The Disease Recovery Evaluation and Modification study  assessed the benefit of initiating paliperidone palmitate (PP), a long-acting injectable antipsychotic, in patients with recent-onset schizophrenia or schizophreniform disorder.To determine whether reductions in psychiatric hospitalizations with early initiation of PP vs oral antipsychotic (OAP) therapy observed in a DREaM post hoc analysis are transportable to a real-world population of patients with recent-onset schizophrenia.Patients enrolled in DREaM were randomized to receive OAP or PP for 9 months, after which OAP recipients were re-randomized to receive OAP or PP for another 9 months. We used this design to form treatment arms: OAP-OAP, OAP-PP, and PP-PP. Inclusion/exclusion criteria were used to identify a Medicaid Managed Care (MMC) OAP-treated cohort of 1,000 patients diagnosed with schizophrenia using IBM Truven databases from 2015 to 2019. The MMC cohort was combined with the subset of patients diagnosed with schizophrenia enrolled in DREaM from US sites . Propensity scores for the MMC cohort were estimated using baseline variables identified via double-lasso regression. Estimated propensity scores were used to weight psychiatric hospitalizations in the DREaM OAP-OAP group and compared with observed MMC OAP cohort psychiatric hospitalizations. After the successful calibration of the DREaM OAP-OAP group, similar approaches were taken for the OAP-PP and PP-PP groups to transport DREaM effects to MMC data.Standardized mean differences in baseline covariates between DREaM treatment arms and MMC groups were substantially reduced after calibration. The 18-month cumulative numbers of psychiatric hospitalizations per patient (SE) were 0.83 (0.14) for the MMC cohort, 0.43 (0.14) for the unweighted OAP-OAP, and 0.80 (0.37) for the calibrated OAP-OAP. The difference between the calibrated OAP-OAP and MMC was not statistically significant , indicating successful calibration. The mean difference in 18-month cumulative psychiatric hospitalizations relative to the MMC cohort was -0.77 (95% CI = −1.08 to −0.47) for OAP-PP and −0.83 (95% CI = −1.15 to −0.60) for PP-PP.Our study demonstrates that results from the DREaM OAP-OAP group reflect psychiatric hospitalizations in a real-world population when calibrated using specific baseline characteristics. Transporting the DREaM effects, we find that using OAP-PP and PP-PP treatment strategies for patients with recent-onset schizophrenia in the MMC population could reduce psychiatric hospitalizations compared with the use of OAP. These findings, along with the potential reduction in associated costs, should be considered when assessing the value of PP formulations. Paliperidone palmitate (PP) is an injectable medicine used to treat schizophrenia. In the Disease Recovery Evaluation and Modification (DREaM) clinical trial, PP reduced the number of psychiatric hospital visits for patients. In this study, we investigated whether PP could have a similar effect on nontrial patients. We identified a cohort of patients enrolled in Medicaid who shared features with the patients from the DREaM trial. Our analysis showed that PP could reduce psychiatric hospital visits in these patients as well. Implications for managed care pharmacyIn this calibration of DREaM clinical trial data to a real-world cohort of patients enrolled in Medicaid, treatment strategies that included long-acting injectable PP were predicted to reduce psychiatric hospitalizations over 18 and 30 months in patients with recent-onset schizophrenia vs strategies that included the use of oral antipsychotics. The significant reduction in psychiatric hospitalizations, taken together with the potential reduction of associated health care costs, demonstrates the benefit of including PP in Managed Medicaid formularies.1 The trial was conducted in 3 parts . In part I , participants were treated with oral paliperidone or oral risperidone for 2 months. In part II, participants who adequately tolerated OAPs  were randomly assigned 2:1 to continue OAP or switch to PP and were followed for 9 months. Patients randomized to OAPs were allowed to switch to other OAPs prospectively. During this time, participants who were adequately treated with PP once-monthly were transitioned to PP once every 3 months. In part III, participants randomly assigned to PP in part II continued PP for another 9 months, whereas participants randomly assigned to OAPs in part II were randomly assigned a second time 1:1 to treatment with OAPs or PP and followed for another 9 months.1 A previous post hoc analysis using DREaM data 2 capitalized on these successive randomizations and applied the principal stratification approach to study 3 randomized groups of patients with schizophrenia, each exposed to a different sequential treatment strategy: OAP-OAP, OAP-PP, or PP-PP. The analysis revealed that the OAP-PP and PP-PP strategies generated statistically significant reductions in 18-month cumulative psychiatric hospitalizations (−0.27 [95% CI = −0.50 to −0.04] and −0.28 [95% CI = −0.51 to −0.08]), respectively, compared with the OAP-OAP strategy, primarily because of a faster accumulation of psychiatric hospitalizations in the OAP-OAP strategy compared with the OAP-PP or PP-PP strategies over the 18-month period.The Disease Recovery Evaluation and Modification (DREaM) randomized controlled trial (RCT) compared the time to first treatment failure with paliperidone palmitate  or oral antipsychotics (OAPs) in patients with recent-onset schizophrenia or schizophreniform disorder.3 Moreover, when 1 or more treatment strategies are relatively new, real-world data often do not include enough patients receiving these strategies to draw statistical comparisons.When decision-makers use clinical trial results to inform population-level decisions, they often try to assess the generalizability of these data to real-world populations to anticipate the potential realized value of their choices. In a typical comparative effectiveness study using real-world data, observational data methods are used to compare the outcomes for patients receiving different treatments. However, there are challenges to evidence generation for such purposes. These strategies are often subject to sizeable confounding bias problems.6 Such an approach can provide robust real-world evidence early in the adoption timeline of new technologies or therapies.5 Herein, we describe a similar approach to calibrating the comparative effectiveness results from a health care resource utilization analysis of the DREaM study2 to the target real-world population of patients with recent-onset schizophrenia enrolled in Medicaid Managed Care (MMC).An alternate way to generate real-world evidence for comparative effectiveness is to rely on RCT data and calibrate the RCT results to a control cohort extracted from real-world data.In the current study, we evaluated whether the results of the DPH analysis were generalizable to the broader real-world population of patients with recent-onset schizophrenia enrolled in MMC and receiving continuous OAP treatment. We also evaluated how the distribution of baseline risk factors in the target population could modify the treatment effect results observed in the DPH study.1 Briefly, the study enrolled adult men and women aged 18 to 35 years who had a current diagnosis of schizophrenia or schizophreniform disorder and a first psychotic episode within the previous 24 months. Patients were excluded if they met the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria for a moderate or severe substance use disorder (except for nicotine) within 2 months of screening. The present analysis only included patients with a diagnosis of schizophrenia, as that is the US Food and Drug Administration-approved indication for 1-month or 3-month PP extended-release injectable suspension .8 All study participants provided written informed consent.Details of the inclusion/exclusion criteria for the DREaM study have been previously described.We used the 2015 to 2019 MMC dataset provided by IBM MarketScan for the real-world population. This database contains the medical, surgical, and prescription drug experiences of more than 47 million Managed Medicaid enrollees from multiple states. It includes records of inpatient services, inpatient admissions, outpatient services, prescription drug claims, and information about long-term care and other medical care. Data on eligibility (by month), service, provider type, and patient demographics are also included.International Classification of Disease, Ninth Revision [ICD-9]: 295.xx and Tenth Revision [ICD-10]: F20.xx) at any position during 2015 to 2019. We restricted inclusion to those who were enrolled continuously for at least 18 months. Currently, no standard definition for recent-onset schizophrenia is published in the literature. We used a working definition of recent-onset schizophrenia that required patients to have continuous enrollment for at least 12 months before the first (index) diagnosis of schizophrenia and to have incurred no utilization with schizophrenia ICD codes at any position between the start of continuous enrollment and the index diagnosis  marks the index date for the current study.The real-world target population for the DPH was identified in the MMC data by applying specific inclusion/exclusion criteria from the DREaM study . We idenWe compared the 3 treatment strategies  included in the DPH study. OAP medications were identified in the MMC database using National Drug Codes. The OAP-OAP exposure represents the control group of the DPH analysis and is the only strategy that we identified in the MMC data to carry out our calibration exercise. Because of the rare (<1%) use of PP in the MMC population during this period, we did not perform a direct comparative evaluation of PP treatment strategies vs OAP in the MMC data. Instead, once we calibrated the outcomes from the OAP-OAP arms of the DPH study and the MMC database, we used the evidence on outcomes from the OAP-PP and PP-PP treatment strategies of the DPH study and transported them to the MMC population. This exercise informed the counterfactual outcomes as to what would have happened if the real-world OAP cohort had instead followed OAP-PP or PP-PP strategies.9 or ICD-10 codes F20.xx,10 reported in the primary diagnosis field of the hospitalization. These codes are presented in Supplementary Tables 1 and 2. This outcome was chosen because psychiatric hospitalizations are important outcomes for patients with schizophrenia and have served as the primary outcomes in previous studies with LAIs.13 Furthermore, the DPH showed significant effects of different antipsychotic treatment strategies on psychiatric hospitalizations, which were the major driver of the treatment failure endpoint in DREaM.1Psychiatric hospitalizations were identified based on ICD-9 codes 295.xxCalibration variables included those collected as part of the DPH study that were also available in the MMC database. These variables included patient age at index date, race, sex, duration of continuous antipsychotic use before the index drug , we calibrated the DPH results to inform the counterfactual. The DPH results were used to forecast outcomes within the MMC OAP cohort over 18 and 30 months had they instead followed the OAP-PP or PP-PP strategies in DREaM. Here, a linear model was fit to the cumulative levels up to 18 months and then the slope was extrapolated to 30 months. We also carried out sensitivity analyses, directly adjusting for any residual confounding that was due to the imbalances in observed covariates after calibration.The feasibility of calibrating results from the DPH to the MMC data was assessed by comparing calibrated psychiatric hospitalizations from the OAP-OAP group of the DPH with observed psychiatric hospitalizations in the real-world cohort of patients with recent-onset schizophrenia receiving OAP treatment identified from the MMC. Conditional on this step being successful .Compared with the DPH OAP-OAP group, real-world patients with recent-onset schizophrenia in the MMC data were slightly older (26 vs 22 years), more likely to be female (40% vs 19%) or those who self-identified as non-Hispanic White (40% vs 33%), and less likely to be self-identified Hispanic (3% vs 23%). The MMC patients were also more likely to use OAP for less than 6 months during the pre-index diagnosis period (93% vs 44%) and more likely to have a substance abuse issue in the last 2 years (88% vs 21%) compared with the DPH OAP-OAP treatment group . The MMCThe double-lasso method identified the relevant predictors of our propensity score model . The preNext, we applied a similar calibration exercise to the outcomes. The cumulative number of psychiatric hospitalizations per patient (SE) in the DPH OAP-OAP group was 0.43 (0.14) over 18 months . The corConsequently, we calibrated the DPH OAP-PP and PP-PP group outcomes to the MMC cohort. We found that, although the cumulative incremental effects of OAP-PP and PP-PP groups vs OAP-OAP groups in the DPH analysis were −0.31 (95% CI = −0.63 to −0.04) and −0.38 (95% CI = −0.67 to −0.13), respectively, when calibrated to the MMC cohort, the projected reduction in psychiatric hospitalizations over 18 months from the OAP-PP and PP-PP arms were much higher. We estimated that, compared with the observed MMC cohort receiving OAPs, treating this cohort with OAP-PP or PP-PP would have generated a difference of −0.77 (95% CI = −1.08 to −0.47) or −0.83 (95% CI = −1.15 to −0.60) psychiatric hospitalizations per patient over 18 months, respectively . The resAfter similar extrapolation of the calibrated DPH OAP-PP and PP-PP results from the first 18 months, it was estimated that, compared with the observed MMC cohort receiving OAP, treating them with OAP-PP or PP-PP would have generated a difference of −1.37 (95% CI = −1.86 to −0.94) or −1.45 (95% CI = −1.93 to −1.06) psychiatric hospitalizations per patient over 30 months, respectively . ResultsIn this analysis, we aimed to transport DPH results to a real-world population of patients with recent-onset schizophrenia to estimate the potential real-world impact of the early use of PP, based on the results of the DREaM trial. We found that psychiatric hospitalizations of patients enrolled in the DPH OAP-OAP treatment group could be generalized to the real-world MMC target population through the calibration of selected baseline characteristics. When we transported the DPH treatment effects to the MMC population, we observed even larger reductions in psychiatric hospitalizations among the MMC patients than those estimated in the DPH analysis over 18 months. We next extrapolated the 18-month results to a 30-month follow-up window and found that PP-PP–based regimens can produce statistically significant reductions of up to 1.4 hospitalizations per patient.17 This raises the question of the generalizability of trial results to real-world data. However, one way to address such concerns is to see if calibration of the control arm of the trial using observed baseline covariates can reproduce observed outcomes in the real-world data. We followed this approach in this work. Successful calibration of the control arm outcomes produces stronger assurances that treatment effects from the trial could be reliably transported to the real-world setting. In our case, the transported effects were bigger in the real-world setting as compared with the DPH study because the type of patients incurring more hospitalizations under the control arm in the DPH study were present in higher proportions in the real-world data.Notably, we observed that the absolute risk of psychiatric hospitalizations in the MMC was higher than in the DPH. This may have been due to the impact of enrollment in a clinical trial, in which the increased level of care provided to a patient, including caregiver intervention, may lower the risk of illness exacerbation resulting in acute hospitalization in both treatment arms. Furthermore, the ascertainment of certain comorbidities that may contribute to the risk of acute exacerbation  is likely more reliable in a trial setting than in real-world data. Patients who enroll in clinical trials may also have a higher motivation for self-care and the support of caregivers, which serve as protective factors against acute exacerbation.Our work has implications for future designs of comparative effectiveness studies. Specifically, sampling for a well-defined target population is always helpful for generalizability. Such sampling not only encompasses the clinical inclusion/exclusion criteria but, preferably, targets specific payer systems in which the prevalence of the condition is highest. Also, if transportability analysis such as was used in the current study is planned, collecting a set of baseline covariates in common with those available in real-world data would readily improve the quality of the analyses.2 The current study demonstrates that those trial-based reductions in psychiatric hospitalizations with PP could generalize to a real-world patient cohort and adds to the emerging body of literature supporting LAI use in early schizophrenia. In the DREaM trial and other RCTs, LAIs have been shown to improve outcomes, such as the risk of treatment failure/relapse  and the severity of psychotic symptoms, compared with OAPs in patients with recent-onset schizophrenia.20 Consequently, clinical guidelines, which recommend treatment with LAIs in patients who prefer the injectable formulation and/or are at high risk of nonadherence, increasingly suggest considering LAIs early in the course of illness.25Our prior DPH work has demonstrated that DREaM participants who received PP experienced significant reductions in psychiatric hospitalizations and associated costs compared with OAPs.3; this is a manifestation of our small sample sizes, in which perfect alignment between covariates was not possible. However, we do see that calibration improved SMDs for all covariates. Fourth, the small sample size of the DPH study generated uncertainty in the calibration exercise, especially when the temporal trends were extrapolated to 30 months. However, our effect sizes still reach statistical significance because of the large estimates of the effect sizes and, therefore, are likely to signal a genuine reduction in real-world settings. Fifth, linear extrapolation of the projected 18-month reduction in psychiatric hospitalizations was used to predict subsequent observations through 30 months. This extrapolation relies upon the assumption that data trends are maintained throughout the 30-month period. Lastly, there are also limitations in the MMC data source that may have impacted the calibration results. For instance, Hispanic patients were only 3% of the MMC cohort, whereas approximately one-third of patients enrolled in the DREaM trial were Hispanic. However, the calibration was able to significantly reduce the SMD in these patients from 1.11 to 0.06 for the OAP-OAP group.The study has some limitations. First, claims data were used to identify recent-onset schizophrenia, and these data may not be inclusive of a patient population with recent-onset schizophrenia. We relied on observed and common patient characteristics between the DPH and MMC data to calibrate the DPH and project outcomes to the real world. Second, this exercise could be incomplete if some unobserved characteristics that affect outcomes are different between the clinical trial and the real-world sample. However, the similarity of calibrated DPH OAP-OAP outcomes to the observed MMC outcomes serves as a validation that our approach was not duly affected by such unobserved factors. Third, after calibration, some SMDs did not reach the typical benchmark of 0.1 to signal close alignment of those covariate statisticsDespite these limitations, this study provides valuable insights into the potential benefits of LAI use compared with OAPs among patients with recent-onset schizophrenia. As early LAI use continues to become more commonplace, clinicians may find this insight useful while considering the long-term health outcome and health care cost benefits of treatment strategies for patients recently diagnosed with schizophrenia.Our study demonstrates that the results from the DREaM OAP-OAP group could be calibrated to reflect psychiatric hospitalizations in a real-world population. Transporting the DREaM effects, we find that using OAP-PP and PP-PP treatment strategies for Medicaid beneficiaries with recent-onset schizophrenia could reduce psychiatric hospitalizations. These findings, along with the potential reduction in associated costs, should be considered when assessing the value of treatment options for patients with recent-onset schizophrenia. Such evidence is useful for policymakers to appropriately assess the value of using PP vs OAP in real-world patients with recent-onset schizophrenia.


Coronavirus disease 2019 (COVID-19) infection is a global health crisis resulting in significant morbidity and mortality. The presentation of COVID-19 infection is variable, ranging from an asymptomatic carrier state to multi-organ failure. While cases of COVID-related myocarditis and myocardial dysfunction are well reported, only a few cases of coronary artery thrombosis resulting in myocardial infarction are noted on literature review. However, the previously reported cases were in patients with high risk for coronary artery disease. We hereby report a case of a young man with no significant past medical history or cardiovascular risk factors who presented with severe chest pain and was diagnosed with acute myocardial infarction in the setting of COVID-19 infection requiring intervention. We want to report this case to improve awareness in the community about COVID-related arterial thrombosis and have a high index of suspicion for this regardless of the person’s risk factors for cardiovascular diseases. Coronavirus disease 2019 (COVID-19) infection is a global health crisis, described as a pandemic by the World Health Organization in March 2020 [A 27-year-old male with stage 1 obesity and no significant past medical problems presented with sudden onset of severe, substernal chest pain which awakened him from sleep. He also experienced diaphoresis, nausea and vomiting with chest pain. He denied use of tobacco products or recreational drugs. No personal history of similar symptoms and no family member suffered from premature coronary artery disease.Patient was evaluated in the emergency department. On arrival, he was found to have a temperature of 98.7 F, blood pressure of 136/68 mmHg, heart rate of 92 beats per minute and respiratory rate of 18 breaths per minute. His pulse oxygen saturation (SpO2) was 97% on room air. Initial laboratory work-up was remarkable for positive COVID-19 nucleic acid amplification test. Complete blood count and complete metabolic panel were within normal range with the exception of hypokalemia; potassium of 2.9 mmol/L . Lipid profile included a total cholesterol of 131 mg/dL , low-density lipoprotein (LDL) of 91.5 mg/dL , high-density lipoprotein (HDL) of less than 20 mg/dL  and a triglyceride level of 210 mg/dL . Urine drug screen was positive for cannabinoids and the patient denied any other illicit drug use. Troponins were negative. Electrocardiogram (EKG) on arrival showed ST elevation in the inferior and lateral leads  daily for COVID-19 treatment as per the hospital protocol. It is to be noted that the patient was on room air and exhibited no symptoms of COVID-19 pneumonia.Given a major thrombotic event in the setting of COVID-19 infection in an otherwise healthy individual, a multidisciplinary discussion was held with cardiology and hematology. Decision was made to initiate him on anticoagulation with unfractionated heparin and he was bridged to warfarin. Patient continued to be on dual antiplatelet therapy (DAPT) and statins. Literature review also revealed reports of intracardiac thrombus with COVID-19 infection, and a plan was thereby made to perform transesophageal echocardiography. However, patient refused. As his clinical condition dramatically improved, he was discharged on DAPT, warfarin, high-dose statin, beta-blockers and angiotensin converting enzyme inhibitors (ACEI).COVID-19 infection is an entity that usually presents with respiratory and systemic symptoms including; shortness of breath, fever, anorexia, myalgias, headache, fatigue, non-productive cough, sore throat and rhinorrhea. The most common sequelae of the infection that results in in-hospital admissions are viral pneumonia and acute respiratory distress syndrome.These patients are also at an increased risk of thrombosis . ThromboThe mechanisms that underlie cardiovascular disease in COVID-19 patients are not completely understood. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects cells via the angiotensin converting enzyme 2 receptor (ACE2R), which is expressed in cells across many organs, including endothelial cells in vascular tissue . This inWhen considering the management of ST-elevation myocardial infarction (STEMI) in patients with suspected or positive COVID-19 infection, it is important to note that COVID-19-associated myocarditis also can present with ST-segment elevation. It is critical to differentiate these conditions as the management varies and these subjects should be carefully selected for invasive methods of revascularization and reperfusion .Algorithms have been put forward that might assist clinicians in the triage and decision-making process when deciding to whom and how resources are to be allocated . If therIt is important for all medical personnel involved to employ precautions against airborne, droplet and contact transmission of the virus including the use of personal protective equipment (PPE) and the proper sanitation of the medical equipment and environment in order to decrease the risk of transmission within the hospital and in the community at large . Acute coronary syndrome must be considered in the differential diagnosis in patients with COVID-19 infection presenting with acute chest pain, regardless of their age and cardiovascular risk factors. We need a high index of suspicion to identify these patients and triage them in the right direction. The mechanism that underlies the cardiovascular disease involves entry of the COVID-19 virus via ACE2 receptors into endothelial cells of vascular tissue. The resulting diffuse inflammation results in vasoconstriction, tissue edema and a procoagulant state. This in addition to cytokine storm, hypoxic injury and hypercoagulability induced by COVID-19 predisposes patients to a thrombotic event. The management of ACS in patients with COVID-19 infection follows the same pathways as those without COVID-19 infection. However, it is essential to differentiate COVID-19-associated ACS from COVID-19-induced myocarditis to reduce the risk of unwarranted invasive procedures and possible complications.


High-risk human papillomavirus (HR-HPV) is the primary cause of cervical cancer, leading to over 311 000 global deaths, mainly in low- and middle-income countries. Kenyan women living with HIV (WLHIV) face a disproportionate burden of HR-HPV.We determined the prevalence of HR-HPV infections and their association with cervical cytology findings among Kenyan WLHIV.® assays and HPV Genotypes 14 Real-TM Quant V67-100FRT. Bivariate analysis explored the associations.We conducted a cross-sectional study among WLHIV attending the HIV care and treatment clinic at the Kenyatta National Hospital (KNH), Kenya’s national referral hospital. Study nurses collected a cervical sample with a cytobrush for HR-HPV genotyping using Gene XpertP = 0.001). Women with HR-HPV infection (single or multiple) were more likely to be on the second-line ART regimen compared to those without HR-HPV infections .We enrolled 647 WLHIV (mean age of 42.8 years), with 97.2% on antiretroviral therapy (ART) and 79% with a suppressed viral load (< 50 copies/mL plasma). The prevalence of any and vaccine-preventable HR-HPV was 34.6% and 29.4%, respectively, with HPV 52 being the most common genotype (13.4%). Among WLHIV with HR-HPV infections, 21.4% had abnormal cervical cytology. Women with multiple HR-HPV infections were more likely to have abnormal cytology compared to those with single HR-HPV infections (34.9 vs 9.3%, adjusted odds ratio [aOR] = 6.2, 95% confidence interval [CI]: 2.7–14.1, Among WLHIV at KNH, abnormal cytology was common and more frequent among women with multiple HR-HPV infections. What this study adds: These results add to the growing evidence that more efforts are needed to improve routine screening for high-risk human papillomavirus (HR-HPV) infections and cervical cancer among WLHIV as well as optimised HPV vaccination among eligible girls.2 In the year 2020, over 550 000 incidental cases of cervical cancer were reported, with a staggering 90% of these cases and 300 000 cervical cancer-related deaths occurring in low-income countries.3 Persistent infection with high-risk human papillomavirus (HR-HPV) types is responsible for more than 70% of global cervical cancer cases, with varying prevalence rates of HR-HPV infections observed among different countries.5 In a global context, eastern, western and southern African regions exhibit the highest incidence rates of cervical cancer, with age-standardised rates of 34.5, 33.7, and 26.8 cases per 100 000 populations, respectively. In Kenya, the annual incidence rate of cervical cancer is 15 cases per 100 000 women, and the corresponding annual mortality rate is 12 deaths per 100 000 women.6 This substantial disease burden can largely be attributed to insufficient access to screening services and suboptimal screening uptake rates, stemming from limited knowledge or apprehensions regarding cervical cancer and HR-HPV screening among women. Other factors that have led to a high HR-HPV disease burden include low vaccine coverage and high rates of HIV and HPV co-infection as well as limited access to screening services.8Cervical cancer is one of the AIDS-defining cancers and is ranked fourth among the most common cancers affecting women worldwide.9 indicating that the infection occurs earlier in life and progresses slowly to cancer. Metaplastic changes in the endocervix continue to occur throughout a woman’s lifetime, with the period of greatest activity coinciding with the highest risk of HPV infection during puberty and the first pregnancy. Metaplastic changes gradually decline after menopause.11 Precancerous stages or pre-invasive precursor lesions are graded based on cytological examination and include atypical squamous cells of undetermined significance (ASCUS), low-grade squamous intraepithelial lesions (LSIL), high-grade squamous intraepithelial lesions (HSIL), and invasive cervical cancer (ICC).14The persistence of HR-HPV infections can result in the development of cervical lesions. Pre-cervical cancer lesions and cervical cancer lesions are most frequently observed in women aged 30 years and above,16 In contrast, HR-HPV infections in HIV-negative women may be cleared in some individuals by the stable cell-mediated immune system or tend to regress.17 Although antiretroviral therapy (ART) has been associated with a decrease in the incidence of other AIDS-defining cancers, its impact on cervical lesions remains unclear. In HIV-infected women, cervical lesions and the progression to malignancy tend to occur at an earlier age (around 20–25 years) when there is immunosuppression and when other competing health factors are present. Due to the presence of multiple HR-HPV infections, invasive malignancies may progress more quickly to unusual locations and respond poorly to therapies. Additionally, the risk of recurrence from latent and sanctuary sites is high, resulting in a poor prognosis.18 The prevalence of HR-HPV infections among WLHIV on ART and resulting cervical cytology patterns remains unclear in low-income settings, with some studies reporting no effects of ART on cervical cancer.19Women living with HIV are at a disproportionate risk of acquiring HR-HPV infections, harbouring multiple HR-HPV infections, and developing persistent infections that can result in abnormal cervical lesions due to their compromised immune status.22 However, annual reports indicate sustained cervical cancer incidental and mortality rates among WLHIV in the ART era in sub-Saharan Africa (SSA).6 The development of three different HPV vaccines that are strongly efficacious against some HR-HPV types offers protection against cervical infections caused by the HR-HPV genotypes in the vaccines as well as HPV-associated cancers and condylomas. The synergy between primary and secondary prevention efforts of cervical cancer among WLHIV is still unclear. One of the most neglected aspects of the potential effect of prophylactic vaccines in SSA is the evaluation of existing screening practices and existing HR-HPV genotypes. There may be unique challenges and considerations for this population regarding HPV vaccination and screening.6 Women living with HIV have a higher risk of developing HPV-related cancers due to their compromised immune systems, which may limit the effectiveness of the HPV vaccine.17 Furthermore, WLHIV may experience barriers to accessing both HPV vaccination and cervical cancer screening services due to stigma, discrimination, and limited healthcare resources.23 Therefore, it is crucial to consider these factors when implementing HPV vaccination and cervical cancer screening programmes for WLHIV.24Primarily, cervical cancer is preventable through the vaccination of young girls aged 9–14 years with the HPV vaccine. The secondary prevention strategy for cervical cancer prevention is through cervical cancer screening among women aged 30 years and above, which has been implemented.25 The algorithm involves screening WLHIV for HR-HPV using a point-of-care HPV DNA molecular rapid platform, and, if the test is positive, performing visual inspection with acetic acid (VIA) and treating precancerous lesions with cryotherapy on the same day.25 HR-HPV DNA testing has been utilised as a screening and triage test due to its increased sensitivity.27 The algorithm can help to identify and treat precancerous lesions before they progress to cancer. The same-day treatment approach can also improve patient satisfaction and reduce the burden of multiple clinic visits. However, there are also potential barriers to implementing the ‘test and treat’ algorithm. One of the main challenges is the lack of trained healthcare providers and infrastructure in many low- and middle-income countries where the burden of HIV and cervical cancer is highest. The algorithm also requires reliable electricity, equipment, and supplies for HR-HPV DNA point-of-care consumables and cryotherapy, which may not be available in some settings.28 There is also a need for community engagement and education to increase awareness and uptake of cervical cancer screening among WLHIV.The World Health Organization (WHO) recommends novel approaches to increase the uptake and utilisation of cervical cancer screening and fast-track same-day ‘test and treat’ algorithms for WLHIV.There is limited information on the epidemiology of the current HR-HPV infections among WLHIV and the associated cervical cytology patterns in the ART era in SSA. With the increased risk of cervical abnormalities among WLHIV in Kenya and the further development of cervical cancer, there is an urgent need to invest more in interventions targeting HR-HPV genotype screening and prevention. These interventions largely require HR-HPV genotypes and cytological patterns data for effective implementation. Currently, there are no comprehensive insights into the prevalence rates and distribution of HR-HPV infections and their correlation with cervical cytology among Kenyan WLHIV enrolled for care and treatment.This cross-sectional study recruited WLHIV aged 18 years and above attending the ART clinic at Kenyatta National Hospital (KNH) from June 2021 to March 2022. Those who were willing to participate consented and were counselled on the benefits of cervical cancer screening. The study excluded the following participants: pregnant women, history of previous total hysterectomy, radiotherapy or chemotherapy, those currently menstruating, and those with abnormal vaginal bleeding.Kenyatta National Hospital is the largest tertiary health facility in Kenya, with a bed capacity of 1800 and a bed occupancy rate of 90% – 95%. The ART clinic at KNH was established 20 years ago for the prevention and treatment of HIV and associated morbidities in men and women including adolescents and children. On average, the ART clinic offers services to nearly 10 000 clients, with the highest proportion being women. Cervical cancer screening commenced 12 years ago as part of integrated service for HIV care for WLHIV at the ART clinic. Trained nurses performed routine annual visual inspections with acetic acid or Lugols iodine (VIA or VILI). Women found to be positive are offered cryotherapy or loop electrosurgical excision (LEEP), depending on the accessibility to the transformation zone, by the gynaecologists upon referral to gynaecological specialised clinic at KNH. Cytological screening and HPV genotyping of high-risk types are not routinely done for patients.® , and cytology smears were prepared for examination by a trained cyto-screener in the cytology laboratory at KNH. The additional individual HPV genotyping was done using HPV Genotypes 14 Real-TM Quant V67-100FRT . Briefly, the study procedure involved face-to-face interviews after written informed consent was obtained. The interview covered sociodemographic, behavioural and sexual characteristics, history of HIV diagnosis, investigation, and treatment. Afterward, each participant was examined by a trained research nurse at the ART clinic, including a general physical and pelvic examination. In the lithotomy position, a nurse passed a sterile Cusco speculum to visualise the cervix, and a cytobrush was inserted into the endocervix and rotated 360 degrees twice. Part of the sample collected was used to prepare a slide for cytological assessment and the remaining samples were sent to the laboratory for HPV genotyping. The nurse also reviewed the HIV electronic medical records (EMR) of each participant and copied relevant information into the data collection form.In this study, eligible WLHIV were offered initial partial HPV testing using Gene XpertAll participants had post-test counselling, irrespective of the HPV test and cervical cytology results. Women that had abnormal cytology using ASCUS classification  were referred to a gynaecologist for further evaluation and treatment based on KNH guidelines.All eligible participants at the ART clinic were informed as a group about the study before the commencement of the clinic session. Women that signified intention to participate in the study had further discussions with a research assistant individually on the study objectives and procedure. At each clinic session, a sampling frame was generated from a list of all eligible women in attendance. We used a simple random sampling technique to select eligible women from the sampling frame. In this technique, random numbers generated from Excel were used to select women before consent was taken.14 The leftover smear sample in the brush was placed in a PreservCyt solution  and taken to the laboratory for HPV detection of high-risk HPV types  using the Xpert HPV platform . Thereafter, advanced individual HR-HPV genotyping was conducted. First, the DNA was extracted using a QIAamp DNA Mini Kit in accordance with the manufacturer’s protocol . The HPV detection was done, and specific genotypes were then identified and interpreted using the HPV Genotypes 14 Real-TM Quant V67-100FRT kit .The slide for the cervical spear was prepared by the oncology-trained nurse using the standard protocol of KNH for Papanicolaou smear preparation. The prepared slides were shipped to the cytopathology laboratory for staining and reading by a cytopathologist. The results were interpreted using the Bethesda system.® version 23.0 . Descriptive statistics were presented in frequencies and proportions for categorical variables and mean or median for continuous variables. The primary outcome of this study was the presence or absence of abnormal cervical cytology readings . Bivariate analysis was also done to explore the association between sociodemographic, clinical characteristics, and lifestyle characteristics with having normal or abnormal cytology using Chi-square test of associations, after which a multivariate logistic regression model was built to adjust for potential confounders.Data collected were entered into the ODK tool kit and exported as a CSV file before importing into SPSSAs depicted in Participant characteristics are shown in As shown in The prevalence of any and vaccine-preventable HR-HPV was 34.6% and 29.4%, respectively. As shown in Based on age categories, WLHIV aged less than 25 years had the highest rate of HR-HPV infections (46.7%) followed by those aged 35–44 years (36.6%). Those aged 55 years and above had the lowest rate of infection (26.6%), as shown in the Appendix.Out of the 224 WLHIV having HR-HPV infections, 21.4% had abnormal cervical cytology. Of those with abnormal cytology, 56% had ASCUS, 12% had LSIL, 19% had HSIL and 13% had ICC, as shown in Among WLHIV with normal cervical cytology, the most dominant HR-HPV genotype was HPV 52 (30.7%). Participants having ASCUS had HR-HPV type 56 as the most detected genotype (81.5%), those with LSIL had HR-HPV 16 dominating (66.7%), and HR-HPV 31 dominated in HSIL (66.7%). Women living with HIV with cervical cancer had HR-HPV type 16 and 52 equally dominating (50% each), as shown in P = 0.015). Women living with HIV with multiple HR-HPV infections were more likely to have abnormal cytology as compared to those with single HR-HPV infections . No other risk factor was significantly associated with abnormal cytology, as shown in Participants aged 35 years and above were more likely to have abnormal cytology .Women living with HIV having HR-HPV infection (single or multiple) were more likely to be on second-line ART regimen compared to those without HR-HPV infection  of the participants with HR-HPV infections in our study were discovered to have different types of cervical abnormalities. This finding emphasises the importance of regular cervical cancer screening in WLHIV.HPV is the most prevalent STI worldwide and is a well-known risk factor for the development of cervical cancer, especially in WLHIV.34 This finding is notable because these three HPV types are the most oncogenic and are responsible for the majority of cervical cancer cases worldwide. The lower prevalence of types 16, 18 and 45 in our study may be due to regional differences in HPV prevalence or differences in the population studied, differences in the sample size, and laboratory methods used for HR-HPV testing.26 Additionally, it is plausible that the prevalence of distinct HR-HPV genotypes exhibits temporal variations due to shifts in sexual practices or variances in HPV vaccination rates across diverse populations.8 The immune status of the WLHIV participants may have played a role in the different distribution of HR-HPV genotypes observed in this study. This highlights the need to focus on other HR-HPV infections in addition to types 16, 18, and 45 in WLHIV enrolled for ART care.We found that HPV 52 was the most common HR-HPV genotype (13.4%), followed by types 16 (9.9%) and 18 (8.2%), while HPV 59 was the least prevalent (1.7%). Notably, types 16, 18 and 45 were not dominant in this study, a trend observed in other studies among WLHIV and the general population in the region.35 Cervical abnormalities from additional HR-HPVs have received little attention in low-income settings, indicating the importance of individual genotyping of all HR-HPV types and implementation point-of-care molecular screening in the same-day screen-and-treat strategy for cervical cancer screening among WLHIV. Screening for a limited subset of HR-HPV genotypes may not optimally identify those at risk of infection and cervical lesion development. According to the findings of this research, WLHIV face a heightened vulnerability to contracting multiple HR-HPV infections, such as HPV 52 and other HR-HPV genotypes that are not safeguarded by the existing Cervarix or quadrivalent Gardasil HPV vaccines offered in Kenya. Given these circumstances, there is a pressing requirement to initiate HPV vaccination using Gardasil-9, which has demonstrated comparable or superior efficacy against seven HR-HPV types.38Previous studies in Kenya have also reported a high prevalence of HR-HPV 52 and 35.34 While HR-HPV infections among young women may regress with time due to viral transience, persistence or latency may also occur, which could increase the risk of developing cervical cancer over time.39 These findings suggest the need for targeted interventions to address the high prevalence of HR-HPV infections among young WLHIV, particularly those aged less than 25 years. Such interventions should focus on promoting safe sexual practices, HPV vaccination, early detection and treatment of HR-HPV infections, and related conditions, such as abnormal cervical cytology. Therefore, ongoing monitoring and screening for HR-HPV infections and related conditions are critical for the long-term health of WLHIV, especially those in the younger age group. In addition, it was observed that among WLHIV aged 35 years and over, there is an increased prevalence of abnormal cytology in the presence of HR-HPV infections. The heightened occurrence of abnormal cytology can be attributed to the persistent and reactivated state of latent HR-HPV infections, which were acquired during earlier sexual activity. Therefore, it is inadequate to rely solely on HPV vaccination as an intervention to eliminate HR-HPV infections and cervical cancer. It is imperative to implement adequate routine cervical cancer screening, as emphasised by the Ministry of Health and Cubie and Campbell, to enable timely detection and management of cervical cancer in this vulnerable population.41This study found that young WLHIV aged < 25 years had the highest prevalence of HR-HPV infection (46.7%). This increased prevalence among young women may be due to their heightened susceptibility to HR-HPV as a result of early sexual debut and increased sexual activity. Though not statistically significant in this study, participants who had their first sexual debut before 18 years of age were more likely to have HR-HPV infections as compared to others. Similar findings were reported by Guthrie et al. among WLHIV in discordant relationships in Kenya.15 in their study among WLHIV in South Africa and Burkina Faso, demonstrated this vulnerability. Our study also found abnormal cytology in 21.4% of WLHIV with detectable HR-HPV infections, of which 68% were low-grade precancerous lesions and 32% were high-grade pre-cancer lesions. However, the prevalence of cervical lesions in our study was lower than that reported by Guthrie et al.34 in their study of WLHIV in discordant relationships in Kenya. Importantly, it is worth noting that spontaneous regression of cervical lesions is common in over 75% of women, and thus, these lesions should be viewed as reflective of an infection rather than a disease stage or progression. This implies that the interpretation of cervical lesions should be done carefully to prevent stigmatisation, anxiety, and fear among the screened women. Furthermore, clearance of HR-HPV infections should also be approached with caution since it may be misinterpreted as an inability of the screening method used to detect existing HPV infections, as Krings et al. emphasised.42The immunocompromised state of WLHIV makes them susceptible to HR-HPV infections with increased persistence, leading to a higher incidence of cervical lesions compared to HIV-negative women. Kelly et al.,16 Menon et al., in their study conducted in Western Kenya, demonstrated a 2.3-fold higher prevalence of cervical lesions in individuals with multiple HR-HPV infections compared to those with a single HR-HPV infection.19 This finding provides evidence to support the hypothesis that the presence of multiple HR-HPV infections increases the risk of developing pre-cervical cancer lesions if HR-HPV infections do not regress. The coexistence of multiple HR-HPV infections may lead to a higher HR-HPV viral load, increased persistence of the virus, and increased oncogenic potential, resulting in an increased likelihood of developing cervical lesions.19 Taken together, these results underscore the importance of vigilant monitoring for the presence of multiple HR-HPV infections among WLHIV, as they may serve as a predictor for the development of cervical lesions if they do not regress naturally or are managed promptly. The South African study further reported that participants with multiple HR-HPV infections were found to exhibit inadequate responses to therapy. This highlights the urgent need for increased investment in HR-HPV vaccinations, particularly among eligible girls, to prevent the occurrence of multiple infections. This recommendation aligns with the findings of a study conducted by Haque and colleagues, which reviewed insights and solutions for the elimination of HR-HPV infections and cervical cancer in SSA.43 The implementation of comprehensive vaccination programmes targeting multiple HR-HPV types has the potential to substantially reduce the burden of cervical cancer in this region. In the current study, only 1.1% of the participants had been vaccinated for HPV. This is similar to previous research conducted in Kenya on the uptake of the HPV vaccine, which reported poor uptake of the vaccine (33% for the first dose and 16% for the second dose). The poor uptake was associated with lack of awareness and education about the virus. In addition, their study also found that only 30% of parents had heard of the HPV vaccine, and only 13% had knowledge of its purpose. This lack of knowledge and awareness can lead to misconceptions about the vaccine and, ultimately, low uptake. To address this barrier, public education campaigns and community outreach programmes could be implemented to increase knowledge and awareness about the HPV vaccine.44 Cultural beliefs and practices have also been identified as barriers to HPV vaccine uptake in Kenya. Some parents believe that the HPV vaccine could encourage sexual promiscuity among their daughters, which goes against their cultural values. Additionally, some parents believe that the HPV vaccine is not necessary because their daughters are not sexually active.45 In addressing this barrier, it is important to engage with local communities and involve cultural leaders in public education campaigns. The cost of the vaccine has also been identified as a barrier to HPV vaccine uptake in Kenya for adolescent girls aged >14 years. Many parents do not have health insurance and are not able to access the vaccine through the national immunisation programme.46 It may be necessary to explore alternative financing mechanisms, such as public-private partnerships or donor funding, to increase access to the vaccine. Fear of side effects is another barrier to HPV vaccine uptake in Kenya. Some parents are concerned about the safety of the HPV vaccine and are worried about potential side effects, including the future fertility impacts on young girls. This fear can lead to low uptake of the vaccine, despite its proven effectiveness.47In the context of WLHIV, the co-occurrence of multiple HR-HPV infections is frequently observed. The findings of this study demonstrate a significant correlation between the presence of multiple HR-HPV infections and abnormal cervical cytology. This outcome is consistent with a prior investigation conducted in South Africa, which evaluated WLHIV with cervical intraepithelial neoplasia and found a similar association.48 Specifically, our study found that 22.1% of the participants had been on ART for more than five years and had abnormal cervical cytology results. These findings highlight the ongoing need for continued research and interventions to address the complex health needs of WLHIV, including the potential for co-infections and comorbidities such as HPV-related conditions. In the present study, there was also no significant association between unsuppressed viral load and HR-HPV infections. This denotes that there was no relationship between HR-HPV infections or abnormal cervical cytology, and poor HIV treatment outcomes indicated by the unsuppressed viral load. Contrary to our findings, other studies reported that women on ART for a shorter period and those with unsuppressed HIV viral loads were associated with increased HR-HPV infections and cervical abnormalities.15 In 2017, the WHO recommended immediate ART initiation, regardless of the WHO clinical stage or CD4 count.49 Thus, women on ART have an increased life expectancy due to less competing risk of dying from opportunistic infections. Due to the improved cell-mediated immune status leading to prolonged life, incidences of HR-HPV infections, persistence, and later development to cervical lesions could be on the rise.50Despite the decreasing incidence of other AIDS-defining cancers, HR-HPV infections and cervical lesions have not shown a similar decline among WLHIV who are using ART.51 Although we found there was no statistical association between the number of sexual partners and HR-HPV infection rates in the overall population, 34.8% of the respondents had two or more sexual partners, which could have led to increased HR-HPV infections and abnormal cytology. Other studies have also reported a higher risk of HR-HPV infections among individuals with multiple sexual partners, such as Okunade et al. and Wencel-Wawrzeńczyk et al.53 The present study found that condom use was not significantly associated with either HR-HPV infections or abnormal cytology. However, lack of condom use in conjunction with multiple sexual partners have been linked to an increased risk of STIs such as HR-HPV infections with progression to abnormal cytology. A study conducted among women of reproductive age in Gambia reported an increased risk of HPV infections among participants with multiple sexual partners and those who did not use condoms.39 These findings suggest that interventions aimed at reducing the number of sexual partners and promoting condom use may be effective in reducing the risk of acquiring new HR-HPV infections among WLHIV.The acquisition of new HR-HPV infections among WLHIV may be linked to having multiple sexual partners, according to research conducted by Brown and Weaver.54 Smoking has been shown to impair the function of Langerhans cells, which act as immune cells in the cervical region, thus increasing the vulnerability of smoking women to HR-HPV infections. This was observed in studies conducted by Skinner et al.55 and Mayaud et al.8 In the present study, approximately 18.3% of the participants with abnormal cytology were using alcohol, and 25% smoked cigarettes. However, these lifestyle factors were not statistically significant. Tobacco-associated carcinogens have also been found in the genital tract of women and may act as co-factors for the development of cervical lesions, particularly in the presence of other coexisting factors such as HIV infection and alcohol consumption.57Alcohol consumption and cigarette smoking have also been linked to new HR-HPV infections and persistence, as noted in research conducted by Soh et al.60 This suggests that interventions targeting these risk factors could be effective in reducing the incidence and persistence of HR-HPV infections and associated complications.Lifestyle-related factors, such as early initiation of sexual intercourse, cigarette smoking, and promiscuity, have been found to increase the risk of HR-HPV infections and progression to cervical lesions in alcoholic women.One of the strengths of this study is the inclusion of a relatively large sample of WLHIV with factors associated with HR-HPV infections and cervical cytology. However, it is important to acknowledge certain limitations of our study. Firstly, it was limited to WLHIV who are currently receiving ART and, therefore, the findings may not apply to women who are not on ART. According to Kenya Ministry of Health data, 96.6% of WLHIV who know their status in Kenya are currently on ART and therefore our sample is representative of most WLHIV in this setting. Additionally, since this was a facility-based study, the results may not be representative of the general population, where ART use may be less common. Without ascertaining any reason why, over 200 eligible women declined enrollment. The decliners were younger, aged 18–22 years. We were not able to send WLHIV with HR-HPV for histology or colposcopy, although participants with abnormal cytology were referred to the gynae-oncology clinic for further management and follow-up. Exploring the relationship between histology or colposcopy findings and HPV positivity among WLHIV would be an intriguing area to investigate further. Such research could provide insights into the diagnostic utility of combining these modalities and help optimise screening and management strategies for cervical abnormalities. We also suggest conducting future investigations to establish a correlation between multizonal HPV disease and WLHIV who initiate ART with a low CD4 count.This study found that more than one-third of WLHIV had HR-HPV infections. There was a strong correlation between the presence of abnormal cervical cytology and having multiple HR-HPV infections, regardless of ART duration, CD4 count and behavioural factors. It is noteworthy that HR-HPV genotypes 52 and 35 were found to have a higher prevalence, emphasising the importance of considering all HR-HPV genotypes in cervical cancer prevention, management, and elimination efforts. Furthermore, a majority of respondents with HR-HPV infections exhibited ASCUS. Overall, this study underscores the importance of ongoing monitoring and screening for HR-HPV infections and related conditions for the long-term health of WLHIV.


The science and technology of X-ray optics have come far, enabling the focusing of X-rays for applications in high-resolution X-ray spectroscopy, imaging, and irradiation. In spite of this, many forms of tailoring waves that had substantial impact on applications in the optical regime have remained out of reach in the X-ray regime. This disparity fundamentally arises from the tendency of refractive indices of all materials to approach unity at high frequencies, making X-ray-optical components such as lenses and mirrors much harder to create and often less efficient. Here, we propose a new concept for X-ray focusing based on inducing a curved wavefront into the X-ray generation process, resulting in the intrinsic focusing of X-ray waves. This concept can be seen as effectively integrating the optics to be part of the emission mechanism, thus bypassing the efficiency limits imposed by X-ray optical components, enabling the creation of nanobeams with nanoscale focal spot sizes and micrometer-scale focal lengths. Specifically, we implement this concept by designing aperiodic vdW heterostructures that shape X-rays when driven by free electrons. The parameters of the focused hotspot, such as lateral size and focal depth, are tunable as a function of an interlayer spacing chirp and electron energy. Looking forward, ongoing advances in the creation of many-layer vdW heterostructures open unprecedented horizons of focusing and arbitrary shaping of X-ray nanobeams. X-ray self-focusing sources are demonstrated by free electrons coherently interacting with van der Waals heterostructures, bypassing the need for X-ray optics that are often inefficient and challenging to fabricate. However, the intrinsically weak interaction between X-rays and matter limits the ability to coherently manipulate X-ray waves using optical components. This limit is especially pronounced when compared to the abundance of methods of coherent wave shaping in the optical regime, from high-quality lenses to phase masks and spatial light modulators9. Such optical elements opened the way to breakthroughs and important applications in the optical regime12. It is a long-standing challenge to transfer more novel ideas that rely on coherent wave shaping from the optics to X-ray science13.X-ray-based technology enables a wealth of applications in fundamental science14 and Bragg mirrors16. However, such manipulations often necessitate high-quality X-ray beams that are only available in large facilities such as synchrotrons and free-electron lasers17. These facts prevent the wider spread of X-ray applications to more compact platforms, especially the applications that benefit from coherent wave shaping18.Certain coherent manipulations of X-ray waves are accessible using state-of-the-art zone-plates19. In refractive and diffractive optics, a large numerical aperture (NA) and short focal length can be achieved by compound devices, but typically at the cost of loss of coherence and low efficiency20.The focusing of X-ray waves on nanoscale spot sizes and microscale focal distances is especially challenging. Using reflective optics for such purposes is usually limited by the quality of the mirror surface, which generally requires nanometer to sub-nanometer roughness over tens of micron apertures24 hotspots during the X-ray generation process. In particular, van der Waals (vdW) materials have been shown useful for tunable X-ray generation27. This X-ray generation process is based on the interaction of free electrons with the crystalline structure of the material, in a process known as parametric X-ray (PXR) radiation. Our work now shows how engineering many-layers vdW heterostructures can alter the intrinsic interaction of the electrons with the crystalline structure in a way that alters the phase-front of the emitted wave, producing coherently shaped X-rays.Here, we propose a different strategy, integrating the focusing operation to be part of the X-ray generation mechanism. We rely on recent breakthroughs in two-dimensional (2D) materials that can be engineered on the atomic scale and show how to utilize such materials for focusing of the emitted radiation with diffraction-limitedOur work uses the unique properties of vdW heterostructures to integrate the X-ray wave shaping into the emission process, creating a unified source that produces shaped X-ray wavepackets. The efficiency remains equivalent to that of the original free-electron-based source, bypassing the losses from X-ray optics. Specifically, we implement this concept by carefully designing aperiodic vdW heterostructures with focusing parameters that can be tuned by customizing the chirp of the crystal periodicity. We demonstrate our scheme by a full-wave numerical simulation and compare the radiation to that of a conventional periodic vdW material. As an example, we present a focusing X-ray beam at 4 keV photon energy with a diffraction-limited beam width of just ~10 nm, at a focal distance of 10 μm.28, atomic-scale transistors and diodes, quantum capacitance, and tunneling devices30. Nevertheless, the prospects of such custom-built heterostructures in X-ray science have so far remained unexplored.Looking at the bigger picture, research on vdW materials and their heterostructures has opened new avenues to access versatile material properties. Custom-designed vdW heterostructures have revealed exotic phenomena and novel applications that are not accessible by the constituent layers alone, such as 2D superconductivity34, pressure36, temperature37, and optical excitation39. As an example, tuning the interlayer spacing of MoS2 has found important applications in energy storage, catalysis, and environmental remediation32. In intercalation, the addition of foreign species, such as polyethylene oxide (PEO), to MoS2 during the exfoliation/restacking steps can expand the interlayer spacing, with the extension controlled by the species and the infiltration densities32. Therefore, one can create a chirped vdW heterostructure by intercalating different foreign species accompanied by different infiltration densities across the layers.Of special importance to our work is the tunability of the interlayer spacings in vdW materials, which can be tuned in reversible ways via intercalation40. However, conventional crystals have strong bonds across layers and, thus, are more limited in the choice of materials that can be grown on top of one another. A well-known limitation is a requirement for transverse lattice-matching44, which could cause dislocation or strain when not perfectly matched. In contrast, the layered structure of vdW materials allows different materials to be bonded via the relatively weak vdW forces, which reduces the challenge of tuning interlayer spacing. The large number of vdW materials that are currently available allows a wide range of combinations compared with traditional methods for crystal growth. Part of this versatility arises from the weak interlayer bonds relative to the strong intralayer bonds of van der Waals (vdW) materials, bypassing traditional constraints of lattice-matching44.This tunability in interlayer spacings is precisely the degree of freedom that we use below. It is noteworthy that our proposed methods for generating shaped X-rays from crystalline materials are not limited to vdW structures. Traditional processes, such as atomic layer deposition, can grow layered atomic-thick crystalline films with precise thickness control30. Large-scale assembly techniques46 have been implemented for scalable and practical manufacturing of vdW heterostructures. With rapid advances in integration technologies, vdW heterostructures have improved from a few to tens of layers47, reaching micrometer-scale nanowire heterostructures49. Hybrid vdW and conventional bulk-material heterostructures50 bring more flexibility in fabricating bulky crystalline structures. In our work below, we consider both the traditional structures made layer-by-layer, and thicker structures made by stacking multiple slabs of nanoscale thicknesses, each composed of tens to hundreds of layers.The techniques for the vertical assembly of different vdW materials usually boil down to the construction of heterostructures one monolayer at a time with mechanical and deposition-based methods52 for a modified Smith–Purcell radiation55. A recent experiment reported the first observation of this effect using a chirped grating for optical Smith–Purcell-type radiation inside a scanning electron microscope52. Our study can be seen as a complementary scheme wherein the grating is realized on the atomic scale using a versatile crystalline material. Specifically, vdW heterostructures provide this versatility, allowing us to realize beam shaping and diffraction-limited focusing in the X-ray regime. Importantly, we highlight a fundamental difference between our heterostructure approach and the Smith–Purcell-type approach—a difference that goes beyond the choice of wavelength: whereas Smith–Purcell-type effects all rely on electrons passing by a grating, grazing the surface at a certain distance, the PXR-type effects that we study here rely on electrons penetrating the material, interacting with its bulk. The interaction with the bulk material triggers emission from multiple atomic layers that must coherently interfere for an effective emission process. This additional condition, when properly satisfied, can provide higher monochromaticity and directionality for the emitted radiation26.Our proposal in this work is inspired by analogous schemes for beam shaping and focusing that were investigated in the optical regime using chirped gratings56: parametric X-ray radiation (PXR) and coherent bremsstrahlung (CBS). Radiation by either of these mechanisms has the same dispersion relation, which relates the emission direction to the crystal structures. In a regular periodic crystalline structure shown in Fig. φ is the radiation angle relative to the electron velocity, λ is the X-ray wavelength, d is the interlayer spacing, and n is the integer emission order. The above dispersion relation implies that the generated radiation can be made to converge by chirping the interlayer spacing d, as sketched in Fig. 57, which also gradually shifts the phase of the incident coherent light from subwavelength-spaced optical scatterers. Unlike metalenses, which require external light sources, our scheme integrates electron-driven light generation and tailoring in the same process, bypassing the need for subsequent X-ray optical components.Free-electron-driven coherent X-ray emission incorporates two different mechanisms34. In addition, vdW heterostructures assembled by materials of similar structure but different chemical compositions can also display quasi-continuous variations of interlayer spacings. For example, WSe2 and TaSe2 both adopt a hexagonal crystalline structure, but have a 2% difference in interlayer spacings.Chirping the interlayer spacing is challenging in the X-ray regime because focusing requires deep-subwavelength manipulation of the interlayer spacing. In this context, vdW materials constitute a versatile platform enabling the required precise adjustment of the interlayer spacings. For example, by intercalating external atoms in vdW materials, the interlayer spacing can be continuously increased by more than a factor of two58. Since the focusing conditions derived below apply to the polar angle, the resulting X-rays will be focused along a circle that is cylindrically symmetric around the electron trajectory mentclass2pt{minim2. When a free electron of 1 MeV traverses a regular TaSe2 multilayer structure, shown in Fig. n = 4). However, when the same electron passes a customized heterostructure with an interlayer spacing chirp . We find that, from ray optics considerations, the NA of the focused X-ray beam studied here depends on the maximum chirp in the interlayer spacings rather than on the total sample thickness (see Methods), under the approximation of smooth chirp. Nevertheless, as shown in the discussion, the sample thickness provides a diffraction limit on the hotspot. We plot in Fig. 19 and electron scattering inside the crystal56 . However, realistic e-beams have a finite divergence angle due to the space charge effect42, as illustrated in Fig. 59. Exemplary designs for focused X-ray beams with focal distances of 3 and 1 μm are shown in Figs. The chirp in the interlayer spacings of the heterostructure can be realized by assembling different vdW materials of similar crystal structures but different chemical compositions11 photons sec−1 mm−2 0.1% BW−1  photon coherence, that is, x-direction) photon coherence is limited by the transverse momentum uncertainty of the electrons (see Methods). The red curves in Fig. 67 , corresponding to hundreds of The incident electron recoils while emitting each photon. As a result, the emitted photonic state is entangled with the post-emission electron state. The coherence of the X-ray emission , the latter being a boundary effect from an electron traversing the interface between two media. The interaction range of TR can be estimated from the formation length equation, which is d, respectively. From Eq.  be distributed along an isoenergetic surface (the black curve in Fig. 67.The transverse electron wave vector uncertainties Supplementary Material


Spinal intradural abscesses are extremely rare. To our knowledge, only a few cases have been described in the literature. We report 2 cases of spinal intradural abscesses in patients presenting to our institution with different symptomatology. Both cases involved the lumbar spine, with different etiologies: Case 1 was presumptively related to spondylitis phenomena, with surgery confirming the intradural localization of the abscess; case 2 was of probable iatrogenic nature (secondary to lumbar drain positioning). The aim of this report is to briefly discuss the clinical significance and pathogenesis of these cases. Spinal intradural abscesses are an extremely rare condition. To our knowledge, only a few cases have been described in the literature with long-term sequelae  and poor prognosis if untreated We would like to report 2 cases of patients presenting to our institution with different symptomatology and a common diagnosis of intradural spinal collections.A 71-year-old female patient presented to our attention with a 1-month history of progressively disabling and intense back pain with bilateral cruralgia, not responsive to medical therapy. Neurological examination revealed chronic lateral hypoesthesia of the right thigh. Blood tests showed elevated values of C-reactive protein, normal white blood cell count with mild relative neutrophilia, and relative lymphopenia.MRI of the spine demonstrated the presence of suspected intradural collections in the lumbosacral region at the L2-S2 level with low values of ADC, intense peripheral enhancement after gadolinium injection, and internal colliquative appearance. There was a pathological dural enhancement extended cranially up to T9-T10. In addition, there was a focal inflammatory/infective spondylitis involving the left facet joint at the level L2-L3 .Fig. 1MaDuring surgery, a durotomy was therefore necessary, confirming the radiological suspicion of the intradural location of the collections.Postoperatively, the patient received empirical intravenous antibiotic treatment with vancomycin, ceftriaxone, and metronidazole, awaiting cultures. Follow-up MRI performed 2 days after the surgery showed markedly decreased abscess size.The biological examination of the purulent sample did not show any micro-organism growth neither blood cultures were positive.The last follow-up MRI (2 months later) showed the disappearance of lumbar intradural collections, with the presence of arachnoiditis as a sequela.Pseudomonas aeruginosa.A 70-year-old male patient with a history of a kidney tumor and brain meningiomatosis was treated with surgeries and stereotactic radiation therapy. During recovery due to a cerebro-spinal leak from the surgical site, a lumbar drain was positioned. Sudden onset of fever and increased inflammatory markers  appeared and follow-up MR images of the spine demonstrated the presence of an intradural collection in the lumbo-sacral region (L3-L4 level), with marked restricted diffusion on DWI and mild postcontrastographic enhancement; in addition, there were signs of arachnoiditis affecting the roots of the cauda which were particularly glued together, in an antigravity position . The patHe has not undergone new surgical procedures in both the cranial and spinal areas due to his poor clinical conditions.Intradural spinal abscesses are extremely rare in comparison to epidural ones In both our cases, MRI images led us to suspect that the localization of the infectious collections was inside the intradural space. Indeed, the dural profile appeared as a continuous ipo-intense line (0.5-1 mm) delimiting the epidural fat, on the external side, from the abscess collections, on the internal side. A pial involvement was present due to the residual adhesiveness of caudal roots with antigravity position appreciable at MRI images in both cases.Staphylococcus aureus is the most predominant pathogen isolated In case 1, the intradural localization of the abscesses, confirmed by surgery, was probably related to spondylitis phenomena and a secondary dural breach at the left L2-L3 interfacetal joint. As described in the literature it is possible that transient bacteremia from a self-limited infection site may have been the underlying cause of interfacetal inflammation In case 2 due to the unstable clinical condition of the patient, who was bedridden, surgery was not recommended and antibiotic treatment alone was initiated. Follow-up MRI images showed a slight reduction in the size of the lumbar intradural collection.Intradural abscess is a rare and potentially dangerous condition. Despite its rarity, a high level of suspicion must alert the radiologist when dealing with a patient with intense back pain, neurological symptoms, and increased inflammatory markers. Generally, if promptly diagnosed, surgical drainage, combined with antibiotic treatment, results in a favorable outcome.I hereby confirm that I have obtained written informed consent from the patients for the publication of their cases.


Overlapping eligibility to different biologics for severe asthma is still challenging, especially when addressing the same target. We aimed to characterize severe eosinophilic asthma patients according to their maintained or reduced response to mepolizumab over time and to explore baseline variables significantly associated with the occurrence of switching to benralizumab. We performed a multicentre retrospective observational study evaluating OCS reduction, exacerbation rate, lung function, exhaled nitric oxide levels (FeNO), Asthma control test (ACT), and blood eosinophil concentrations at baseline and before and after switching occurrence among 43 female and 25 male patients with severe asthma aged 23 to 84 years. Younger age, higher OCS daily dose and lower blood eosinophils at baseline were associated with a significantly higher risk (odds) for switching occurrence. All the patients showed an optimal response to mepolizumab, up to six months. The need for switching, according to the above-mentioned criterion, occurred for 30 out of 68 patients after a median time of 21 months (Q1–Q3: 12–24) from mepolizumab initiation. At the follow-up time-point after the switch , all the outcomes substantially improved and no cases of poor clinical response to benralizumab were detected. Although the small sample size and the retrospective design represent major limitations, to our knowledge, our study provides the first real-word focus on clinical variables potentially predicting a better response to anti IL-5r in patients fully eligible for both mepolizumab and benralizumab and suggests that in late non responder patients to mepolizumab, more robustly targeting the IL-5 axis may be effective. Overlapping eligibility to different biologics for severe asthma is still challenging, especially when addressing the same target. Such is the case of mepolizumab and benralizumab, targeting IL5 and IL5 receptor, respectively . MepolizIn fact, the prescription requirements established by the regulatory agencies are extremely similar, not supporting the identification of the best responder to each drug ,3. AvailWe aimed to characterize severe asthma patients according to their maintained or reduced response to mepolizumab over time and to explore baseline variables significantly associated with the occurrence of switching to benralizumab.n = 68). Severe asthma diagnosis was established according to the ERS/ATS guidelines [We performed a retrospective observational study involving five Referral Centres for severe asthma across Italy . All consenting patients affected by severe eosinophilic asthma and prescribed with mepolizumab during the period January–December 2015 were enrolled  with 95% CI. Associations were also estimated after adjustment for OCS dose at baseline as a proxy indicator of disease severity.Changes over time of lung function, exhaled nitric oxide levels (FeNO), Asthma control test (ACT) and blood eosinophil concentrations were also assessed. This secondary analysis was restricted to the subsample of patients with available information, which were 38 and 15 in the non-switch and the switch group, respectively. The 15 patients excluded were not lost to follow up, but the full set of clinical data could not be provided by all the collaborating centres for the time-points after month 6. Baseline and six months follow-up data for both subgroups were analysed. Two further time-points were considered for patients subsequently addressed to switching: the benralizumab-related baseline and the last available follow-up visit. Comparisons of outcomes between time-points were conducted using the Wilcoxon matched-pairs signed-rank test (with the 6-month visit as reference). Missing data were deleted listwise. Statistical analyses were done using STATA release 17.0 .We included 43 female and 25 male patients with severe asthma aged 23 to 84 years. p = 0.054), blood eosinophils , and OCS dose  (n. of subjects in the model = 57).Younger age, higher OCS daily dose and lower blood eosinophils at baseline were associated with a significantly higher risk (odds) for switching in univariate analysis. The results were very similar when adjusting for OCS dose at baseline , a proxyp < 0.001) and the switch subgroups . A significant reduction was also observed in the exacerbation rate in both the non-switch  and the switch subgroups .All the patients showed an optimal response to mepolizumab according to all the evaluated clinical variables , up to sThe need for switching, according to the above-mentioned criterion, occurred for 30 patients after a median time of 21 months (Q1–Q3: 12–24) from mepolizumab initiation. At the time of switching, a significant worsening of most the outcomes was detected in comparison to the 6 months assessment . At the Little real-life evidence focused on the clinical profile of responders to benralizumab after ineffective mepolizumab treatment. A large study described benralizumab efficacy in patients not responding to mepolizumab or reslizumab, without any subgroup-focused analysis, thus not excluding the potential confounding effect related to the weight-adjusted reslizumab dose . In anotThe proportion of late non-responders to mepolizumab we have described in our report seems not to be in line with other studies on the long-term efficacy of the same drug ,9. COLUMREALITI-A is a prospective single arm observational cohort study aiming to collect real-world data on asthma patients undergoing mepolizumab treatment. The initial analysis  on 368 sIn fact, in our study, the timing of poor response onset suggests that in a subset of patients initially well controlled by mepolizumab a change in the immunological background occurred. According to the low levels of blood eosinophils even at the switch time-point the development of anti-drug antibodies is unlikely. The known heterogeneity of inflammatory phenotype, which is intra-individually dynamic over time in asthma patients, may account for the “late non-response” . Under tWhat mentioned above may account for the different clinical response following the inhibition of IL-5 or the interaction with all the cells expressing its receptor, besides eosinophils, and substantially contributing to the T2 high inflammation.On clinical grounds, a higher OCS use has been described by Bleecker et al. as a predictor of better clinical response to benralizumab, independently of baseline blood eosinophilia, in the pooled-data analysis from the SIROCCO and CALIMA benralizumab trials . OCS useThe small sample size and the retrospective design represent major limitations. Further studies with larger sample sizes and prospective design are needed to confirm our findings and to reinforce their external validity and applicability to other populations.However, to our knowledge, our study provides the first real-word focus on clinical variables potentially predicting a better response to anti IL-5r in patients fully eligible for both mepolizumab and benralizumab.Taken together, our data suggest that in patients eligible to monoclonal antibodies interfering with Il-5 driven cascade, younger age, higher OCS daily dose and lower blood eosinophils at baseline were associated with a significantly higher risk for switching from mepolizumab to benralizumab, somehow predicting a better response to anti IL-5r. Furthermore, according to our observations, in late non-responder patients to mepolizumab, more robustly targeting the IL-5 axis may be effective.Overlapping eligibility and monoclonal antibody switching deserves larger investigations, also by exploring data from the national and international severe asthma registries, and consensus recommendations due to its major clinical and pharmaco-economical relevance.