination goal in our six region-stratified analyses, showing that human rabies deaths in all those areas will be zero by 2029  and the one combining mass dog vaccination with the use of IBCM (scenario 4c) might be most affected by uncertainty in the incidence of rabid dog bites  and the revision of the Animal Epidemic Prevention Law (2021) . NeverthThe WHO Rabies Modelling Consortium study suggested expanding PEP access to be highly cost-effective in 67 rabies-endemic countries . In contThe current study showed that it is expected to achieve the elimination goal in China as soon as 2033 by implementing mass dog vaccination coverage of 70%, highlighting dog vaccination in the "One Health" approach for rabies control, which is consistent with findings from other countries , 35. In The WHO proposed the role of IBCM in evaluating the risk of rabies exposure, which formally engages medical and veterinary multi-sectors from the "One Health" viewpoint; however, it has not been implemented in China at all . The purTo the best of our knowledge, this is the first study that used the updated national data to predict the future burden of human rabies and assess the cost-effectiveness of comprehensive rabies-control strategies in China. Moreover, we considered the regional disparities in the rabies epidemic and the economic level in China to inform the evidence-based practical implementation of these strategies for rabies elimination by areas. Nevertheless, as with other modelling studies, our study also has limitations that warrant consideration when interpreting the results. First, some of our assumptions in the model may vary over time; for example, the natural growth rate of the human population will change with time, while we assumed that the values of these parameters were constant for simplicity. In addition, we used similar methods and assumptions to the WHO Rabies Modelling Consortium study for international comparisons. Second, the parameters used in analyses were mainly from official data confirmed in the national rabies surveillance system or published results in other countries; for example, the estimation of the bitten incidence of rabid dogs was from Tanzania . HoweverIn summary, the burden of Chinese rabies death remains stable in the next decade under the status quo; however, scaling up dog vaccination instead of expanding PEP access is crucial to achieving the elimination goal in China as early as 2033. The combined strategy of mass dog vaccination and IBCM could substantially reduce the rabies burden and costs of unnecessary PEP use. Eliminating dog-mediated rabies in China cost-effectively requires the "One Health" approach to prioritize progress in the livestock/veterinary sectors for widespread rural dog vaccination. The successful implementation of IBCM also calls for collaboration between the health and livestock/veterinary sectors. It would be the most cost-effective strategy recommended for interrupting rabies transmission in China, thus eventually contributing to the global plan of ending dog-mediated human rabies death.Additional file 1: Statistical Analysis Plan. A health economic analysis plan. CHEERS 2022 Checklist. Our study followed the updated Consolidated Health Economic Evaluation Reporting Standards 2022 (CHEERS 2022) checklist. Fig. S1 Epidemiology of dog-mediated human rabid deaths of China during 2011–2020. Fig. S2 Diagram of the decision tree model. Fig. S3 Numbers of reported dog-mediated human rabid deaths in China during 2011–2020. Fig. S4 The trends of the number of dog-mediated human rabies deaths, the number of people receiving the PEP, and the vaccine vials used in different scenarios with IBCM from 2023 to 2035 in China. Fig. S5 One-way sensitivity analyses. Fig. S6 Probabilistic sensitivity analyses of the total rabies deaths, DALYs, cost per death averted and cost per DALY averted during 2024–2035 in China. Table S1. The description of the scenarios in the STRATEGIC study. Table S2. The nation-level parameters under the scenario of the status quo (Scenario 1) in China. Table S3. The parameter values under scenarios using different strategies for rabies control in China. Table S4. The region-specific parameters under the scenario of the status quo (Scenario 1). Table S5. The life table for the estimation of life expectancy. Table S6. The predicted number of dog-mediated human rabies deaths in different scenarios with IBCM during 2023–2035 in China by regions. Table S7. The incremental cost-effectiveness ratio per death prevented by different strategies compared with the status quo in China during 2024–2035. Table S8. The ICER per death prevented by different strategies compared with the status quo during 2024–2035 in Shandong (East China). Table S9. The ICER per death prevented by different strategies compared with the status quo during 2024–2035 in Hunan . Table S10. The ICER per death prevented by different strategies compared with the status quo during 2024–2035 in Tianjin (North China). Table S11. The ICER per death prevented by different strategies compared with the status quo during 2024–2035 in Guangxi (South China). Table S12. The ICER per death prevented by different strategies compared with the status quo during 2024–2035 in Shaanxi (Northwest China). Table S13. The ICER per death prevented by different strategies compared with the status quo during 2024–2035 in Guizhou (Southwest China).