Infectious bronchitis virus (IBV) is a vital pathogen in poultry farms, which can induce respiratory, nephropathogenic, oviduct, proventriculus, and intestinal diseases. Based on the phylogenetic classification of the full-length S1 gene, IBV isolates have been categorized into nine genotypes comprising 38 lineages. GI , GVI-1 and GVII-1 have been reported in China in the past 60 years. In this review, a brief history of IBV in China is described, and the current epidemic strains and licensed IBV vaccine strains, as well as IBV prevention and control strategies, are highlighted. In addition, this article presents unique viewpoints and recommendations for a more effective management of IBV. The recombinant Newcastle Disease virus (NDV) vector vaccine expressed S gene of IBV QX-like and 4/91 strains may be the dominant vaccine strains against NDV and IBV. Since the outbreak of Coronavirus Disease 2019 (COVID-19), there are more than 642 million confirmed cases and 6.6 million confirmed deaths caused by the coronavirus infection by December 7, 2022 in World Health Organization website. Since the first confirmed case was announced, the COVID-19 pandemic has lasted almost 3 years, and the virus has caused significant economic loss throughout the world , porcine epidemic diarrhea virus (PEDV), porcine Delta coronavirus (PDCoV), canine coronavirus (CCoV), feline coronavirus (FCoV) and avian infectious bronchitis virus (IBV) . AlthougIBV belongs to gamma group of coronavirus. Its complete genome is about 27.6 kb and composed of 5′-1a-1b-S-3a-3b-3c(E)-M-5a-5b-N-Poly(A)-3′ from 5′ end to 3′ end . A smallCoronaviridae by the International Committee on Nomenclature of Viruses ) and the Coronaviridae is currently divided into two genera Coronavirus and Cyclovirus based on the viral serological characteristics and nucleotide sequence differences. The common important coronavirus such as SARSV, IBV, TGEV and PEDV belongs to coronavirus genus.IB was first described in United States in 1931 as a respiratory disease of chickens . In 1965IBV has existed more than 60 years in China . In 1958S1 gene) may give rise to variants or new genotypes. Many SARS-CoV-2 variants emergence in the past 3 years told us the rapid mutation rate of all coronaviruses including IBV, which can induce the emergence of new virus types with the potential to cause disease  serotype isolation strain was isolated in France in 1985 and then entered the United Kingdom in the winter of 1990 , 37. SubTW genotype is an important gene type and the starts to become the most common genotype in mainland of China recently , 41. IBVTwo novel serotypes have been added into Genotype I IBV in China. The IBV strain ck/CH/LGX/111119 was found to be genetically and antigenically different from other known IBV types and designated as GI-28 based on the results of S1 sequence analysis and virus cross-neutralization tests. It is a nephropathogenic strain with a broader tissue tropism and may be a recombination of LX4 genotype (GI-19) and as-yet-unidentified IBVs . Then, mThe GVII-1 genotype was another novel IBV lineage in China. The GX-NN130021 strain was isolated from suspected IBV-positive 21 day-old diseased chickens, which were vaccinated by the H120 vaccine, in Guangxi province of China in 2013 and were designated as new-type I . An epidCurrently, vaccination inoculations with live attenuated or inactivated vaccines remain the most effective technique for protecting chickens from IBV infection in poultry farms around the globe. In addition to comprehensive biosafety epidemic prevention measures, it is crucial to develop appropriate immunization protocols to prevent and control the IBV infection. There are numerous types of IBV vaccinations in China, including live and inactivated vaccines as well as single and multiple combined vaccines. Moreover, there are also many types of IBV vaccine strains, such as Mass, QX-like and 4/91-like types.All available commercial IBV vaccines were summarized in Although there are numerous vaccines available, there are numerous predominant IBV serotype strains that compromise the vaccine’s effectiveness. Different IBV serotypes only induce limited cross-protective immunity between different serotypes, thus vaccination immunization failures are often reported. Therefore, the key to preventing IBV infection is timely knowledge of the precise local epidemic strain and selection of the appropriate IBV serotype vaccination.Houttuynia cordata (Saururaceae) had more than 90% inhibition rate against IBV infection in cells and more than 50% protection rate in SPF chickens against IBV challenge  vaccine, viral vector vaccine and subunit vaccine against IBV infection might be the future research direction.in vitro, laying the groundwork for further in vitro mRNA research , fowl adenovirus (FAdV), herpesvirus of turkey (HVT), have been reported. Each virus vector vaccine has its own advantage. Among NDV, FAdV and HVT virus vector, NDV might be the best viral vector for IBV in three aspects. Firstly, IBV and NDV are vaccinated at the same time in most cases in poultry farm, that is why all registered IBV combined vaccines contain NDV vaccine, of which most are the LaSota strain . Comparehaemophilus parasuis combination vaccine. Moreover, there is a recombinant subunit vaccination for sheep against Chlymidia psittaci. Overall, many difficulties need to be overcome to develop IBV subunit vaccine. A sustained and stable immune response cannot be produced by the purified pathogen protein generated in vitro due to the difficulty in maintaining stable protein structural epitopes. The immune response typically only affects humoral immunity and is unable to activate cellular immunity. Consequently, the number of doses of subunit vaccination increases, which indirectly raises the labor expenses of chicken farms. Moreover, the production method of protein extraction and purification directly raises the production cost of subunit vaccination. Therefore, the subunit vaccine, which is arduous and time-consuming, is not the optimal method for generating a novel IBV vaccine.At the present, the only genetic engineering subunit vaccine for poultry is infectious bursal disease virus subunit vaccine in China. Several registered subunit vaccinations are available for pigs, including swine fever, porcine circovirus type 2, streptococcus and Respiratory mucosal immunity plays an important role in preventing respiratory diseases, especially coronavirus infection. An aerosolized adenovirus type-5 vector-based COVID-19 vaccine (Ad5-nCoV) has been evaluated in a clinical trial and displayed good neutralizing antibody responses . Meanwhiin ovo vaccination may be available immunization route. In ovo vaccination is performed at 18 day-old embryonated egg in broiler eggs coinciding with transfer of eggs from setter to hatcher compartment and it is adapted as a common practice worldwide now. Unlike coarse spray or water vaccination, in ovo vaccination ensures that each chicken can be immunized with precise, homogeneous distribution of vaccinations. More importantly, in ovo vaccination can induce early immune responses of the day-old chickens against circulating pathogens than post-hatch vaccination does. Therefore, in ovo vaccine is available against IBV combined with NDV, though there are some problems to be considered, including the virulence of vaccine strains on eggs, potential maternal antibody interference and immunosuppression observed with some vaccines , Guangxi Science and Technology Base and Talent Special (2021AC19372) and scientific research startup funds of Guangxi University.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


During the 5-year follow-up within the study period, the cumulative incidence of all-cause death was notably lower in the metformin treatment group compared to the non-treatment group (27.5% vs. 32.8%). The analysis further revealed a significantly reduced hazard ratio (HR) for all-cause death in the metformin treatment group . This population-based cohort study provides evidence that long-term metformin treatment is associated with a decreased risk of mortality among individuals who have both diabetes and gastric cancer.Importance: Despite the existing guideline’s recommendation of metformin therapy as the initial approach for managing diabetes mellitus (DM), there remains a scarcity of comprehensive documentation regarding metformin’s impact on outcomes that are important for patients. Objectives: The objective of this study was to assess the potential impact of metformin treatment on the risk of death in individuals diagnosed with both gastric cancer and pre-existing diabetes mellitus (DM); Design, Setting, and Participants: The study made use of a dataset encompassing nationwide health insurance claims, allowing for a retrospective analysis of all patients with a history of gastric cancer diagnosis  spanning from 1 January 2002 to 31 December 2012. The primary objective was to observe death within a 5-year follow-up period. The study population comprised 63,664 individuals who fell into two categories: those treated with metformin  and those who did not receive metformin treatment . This classification was based on the initial treatment allocation following the diagnosis of gastric cancer. Exposures: Metformin treatment, comorbidities, concurrent medication, and procedural information. Outcomes: All-cause death, disease-specific death, cardiovascular death. Results: During the 5-year follow-up period, the metformin treatment group exhibited a lower cumulative incidence of all-cause death (27.5%) in comparison to the group not receiving metformin treatment (32.8%). Furthermore, the relative hazards for all-cause death were significantly reduced in the metformin treatment group , indicating a lower risk of death when compared to the non-metformin group. In addition, metformin treatment was associated with lower occurrences of disease-specific death (related to gastric cancer) and cardiovascular death when compared to the group not undergoing metformin treatment. Conclusions: The findings demonstrated that the use of metformin was effective at improving prognosis among gastric cancer patients documented with prior DM. In this population-based cohort study, metformin treatment was associated with reduced risk of mortality. Malignant neoplasm is the leading cause of death worldwide, contributing to approximately 19.3 million new cancer cases and 10 million deaths in 2020 . ConsistDiabetic patients with concurrent gastric issues are considered to be at an elevated risk of future mortality and morbidity . HyperinAccording to current guidelines provided by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD), metformin is recommended as the primary oral therapeutic approach for managing diabetes. Metformin is a widely utilized medication that offers evident advantages in terms of glucose metabolism . The proHowever, direct evidence that comprehensively supports the efficacy of metformin in patients with both concurrent diabetes mellitus (DM) and gastric cancer is still lacking. Physiologically, metformin has been shown to reduce glucose production and potentially have an anticancer effect . NeverthIn the context of gastric cancer, metformin has recently garnered attention as a potential treatment with anticancer properties . MoreoveThe study was based on the National Health Insurance Service (NHIS) database. The NHIS is a nonprofit and single-payer system generally administered by the Ministry of Health and Welfare. This study was conducted according to the Declaration of Helsinki and approved by the independent Institutional Review Board of Yonsei University Health System (IRB 4-2021-0374) with no written informed consent because patients’ records/information was anonymized prior to analysis. The data, comprising health insurance claims for the nationwide population, were utilized to retrospectively examine all patients with a history of gastric cancer diagnosis using the International Classification of Diseases 10th (ICD-10) code corresponding to ‘C16.X’ from 1 January 2002 to 31 December 2012. Then, the study was designed to observe the occurrence of death at a 5 year follow-up period.The total of 281,906 newly diagnosed gastric cancer patients was derived from the NHIS claims data after a 1-year washout period, fitting well with the number reported by Korean National Cancer Registration (KNCR) Statistics. From the selected study population, patients with missing demographic information (n = 1119) and patients with multiple cancers  were excluded. Accordingly, 240,104 gastric cancer patients were eligible for the analysis between 2003 and 2012.Of the eligible gastric cancer patients, 154,640 patients with no prior history of DM were excluded. Additionally, those with less than 30 days of follow-up duration  were excluded.Consequently, this study comprised the remaining 63,664 patients who were treated with metformin  and who were never treated with metformin  during the initial treatment allocation after a gastric cancer diagnosis .All-cause death is determined based on death certificates obtained from the NHIS  database. Disease-specific death was defined using the Tenth Revision of the International Classification of Diseases (ICD-10) codes corresponding to ‘C16.X’, which were recorded on the death certificates.In light of metformin’s impact on low-density lipoprotein (LDL) cholesterol and its potential to stimulate cholesterol transport, this study also incorporated cardiovascular death as one of the outcome measures . Cardiovp-value = 0.721).DM was identified through the ICD-10 code recorded in the claims data. Patients who received a diagnosis with the ‘E10.X-E14.X’ code in their claims records prior to the diagnosis of gastric cancer were categorized as having prior DM. The duration of DM prior to the gastric cancer diagnosis was 4.48 years (SD: 3.09) in the metformin treatment group and 4.53 years (SD: 3.11) in the no-treatment group. An analysis of variance (ANOVA) was conducted to test for statistically significant differences in the duration of diabetes between these two groups, and no significant difference was found  were prescribed metformin for 365 days, while 29,852 (46.9%) had no metformin prescription. The remaining 4264 patients (6.7%) in the final sample received less than 90 days of prescription during the first year. These patients with limited prescription days were included in the no-treatment group to prevent selection bias , as remop < 0.001) , 46.4% continued to receive metformin during the first year (refer to .This study followed an intention-to-treat (ITT) approach, commonly employed in randomized clinical trials (RCTs), which involves the inclusion of all patients in the final analysis. Consequently, the treatment allocation established at baseline remains a fixed exposure (treated vs. not treated) for the patients, and subsequent changes in metformin usage are not taken into account. Excluding noncompliant patients could introduce prognostic imbalance among the treatment groups .Continuous variables were expressed as mean ± standard deviation, while dichotomous variables were presented as frequencies and percentages. The estimation of inverse probability of treatment weights (IPTWs) was accomplished using the propensity score, which was determined through logistic regression involving baseline factors such as age, sex, comorbidities, concurrent medication, procedural information, and the year of gastric cancer diagnosis. This approach aimed to minimize confounding bias. In retrospective observational studies based on historical data, many baseline covariates at the subject level are likely to impact both the exposure and the outcome . Thus, iTo stabilize the IPTW, it was multiplied by the marginal probability of receiving each treatment. The imbalance between the two groups for baseline comorbidities and medications was assessed by calculating the difference in effect size using standardized mean difference and visualized using Kernel density plots refer to . Values Landmark analysis was employed to address immortal bias. Participants who were right-censored due to early death before reaching the landmark time were not included in the calculation of risk for death . FurtherThe average survival duration of untreated gastric cancer patients across TNM stages has been reported as 63 months for T1, 25 months for T2, 13 months for T3, and 10 months for T4 . AdditioTo ensure the robustness of the primary findings, several sensitivity analyses were performed, including the utilization of a time-dependent Cox proportional hazard model and conducting a per-protocol analysis. The time-dependent Cox proportional hazard model takes into account fluctuations in treatment status. In this context, if a patient undergoing treatment ceases to receive prescriptions for a period of 60 days during the study duration, this interval is treated as a period of being unexposed . On the p-value of less than 0.05 was considered as the threshold. All statistical analyses were carried out using SAS version 9.4  and R version 4.0 .To determine statistical significance, a two-sided The patients were followed for an average of 4.1 ± 1.7 years in the metformin treatment group and 4.0 ± 1.7 years in the no-metformin group. The baseline characteristics of the study population are presented in The results of sensitivity analyses are provided in The results of the study revealed that the utilization of metformin had a positive impact on the prognosis of gastric cancer patients with a prior diagnosis of diabetes mellitus (DM). Within this population-based cohort study, extended metformin treatment was linked to a decreased risk of multiple outcomes, including (1) all-cause death, (2) disease-specific death related to gastric cancer, and (3) cardiovascular death. These findings collectively suggest that metformin treatment holds the potential to lower the incidence of different types of mortality.Despite the existing guideline’s recommendation of metformin therapy as the initial approach for managing diabetes mellitus (DM), there remains a scarcity of comprehensive documentation regarding metformin’s impact on patient-relevant outcomes. Despite its availability for over 60 years , only a In contrast, the present nationwide cohort study included 29,548 gastric cancer patients with DM who received metformin treatment—approximately ten times the enrolment of previous RCTs (with enrollments ranging from 174 to 2895). Consequently, this study showcased a markedly improved statistical power, enabling a more robust demonstration of the favorable effect of metformin treatment in comparison to no treatment, particularly concerning all-cause death.Patients diagnosed with diabetes mellitus (DM) are at a heightened risk of experiencing cardiovascular events, and those with concurrent DM and gastric cancer face an even greater risk of mortality. Consequently, this specific population necessitates a well-structured treatment regimen aimed at reducing glucose levels and preventing adverse cardiovascular outcomes. The cardiovascular safety of metformin has been a topic of discussion since the publication of the groundbreaking UK Prospective Diabetes Study-34 (UKPDS-34) trial in 1998. The UKPDS study demonstrated that early intensive glycemic control using metformin is associated with a lowered risk of diabetes-related complications and mortality . BuildinThe glucose-lowering effects of metformin primarily involve inhibiting hepatic gluconeogenesis and enhancing insulin sensitivity in musculoskeletal tissues. The mechanisms of metformin action are multifaceted, encompassing both AMPK-dependent and AMPK-independent pathways. These include inhibiting mitochondrial respiration, restraining mitochondrial glycerophosphate dehydrogenase activity, and involving lysosomal mechanisms ,35,36,37Regarding gastric cancer, metformin has recently gained attention as a potential treatment with anticancer properties ,16. The A randomized clinical trial (RCT) conducted by Lee et al. demonstrated that in gastric cancer patients with diabetes, an extended cumulative duration of metformin usage was linked to decreased rates of all-cause mortality and cancer-specific mortality . In our Conversely, concerns surrounding the potential adverse effects of metformin usage have been raised. Among these concerns, gastrointestinal symptoms such as diarrhea, abdominal pain, dyspepsia, and constipation are the most commonly reported due to metformin’s impact on reducing hepatic gluconeogenesis and glucose uptake ,39. A prHigh levels of heterogeneity are likely to emerge in pharmacological observational studies that explore the relationship between metformin usage and the risk of adverse outcomes. One factor contributing to this heterogeneity is the presence of immortal time bias, which has been a longstanding concern in observational studies ,42. ImmoA recent publication from the National Cancer Center highlighted temporal trends in 5-year survival rates among gastric cancer patients, revealing rates of 68.4% in 2006~2010 and 78.0% in 2016~2020 . In compThe current study is subject to several limitations. First, the absence of detailed information regarding gastric cancer stages  represents a limitation, as these data were not available. Instead, the prognosis of gastric cancer was inferred from procedural information during the initial year following diagnosis. Patients’ procedural data were categorized according to the National Comprehensive Cancer Network (NCCN) Guidelines for gastric cancer, factoring in the TNM stage , and cardiovascular death among patients who have both diabetes and gastric cancer. This observation underscores the potential benefits of metformin therapy in improving outcomes for individuals facing this dual medical challenge.


Phosphaturic mesenchymal tumor is a rare tumor characterized by paraneoplastic osteomalacia. The diagnosis is often delayed because of nonspecific symptoms and difficulty to localize the tumor. In this study we report a case of PMT of the left femur detected by Ga-68-DOTATATE PET-CT with radiological features mimicking osteoid osteoma. We report a 31-year-old female patient who presented to our hospital for evaluation due to progressive bone pain and muscle weakness. Her laboratory data showed hypophosphatemia and increased fibroblast growth factor 23 (FGF-23) together with reduced bone mineral density on bone densitometry. The diagnosis of PMT was suspected and the tumor was identified on Ga-68-DOTATATE PET-CT as a focal uptake in a lucent lesion of the left femoral head with a central sclerotic dot mimicking a nidus as seen in osteoid osteoma. The lesion was treated with percutaneous radiofrequency ablation. Laboratory tests and bone densitometry rapidly improved post-treatment. The present case emphasizes the difficulty to diagnose PMT due to its nonspecific biochemical and clinical presentation and the relevance of functional imaging for locating these tumors despite different radiological presentation. Tumor-induced osteomalacia (TIO) also known as oncogenic osteomalacia is a rare paraneoplastic syndrome due to phosphaturic mesenchymal tumor (PMT). Wiedner and Santa Cruz coined the term PMT in 1987. Most tumors occur in middle-aged adults and are more prevalent in males, but it has also been described in the pediatric and elderly population. Less than 1000 cases have been reported in the literature, thus the incidence has not been established yet. These tumors arise from mesenchymal tissue and are mainly benign with less than 10% of all reported cases being malignant We present a patient with a rare bone PMT detected on Ga-68-DOTATATE PET-CT demonstrating radiological features of an osteoid osteoma (OO). This case emphasizes that Ga-68-DOTATATE PET is the imaging of choice and highlights the input of percutaneous treatment with good clinical and biological outcome.We present a 31-year-old woman with no medical history who suffered from painful nonunion traumatic rib fractures after a car accident 7 years earlier, chronic lower back pain, left hip pain, and muscle weakness over the past 5 years, and more recently a delayed osseointegration after dental implants.2; reference range >60).In this context, the patient underwent a bone densitometry which showed reduced bone density with a T-score of −3.0 standard deviations (SD) at the femoral neck and −2.3 SD at the lumbar spine. The baseline laboratory revealed hypocalcemia , decreased calcitriol  and 25-hydroxy vitamin D , elevated serum alkaline phosphatase (ALP) , and elevated beta-crosslaps , while parathormone (PTH) was in the normal range , with preserved kidney function . As the patient also presented iron deficiency, malabsorption was explored and excluded with endoscopic biopsies and MRI. Renal phosphate losses were then evaluated, with the tubular maximum reabsorption of phosphate showing a decreased value of 0.36 mmol/L  despite normalization of calcitriol . In this context, an estimation of the plasma c-terminal fibroblast growth factor 23 (FGF-23) was performed, revealing its abnormal increase , thus suggestive of an FGF-23-related hypophosphatemia inducing osteomalacia presumably secondary to a PMT. To confirm this suspicion, a functional imaging with Ga-68-DOTATATE PET-CT was performed as it is known to have an excellent sensitivity and specificity for these tumors. This exam revealed a focus of increased uptake on the left femoral head, corresponding to the lesion previously seen on MRI, presenting on CT as a well circumscribed lucent lesion surrounded by a sclerotic rim and a central sclerotic dot mimicking a nidus as seen in osteoid osteoma . A bone Despite the nonspecific molecular finding, the diagnosis of PMT was retained and a Ga-68-DOTATATE PET-CT was repeated 2 months later, showing a persistent single increased focal uptake on the left femoral head lesion, unchanged, still suspicious for a PMT with TIO.After discussion with the orthopedic team, surgical treatment with total hip replacement was dismissed because of the patient's young age and fragile bone, and she underwent CT-guided radiofrequency ablation instead (RFA).Following this procedure, laboratory showed a normalization of phosphatemia (1.43 mmol/L)  and the PMTs are a rare mesenchymal tumor frequently associated with TIO due to the excessive secretion of FGF-23, a substance recognized as the principal regulator of phosphate homeostasis. FGF-23 binds to FGFR1 receptor, decreases renal phosphate resorption in the proximal tubule, and inhibits 1-alpha-hydroxylase thus reducing calcitriol (active form of vitamin D) Classically blood laboratory show low or inappropriately low-normal calcitriol, hypophosphatemia, elevated bone fraction of ALP, normal calcium and PTH levels, together with elevated levels of urine phosphate. In some cases, PTH can be elevated, reflecting secondary hyperparathyroidism caused by low levels of calcitriol The diagnosis is often delayed because it is a rare disease with unspecific symptoms including severe bone and muscle pain, fatigue, and pathological fractures. The average time to the correct diagnosis after symptoms onset is 2.9 ± 2.3 years P < .005). Although, the difference in sensitivity between Ga-68 DOTA-SSTR PET-CT and Octreoscan was not significant (P = .161) Functional imaging is used to further explore this pathology primarily with Ga-68 DOTATATE, a somatostatin analog with high affinity for the somatostatin receptor 2, overexpressed in PMTs Once the culprit tumor has been identified, anatomic imaging is used to characterize the lesion, including CT and MRI. When compared with OO which typically presents on CT as a lucent lesion with a central nidus mineralization and surrounding sclerotic reactive bone FN1::FGFR1 or FN1::FGF1 fusion is not essential for the diagnosis, as it has been reported in only 42% and 6% of PMT cases, respectively FN1::FGFR1/FGF1 fusion.Histologically, PMTs can have a heterogeneous morphology with variable patterns, but usually show bland, spindle to stellate cells, which produce a characteristic hyalinized to smudgy-appearing matrix. Detection of As a differential diagnosis, TIO with elevated FGF-23 levels has also been described with different types of carcinomas including colonic adenocarcinoma, ovarian serous carcinoma, clear cell renal carcinoma, lung small cell carcinoma, and anaplastic thyroid carcinoma Complete surgical resection with wide margins is the current standard of care and is the only definitive therapy of TIO Finally, when the tumor cannot be identified nor resected, apart from the classical medical treatment with phosphate and activated vitamin D, new therapies have emerged especially Burosumab, a fully human monoclonal antibody against FGF-23, first approved for the treatment of X-linked hypophosphatemia in children and adults, which has demonstrated a good improvement of biochemical and clinical symptoms in TIO After treatment, serum FGF-23 level falls rapidly and phosphate returns to normal during the first week postsurgery and patient's symptoms regress within days to weeks after tumor removal as in our case. Follow-up of those patients should be done as delayed metastasis has been observed PMT is a rare tumor but should be considered into the differential diagnosis of osteomalacia with hypophosphatemia. Whole-body Ga-68-DOTATATE PET is recommended as the first-line imaging for these tumors. Treatment with RFA is an effective alternative to surgery when it cannot be performed.All listed authors have substantially contributed in the conception and the creation of the article and have approved the final version of the manuscript. The participant has given written informed consent for publication.Written informed consent was obtained from the patient(s) for publication of this case report, including accompanying images.


Chronic lymphocytic leukemia (CLL) treatment scenario is rapidly evolving. As a consequence of longer observation, despite remarkable clinical results, treatment with ibrutinib is associated with long-term toxicities and resistance. New strategies based on BTK inhibition are under development, offering effective salvage treatment both to intolerant and refractory patients. This review is aimed at summarizing and discussing the role of next-generation BTK inhibitors in CLL.Ibrutinib revolutionized the CLL treatment approach and prognosis demonstrating its efficacy and safety even at extended follow-up. During the last few years, several next-generation inhibitors have been developed to overcome the occurrence of toxicity or resistance in patients on continuous treatment. In a head-to-head comparison of two phase III trials, both acalabrutinib and zanubrutinib demonstrated a lower incidence of adverse events in respect to ibrutinib. Nevertheless, resistance mutations remain a concern with continuous therapy and were demonstrated with both first- and next-generation covalent inhibitors. Reversible inhibitors showed efficacy independently of previous treatment and the presence of BTK mutations. Other strategies are currently under development in CLL, especially for high-risk patients, and include BTK inhibitor combinations with BCl2 inhibitors with or without anti-CD20 monoclonal antibodies. Finally, new mechanisms for BTK inhibition are under investigations in patients progressing with both covalent and non-covalent BTK and BCl2 inhibitors. Here we summarize and discuss results from main experiences on irreversible and reversable BTK inhibitors in CLL. The continuous improvement in the understanding of chronic lymphocytic leukemia (CLL) biology over the past decade has led to the development and introduction of several targeted drugs, with demonstrable advances in the prognosis of this incurable condition.Bruton tyrosine kinase (BTK) is a cytoplasmic, nonreceptor tyrosine kinase from the tyrosine kinase expressed in hepatocellular carcinoma (TEC) kinase family that is primarily expressed in hematopoietic cells, particularly in B lymphocytes, but not in T cells or plasma cells.BTK acts as a mediator in the B-cell receptor (BCR) signaling cascade, being involved in B-cells’ proliferation, differentiation and survival. Aberrant BCR signaling pathways contribute to the pathogenesis of B-cell malignancies and are therefore an important target in the treatment of inflammatory reactions and autoimmune diseases, as well as of B-cell malignancies, including CLL ,2,3.Irreversible BTK inhibitors (BTKi) covalently bind to cysteine 481 in the ATP-binding pocket of BTK, while reversible BTKi bind BTK non-covalently and do not require C481 to be present  or del[17p]). Updates of this trial were recently published by Brown et al. . Zanubrutinib met and outperformed the primary non-inferiority endpoint, achieving significantly superior ORR . This difference showed a greater magnitude in 17p deleted patients . Importantly, ORR in this trial was defined as the rate of partial + complete remissions , and excluded patients achieving PRs with lymphocytosis (PR + Ly). Lymphocytosis is an expected pharmacodynamic event with BTKi, which was shown to be not associated with inferior efficacy or long-term survival outcomes with ibrutinib . Taking p = 0.002) both as per investigators and independent reviewer committee assessment. The PFS results favored zanubrutinib consistently across major pre-defined subgroups including IGHV status and patients with del(17p)/TP53. Median OS was not reached in both groups with no statistic differences observed . Finally, compared to ibrutinib, zanubrutinib showed a higher ORR (83.5% versus 74.2%) as per investigators’ assessment, which was consistent with that of the independent review committee.With a median follow-up of 29.6 months, zanubrutinib showed a significantly longer PFS in respect to ibrutinib  across 3 to 8 years of observation ,6,7,9. However, when focusing on specific adverse events, some difference in toxicity emerged in the elderly. At indirect comparison, in fact, patients enrolled in the ibrutinib + rituximab arm of the ALLIACE 041202 trial   showed sNext-generation BTKi were developed to maximize the on-target inhibition of BTK with a supposed reduction of adverse events in vivo.Direct comparisons between BTKi in first-line studies are missing. Long-term data from ELEVATE TN suggest that the addition of obinutuzumab to acalabrutinib does not increase toxicity . Despite all the limitations of indirect comparison, when considering two first-line studies analyzed at a similar timepoint, the ILLUMINATE  and the ELEVATE TN trials ,28, at 4Differently from the first-line treatments, reliable data on the direct comparison of ibrutinib versus acalabrutinib are provided by the ELEVATE RR trial in previously treated patients.According to study results, overall fewer patients receiving acalabrutinib versus ibrutinib developed severe adverse events, thus translating to a lower rate of definitive discontinuations due to toxicity  . The incAs for acalabrutinib, only direct comparisons of zanubrutinib with CIT are currently available in first line. The shorter time of observation of zanubrutinib studies does not allow us to draw any comparison with long-term data of the other BTKi in treatment naïve. However, in the phase I zanubrutinib trial, with about 4 years follow-up, rates of toxicity-related discontinuations <10% and AF < 5% seem particularly favorable even in the setting of TN .Again, direct comparison is available in relapsed/refractory population. Treatment management favored zanubrutinib in respect to ibrutinib in the ALPINE trial , with a Of note, six grade 5 cardiac events occurred during the study, all in the ibrutinib arm. Whereas cardiological toxicity appears to be the only relevant factor differentiating the safety profile of the two BTKi and clearly favoring zanubrutinib over ibrutinib, it is possible to speculate that the management of cardiac events might be the event weighing most on the differences observed for treatment discontinuations in this study.Clinical trials on the use of an alternative BTKi in case of intolerance are available for both acalabrutinib and zanubrutinib ,46. IntoTo summarize, any conclusion about the potential advantage of next-generation BTKis in first line should be taken with caution as it comes from cross-trial comparisons and might fail to recognize inherent differences across studies. On the other hand, the availability of two randomized, controlled phase III trials allows a more appropriate comparison of the safety profile of ibrutinib versus next-generation inhibitors in a previously treated population. Compared to ibrutinib, incidence of atrial fibrillation is lower with both acalabrutinib and zanubrutinib and this is probably the event affecting most ibrutinib management. As regards this specific toxicity, zanubrutinib seems to be even more safe than acalabrutinib at indirect comparison. Nevertheless, it should be kept in mind that no definitive conclusions can be drawn so far, given the shorter follow-up (~2–4 years) of zanubrutinib. New onset or worsening of hypertension does not differ between ibrutinib and zanubrutinib, but seems to be significantly reduced in patients receiving acalabrutinib, thus suggesting favoring the use of this inhibitor in this particular setting. Further studies on direct comparisons between next-generation BTKi and studies on TN patients are warranted. Safety results on acalabrutinib and zanubrutinib are reported and summarized in Several other next-generation covalent BTKi are currently under investigation for B-cell malignancies including CLL.Spebrutinib (CC-292) inhibits BTK by binding irreversibly the same cysteine 481 of ibrutinib . In a phOrelabrutinib (ICP-0229) in vitro showed to be more selective than ibrutinib at 1 µM concentration while targeting BTK with >90% inhibition. The BTKi is currently approved in China for previously treated CLL/SLL , followiTirabrutinib (ONO/GS-4059) as well demonstrated greater selectivity on BTK than ibrutinib. Its activity on B-cell malignancies was reported in 90 R/R patients including 25 CLL. All but one obtained a response within 3 months from treatment start. Low grade diarrhea was the most common AE reported occurring in 18% of patients; hematologic toxicity was the most common grade ≥3 event recorded in CLL, while no cardiac toxicities occurred . TirabruDisease progression is responsible for BTKi discontinuation in 16% to 23% of patients on continuous treatment ,9,54,55.Most of the knowledge on resistance comes from ibrutinib experiences; however, similar resistance mechanisms were identified with acalabruitnib . MoreoveResistance typically arises in the context of indefinite treatment leading to disease progression and treatment cessation more commonly in pretreated and in patients with TP53 abnormalities .Non-covalent BTKi bind the BTK pocket in a site different from the Cys481 amino acid residue, and thereby they can act both in wild-type and Cys481-mutated patients. Four of these agents were developed in clinical trials and include vecabrutinib, fenebrutinib, nemtabrutinib , and pirtobrutinib (formerly LOXO-305).Pirtobrutinib has marked selectivity for BTK and is able to maintain plasma levels above the BTK IC90 with well-tolerated daily dosing. The first-in-human multicenter phase 1/2 study BRUIN clinical trial was addressed to patients with B-lymphomas including 247 CLL/SLL . No doseNemtabrutinib was administered in 57 R/R CLL patients enrolled in a phase I/II trial on B-cell malignancies. Overall response rate was 56% in a high-risk population with a median of 4 prior lines including BTKi and Bcl2i in most of cases. Treatment was well tolerated. No difference in responses was reported according to the presence of BTK Cys481S mutation, double refractory status, 17p deletion or IgHV unmutated status .Two non-covalent BTKi, vecabrutinib (SNS-062) and luxeptinib (CG.806), have curbed their clinical development due to suboptimal activity in CLL ,64.In a phase I study instead, fenebrutinib presented unexpected toxicity in patients with CLL thus limiting its further development in clinical trials .Several factors support the role of a time-limited treatment combination with BTK and Bcl2 inhibitors. These agents, in fact, present a non-overlapping mechanism of action and toxicity profile and act on different compartments. Preclinical studies demonstrated increased functional dependence on Bcl-2 after BTK inhibition , potentiWhile ibrutinib-based combinations are the ones later in clinical development, several trials are currently exploring the activity of zanubrutinib or acalabrutinib together with venetoclax with or without anti CD20 MoAb.A triple combination of acalabrutinib, venetoclax and obinutuzumab (AVO) led to undetectable MRD in 86% of participants, independently of TP53 status. Treatment was safe with a significantly lower rate of AF and hypertension than those previously reported with continuous single-agent acalabrutinib . Given tZanubrutinib combinations are also on study in a frontline setting. The arm D of the above-mentioned SEQUOIA trial consisted of a non-randomized cohort specifically addressed to TN 17p deleted patients . This waIn this population enriched with high-risk prognostic features , ORR was 97.2%, including 36% of CR. Notably, the rate of patients with deep response may be underestimated in this trial due to the unavailability of BM evaluations due to COVID-19 restrictions. With a median follow-up of 12 months, one patient progressed and one died due to a secondary malignancy.Zanubrutinib with obinutuzumab and venetoclax as initial MRD-directed therapy was given in the open label phase II study BOVen . TherapyFurther studies are needed to evaluate if the addition of antiCD20 MoAb to the BTK+Bcl2 combination really gives an advantage and which BTKi should be preferred to use in combination.Several processes involved in the homeostasis of cellular functions, such as proliferation, differentiation and apoptosis, are regulated by the degradation of intracellular proteins.The regulation of intracellular protein levels depends on a system of ubiquitin-dependent proteolysis that is composed of 3 enzymes: ubiquitin-activating enzymes (E1), ubiquitin-conjugating enzymes (E2) and ubiquitin–protein ligases (E3). The catalyzation of the bond between the ubiquitine polymer and lysine residues of substrate proteins by these intracellular proteins leads to proteosome recognition and protein degradation ,72.The use of a proteolysis-targeting chimera (PROTAC), able to selectively degrade intracellular proteins, is emerging as a new potential approach in B-cell malignancies. These molecules are composed of a target protein binding arm, a degradation machinery-recruiting unit and a linker. While the targeting arm binds target proteins, the degradation machinery-recruiting unit links an E3 ubiquitin ligase, thus resulting in the creation of ubiquitin polymers . ConsideNX-2127 is a first-in-class targeted protein degrader of BTK that in a preclinical work was shown to induce the degradation of both wild-type and mutant BTK . Clinical results from a first-in-human phase I study on NX-2127 were recently presented at the last ASH meeting . OverallIbrutinib has revolutionized CLL treatment over the years, allowing the successful treatment of even high-risk diseases. Despite these remarkable results, a proportion of patients will discontinue treatment due to toxicity or resistance. Next-generation BTKi have shown to be better tolerated, thus allowing the gain in clinical practice of a significant advantage in terms of treatment management. Furthermore, these agents, with lower rates of cardiovascular effects and bleeding, appear particularly suitable for elderly and unfit patients, which represent the typical CLL population in common practice. Reversible BTKi represent an effective salvage treatment in covalent BTKi-pretreated patients. Unfortunately, as most trial participants received these agents in advanced lines of therapy, remissions are short, especially in double refractory. These patients represent a clear unmet need in CLL. Several trials are currently ongoing aimed to evaluate the efficacy of non-covalent BTKi in earlier phases of disease treatment.Finally, with the view to reduce toxicity and resistance, time-limited schedules with BTKi plus Bcl2 backbone are appealing options. Doublet and triplet combinations with different classes of agents are currently under evaluation. Although further investigations and longer follow-up are needed to validate the long-term efficacy of these schedules, their introduction in first-line treatment may deeply overturn the CLL concept of therapeutic sequencing in the near future.


This cross-sectional study uses a mystery shopper survey to examine variation in state Medicaid agency responses to coverage questions on out-of-state abortion care. Dobbs v Jackson Women’s Health Organization decision has exacerbated state-level variability in abortion access.1 Some pregnant people have turned to abortion care out of state.The Supreme Court 2 The Hyde Amendment prohibits use of federal funds for abortion except in cases of life endangerment, rape, or incest, although some states use state funding to cover in-state abortions beyond these exceptions.4 Federal regulation requires state Medicaid plans to cover out-of-state services in medical emergencies.5 Little is known about whether state Medicaid agencies cover abortion care obtained out of state. This cross-sectional study used a mystery shopper survey to examine variation in state Medicaid agency responses to coverage questions on out-of-state abortion care.Approximately 35% of people seeking abortion care rely on Medicaid.STROBE reporting guideline was followed.The Yale University institutional review board deemed this cross-sectional study nonhuman participants research, so informed consent was not required. The Between August 22 and September 9, 2022, 3 female callers surveyed Medicaid agencies in all 50 states and the District of Columbia using a mystery shopper design  responded to questions about coverage for out-of-state abortion, 7 (14%) were unreachable, and 4 (8%) could not be surveyed. Of 40 representatives surveyed, 4 (10%) did not know if out-of-state abortion was covered, 4 (10%) said out-of-state abortion was not covered in a medical emergency, 32 (80%) said out-of-state abortion for a medical emergency would be covered; of these, 8 indicated it was also covered in other circumstances .Of 32 representatives reporting coverage for medical emergencies, 20 defined medical emergency as a life-threatening circumstance . Represe6We found variability in agency staff representation of coverage policies for out-of-state abortion care. Some representatives provided information inconsistent with federal policy . Two of these states, Mississippi and Louisiana, had near-total abortion bans in effect at time of data collection. Most representatives (80%) told callers that abortion care rendered out-of-state would be covered only in a medical emergency. This highlights the need for states to establish Medicaid waivers for pregnant people traveling across state lines to seek abortion care.Even in a medical emergency, coverage barriers exist, primarily lack of a consistent, pragmatic definition of medical emergency that can be implemented in real time. Most agencies defined medical emergency as “life endangerment.” Yet, agencies commonly indicated that determination of life endangerment was made retrospectively by various entities, some without expertise in emergency care. Furthermore, some states required emergency physicians to submit prior authorization. Delayed or retrospective application of a life-endangerment standard threatens the lives and livelihoods of pregnant people and creates legal risk and moral distress for clinicians. Federal policy should establish common administrative requirements for out-of-state abortion coverage and monitor states’ abortion claims decisions to ensure adherence to federal regulations. Our study was limited in that findings were based on 1 round of calls to each state agency, so we could not assess for consistency in coverage information within states.


This study examined differences in ADHD symptoms and diagnosis between preterm and term-born adults (≥18 years), and tested if ADHD is related to gestational age, birth weight, multiple births, or neonatal complications in preterm borns.n = 1385 preterm, n = 1633 term; born 1978–1995) examined differences in self-reported ADHD symptoms[age 18–36 years]; and (3) a population-based register-linkage study of all live births in Finland  examined ADHD diagnosis risk in adulthood (≥18 years) until 31/12/2016.(1) A systematic review compared ADHD symptom self-reports and diagnosis between preterm and term-born adults published in PubMed, Web of Science, and PROQUEST until April 2021; (2) a one-stage Individual Participant Data(IPD) meta-analysis . Whereas in the register-linkage study, adults born preterm had a higher relative risk (RR) for ADHD diagnosis compared to term controls . Among preterms, as gestation length  and SD birth weight z-score  increased, ADHD risk decreased.Systematic review results were conflicting. In the IPD meta-analysis, ADHD symptoms levels were similar across groups (mean While preterm adults may not report higher levels of ADHD symptoms, their risk of ADHD diagnosis in adulthood is higher.Preterm-born adults do not self-report higher levels of ADHD symptoms, yet are more likely to receive an ADHD diagnosis in adulthood compared to term-borns.Previous evidence has consisted of limited sample sizes of adults and used different methods with inconsistent findings. This study assessed adult self-reported symptoms across 8 harmonized cohorts and contrasted the findings with diagnosed ADHD in a population-based register-linkage study.Preterm-born adults may not self-report increased ADHD symptoms. However, they have a higher risk of ADHD diagnosis, warranting preventive strategies and interventions to reduce the presentation of more severe ADHD symptomatology in adulthood. The conflicting information may reflect the varying quality of evidence, diverse methods, and small sample sizes of the cohort studies with adult follow-ups,6 Moreover, not all children with ADHD diagnosis in childhood continue to meet the diagnostic criteria in adulthood and the symptom profiles may change with inattention showing the highest and impulsivity-hyperactivity the lowest continuity.7 Also, the predominately male presentation of ADHD in childhood may no longer be present in adulthood.6Studying ADHD in preterm borns beyond childhood is important as the prevalence rate of ADHD diagnosis in the general population declines with age.We conducted a systematic review of existing studies examining associations between preterm birth and ADHD symptoms and diagnosis in adulthood, with evidence quality evaluation. We performed an Individual Participant Data (IPD) meta-analysis to determine if preterm and term-born adults differed in self-reported ADHD symptoms. In a population-based register-linkage study, we investigated the risk of receiving an ADHD diagnosis in preterm compared to term-born adults. We examined the effects of gestational age, birth weight, multiple birth status, bronchopulmonary dysplasia (BPD), and intraventricular hemorrhage (IVH) on later ADHD symptoms and diagnosis for preterm-born adults.8 The IPD meta-analysis and population-based register-linkage study were a part of the Research on European Children and Adults born Preterm (RECAP) consortium (https://recap-preterm.eu/) and Adults Born Preterm International Collaboration (APIC) (https://www.apic-preterm.org/members/). The analysis plan was submitted and approved by the RECAP consortium prior to the study (04/05/2019).The systematic review was performed in line with the preferred reporting items for Systematic Review and Meta-Analyses of Individual Participant Data (PRISMA IPD).We conducted systematic searches in PubMed, Web of Science, and PROQUEST from Inception to October 2019 and an updated search in April 2021 Fig. . DuplicaCohort, case–control, register-linkage studies, and meta-analyses assessing ADHD self-reported symptoms or diagnosis in adulthood (≥18 years) with data on gestational age, were included in the systematic review. Eligible symptom measures included a validated scale providing an overall ADHD symptom score, inattention, hyperactivity/impulsivity, attention problem scores, or clinical cutoffs. Eligible ADHD diagnosis included data from medical records, medical registers, or a structured diagnostic interview. Attention scales derived from neurocognitive tests were beyond the scope of this review. Due to profound changes in medicine during recent decades, we excluded studies with participants born before 1970. There were no language restrictions. Studies were excluded based on criteria presented in Supplemental Table Self-reported symptom studies, which met inclusion criteria for the systematic review and were a part of the RECAP project and APIC consortia were eligible to participate in the IPD meta-analysis. Cohorts with adult follow-up were invited to provide a data dictionary, which was checked for ADHD symptom scales. Studies that declined to provide a data dictionary, did not have an adult ADHD measure, or were not a part of the RECAP/APIC consortia were excluded.In the population-based register-linkage study, the participants were identified from the Finnish Medical Birth Register. We included all live births in Finland from 01/01/1987 to 31/12/1998.z-score and probable clinical ADHD based on clinical cutoffs. Secondary outcomes were inattention, hyperactivity/impulsivity, and attention problems z-scores.For the IPD, all included cohort studies utilized at least one ADHD self-reported symptom scale in adulthood  Revision (code: F90 for ADHD). The Care Register for Health Care is a validated research tool.z-scores were determined using the Intergrowth 21 reference10 and small-for-gestational age (SGA) was defined as birthweight z-score < −2 SD and those not born SGA as birthweight −2 SD or above.Gestational age was calculated from the mother’s last menstrual period or by ultrasound. Preterm birth was further categorized into extremely preterm , very preterm , moderate-to-late preterm  and term . Post term  births were excluded. Birthweight As cohort definitions varied, we harmonized BPD into “no BPD” versus “any BPD” and IVH as “no IVH” versus “any IVH” (Grades 1–4). In the register-linkage study, BPD was defined using the codes 770.7  and P27 (ICD-10) and IVH using codes 772.1 and 772.2 (ICD-9) and P52 (ICD-10). In both studies, multiple births were classified as a binary variable .11 Neurosensory impairment (NSI) was accounted for in sensitivity analyses. For the cohorts, NSI was defined as “no NSI” versus “any NSI” if the participant had severe visual (blind in both eyes) or hearing impairment (not corrected by hearing aids), cerebral palsy, or cognitive impairment (childhood IQ < 70). Missing NSI data in cohorts were treated as no evidence of NSI. In the register study, NSI was defined with the codes 369, 389, 343, and 318–319 (ICD-9) and F70-F79, H54, H90, H91, and G80 (ICD-10).Covariates included participant’s sex, age , and parental education (of either parent/of the mother), which was harmonized according to the International Standard Classification of Education (ISCED) into low (ISCED level 0–2), medium (3–5), and high (6–8).12 The assessment criteria for each NOS domain  were set out at the onset of the study  independently assessed the evidence quality of studies included in the systematic review using the Newcastle–Ottawa–Scale (NOS).IPD and data dictionaries were provided by each of the participating cohorts via the RECAP platform data nodes. The adult data were cleaned and harmonized by the University of Helsinki (RR and reviewed by PG). Perinatal data for the IPD were harmonized by the University of Warwick. The register data were cleaned and harmonized by the Finnish Institute for Health and Welfare. The data underlying this article cannot be shared publicly due to the personal and sensitive information of the participants. If requested, access to this data is subject to data sharing agreements.The IPD meta-analysis was conducted using a one-stage meta-analytic approach where IPD from all cohort studies were analyzed simultaneously. We applied linear mixed-effects models with the restricted maximum likelihood estimation method for the covariance parameters to examine mean differences with 95% confidence intervals (95% CI) in ADHD symptoms between preterm and term-born adults. We applied generalized linear mixed-effects models for binomial data to estimate the odds ratio (OR) with 95% CI of scoring above the clinical cutoff on any of the ADHD scales in preterm compared with term-born adults. In mixed-effects models, random intercepts were specified to account for the clustering of participants within cohorts.ADHD scores were normalized with rank normalization and standardized to the mean of 0 and SD of 1 within each of the studies. As all but two  of the included cohorts had two different ADHD measures, the mean of available standardized ADHD scores was taken.In the register study, we applied binomial logistic regression to estimate the relative risk (RR) with 95% CI of being registered with ADHD diagnosis in public specialized medical care in adulthood between preterm compared with term-born adults.z-score, multiple births, BPD, and IVH were associated with ADHD symptoms and diagnosis among adults born preterm. The effect sizes were estimated in adjusted models. Finally, in sensitivity analyses, we tested whether excluding participants with NSI affected the associations and in the register study, we also excluded participants who died or emigrated at 18 years of age or older.In both study designs, we tested whether the associations varied according to the degree of prematurity and SGA status. Then we tested whether gestational age, birth weight 13 had more than 50% attrition rate. Neither of the two cohorts  which utilized diagnostic interviews (MINI), observed differences between VLBW/ELBW preterms and normal birth weight (NBW) term controls.15 Of the 11 studies,21 with adult self-reported questionnaires, only three cohorts  found differences between preterms and term controls ,26 Germany ,28 UK & Ireland ,25 Norway ,27 Australia 29 and New Zealand .18 The POPs cohort 30 provided data but was subsequently excluded for lack of a control group. The two North American cohorts identified that did not provide data were the McMaster 13 and the Rainbow Babies and Children’s Hospital .16 For all three RECAP/APIC studies not included in the IPD meta-analysis,30 the previous findings are indicated in Table EightAll IPD data sets were checked for data integrity . Any questions were resolved with representatives of specific cohorts. Ultimately, no major issues were identified with the data sets.z-score and probability to score above the ADHD clinical cutoff  .Preterm birth was not associated with total ADHD symptoms off Fig. , hyperacz-score, multiple birth, and BPD were not associated with ADHD symptoms in adulthood .In preterm only analyses, gestational age, birth weight od Table . ADHD syVH Table . This diThe register study characteristics are described in Table Compared to term-born controls, the RR of ADHD diagnosis in adulthood was higher for preterms born SGA and not SGA and for those born VP  or emigrated (n = 90) after 18 years of age and those with NSI (n = 10157) . After excluding individuals with NSI, two associations became apparent: RR of ADHD diagnosis was higher for EP than term-born controls  and for preterms with any BPD compared with those with no BPD .The associations remained when we excluded those individuals who died  and the register-linkage studies (RR = 1.20) provided ample statistical power  to detect small effect sizes, the statistical power in the register-linkage study was superior. This is particularly true for comparisons of ADHD symptoms above the clinical cutoff in the IPD meta-analysis and ADHD diagnosis in the register-linkage study. The statistical power is, however, smaller in comparisons of different gestational age groups and in the comparisons limited to preterm borns only. Moreover, the discrepancies may also be attributable to the composition of the total IPD sample which comprised preterm and term-born individuals from seven different countries, while the register-linkage study comprised only Finns. It is also important to note, that due to differences in the study designs, the samples included in the IPD meta-analysis comprised different numbers of different gestational age groups. For instance, 36.7% of the total IPD EP participants came from the UK, 20.7% from Australia, 17.9% from New Zealand, 13.7% from Finland, 5.6% from Norway, and 5% from Germany., whereas over 70% of MLP and term-born gestational age groups came from Finland. That preterm and term-born adults self-reported equal levels of ADHD symptoms may also suggest that ADHD symptoms do not hinder the daily functioning of adults born preterm. While ADHD in the general population is associated with risk-taking behaviors and criminality,33 preterm-born individuals report less externalizing behaviors,22 less smoking and substance abuse,34 fewer contacts with police,34 have less often experienced sexual intercourse36 by young adulthood, and they also less often have substance use disorders and criminal convictions.4 The lack of differences may also reflect preterm personality: in comparison to term borns preterm borns report being more conscientious, shyer, and less impulsive, less excitement seeking, and less open to new experiences.38The discrepant IPD meta-analysis and the register-linkage study findings may relate to differences in the severity of ADHD symptoms detected by the meta-analysis of self-reports and register-linkage study of diagnosis. ADHD self-reports may have captured milder, sub-clinical symptoms, whereas the register-linkage study on ADHD diagnosis may have captured the most severe end of the ADHD spectrum, attending public specialized medical care. Only 0.64% of the individuals in our study had been registered with an ADHD diagnosis in adulthood. This is slightly lower than the estimated adult prevalence of 2.5–4.2% in high-income countries.22 which however included fewer cohorts with adult follow-up than included here. The register-linkage study findings indicating higher RR for ADHD diagnosis for preterms than term controls are consistent with another Finnish register study, which examined ADHD specialty care diagnosis between ages 3 and 19,1 and with a Swedish register study assessing specialty care diagnoses at ages 5–19 y.4 Our findings are also in agreement with Norwegian, and one Swedish, register studies assessing psychostimulant medication use at 18–38 y,39 30 y,40 and at 26–33 y.41The lack of differences between preterm and term adults in self-reported symptomatology in the IPD meta-analysis are consistent with a previous meta-analysis,6 This may be due to women with ADHD, at least in childhood, presenting less disruptive ADHD-like behaviors,42 and in parent and teacher reports girls with ADHD show lower levels of hyperactivity, impulsivity, inattention and externalizing symptoms and higher levels of internalizing symptoms.32 However, it has also been suggested that differences between men and women in ADHD may level off as the individuals’ age, and some studies have reported that in adulthood women report higher ADHD symptomatology than men.43Highlighting further differences between the results of the IPD meta-analysis and register-linkage study, women in the IPD meta-analysis of cohorts reported higher levels ADHD symptoms, while in the register-linkage study men had a higher RR for ADHD diagnosis in adulthood. The higher ratio of men to women, may suggest that women may be more likely to be underdiagnosed.The only agreed finding between the cohort IPD meta-analysis and the register-linkage study was that participants with lower parental/maternal education had higher ADHD symptoms and RR for diagnosis.44 This is important, as generally, the rates of ADHD tend to decline with age.5 Additionally, the limited range of birth years included allows contextualization of the medical practices or interventions, which may have played a role in the outcomes observed in this generation. Furthermore, performing an IPD meta-analysis allows for the same covariates and confounders to be accounted for across all studies, typically a weakness in standard aggregate data meta-analyses. Moreover, in both the IPD meta-analysis and the register-linkage study, we were able to uniquely parcel out gestational age and birth weight categories and study neonatal complications in relation to the risk of ADHD symptoms and diagnosis in those born preterms, for which individual cohort studies lack the power to do.A strength of our systematic review and IPD meta-analysis includes a focused age group, allowing for a better understanding of the symptomatology of adults, instead of summarizing the symptoms or diagnosis across the entire lifespan as done in other studies.44 Hence, the generalizability of the findings is limited. Additionally, although we had IPD data, we were not able to account for additional potential confounders, and residual confounding cannot be excluded. We were not able to obtain IPD from all cohorts with self-reported ADHD symptom scales in adulthood with preterm or VLBW participants. It is unlikely that the inclusion of these three studies would have changed the results, since these studies have previously reported no differences.21 Finally, while the Care Register for Health Care is a validated research tool, including ADHD diagnosis in childhood,9 comparable data on adulthood ADHD diagnosis is lacking.A common weakness, our results do not represent low- or middle-income countries, as the IPD meta-analysis included only high-income country populations.45 and with ADHD,46 understanding the intersections of the two is important. Pinpointing that preterms or specific preterm and birth weight groups are at a slightly increased risk of receiving ADHD diagnosis in adulthood than others may pave the way for targeted interventions to reduce the burden. On the other hand, the lack of differences in self-reported ADHD symptoms between preterm and term-born adults delivers a positive message for the preterm-born individuals themselves, their families, and healthcare professionals.Considering the substantial economic burdens associated with preterm birthSupplementary informationSupplementary Material


Patients with kidney failure from racial and ethnic minority groups and older patients have reduced access to the transplant waitlist relative to White and younger patients. Although racial disparities in the waitlisting group have declined after the 2014 kidney allocation system change, whether there is intersectionality of race and age in waitlisting access is unknown.Retrospective cohort study.439,455 non-Hispanic White and non-Hispanic Black US adults initiating dialysis between 2015 and 2019 were identified from the United States Renal Data System, and followed through 2020.Patient race and ethnicity (non-Hispanic White and non-Hispanic Black) and age group .Placement on the United Network for Organ Sharing deceased donor waitlist.Age- and race-stratified waitlisting rates were compared. Multivariable Cox proportional hazards models, censored for death, examined the association between race and waitlisting, and included interaction term for race and age.Over a median follow-up period of 1 year, the proportion of non-Hispanic White and non-Hispanic Black patients waitlisted was 20.7% and 20.5%, respectively. In multivariable models, non-Hispanic Black patients were 14% less likely to be waitlisted . Relative differences between non-Hispanic Black and non-Hispanic White patients were different by age group. Non-Hispanic Black patients were 27%, 12%, and 20% less likely to be waitlisted than non-Hispanic White patients for ages 18-29 years , 50-64 , and 65-80 years , respectively, but differences were attenuated among patients aged 30-49 years .Race and ethnicity data is physician reported, residual confounding, and analysis is limited to non-Hispanic White and non-Hispanic Black patients.Racial disparities in waitlisting exist between non-Hispanic Black and non-Hispanic White individuals and are most pronounced among younger patients with kidney failure. Results suggest that interventions to address inequalities in waitlisting may need to be targeted to younger patients with kidney failure.Research has shown that patients from racial and ethnic minority groups and older patients have reduced access to transplant waitlisting relative to White and younger patients; nevertheless, how age impacts racial disparities in waitlisting is unknown. We compared waitlisting between non-Hispanic Black and non-Hispanic White patients with incident kidney failure, within age strata, using registry data for 439,455 US adults starting dialysis (18-80 years) during 2015-2019. Overall, non-Hispanic Black patients were less likely to be waitlisted and relative differences between the two racial groups differed by age. After adjusting for patient-level factors, the largest disparity in waitlisting was observed among adults aged 18-29 years. These results suggest that interventions should target younger adults to reduce disparities in access to kidney transplant waitlisting.  KAS was designed to reduce racial disparities in access to deceased donor kidney transplantation by redefining the start of waiting time from the time of waitlisting to the time of kidney failure treatment initiation. Early data suggests declines in racial disparities in waitlisting,We identified all adult (18-80 years) patients with kidney failure initiating dialysis between January 1, 2015, and December 31, 2019 , from the United States Renal Data System (USRDS)Patient information was obtained from the USRDS patient data, Medical Evidence Form (CMS-2728) data, and the USRDS data on waitlisting events obtained from the United Network for Organ Sharing (UNOS) data on kidney transplantation waiting list and transplant events. Given that some patients had multiple CMS Medical Evidence Forms, the first record providing information on comorbidity status at kidney replacement therapy (KRT) initiation was used. Outcome data on waitlisting was obtained from the UNOS data contained within the USRDS waitlisting dataset. Neighborhood-level characteristics were determined by linkage to the 2015-2019 American Community Survey using the patients’ 5-digit ZIP code. Dialysis facility-level information was obtained from the USRDS facility dataset. Sources of data within this file are the CMS end-stage renal disease Annual Facility Survey and the Centers for Disease Control and Prevention Dialysis Surveillance Survey collected between January 1, 2018, and December 31, 2018. This data was linked to patient observations from the USRDS using the USRDS Assigned Facility ID. This study was exempted from review and a waiver of informed consent was granted for this retrospective, deidentified study by the Emory Institutional Review Board.a priori by mirroring the age stratification used in Kucirka et al,The primary outcome was placement on the UNOS waiting list for a deceased donor kidney . Study participants were identified at the initiation of dialysis and followed until waitlisting, death, or the end of the study , whichever occurred first. Race and age were the primary exposures in the analysis. Race was defined as non-Hispanic White or non-Hispanic Black. Here, we consider race a social construct, not a biologic categorization.Descriptive statistics were calculated for patient- and neighborhood-level factors for the study population and stratified by race and age. The cumulative incidence estimated probabilities of placement of patients with kidney failure on the waitlist during follow-up by race and age, treating death as a competing risk using the model of Fine and Gray.a priori if they had previously been shown to be associated with race and/or age, or waitlisting.8,,P < 0.001). After a significant interaction, we stratified all analyses by age. Given our large sample size, the proportional hazards assumption was tested by examining log-log curves, with no evidence of non-proportionality. To avoid selection bias, we included patients who were preemptively waitlisted , and their time to waitlisting was coded as 1 day. A complete case analysis, omitting cases with missing data, was used to account for the presence of missing patient data for explanatory variables included in the model. Less than 10% of the data was missing for all variables, excluding dialysis facility patient-to-social worker ratio information (15.75% missing).We used crude and multivariable-adjusted Cox proportional hazards models, adjusted for patient demographic and clinical characteristics and censored for death,Given high race-based disparities in young adults, we conducted additional subgroup analyses to examine the association between race and waitlisting among adults aged 18-29 years stratified by sex, insurance type, body mass index, pre-kidney failure nephrology care, primary cause of kidney failure, and percentage of neighborhood poverty subgroups to determine whether racial disparities in young adults were specific to patients with certain demographic characteristics or comorbidities. Crude and multivariable-adjusted Cox proportional hazards models, censored for death, were repeated within each subgroup. Additionally, sensitivity analyses were conducted to evaluate racial differences in the placement on the waitlist, accounting for death as competing events using Fine and Grey models to calculate the adjusted subdistribution hazard ratios. In a sensitivity analysis, descriptive statistics were calculated for patient- and neighborhood-level factors for patients who were preemptively waitlisted in comparison to those who were not, and evaluated the impact of including these preemptively waitlisted patients on differences in the incidence of waitlisting by race and age during the study period by obtaining the cumulative incidence estimated probabilities, excluding patients who were preemptively waitlisted. SAS 9.4  was used for data management and analyses.Among 439,455 patients with incident kidney failure with a median age 63.0 years , there were approximately twice as many non-Hispanic White patients  compared to non-Hispanic Black patients . Non-Hispanic White (vs non-Hispanic Black) patients were more likely to have private insurance and diabetes as the underlying cause of kidney failure. In comparison, non-Hispanic Black (vs non-Hispanic White) patients were more likely to have hypertension as the most frequently attributed causes of kidney failure and a higher percentage of patients with ZIP codes containing ≥20% of residents below the poverty. Racial differences in population characteristics persist across all age groups. The percentage of patients receiving pre-kidney failure nephrology care increased with age, with care less common among patients aged 18-29 years. Other comorbidities were similar between non-Hispanic White and non-Hispanic Black patients with kidney failure being common for all ages .Table 1BOverall, the probability of waitlisting for patients with kidney failure was 20.5% for non-Hispanic White and 20.7% for non-Hispanic Black patients, during a median follow-up of 588  and 728  days, respectively . About oBy age, waitlisting was highest among patients aged 18-29 years  and lowest in adults aged 65-80 years  . Non-HisIn multivariable models, race-based disparities in waitlisting differed by age group. Specifically, non-Hispanic Black patients were 27%, 12%, and 20% less likely to be waitlisted than non-Hispanic White patients for ages 18-29 , 50-64 , and 65-80  years, respectively, but similarly likely to be waitlisted among patients 30-49  .Among patients with kidney failure aged 18-29-years, race disparities were consistent across sex, insurance status, body mass index, prekidney failure nephrology care (yes/no), primary cause of kidney failure , and neighborhood poverty .In multivariable-adjusted subdistribution hazard models, adjusting for death as a competing risk, we found similar findings with the main analyses. Non-Hispanic Black patients had lower rates of waitlisting compared with non-Hispanic White patients in unadjusted  and multivariable models (aSHR, 0.88; 95% CI, 0.79-0.99, In this study, we show that in the post-KAS era, racial disparities persist, and non-Hispanic Black patients with kidney failure are 14% less likely to be waitlisted compared with non-Hispanic White patients with kidney failure. Furthermore, we show this relative disparity is largest among younger adults, with non-Hispanic Black patients aged 18-29 years being 27% less likely to be waitlisted compared with their non-Hispanic White counterparts. Indeed, in this young age group, the race-based disparity is similar across sex, insurance type, body mass index, pre-kidney failure nephrology care, primary cause of kidney failure, and neighborhood poverty subgroups. These findings have important implications for the development of interventions to address racial disparities in access to kidney transplant waitlist. Specifically, we posit that interventions may have the most effect if they are targeted toward young Black patients with kidney failure.,,,,,,,,,Since implementation of KAS, there has been a 12%-19% decline in racial inequities in waitlisting in Black vs White patients.,,,There are other unmeasured factors that may explain the observed racial disparities in waitlisting, especially among younger patients, including social networks, information about the transplant process, cultural/personal beliefs, structural racism, and patient preference.,,,Prior research on disparities in the care of patients with kidney failure has suggested that older, but not younger, Black patients receiving dialysis have a survival advantage, similar to our findings. However, the mechanisms are unclear.,Given the numerous upstream social determinants of health that influence racial disparities in kidney transplantation, it is important to focus interventions on these complex and multilevel factors which serve as the underlying fundamental causes of these inequities.,,,This study has several limitations. First, there are potential factors that may be associated with placement on the waitlist, such as educational attainment, patient preferences, cultural/linguistic barriers, employment status, and other patient comorbidities, that were not measured in the current analysis.8In conclusion, this study provides evidence that in the post-KAS era, racial disparities in waitlisting persist between non-Hispanic Black and non-Hispanic White patients and these disparities are greatest in younger adults. Determining the reasons for greater disparities in waitlisting between non-Hispanic Black and non-Hispanic White patients, especially among the younger patients who experienced greater disparities, can help to inform future interventions and policies to improve equity in access to transplantation.