The generalized g-formula can be used to estimate the probability of survivalunder a sustained treatment strategy. When treatment strategies aredeterministic, estimators derived from the so-called efficient influencefunction (EIF) for the g-formula will be doubly robust to modelmisspecification. In recent years, several practical applications have motivatedestimation of the g-formula under non-deterministic treatment strategies wheretreatment assignment at each time point depends on the observed treatmentprocess. In this case, EIF-based estimators may or may not be doubly robust. Inthis paper, we provide sufficient conditions to ensure the existence of doublyrobust estimators for intervention treatment distributions that depend on theobserved treatment process for point treatment interventions and give a class ofintervention treatment distributions dependent on the observed treatment processthat guarantee model doubly and multiply robust estimators in longitudinalsettings. Motivated by an application to pre-exposure prophylaxis (PrEP)initiation studies, we propose a new treatment intervention dependent on theobserved treatment process. We show there exist (1) estimators that are doublyand multiply robust to model misspecification and (2) estimators that when usedwith machine learning algorithms can attain fast convergence rates for ourproposed intervention. Finally, we explore the finite sample performance of ourestimators via simulation studies. Therefore, estimators of the g-formula and associated contrasts indexed bydifferent strategies may be used to estimate causal effects.The goal of many observational analyses is to estimate the causal effect on survivalof different time-fixed or time-varying treatment strategies, interventions, orrules in a study population. These causal effects can be formally defined by acontrast (e.g. difference or ratio) in the distributions of counterfactual outcomeshad interventions been implemented to ensure those strategies are followed in thatpopulation. Robins1 iterated conditionalexpectation (ICE) estimators,3 inverse probability weighted(IPW) estimators,5and estimators derived from the efficient influence function (EIF).7 EIF-based estimators  have severaltheoretical advantages over the other approaches including they may be 810In practice, the g-formula typically depends on high-dimensional nuisance parameters.In this case, many estimators of the g-formula and associated contrasts have beenproposed including the density-based parametric g-formula,deterministic treatment strategy at most dependent onpast treatment and confounders.12 However, the identificationresults of Robins1 were not limited to such deterministic strategies butgeneralized to allow identification of stochastic treatmentstrategies at most dependent on the measured past. The latter identifying functionalor generalized g-formula depends on the interventiontreatment distribution, that is, the distribution of treatment under anintervention that ensures the strategy of interest is followed conditional only onthe measured past in the observational study. The generalized g-formula coincideswith the more familiar g-formula indexed by a deterministic strategy when theintervention treatment distribution is chosen as degenerate conditional on any levelof the measured past.EIF-based estimators may also have a model double-robustness property in that whennuisance functions are estimated via parametric models, these estimators may remainconsistent and asymptotically normal if models for only one of two (sets of)nuisance functions are correctly specified, not necessarily both. This modeldouble-robustness property always holds for EIF estimators when the g-formula isindexed by a observed treatment process, that is, the observed treatmentdistribution conditional on the measured past.1317 The generalized g-formulaindexed by an intervention treatment distribution dependent on the observedtreatment process has the particular advantage of relying on relatively weakpositivity conditions18 even, for example, in observational studies where thepropensity score is equal or close to zero for certain measured confounderhistories.16 When the (degenerate or non-degenerate) interventiontreatment distribution does not depend on the observed treatmentprocess, EIF-derived estimators of the generalized g-formula will be model doublyrobust. However, when the intervention treatment distribution doesdepend on the observed treatment process, such estimators may or may not be doublyrobust.1419Recently, several practical applications have motivated estimation of the generalizedg-formula indexed by intervention treatment distributions that depend on the16 We show that estimators based on the EIF for our proposedintervention treatment distribution are model doubly/multiply robust, and can attainfast convergence rates even when used in combination with machine learningalgorithms, where modeling assumptions are relaxed. We illustrate both EIF-based, aswell as simpler singly robust, estimators of the g-formula indexed by this class ofintervention treatment distribution in simulated data and in an illustrative dataapplication.In this paper, we exploit particular representations of the generalized g-formula togive sufficient conditions for the existence of doubly robust estimators for pointtreatment interventions when the chosen intervention treatment distribution dependson the observed treatment process. We also provide a general form of EIFs for aclass of intervention treatment distributions that may depend on the observedtreatment process in longitudinal settings that guarantee model doubly (andmultiply) robust estimators. Motivated by observational studies of the effects ofrealistic HIV PrEP initiation interventions, we consider a new class of interventiontreatment distributions dependent on the observed treatment process that is avariation on the incremental propensity score interventions proposed byKennedy.2Consider a longitudinal study with 320 denote intervention treatment distribution at Let static deterministic rules that assignthe same level of treatment to all surviving individuals at all follow-up times anddynamic deterministic rules that assign treatment based on themeasured past.When treatment assignment at any time under a selected rule through its dependence on theobserved treatment distribution conditional on the measured past asspecified by observed treatment process conditional on the measured past.The observed treatment process evaluated at propensity score21 at By contrast, when a selected rule 416posed incremental propensity score interventions that at each 2224 Some MSM are motivated to usePrEP not only to reduce HIV risk but also to improve sexual well-being,26 includingincreased intimacy and pleasure facilitated by condomless sex without fear of HIVacquisition.27 Reduced condom use among PrEP users may increase the riskof STIs, making STI screening and treatment an important part of comprehensive PrEPcare.28 In our motivating example, we investigated the effect ofincreases in PrEP uptake on the incidence of bacterial STIs among MSM.KennedySpecifically, for incremental propensity score interventions, distinguishing themby the classifier odds shift or multiplicativeshift, respectively.In words, the probability of initiating PrEP conditional on the past under ion Lj*=. Choosiny either asincre5deterministic strategies at most dependent on this past thatindividuals could be observed to follow under the selected rule Exchangeability: Consistency: If Positivity: Robins1showed that given these exchangeability, consistency and positivity conditions holdfor all deterministic generalized g-formula indexed by the intervention treatmentdistribution 18Consider a treatment assignment rule 5.1Note the assumption that the positivity condition above holds for alldeterministic follows:qg zero for individuals with certainlevels of the measured confounders. In conjunction with these challenges, suchdeterministic treatment effects are not of greatest interest for treatments suchas PrEP, where biological benefits are established but population disease burdenmay be impacted with even small increases in treatment uptake. In the followingsections, we will describe efficient estimators for the multiplicative shiftincremental propensity score interventions.630 In this section, we provideresults that aid the intuition on the existence of doubly robust estimators of Suppose that the observed data 6.1We begin with the special case of a point treatment where iscase,  reduces Theorem 1.Suppose can be written as a linear combination of theform:7 A heuristicjustistification for Theorem 1 follows from the fact that the EIF of as the function . Furthermore, it is established that anestimator derived from the influence function =I=I.37Unlike the otherestimators, the one-step augmented IPW estimator that solves the empirical EIFdoes not guarantee sample-boundedness. Weighted ICE and TMLE are variations ofBang and Robins.6 Compared with the one-step AIPW estimator and Bang andRobins,6 weighted ICE can give better performance.2 Unlike Bangand Robins6 and weighted ICE, the one-step AIPW estimator and TMLE canincorporate any machine learning algorithms2 for bothsets of nuisance functions. In the absence of machine learning algorithms,weighted ICE and TMLE perform similarly,2 but weighted ICE is easierto implement. In this section, we will consider two estimators: (1) weighted ICEestimator that uses parametric models to estimate the nuisance functions therebyallowing for 10 to allowone to incorporate machine learning algorithms to estimate the nuisancefunctions.Several EIF-based estimators for 7.1.1Let fined in  for a ch formula  with the39) and weights given by where 7.1.230 In SupplementalAppendix F, we prove the asymptotic normality of this estimator under thecondition that the nuisance functions are estimated consistently at ratesfaster than This algorithm utilizes sample-splitting and cross-fitting to allow flexiblemachine learning algorithms for estimating nuisance functions whilecircumventing Donsker class conditions.ventions .obtained from machine learning algorithms to individuals in .Suppose that a sample of size Here 7.241Alternatively, the singly robust ICE estimator, which we will denote We also consider less optimal but computationally simple singly robust estimatorsof dexed by. An IPW raw from  given th7.342 withstraightforward extensions of the g-formula Straightforward extensions of the identification arguments in Section 5 instudies with censoring follow by implicitly including in 8We conducted two different simulation studies. The first simulation study aims tocompare the performance of the weighted ICE, IPW, and ICE estimators when thenuisance functions are estimated through parametric models under various modelmisspecification scenarios. The second simulation study aims to compare theperformance of TMLE with sample-splitting and cross-fitting, IPW and ICE when thenuisance functions are estimated through machine learning algorithms.8.1In this simulation study, we compare the performance of the weighted ICEestimator with the singly robust estimators (IPW and ICE estimators) for ribution  which, uWe simulated 1000 samples of The true cumulative probabilities of survival were calculated by using the trueparametric models to generate a Monte Carlo sample of size We considered three estimation scenarios for each choice of dexed by for δ=, Bayesian generalized linear models (SL.bayesglm),generalized additive models with smoothing splines (SL.gam), multivariateadaptive regression Splines (SL.earth), neural networks (SL.nnet), and randomforest (SL.ranger).Nuisance functions were estimated using the Super Learner ensemble, which usescross-validation to select the best convex combination of predictions from apool of prediction algorithms.9We illustrate the application of the estimators discussed in Section 7 usingelectronic health record data from the Cambridge Health Alliance—a large communityhealthcare system in Eastern Massachusetts—to estimate the effects of increasingPrEP uptake on bacterial STI diagnosis by time test and no prior diagnosis of HIV at time Specifically, we consider multiplicative shift interventions that, beginning at thetime of an HIV-negative test, successfully increase the proportion initiating PrEPin each follow-up week Our analytic dataset was restricted to patients who met all the following inclusioncriteria at some point during 2012 to 2017: (1) Cis male with a report of the malegender of sex partner(s); (2) 15 years of age or older; (3) an HIV-negative test;(4) had no PrEP prescription in the 3 months prior to baseline; and (5) had no STIdiagnosis in the 12 months prior to baseline. The baseline  to estimate all nuisance functions for TMLE with Our estimate of the probability of not receiving an STI diagnosis under nointervention by 26-week follow-up (10Many methods have been proposed for estimating causal estimands in time-varyingtreatment settings for survival analysis, and among these methods are estimatorsthat offer protection against model misspecification and can also attain thesemiparametric efficiency bound. However, most of these doubly robust estimatorshave been in the setting of deterministic treatment interventions. In this paper, weprovided some sufficient conditions for the existence of doubly robust estimatorswhen a treatment intervention distribution can depend on the observed treatmentprocess for point treatment processes. We also discussed a class of interventiondistributions that are always guaranteed to give doubly/multiply robust estimatorsand gave a general form of the EIFs that are associated with these interventiondistributions. Among these intervention distributions is our multiplicative shiftincremental propensity score intervention distribution, which aims to increasetreatment uptake in a group of individuals who are at high risk of the outcome buthave low exposure to treatment. We provided various estimators that can be used forour proposed treatment intervention for both parametric and machine learningalgorithms.We conducted two simulation studies for our proposed multiplicative shiftintervention distribution. Our first study shows that even in finite samplesettings, the weighted ICE is more robust to model misspecification than IPW and ICEwhen the nuisance functions are estimated using parametric models. Our second studyshows that TMLE with sample-splitting and cross-fitting can outperform singly robustestimators when machine learning algorithms are used. Indeed, the TMLE withsample-splitting and cross-fitting is consistent as long as the nuisance functionsare estimated consistently at fast enough rates using machine learning methods,which may not necessarily be 20 and Young et al.18Note that our proposed intervention treatment distribution  isguararaw from . The ideribution quantifiFinally, we note that while machine learning algorithms are more robust to model formmisspecification, they are also computationally complex and may be practicallyinfeasible for very large datasets without powerful computing systems. Even thoughthe Super Learner ensemble performed well in the simulation study as it includedlearners that converged to the truth at fast enough rates, in real-worldapplications there is no guarantee that such learners exist. When more flexiblelearners such as neural networks or random forests are required, it is unclear ifthese machine learning methods will exhibit more or less bias compared withparametric models. Moreover, issues related to data privacy make access to advancedcomputational resources impossible in many cases. Therefore, estimators that offermodel double/multiple robustness are useful in practice as they offer protectionagainst model misspecification and can be easily computed using standardoff-the-shelf regression software in R.Click here for additional data file.Supplemental material, sj-pdf-1-smm-10.1177_09622802221146311 for Interventiontreatment distributions that depend on the observed treatment process and modeldouble robustness in causal survival analysis by Lan Wen, Julia L. Marcus andJessica G. Young in Statistical Methods in Medical Research


Simultaneously occurring bilateral herpetic keratitis is a rare clinical manifestation of ocular herpes. Immunocompromised patients are more susceptible to develop bilateral disease. The purpose of this study is to review recent literature on the topic and to highlight latest updates, regarding risk factors and possible correlations to the disease, as well as new therapeutic options. A literature search was performed in PubMed and Google Scholar databases using the terms “bilateral herpetic keratitis”, “bilateral HSV keratitis” and “bilateral ocular herpes”. Search results were narrowed down to 86 by filtering out all articles prior to the year 2000. We also excluded all non-human studies and those written in language other than English, leaving 58 eligible. Two duplicates were also removed. After initial screening and manual evaluation of abstracts, another 7 were removed as irrelevant to the topic, describing either unilateral cases or ocular herpetic manifestations other than keratitis. The remaining 49 articles were included in the present review. Following a suggestion from our reviewers, we also included 6 additional articles to properly cite material discussed in the section regarding newer drugs in the treatment of herpetic keratitis .Herpetic keratitis is the result of a corneal infection with Herpes Simplex Virus (HSV) and it is recognized as a leading cause of corneal blindness worldwide ,2. Bilatérpin], which means “creeping or crawling” and stands for the characteristic creeping of the eruptions caused by the virus [The term “herpes” is derived from the Greek word “herpein” [pronounced: he virus .Herpes Simplex Virus is a linear double-stranded DNA virus that is an Alpha-herpesvirinae member of the Herpesviridae family. Common pathogens in the Herpes family are Herpes Simplex Viruses 1 and 2 (HSV-1 and HSV-2), Varicella-Zoster Virus (VZV). Another common pathogen (member of Gamma herpes virus family) is Epstein–Barr Virus (EBV). All the above-mentioned viruses are neurotrophic, meaning that they have the ability to reside in a latent state within neurons of the sensory and autonomic ganglia from where they can reactivate occasionally, making the host a lifetime carrier [While Herpes Simplex Virus (HSV) can infect any part of the body and elicit a variety of serious diseases in humans, it commonly infects the face, genitals and eyes with skin/face infections, typically a consequence of either oral or ocular infection ,2. The vPrimary ocular HSV infection is usually asymptomatic depending on immunological status of the host . CornealOnce the primary infection resolves, the virus becomes latent and stores its genome in the nucleus of a host cell, unlike retroviruses, which integrate their genome into the host’s DNA. During its latency, HSV-1 produces latency-associated transcripts (LATs) that maintain the integrity of the viral genome and reduce cellular apoptosis . Later, Recrudescent HSV infections are usually due to reactivation of the HSV strain acquired during primary infection. However, superinfection with a new HSV strain at the site of primary infection has also been documented .HSV-1 and -2 infect up to 90% of adults in the world. HSV-1 alone infects 66% of the world’s population. However, in some developing parts of the world, such as Latin America and sub-Saharan Africa, the prevalence of HSV-1 surpasses 90% .Bilateral herpetic keratitis reported incidence in literature varies from 1.3% to 12% depending on the criteria used to diagnose it ,9. A 30-HSV can affect all layers of the cornea. Depending on the clinical features identified on slit-lamp examination, herpetic keratitis is characterized as: Epithelial keratitis, immune or necrotizing stromal keratitis, neurotrophic keratopathy and endotheliitis, according to a recent renewal of the classification of HSK .Common symptoms include redness, discharge, watery eyes, irritation, itching or foreign body sensation, and photophobia. In most patients, symptoms begin to subside after the first 2 weeks .The most common subtype, epithelial keratitis, is usually due to an actively replicating virus and appears as coarse granular spots that form punctate or stellate lesions, but these quickly coalesce to form dendritic lesions. On the slit-lamp examination, epithelial keratitis presents as a dendritic lesion with terminal buds, swollen borders and intraepithelial cell infiltration. The ulcer may progressively increase in size to give a “geographical” or “amoeboid” configuration ,5,9, espStromal keratitis on physical examination appears opaque or whitened, due to stromal infiltration. Descemet membrane folds might be present as well. Corneal sensation is often reduced . SimilarAnother form of HSK, disciform lesion, has a ground-glass appearance and is disk-shaped with stromal edema  on slit-lamp examination. Neurotrophic ulcer appears with persistent central epithelial defects with a grey thickened border (Wessely immune ring) . Lastly,Intraocular pressure could be elevated  when theHerpes Simplex is usually diagnosed clinically and requires no laboratory confirmation. If the diagnosis is in doubt, the following tests may assist: ,9,21Polymerase chain reaction (PCR).Scrapings of corneal or skin lesions for Giemsa stain or Tzanck smear—ELISA testing.Viral culture.HSV antibody titers. They rise after primary but not recurrent infection.Immunofluorescence antibody assay (IFA) of tears.PCR is highly sensitive, but large variation has been observed in numerous studies between the rates of HSV detection by PCR when compared to clinical diagnosis. PCR diagnostic effectiveness may be affected in patients under prophylactic anti-viral treatment with acyclovir. In addition, topical anesthetics and dyes, such as fluorescein, Bengal rose and lissamine green used for clinical diagnosis of HSV may result in decreased sensitivity of the PCR assay. The type of specimen used in detection of HSV with PCR is also an important factor. Tear specimen produces significantly less sensitive results than corneal scrapings . PCR andMisdiagnosis in clinical settings is not uncommon. Simultaneously bilateral corneal lesions resembling herpetic keratitis can be due to multiple causes such as infectious keratitis from other pathogens, post-traumatic corneal erosions, chemical injury, dystrophies, degenerations and rarely acute hydrops. Sterile corneal melt resulting from multiple eye conditions such as dry eyes, connective tissue disorder and nutritional deficiency can also result in involvement of both eyes at the same time ,9.Literature underscores that a significant percentage of the clinically diagnosed bilateral HSV lesions were actually caused by Varicella-Zoster Virus, adenovirus, Cytomegalovirus or Enterovirus, as confirmed by laboratory tests .Herpes Simplex Keratitis is, in general, a unilateral disease. Simultaneously occurring bilateral involvement is a rare phenomenon  and is kIn literature, bilateral Herpes Simplex Keratitis has been reported for patients with congenital immune deficiencies, atopy , autoimmBelow, we list a number of factors known to predispose individuals to develop bilateral herpetic keratitis. Rheumatoid arthritis (RA) is an autoimmune disease, characterized by an irregular immune response towards components of the connective tissue, such as collagen and elastin, also present in the structure of the cornea, and it is associated with higher incidence of bilateral HSV keratitis (40%). The characteristics of HSK in patients with RA differ from HSK in immunocompetent patients. Stromal keratitis cases were very aggressive and difficult to manage, with perforation and Gram-positive bacterial co-infection as frequently associated conditions. Prophylactic therapy at standard doses has proven unsuccessful to prevent recurrences . These pHuman Immunodeficiency Virus (HIV) infection results in many cases in acquired immunodeficiency syndrome (AIDS), which is characterized by depletion of CD4+ white blood cells. A 10-year retrospective study in Tunisia reported the ocular disorders related to the disease in people living with HIV (PLWH). Most patients (86%) were on ART (Tenofovir + emtricitabine + efavirenz) combination therapy. Immunodeficiency caused by the virus increased susceptibility to opportunistic infections and neoplasms. Herpes Simplex Keratitis was found in 5% of those patients. The risk of developing ocular disease in PLWH is higher when the CD4+ count is <200 cells/μL .Another category of immunocompromised patients is organ transplant recipients, as they are under long-term treatment with immunosuppressive drugs to prevent graft rejection—failure.Cancer patients are also prone to develop bilateral herpetic keratitis. A 10-year review studied patients with malignancies that developed herpes simplex or zoster keratoconjunctivitis; 13.3% of them had bilateral disease. For the bilateral cases, the cancer diagnoses included leukemia, lymphoma/myeloma, breast and colon cancer. Only 16% of the patients were not immunocompromised or suppressed (receiving only X-ray treatment), but all others were either being actively treated for their relapsed cancer (with chemo/steroids) or immunosuppression after allogeneic stem cell transplantation (SCT) .There are several studies highlighting that HSV keratitis occurs more frequently as bilateral disease in the pediatric population ,14,31,32A Nigerian study in children with keratitis reported that approximately 79% of patients with HSV had combined epithelial and stromal disease. Keratitis was associated with a recent measles infection and protein calorie malnutrition. Bilateral HSV was recorded in 12.7% among herpetic cases .Increased age has been associated with reduced cell-mediated immunity, which is a crucial factor to avoid reactivation of latent viral infections, such as herpes zoster .A large 30-year retrospective study in Minnesota found an age-related increased incidence in new cases of HSV keratitis, suggesting similarly the decreased immunity in elderly people as the possible cause .Various immunosuppressive drugs have been linked to the reactivation of viral infections.Corticosteroids are widely used as systemic treatment in a plethora of indications, including autoimmune diseases and atopy, to mitigate the immune system’s response and reduce inflammation. A latent HSV infection could be reactivated by rapid tapering of systemic corticosteroids, as both steroid use and rapid tapering may act as a triggering factor for viral infection or reactivation of herpes .Rituximab is a B cell depleting anti-CD20 monoclonal antibody that is increasingly used to treat autoimmune disorders and B cell non-Hodgkins lymphoma. As with other immunosuppressive agents, there is the risk of opportunistic infections or reactivations, including Hepatitis-B virus and Herpes viruses (HSV). There is a rare case report of a patient suffering from severe mucous membrane pemphigoid treated with rituximab who developed herpetic keratitis. A 71-year-old patient suffered from severe mucous membrane pemphigoid (an autoimmune blistering disease affecting predominantly the mucosae) with ocular, oral pharyngeal and laryngeal involvement. To control the disease, the patient was given rituximab therapy in combination with oral corticosteroids. He subsequently experienced an epithelial herpes simplex virus keratitis in one eye and 3 months later in his other eye .Ocular anti-hypertension drugs and prostaglandin analogs. There is a strong debate in literature about the role of anti-glaucoma drugs and prostaglandin analogs, especially in triggering recurrent herpetic keratitis.Several case reports suggested a causal relationship between the use of topical prostaglandin eye drops and episodes of bilateral HSV keratitis. Both latanoprost , travoprSome authors, however, acknowledge that corneal toxicity from the preservative contained in eye drops may have contributed to herpes’ reactivation . In addiCorneal toxicity usually appears as punctate epithelial defects, which over time collide to form linear or branch-like lesions resembling the characteristic herpetic dendritic lesions. The main distinctive details are that the pseudodendritic lesions have rather heaped-up edges, they lack terminal buds and they are usually surrounded by diffuse punctate defects. The authors using specific clinical criteria determined that their patients’ lesions were not actually related to HSV and confirmed their findings with negative viral cultures. All patients recovered after removal of the presumed triggering medication or by applying ocular surface protecting methods, including topical lubricants or therapeutic soft contact lens, and without the need of anti-viral treatment .Recent literature reports describe rare or unique cases of certain conditions or surgical procedures that were observed along with incidents of bilateral herpetic keratitis, indicating a possible causal relationship.Rare case of pemphigus foliaceus complicated by Kaposi’s varicelliform eruption and bilateral HSV keratitis: Pemphigus foliaceus (PF) is a chronic autoimmune blistering dermatosis (ABD) that often involves the face, scalp and trunk. Kaposi’s varicelliform eruption (KVE) is an uncommon widespread skin viral infection over some pre-existing skin disease with variable severity that rarely complicates ABD, and it is most predominantly caused by herpes simplex virus (HSV) infection. In addition, KVE infrequently causes ocular involvement including Herpes Simplex Keratitis (HSK) presented with large geographic corneal lesions. Timely diagnosis of KVE may be difficult in patients with PF due to their overlapping clinical features. PF complicated with KVE and HSK is extremely rare, and there is only one such case reported up to date. Therefore, it is important to raise high suspicion of HSV infection in patients with underlying ABD if recurrence or resistance to treatment occurs, especially when combined with ocular symptoms .Another similar case report described a patient with PF treated with azathioprine and high-dose corticosteroids developing bilateral HSV keratitis following rapid tapering of steroids, which is known to trigger Herpes reactivation .In a third case, a young man with chronic atopic dermatitis developed Kaposi’s varicelliform eruption and simultaneous onset, bilateral HSV-1 (confirmed by direct immunofluorescence) dendritic epithelial keratitis with corneal epithelial edema during a generalized dermatitis incident .A young woman developed bilateral HSK during pregnancy. Her ocular history included use of contact lenses. Pregnancy can resemble a modified state of immunosuppression resulting in an increased risk for HSV keratitis. This combined with contact lens wear may have an additive effect and increase the possibility of HSV recurrence .A young lactating woman with a clear medical history presented simultaneous bilateral keratitis that was confirmed to be herpetic with PCR. The authors suggest that lactation in this case may have aggravated malnutrition and anemia leading to a certain immune susceptibility, allowing a latent herpetic infection to reactivate. Even though the virus can spread from mother to child through direct contact with infected secretions  or skin and mucosal lesions, breast feeding is not contraindicated in any active herpetic infection unless lesions are on the breast .A premature baby delivered by cesarean section at 26 weeks of gestation. Mother had no history of HSV or signs of active disease at the time of birth. Nine days later the newborn child developed facial vesicle and bilateral eyelid edema. Examination revealed corneal epithelial lesions also. There was also central nervous system (CNS) involvement. Laboratory workup showed HSV-1 infection. At the time of diagnosis, maternal serology was also negative, indicating first-episode primary infection. It is important to highlight that half of the infants with HSV infection are born prematurely, usually between 30 and 37 weeks of gestation .In another case, a newborn delivered vaginally developed herpetic vesicular rash and bilateral corneal ulcers. In this instance, HSV-2 was identified by direct immunofluorescent staining of vesicle fluid. Many neonatal infections occur because of asymptomatic cervical shedding of virus, usually after a primary episode of HSV infection. The infant is protected for the first few months of life by circulating maternal antibodies, but this might not be the case always .Although rare, bilateral herpetic keratitis has been reported in patients with GVHD. In a case report an 11-year-old boy underwent allogeneic bone marrow transplantation as treatment for myelocytic leukemia. Three months post-transplantation he developed symptoms of the skin, eyes and mouth, and a lip biopsy indicated chronic graft-versus-host disease (GVHD). GVHD is a major complication of allogeneic bone marrow transplantation that occurs due to the reactivity of transplanted immunocompetent cells against host cells. The child had a persistent keratitis with corneal filaments and neovascularization in both eyes and received long-term treatment with fluorometholone eyedrops among other medication. He later developed bilateral Herpes Simplex Keratitis with geographic ulcers, but responded well to acyclovir ointment .Viral conjunctivitis: Bilateral disciform keratitis is a late complication of viral conjunctivitis. A young man in the course of viral conjunctivitis developed bilateral disciform keratitis in the span of 3 weeks with widespread sub-epithelial corneal infiltrates in addition to a central corneal edema with a white distinct border resembling Wessely ring, as well as Descemet’s folds and keratic precipitates in the central area. The patient was treated with both oral and topical antiviral, and showed significant improvement. Herpetic disciform keratitis is a primary endotheliitis resulting in both stromal and epithelial edema in a round (disciform) distribution with keratic precipitates underlying the area of edema .COVID-19: Continuing research on the novel SARS-CoV2 virus brings to light more and more of the virus’ wide spectrum of clinical features and correlations. A recent Slovakian study noted that during the first pandemic wave, a 2.5- and 2-fold higher incidence of herpetic keratitis was recorded in the area of the study in comparison to the same period in 2019 and 2018, respectively. It is known that viral reactivation may occur in critically ill patients or due to a weakened immune system, fever or hormonal changes. COVID-19 patients undergo immunosuppression and cytokine storm syndrome. These characteristics are mostly found among critically ill patients. T lymphocytes and natural killer cells decrease in number and become functionally exhausted, particularly CD8+ T cells. These cells are responsible for the control of viral infections. HSV-1-specific CD8+ T cells keep herpes in a latent state. The exhaustion of these cells leads to impaired effector function and may allow the reactivation of HSV-1 that resides in the trigeminal ganglion. According to these mechanisms, COVID-19 may be a potential activator of HSV-1 infection .Refractive laser surgery: Only a few human cases of Herpes Simplex Keratitis associated with Laser in Situ Keratosmileusis (LASIK) and Photo-Refractive Keratectomy (PRK) have been reported. Chao-Kung Lu et al. described a case of simultaneous bilateral HSK one month after uneventful LASIK surgery for correction of myopia in an otherwise healthy woman without prior history of herpes. The dendritic lesions appeared on the corneal flap in both eyes. Laser irradiation may have triggered reactivation of a latent previously asymptomatic HSV infection .A similar effect can result from excimer laser photokeratectomy (PTK). A PCR assay detected viral DNA in tears’ specimen postoperatively. It is suggested that the procedure may stimulate viral reactivation and consequent shedding in the tear film .Corneal collagen crosslinking (CXL) utilizes ultraviolet radiation to enhance corneal collagen bonding in order to stabilize progression of keratoconus. Exposure to ultraviolet A (UVA) light induces the secretion of interleukine IL-10, which suppresses the immunological response against infectious agents. Therefore, CXL treatment could be a stimulus to trigger reactivation of latent HSV infections even in patients with no history of clinically evident herpes virus ocular infections. Among the various complications of this procedure, recrudescence or a first episode of viral keratitis has been reported in literature. An interesting case report presented a young immunocompetent patient treated with CXL in both eyes at the same setting  for bilateral progressive keratoconus. Shortly after surgery he developed clinical signs of bilateral HSV keratitis. The authors acknowledged that the decision to treat both eyes together resulted in this rare manifestation. Therefore, they suggested that the optimal choice is to avoid simultaneous application of CXL and that prophylactic administration of anti-virals may be beneficial .Corneal transplantation: A case series study included 30 patients that suffered from recrudescent herpetic keratitis, with 1 of them having bilateral disease. Researchers separated these patients into two groups, depending on whether the patients underwent penetrating keratoplasty (PKP) or not, and they compared the HSV genotype identified with a PCR assay from specimens obtained during the follow-up period, between sequential episodes of keratitis, both prior and after transplantation. Analysis of the collected data showed that many of the patients in the transplantation group had been superinfected with a different HSV strain, while in the other group, all HSK recurrences were due to the original HSV strain. Their findings suggested that PKP may be a risk factor for transmission of HSV-1 with subsequent reactivation of the donor-derived HSV-1 strain in the corneal allograft colonized the recipient. The DNA sequences were identical in both strains isolated from the transplant and the recipient, providing conclusive evidence for graft-to-host transmission of HSV-1 through corneal allograft [Botulinum toxin injection: A 59-year-old immunocompetent woman with functional epiphora was transconjuctivally injected with Botulinum toxin-A into each lacrimal gland. Her medical history included HSV keratitis quiescent for the previous 2 years. Three weeks after the injection she developed bilateral stromal keratitis, suggesting that the procedure may have triggered reactivation. The authors highlighted the need for oral antiviral prophylaxis before BTA injections .Strabismus surgery: Another case report study described a 3-year-old child who underwent bilateral lateral rectus recessions to correct strabismus. She was prescribed with standard post-operative dexamethasone and antibiotic eye drops. One week later the child presented fever along with initially unilateral eyelid swelling and ptosis, which within days progressed in the other eye as well. Clinical examination showed bilateral corneal erosions confirmed to be herpetic by PCR. It is apparent that both the surgery and the use of steroids contributed in this case .Intravitreal anti-VEGF injection: A man suffering from exudative Age-related Macular Degeneration (wet –AMD) had been uneventfully under treatment for approximately 4 consecutive years with multiple intravitreal injections of triamcinolone and antivascular endothelial growth factor agents, as well as Photo Dynamic Therapy (PDT), in both eyes. Then, just days after receiving treatment with bevacizumab injection in one eye and a triple combination of intravitreal bevacizumab, triamcinolone, plus full-fluence PDT in the other eye (both in the same session), the patient developed bilateral dendritic keratitis. He then reported a history of mouth sores arising periodically, with the most recent episode at the time of the injections . The authors mentioned that the patient continued treatment with anti-VEGF injections bilaterally with no recurrence of HSV keratitis or other complications up to publication date. They also suggested that his history of long-standing diabetes mellitus, if poorly regulated, may have posed a vulnerability contributing to the reactivation of herpes. Of course, the presence of active mouth sores during the time of the ocular injections implies that a generalized herpetic eruption was emerging and along with the ocular manipulations they possibly triggered reactivation of keratitis as well .Trabeculectomy with Mitomycin-C (MMC): Finally, a short case series describes 3 patients who presented clinically diagnosed herpetic keratitis after trabeculectomy with use of the antimetabolite MMC. One of them developed bilateral keratitis. According to the authors, the time interval between the glaucoma surgery and the occurrence of HSV keratitis ranged from 15 days up to 2 years post-operation. They suggested that mitomycin may facilitate development of herpetic keratitis/keratouveitis up to 2 years after glaucoma surgery .Most infections of herpetic keratitis are self-limiting, even without treatment. However, it is essential to treat the infection at the earliest onset to reduce viral replication, shorten disease course and maintain latency in order to prevent further complications. That being said, existing treatment reduces the severity of lesions and controls further viral spread but does not provide a permanent cure. Recurrences can still happen, despite treatment with antiviral drugs .Treatment depends on the type of corneal lesions. Epithelial keratitis can be treated with topical anti-virals only. Corneal debridement under local anesthesia is also beneficial. In immunocompromised patients, patients poorly responding to topical therapy and wherever we need to avoid corneal toxicity associated with certain topical agents such as triflurothymidine drops, the addition of oral anti-virals are suggested. If high intraocular pressure occurs, anti-glaucoma drops may be administered, except for prostaglandin analogues, as they promote viral activity and inflammation in general .Whenever there is stromal involvement, as in cases of disciform, neurotrophic and necrotizing keratitis, topical steroids should be administered along with anti-virals. Gradual tapering of both medications is recommended upon improvement . Current treatment for HSK includes acyclovir, ganciclovir, triflurothymidine, penciclovir and valacyclovir. Acyclovir and its derivatives are nucleoside analogs .Acyclovir has a few downsides as treatment of ocular HSV-1 infections. The first is that it affects only newly synthesized viral DNA, and therefore it does not cure infected cells of the virus, but it does prevent new viruses from being produced . SecondlOn the other hand, valacyclovir, a prodrug of acyclovir, has better bioavailability than oral acyclovir and produces higher acyclovir tissue and serum concentrations. Topical ganciclovir has been shown to be as safe and effective as acyclovir in the treatment of herpetic epithelial keratitis . FurtherSecond-line treatment includes foscarnet and cidofovir, but they have less specificity for viral DNA and are more likely to cause significant toxicity in patients ,26. CidoPenetrating Keratoplasty (PKP) is the last option when the disease causes irreversible corneal damage, scarring or melting. However, recurrence of the disease or rejection may threaten the survival of grafts ,5,19.Long-term administration of low-dose oral antivirals as prophylaxis has demonstrated a significant decrease in recurrence of all forms of herpetic eye disease ,23. The Moreover, the addition of oral ascorbic acid in prophylactic treatment was associated with further reduced risk of HSK recurrence .Currently approved drugs that are active against most ACV resistant mutants have major limitations in terms of toxicities and pharmacokinetic liabilities that prevent their prophylactic use .Another study, though, regarding patients with rheumatoid arthritis and bilateral herpetic keratitis showed that prophylactic therapy at standard doses did not offer any benefit in avoiding recurrences, highlighting, however, the need for intense monitoring .Newer drugs are being tested as alternatives for the treatment of HSV. These molecules target at different phases of HSV-1 infection: Aptamers, retrocyclin 2 and antibodies act against viral attachment ,50; G1, Simultaneously occurring bilateral herpetic keratitis has a high proportion of subsequent complications, either because of greater virulence of the virus or because of altered host susceptibility . TherefoPatients at greater risk for recurrences should be treated long-term with prophylactic doses of anti-virals. In addition, as mentioned above, there are numerous ocular surgical procedures that may trigger herpetic reactivation. Consequently, it may be beneficial to administrate prophylactic treatment to these patients prior to operations.The role of prophylaxis should be reconsidered for another reason as well. As studies have shown, herpetic infection promotes serious structural changes and immunological response in the cornea. Confocal microscopy revealed that these effects are in fact bilateral, even in apparently unilateral cases ,55.Acyclovir resistance is a growing concern, especially in patients with an affected immune system. Hopefully, the development of new anti-viral agents will address this issue. Molecules on trial, used in combination, have shown effectiveness against resistive HSV variants by targeting different stages in the viral life cycle .Studies from developing countries tend to report a higher incidence of bilateral herpetic keratitis ,32. Anot


We trained and tested 70% and 30% of each study cohort, respectively, incorporating spatial coordinates and geometric vessel feature vectors. Cerebral arterial images were analyzed based on the ‘segmentation-stacking’ method using magnetic resonance angiography. We precisely classified the cerebral arteries across the exhaustive scope of vessel components using advanced geometric characterization, redefinition of vessel unit conception, and post-processing algorithms. We verified that the neural network ensemble, with multiple joint models as the combined predictor, classified all vessel component types independent of inter-subject variations in cerebral arterial anatomy. The validity of the categorization performance of the model was tested, considering the control, ICAS, and control-blended stroke cohorts, using the area under the receiver operating characteristic (ROC) curve and precision-recall curve. The classification accuracy rarely fell outside each image’s 90–99% scope, independent of cohort-dependent cerebrovascular structural variations. The classification ensemble was calibrated with high overall area rates under the ROC curve of 0.99–1.00 [0.97–1.00] in the test set across various study cohorts. Identifying an all-inclusive range of vessel components across controls, ICAS, and stroke patients, the accuracy rates of the prediction were: internal carotid arteries, 91–100%; middle cerebral arteries, 82–98%; anterior cerebral arteries, 88–100%; posterior cerebral arteries, 87–100%; and collections of superior, anterior inferior, and posterior inferior cerebellar arteries, 90–99% in the chunk-level classification. Using a voting algorithm on the queued classified vessel factors and anatomically post-processing the automatically classified results intensified quantitative prediction performance. We employed stochastic clustering and deep neural network ensembles. Ma-chine intelligence-assisted prediction of vessel structure allowed us to personalize quantitative predictions of various types of cerebral arterial structures, contributing to precise and efficient decisions regarding the cerebrovascular disease.Identifying the cerebral arterial branches is essential for undertaking a computational approach to cerebrovascular imaging. However, the complexity and inter-individual differences involved in this process have not been thoroughly studied. We used machine learning to examine the anatomical profile of the cerebral arterial tree. The method is less sensitive to inter-subject and cohort-wise anatomical variations and exhibits robust performance with an unprecedented in-depth vessel range. We applied machine learning algorithms to disease-free healthy control subjects ( Previous progressions include atlas-based artery identification and post-processing improvement using iterative region-growing territorial expansion and have suffered from practical limitations attributable to complexities and inter-individual variabilities of the cerebrovasculature covering only the major branches of the Circle of Willis for automated labelling4.Defining the morphological nature of cerebral circulation and providing quantified information, so-called digitisation, are the indispensable hallmark of identifying pathogenic mechanisms, diagnosing disease, and determining the clinical relevance of cerebrovascular dysfunctions. Automated labelling of the major cerebral arterial branch is the first step for quantitatively analysing cerebral arterial morphology from cerebrovascular images. Characterising the considerable variations in complex intracranial vascular structures, half of which are usually located outside the Circle of Willis, has been challenging but is a crucial step in quantifying structural information of the cerebrovasculatureHere, we overcome the problems mentioned above, leveraging geometric features obtained from systematic time-of-flight magnetic resonance angiography (TOF MRA) with a deep neural network and advanced the performance of the models by reorganising vascular units for clinically disparate personalised cerebral vessel modules.The strengths and unique nature of the investigation in this study reside in the validation of vessel unit restructuring and mathematical factor analysis in cerebrovasculature with the jointed assembly of machine learning models up to 62 cerebral branches. The study reveals that the prediction capacity of combined machine learning models fully automated and advanced the cerebral arterial labelling of queued vessel segments and minimised inter-individual anatomical variability confronted in clinical practice. The structural heterogeneity of control, stroke, and ICAS cerebrovasculature rarely undermined the prediction performance of the model ensemble.This study aimed to segment the cerebrovascular arterial branches in a fully automatic manner. We focused on cerebral arterial circuits, systematising and validating neural network models to render them clinically pragmatic.In accordance with the primary purpose of this study which was the development of an automated cerebral arterial labelling algorithm, we used a pre-established cohort retrospectively. The study subjects were healthy controls, stroke patients, and stroke patients with intracranial atherosclerosis (ICAS) over 20 years .The control cohorts for the algorithm development were healthy subjects who visited the comprehensive health promotion centre at the Samsung Medical Center and who underwent MRA from January 1, 2013, to December 31, 2013, excluding those who had the following: (1) stroke including ischemic stroke, hemorrhagic stroke, and transient ischemic attack; (2) coronary artery or heart disease; (3) ICAS; (4) intracranial arterial anomalies corresponding to pathological conditions or variants of normal anatomy; (5) congenital morbidity including cerebral arterial hypoplasia; and (6) miscellaneous abnormal cases diagnosed by angiography.5 with significant and symptomatic intracranial arterial stenosis of > 50% in the middle cerebral artery of the basilar artery.Stroke patients for the external validation of the algorithm were selected from the Samsung Medical Center stroke registry (SMC stroke registry). This prospectively collected stroke registry recruited acute stroke patients seven days after stroke onset. Another specially selected stroke group was intended to provide clinical relevance to the algorithm from the patients who participated in The Intensive Statin Treatment in Acute Ischemic Stroke Patients with Intracranial Atherosclerosis—High-Resolution Magnetic Resonance Imaging (STAMINA-MRI) studyDemographic data and vascular risk factors were collected from the medical records for controls and the stroke registry for the stroke cohort.The Samsung Medical Center Institutional Review Board approved the study design (SMC-2021-04-072). This study was performed in accordance with the declaration of Helsinki. Informed consent was waived by the Samsung Medical Center Institutional Review Board for the control group because the study progressed in a retrospective manner, and we provided the clinical data and brain images in an anonymised form. Written informed consent was obtained from those enrolled in the SMC stroke registry.The intracranial arteries were imaged using a 3.0 T Philips Achieva magnetic resonance imaging scanner  equipped with a 32-element phased-array receiver head coil.3, the parameters were as follows: echo time, 4.59 ms; repetition time, 22 ms; flip angle, 23°; RBW, 130 Hz/pixel; GRAPPA factor, 3; 32 reference lines.This study used whole-brain three-dimensional (3D) MRA images with a TOF protocol collected from each participant. With an isotropic voxel size configured to 0.284 × 0.284 mmWe used the raw input data format DICOM, which employs a TOF modality. Preprocessing procedures included anonymisation using DICOM Anonymizer Pro  and region growing by an in-house vessel analyser program that created segmented brain angiography maps, converting them into the NII format. The internally developed vessel morphology pipelines then analysed and extracted brain vessel features to examine the cerebrovascular structure. Figure 9. The z-axis voxels were tailored to the isovoxel image scale using bicubic interpolation to minimise artefacts and rough image resampling on a regular planar grid12. A continuous 3D space was divided into myriad cells uniformly based on the respective vertices of their isosurfaces. The major arterial centerlines from the boundary surface of each cell were then extracted. At this stage, a set of spatial coordinates, whose nearest vertex among the vertices of the isosurface is homogeneously distributed, works as a unit cell. The framework determines the starting point and skeleton of the centerlines of the significant brain arteries from a lower slice of the vascular region for extraction. Vessel skeleton refinement strengthens the determination of the endpoints of the centerline. Specifically, (i) skeletonising the cerebrovascular region and surface, (ii) pruning the branch under a predetermined threshold, (iii) generating a linked list of a tree structure based on the refined skeletal structure, and (iv) specifying leaf nodes from the linked list determine the endpoints. The centerlines were extracted by tracking the boundary surfaces of the cells connecting the start and end points. Finally, the pipelines characterised numerous blood vessel feature vectors of compartmentalised groups based on a branch point of a centerline. Quantified vessel characteristics include the cerebral blood vessel cross-sectional area, maximally inscribed sphere radius, minimised and maximised diameter, maximum-minimum radius ratio, surface circumference, distortion, curvature, and (hydraulic) luminal circularity  luminal circularity. Subsequently, the final chunk assignment was performed by allocating each spot to a specific chunk (step 1). A similar process was repeated to allocate spots in a specific chunk to a single branch by supervised machine learning, and the subsequent voting process enhanced accuracy (step 2). The voting algorithm obtained profiles of classified vessel labels from spots and selected the most frequently appearing vessel label among vascular chunks and segments.The primary objective of this study was the automatic segmentation and labelling of the cerebral vasculature using the conventional nomenclature (62 branches). To achieve this, we used a stepwise strategy: first allocating each spot of the whole brain to a specific chunk (step 1), and then allocating each spot of a single chunk to a specific branch (step 2). The supervised machine learning procedures initialised the allocation of each spot to a single chunk level using the multi-layer perceptron neural networkAn area under the receiver operating characteristic (AUROC) test was used to assess the internal and external validity and the chunk- and branch-level accuracy. First, we tested the performance of the algorithm in a set of independent stroke patients with ICAS. The structural dissimilarities in the cerebral arterial configuration between the healthy standard controls and those with stroke with ICAS were expected to indicate the clinical relevance of this algorithm in subjects with pathological conditions.t-values with p-values > 0.001 as insignificant.We performed groupwise nce Fig. . We visun = 42). The group had a mean age of 58 years  observed in all cases except for A5 and P5.With regard to sensitivity and specificity, the area under the curve (AUC) of the receiver operating characteristic (ROC) curve showed an overall value of 0.99–1.00 (0.97–1.00), and the precision-recall curve (PRC) was 0.992 (0.626–0.999) for the control, ICAS, and stroke cohorts. The algorithm’s AUC accuracy improved from 0.56–0.96 , and the PRC was 0.992 (0.483–0.975) for the control, ICAS, and stroke cohorts scaled to macro-average and micro-average values Fig. .Fig. n = 40) as external validation subjects, employing healthy subjects as the training set. When externally validated by the stroke-with-ICAS group (n = 46), the micro-average and macro-average performance values were 0.95 and 0.92, respectively  the appropriate combination of classical anatomical rules and computational prediction expedites the exhaustive classification of cerebral arteries; (ii) variations in vessel branches are detectable by employing neural networks. Accordingly, we designed a deep-learning algorithm that intelligently established in-depth vascular territories using strategies stemming from the systematic geometric characterisation of MRA data. The preprocessing modules uniquely reframed the entire cerebrovasculature into clinically redefined compartments: spots, segments, chunks, and branches.This study demonstrated that patient-specific cerebral arterial profiles aid in the quantitative and in-depth labelling of cerebral arterial branches that is clinically useful27. In previous attempts, vascular structures were overlooked, and distortion during thresholding was not adequately accounted for due to the shortage of appropriate geometric characterisation algorithms for examining small vessels. Additionally, these methods inadequately assessed residual variation, leading to overfitting, and thus their conclusions must be considered with caution. Furthermore, the cerebrovascular coverage of previous studies is lacking29, even excluding some vessel categories that were too complex to classify. The arterial geometry has also not been characterised; they are, therefore, vulnerable to normal variations.A quantitative approach to investigating cerebrovasculature has shown limited success, and conventional approaches have used less precise quantitative methods to understand complex cerebrovascular structures with limited clinical relevance33. Therefore, we cannot claim to have included all of the components of the cerebrovasculature in our analysis. Several graph neural network studies have facilitated the construction of arterial morphometry, assuming that arterial traces are entirely intact and typically representative. In other words, their hypotheses are vulnerable to interpreting vascular abnormalities or variations such as vessel occlusion36. Thus, conventional anatomical rules are less appropriate for quantitatively understanding the cerebrovasculature.MRA is one of the most widely used tools for assessing cerebral arterial disease. Using its template alignment, attempts have been made to label cerebral arteries limited to variations of those underlying the anterior circulation and those in clinical datasets or by bifurcations of interest, covering only roughly eight territorial frameworks using typical angiography of healthy subjectsThe deep neural networks employed 3D coordinates and geometric vessel feature vectors Fig.  derived By stochastically clustering the classified vascular regions, we identified blood vessels by exploiting the conventional neuroanatomical branch nomenclature. Finally, we propose that morphological parameters such as diameter, roundness, and tortuosity strengthen characterisation vectors complementing variations under the Cartesian coordinates of angiographical categories. Therefore, reduced dependence on a Cartesian framework, owing to an overall uniform distribution of the contribution of geometric vascular features, lends this study a high level of robustness and reliability of performance.39. Therefore, this algorithm can be applied to investigate cerebrovascular morphological features in various settings, such as in a longitudinal study, assessment of drug effects, and between-group comparison.Cerebral arterial labelling is not only a function of accuracy; therefore, targeted vessel chunks and segment ranges of the ensemble classifier cover should be exhaustive to fulfil clinical potential. Usually, pathological variations in the cerebral vasculature are expected to lower labelling performance. However, the multifaceted structural analysis among healthy controls, stroke patients, and stroke patients with ICAS revealed only a trivial difference in the performance of identifying each cerebral arterial branch Fig. . ConsideA mainstream strength of this study is the vascular framing using ‘chunk’, a critical element referring to a group of cerebrovascular elements sharing functional and anatomical similarities. As substantiated by the comparative analysis of UMAP assessment group-wise chunk-level feature vectors, chunk-level analysis is a rational categorisation method for territorialising cerebrovascular regions. Chunk discernment is a salient approach in a fundamental unit framework dedicated to the quantitative analysis of the cerebrovasculature and as an intermediate stage of vessel classification. Furthermore, this reframing reduces data dimension from about 5,000 spots to 20 chunks level, providing a valuable way of analysing and summarising the massive data into a valid format.Several limitations exist. First, the results of this study have a limitation of generalizability. This study included participants with only an ischemic stroke rather than a hemorrhagic stroke. Thus, there are some potential challenges in discerning the various subtypes of the stroke to improve further the feasibility of the clinical application of neural network ensembles. In addition, all subjects were ethnically Korean. Considering the anatomical and pathological inter-racial differences in the intracranial cerebral vasculature, the performance of the model should be validated in different populations. Bespeaking generalizability and inter-institutional compatibility require additional external validation using images outside the Samsung Medical Center. Second, we acknowledge that the sample size at present is not sufficiently large; however, based on patient-specific profiles, we have provided the potential for finding additional novel brain frailty biomarkers. Third, our results indicate that neural networks effectively identify the cerebral arterial segment. However, a few structure-ambiguous vascular segments suffer from unsatisfactory performance complemented via segment-wise voting post-processing. We hypothesise that the enigmatic nature of some small vessel segments predisposes them to idiosyncratic performances. The geometric features of the developed redefined vascular units provide groundbreaking opportunities to interpret mixed vascular territories intelligently. However, covering various subjects with reproducible iterative measurements and theorising optimised feature combinations remains an important scientific question. Another limitation of this study is that we only used TOF MR angiographic images. MRA does not, per se, provide authentic structural images but includes hemodynamic information. Therefore, modifications are mandatory if we apply the model developed in this study to other imaging modalities, such as digital subtraction angiography or computed tomographic angiography.Our system utilises segment-wise voting algorithms, anatomical post-processing, paradigm-shifting vascular unit reframing, and robust systematic geometric feature characterisation for clinical usability. The model performance was further synchronised and engineered using anatomical rule-assisted post-processing complementation. Exhaustive categorisation resulted in segmenting the 20 vascular chunks, which were narrowed down and further classified into small vessel segment compartments composed of spot cells. The unlimited applicability of orchestrated neural networks to non-matched feature vector data provides patient-specific profiles, facilitating successful clinical interpretations, the potential prognosis of brain debility progression, and post-stroke treatment management.In conclusion, we have pioneered the in-depth labelling cerebral arterial segments by scrutinising neural network ensembles via cerebrovascular structural reframing. By systematically analysing diverse cohorts, our results demonstrate that this technique is feasible and robust in profiling vessel-specific labelling.Supplementary Information.


The global vaccination programme against smallpox led to its successful eradication and averted millions of deaths. Monkeypox virus (MPXV) is a close relative of the Variola  virus. Due to antigenic similarity, smallpox vaccines cross-protect against MPXV. However, over 70% of people living today were never vaccinated against smallpox. Symptoms of monkeypox (MPX) include fever, head- and muscle ache, lymphadenopathy and a characteristic rash that develops into papules, vesicles and pustules which eventually scab over and heal. MPX is less often fatal  than smallpox (up to 30%). MPXV is endemic in sub-Saharan Africa, infecting wild animals and causing zoonotic outbreaks. Exotic animal trade and international travel, combined with the increasing susceptibility of the human population due to halted vaccination, facilitated the spread of MPXV to new areas. The ongoing outbreak, with >10,000 cases in >50 countries between May and July 2022, shows that MPXV can significantly spread between people and may thus become a serious threat to public health with global consequences. Here, we summarize the current knowledge about this re-emerging virus, discuss available strategies to limit its spread and pathogenicity and evaluate its risk to the human population. Monkeypox virus (MPXV) was identified in 1958 during outbreaks of a pox-like disease in macaque monkeys kept at a research facility in Denmark, hence the disease name “monkeypox” (MPX) . The patThis is the largest and most dispersed non-endemic MPXV outbreak known to date. Unlike previous outbreaks, there is no clear link between the infected people or a shared virus exposure source, such as travel to an endemic region or handling infected animals. While the transmission dynamics and route of infection are still uncertain, the virus appears to spread through close physical contact, and the vast majority of the affected are young or middle-aged men who have sex with men (MSM) and had recent sexual contact with new or multiple partners . DiagnosMPXV is a double-stranded DNA virus belonging to the Orthopox genus in the family Poxviridae. Its closest known relatives include Variola (VARV) and Vaccinia viruses (VACV) .The genomes of MPXV and VARV share a high level of sequence similarity 96%); however, phylogenetic studies suggest that they did not evolve from one another. VARV is more closely related to the Camelpox virus and the Taterapox virus found in gerbils (98% genome similarity) and both VARV and MPXV may have originated from poxviruses infecting rodents and/or ruminants 6%; howev,11,12. MMPXV has been detected in various species, and it is still not clear which of them serves as the main animal reservoir. For example, the virus has been isolated from African squirrels and MPXV reactive antibodies or viral DNA have been detected in multiple wild rodent and shrew species as well as pigs ,23,24,25The MPXV genome encompasses ~197,000 bp and includes hairpin termini as well as >190 non-overlapping open reading frames (ORFs) ,32. The Poxvirus particles have two mature forms, both of which can mediate infection: extracellular enveloped virus (EEV) (thought to be responsible for early dissemination) and the intracellular mature virus (IMV) released during cell lysis ,37. The Handling infected rodents appears to be a common source of zoonotic MPXV transmission, and human-to-human spread can occur through close contact with lesions, body fluids, respiratory droplets and contaminated objects . StudiesProteins involved in glycosaminoglycan biosynthesis were also recently identified in a genome-wide screen for factors facilitating MPXV infection . Thus, MPoxviruses use multiple mechanisms to evade the recognition and targeting by the immune system of their hosts. In vitro, MPXV infection of human cells does not induce interferon-stimulated gene (ISG) expression and further suppresses Tumour Necrosis Factor alpha (TNF-α), Interleukin 1 alpha and beta (IL-1α and β), C-C Motif Chemokine Ligand 5 (CCL5) and Interleukin 6 (IL-6) activation in primary fibroblasts . MPXV inDNA genomes such as those found in MPXV mutate much less frequently than those of RNA viruses. This is due to the higher stability of double-stranded DNA and the 3′–5′ proofreading exonuclease activity of poxvirus DNA polymerase . The evoTypical symptoms of MPX include head- and body aches, fever, chills, sore throat, malaise, fatigue, enlarged lymph nodes and a characteristic skin rash that develops into papules and vesicles which eventually crust over and heal. The disease manifestation is very similar to chickenpox and may hence be misdiagnosed, although lymphadenopathy is more common in MPXV infections ,66. HoweDue to the antigenic similarity between VACV and MPXV, smallpox vaccination is considered one of the measures to control MPXV outbreaks . Data coDue to the relatively long incubation period of MPX (5 to 21 days), early post-exposure vaccination can offer benefits to vulnerable patients. A decrease in the severity of MPX disease after post-exposure vaccination was demonstrated by challenge studies of prairie dogs  but no cThe rapid increase in MPX cases in non-endemic regions suggests that this zoonotic virus can efficiently spread between people and thus could pose a risk to global public health. Between 4 May and 12 July 2022, more than 10,000 new non-endemic MPX cases have been reported globally. This number is likely underestimated due to the limited access to MPXV diagnostics in many regions . DiseaseIn the current non-endemic outbreak, a new high-risk group has been identified—men who have sex with men (MSM) with recent contact with new/multiple sexual partners. This suggests that MPXV is being transmitted through close physical contact. Importantly, however, both the past and current MPXV outbreaks show that this virus can infect and be transmitted between individuals of any sex, age and orientation. The lack of reported MPX deaths in the non-endemic regions supports the notion that the clinical consequences of the current outbreak are less severe compared to those observed in endemic regions. However, the current demographic of MPX patients still includes very few cases among the most vulnerable groups, such as young children, pregnant women or immunocompromised individuals. Therefore, the health risks of a widespread MPXV outbreak are likely higher than what has been observed in recent weeks. Due to its wide species tropism, there is a risk that MPXV might establish animal reservoirs in non-endemic regions, which could fuel future outbreaks. Monitoring of changes in the demography of affected patients and possible spillover events to wildlife or domesticated animals is crucial for risk evaluation and making informed decisions about widening or introducing new safety measures against MPX. Meanwhile, intensifying MPX surveillance and increasing access to vaccines and antiviral drugs can help to diminish the threat of MPX.


Malignant pleural mesothelioma (MPM) is related to exposure to asbestos. It is insidious in nature and is generally diagnosed at an advanced stage. MPM is aggressive and portends a poor prognosis. Definitive diagnosis is usually established by obtaining pathological samples of the pleura by medical or surgical thoracoscopy. However, these procedures are invasive and carry a risk of seeding of biopsy sites with tumors. We herein report an infrequently encountered case of simultaneous use of endobronchial ultrasound and endoscopic ultrasound-guided biopsy of malignant pleural mesothelioma in a 48-year-old female patient. Mesothelioma is a neoplasm that arises insidiously from mesothelial surfaces like the pleura, pericardium, peritoneum, and tunica vaginalis. It is not a frequently encountered entity with an annual estimate of around 3300 cases per year in the United States . ApproxiA 48-year-old female patient with a history of hypertension, obesity, congestive heart failure with preserved ejection fraction, and 30 pack-year cigarette smoking presented to the pulmonary clinic due to worsening dyspnea on exercise (DOE) for a period of seven months. The patient was at her normal baseline seven months ago when she started noticing DOE. It gradually got worse, to the point where she was unable to go grocery shopping and required an electronic scooter. She also reported intermittent dry cough for two months. The patient did not have any fever, chills, night sweats, chest pain, wheezing, or hemoptysis. There was no history of lung diseases in the family. She did not have any history of autoimmune or connective tissue diseases. There was no occupational exposure to dust or toxic inhalation. She did not have pets at home. Her vital signs revealed blood pressure 146/83 mm Hg, heart rate 75/minute, regular, respiratory rate 18/minute, afebrile, and oxygen saturation of 93% at rest on room air. Examination of the respiratory system revealed normal vesicular breath sounds bilaterally without any adventitious sounds. Other systemic examinations were unremarkable.A full pulmonary function test showed decreased forced expiratory volume at 1 sec (FEV1) and forced vital capacity (FVC), normal FEv1/FVC ratio. Total lung capacity (TLC) was decreased while Residual volume (RV)/ TLC ratio was normal. The diffusion capacity of carbon monoxide (DLCO) was mildly reduced Table . SubsequIn a patient with clinical suspicion of MPM and relevant abnormal chest X-ray findings, further evaluation with a contrast-enhanced computed tomography (CECT) of the chest is invariably done. Common findings in chest imaging include unilateral pleural effusion, pleural mass or rind-like pleural thickening, and pleural plaques, or calcifications. As with any case of suspected malignancy, establishing a tissue diagnosis is the primary objective in MPM. Attempts can be made to start the work up with less invasive procedures like thoracentesis and pleural fluid cytology or thoracentesis and a closed pleural biopsy. However, studies suggest that the diagnostic yield of MPM is only 26% with pleural fluid cytology and 39 - 44% with thoracentesis and closed pleural biopsy . MedicalMPM per se does not give rise to endobronchial lesions. Thus, the use of flexible fiber-optic bronchoscopy is not routinely utilized in the diagnosis of MPM. EBUS-guided biopsies can be utilized in cases of mediastinal pleural lesions and hilar or mediastinal lymphadenopathy. EBUS-guided biopsies can also help stage the disease if MPM is diagnosed. Endoscopic ultrasound (EUS) can be utilized to enter the esophagus and biopsy paraesophageal lymph nodes under direct ultrasound guidance. A EUS-guided biopsy is reported to be even better tolerated than EBUS-guided biopsies in terms of causing fewer respiratory symptoms such as cough and overall respiratory decompensation . Piro etIn our case, after the initial pleural fluid examination was found to be unrevealing, we proceeded with EUS and EBUS-guided fine needle biopsy of the FDG avid mediastinal lymph nodes and obtained a definitive diagnosis. After obtaining the final diagnosis, palliative systemic chemotherapy was the treatment plan. The mainstay of treatment for our patient was platinum-based chemotherapy with cisplatin and pemetrexed. The addition of bevacizumab can be considered in such scenarios based on the benefit shown in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS)  althoughThe simultaneous use of EBUS and EUS as primary tools for the diagnosis of MPM is not commonly reported or discussed in the prevailing literature. We should recognize the use of EBUS or EUS as an extra tool in the armamentarium of a clinician when dealing with a possible case of MPM with mediastinal adenopathy. In selected cases, these procedures can provide samples for pathological diagnosis and staging in a rather less invasive manner than conventional techniques. This case also emphasizes the importance of care coordination and utilization of expertise between different sub-specialties in medicine to provide comprehensive patient care.


We explore a case of Benign Paroxysmal Positional Vertigo in the context of Persistent Hypoglossal Artery (PHA) and bilateral Madelung Deformity (MD). PHA is associated with a raft of major adverse cardiovascular events. MD can result from manifold conditions such as Turner’s Syndrome and mesomelic dwarfism. In this case, the patient’s positive family history of MD across generations is suggestive of inherited mutation in the Short Stature Homeobox (SHOX) Gene. We discuss the putative impact of SHOX on the genesis of Benign Paroxysmal Positional Vertigo (BPPV) in a patient with PHA and bilateral MD. •Persistent Hypoglossal Artery (PHA) is a developmental condition characterized by an inability to abolish fetal anastomoses.•Persistent Hypoglossal Artery is associated with a raft of major adverse cardiovascular and neurovascular events.•Mutations in SHOX may be causal in the pathogenesis of BPPV in patients with inherited Madelung Deformity.•Short Stature Homeobox genes are hypothesized to participated in the genesis of the bony labyrinth. To explore a case of Benign Paroxysmal Positional Vertigo (BPPV) in a patient with persistent hypoglossal artery (PHA) and bilateral Madelung (MD) deformity.Persistent hypoglossal artery (PHA) is a rare congenital carotid-basilar anastomosis . While pA 76-year-old female with a prior medical history of treated latent tuberculosis, diabetes mellitus, intracranial hemorrhage (ICH), osteoporosis, carotid intima media thickness (CIMT) results consistent with atherosclerosis, and right middle cerebral artery aneurysm status post-clipping presented to the emergency department complaining of new-onset vertigo for past three days. Upon presentation, temperature was 36.8 C, heart rate was 54 beats per minute (BPM), respiration rate (RR) was 15, and blood pressure (BP) was 124/74 with a PO2 of 97%.The patient described the symptoms as feeling as though the ceiling was spinning and that she “was falling into an abyss.” The symptoms worsened when supine and resolved upon upright seating. No nausea, flushing, or loss of consciousness was associated with these events. Furthermore, the patient denied having chest pain, nor shortness of breath associated with these episodes. Upon physical examination, the patient was noted to have bilateral Madelung deformities. The patient was evaluated for suspected vertigo.Holter monitoring (outpatient), transthoracic echocardiogram (TTE), and carotid ultrasound were performed, each of which was unremarkable. The patient noted that she had experienced similar episodes the year prior in which dizzy spells were accompanied by a “ball of fire” in her head. These episodes also abated upon seating and resolved spontaneously within several minutes.Motor examination revealed normal findings. Cranial nerve examination was largely unremarkable, though pronounced bilateral hearing loss to high and low frequencies was documented. After further examination, the patient was assessed as having severe vertigo with right beating nystagmus induced upon performing the Dix-Hallpike maneuver to the right. Due to the presence of horizontal nystagmus, the patient was assessed as having horizontal canal BPPV specifically . The patA CT scan of the head showed a right-sided craniotomy for clip ligation of an aneurysm at the right middle cerebral artery bifurcation. Further evaluation by CT angiogram of the head and neck showed a persistent right hypoglossal artery (PHA) originating from the external carotid artery feeding the basilar artery. MRI could not be performed due to the history of aneurysmal clip. Additionally, a CT of the patient's brain shows encephalomalacia in the right anterior temporal lobe and right superior temporal gyrus as well as bilateral cerebellar infarcts.The patient later revealed that there existed a similar wrist abnormality in her mother, suggestive of an autosomal dominant short stature homeobox (SHOX) genetic disorder. Given the symptoms and initial work-up, including imaging findings, presentation was consistent with a diagnosis of BPPV. She was prescribed meclizine and an Epley maneuver worksheet and reported improvement in symptoms on a follow-up visit one month post consultation. Upon follow up 6 weeks later, the patient was well in appearance and vitals were unremarkable.We described the case of a 67-year-old female with PHA and bilateral MD presenting to the ED with a diagnosis of BPPV.PHA arises during the early stages of embryonic development . PHA repBilateral MD is a rare congenital anomaly affecting the radial epiphysis, producing a prominent distal ulna and often resulting in restricted range of motion and subjective reports of discomfort . ResolutWhile MD is present in early adolescence and tends to be apparent upon physical examination, the diagnosis of PHA is typically incidental. In this particular patient, the diagnosis of PHA was an artifact of CT. Its appearance likely bears no relation to the patient’s BPPV, though the presence of trans-generational MD may be of greater significance.The short stature homeobox gene (SHOX), found in pseudoautomosmal region 1 (PAR1) of sex chromosomes, is highly conserved and is associated with a number of developmental conditions linked to abnormalities in hearing, skeletal development, and chromosomal expression, particularly in the context of Turner’s Syndrome . SHOX isOur patient had an inherited congenital Madelung deformity suggestive of a SHOX gene disorder along with PHA in the setting of BPPV. The relationship between MD and BPPV owing to SHOX mutation cannot be disregarded. Future studies may be warranted to further examine this anecdotal finding.Jacob M. Hands (JMH), Shaweta Khosa (SK), William M. Rienas (WMR), and Shri K. Mishra (SKM), conceptualized and ideated this piece collectively. JMH wrote and edited this manuscript with assistance from SK, WMR and SKM. SK and SKM supervised the creation of this work and guided its development. SKM is the senior author and clinical supervisor.No outside sources of funding were used in the preparation of this manuscript.


Ketamine may model aspects of schizophrenia arising through NMDA receptor activity deficits. Although acute ketamine can induce effects resembling both positive and negative psychotic symptoms, chronic use may be a closer model of idiopathic psychosis.We tested the hypotheses that ketamine users had lower brain volumes, as measured using MRI, and greater sub-threshold psychotic symptoms relative to a poly-drug user control group.Ketamine users (n = 17) and poly-drug using controls (n = 19) were included in the study. All underwent volumetric MRI imaging and measurement of sub-threshold psychotic symptoms using the Comprehensive Assessment of At-Risk Mental State (CAARMS). Freesurfer was used to analyse differences in regional brain volume, cortical surface area and thickness between ketamine users and controls. The relationship between CAARMS ratings and brain volume was also investigated in ketamine users.Ketamine users were found to have significantly lower grey matter volumes of the nucleus accumbens, caudate nucleus, cerebellum and total cortex . Within the cortex, ketamine users had significantly lower grey matter volumes within the frontal, temporal and parietal cortices . They also had significantly higher sub-threshold psychotic symptoms (p < 0.05). Frequency of ketamine use showed an inverse correlation with cerebellar volume (p < 0.001), but there was no relationship between regional brain volumes and sub-threshold psychotic symptoms.Chronic ketamine use may cause lower grey matter volumes as well as inducing sub-threshold psychotic symptoms, although these likely arise through distinct mechanisms.The online version contains supplementary material available at 10.1007/s00213-021-05873-0. There has been considerable interest in the role of N-methyl-D-aspartate (NMDA) receptor dysfunction in schizophrenia. This idea originally arose through the observation that NMDA receptor antagonists such as phencyclidine (PCP) and ketamine induced psychosis-like effects resembling both the positive and negative symptoms of schizophrenia Javitt . SubsequIt has been suggested that ketamine administration might model some of the features of schizophrenia, with the acute effects of ketamine resembling those seen in the prodrome of psychosis  and via word of mouth. After giving informed consent, all participants were required to provide a self-report of their drug use history. Exclusion criteria included history of self-reported mental illness requiring psychiatric input, history of head injury, left-handedness and non-fluency in English. Seventeen ketamine users (with ketamine use at least three times per week for the past year) and 19 poly-drug using controls (with no history of regular ketamine use) were recruited through advertising and word of mouth. Participants were required to abstain from psychotropic drugs for at least 24 h before the study. Abstinence from recent drug use was confirmed with urine dipstick analysis. The study was approved by both the Imperial College Research Ethics Committee and the UCL Graduate School ethics committee. All participants were compensated for their time and travel expenses.All participants were assessed for sub-threshold psychotic symptoms using the Comprehensive Assessment of At-Risk Mental State (CAARMS), a semi-structured assessment tool used to identify individuals at high risk of developing psychosis .Freesurfer image analysis suite . This processing includes motion correction and averaging of T1-weighted images to remove acquisition artefacts and removal of non-brain tissue using a hybrid watershed/surface deformation procedure followed by automated Talairach transformation to align each MR image to a reference image before segmenting the subcortical white matter and deep grey matter volumetric structures into regions of interest. Intensity normalisation was then performed to improve the signal–noise ratio followed by computer-defined delineation of the cortical grey matter/white matter boundary and grey matter/cerebrospinal fluid border. The cerebral cortex was automatically parcellated according to the Desikan-Killiany regions of interest -based method of cortical reconstruction and volumetric segmentation was performed using the IBM SPSS statistics 22 to determine group-level differences in individual cortical ROI volumes, ROI thickness and surface area measurements, as well as cortical volume (as a whole) and subcortical grey and white matter volume. Total intracranial volume (TIV) was used as a covariate in statistical modelling of volume differences. Mathworks MATLAB R2014a was used for false discovery rate (FDR) correction (q < 0.05) of multiple comparisons . Uncorrected partial correlations were performed in IBM SPSS statistics 22 to investigate potential associations between sub-threshold psychotic symptoms and level of ketamine use with the volume of the nucleus accumbens, caudate nucleus, cerebral cortex and cerebellar cortex, within ketamine users only.Multivariate general linear model (GLM) statistics were performed using Ketamine users did not differ significantly from poly-drug using controls in terms of age, sex or years in education Table . They alFreesurfer-based analysis of the apparent volumes of gross cerebral structures revealed that ketamine users had statistically significantly smaller volumes of the whole cerebral cortex, cerebellar cortex, nucleus accumbens and caudate nucleus , temporal cortex  and parietal cortex  . There were no regional differences in cortical thickness between the groups that survived FDR correction.Within the ketamine user group, the frequency of ketamine use inversely correlated with the volumes of the cerebellar cortex  schizophrenia. We attempted to address this possibility by recruiting patients who did not have any personal history of mental illness. Nonetheless, three of the ketamine users had symptomatology that reached diagnostic criteria for psychosis. This was not particularly surprising, given previous reports of schizophrenia-like symptomatology in chronic ketamine users  As mentioned, this study was relatively small, with low power to detect group differences, although this can also be attributed to the difficulty of recruiting poly-drug using controls and ketamine users. Future studies should aim, if possible, for a larger group size in order to address more subtle group differences; (2) despite our best efforts, the matching of the two groups was not perfect, with the ketamine users trending towards being older and having fewer years of education. Although these differences did not reach statistical significance, it is not clear to what extent this may have affected the results; (3) similarly, the ketamine and poly-drug users were not fully matched for their other drug use. We chose to match with a poly-drug control group to try to take account of the effect of these drugs on the brain to tease out the effect of ketamine alone. However, ketamine users were more likely to also be users of MDMA, cocaine, amphetamine and heroin than the poly-drug users and were also heavier users of alcohol and cannabis, which is a particular challenge for studies of this type. This means that it is not possible to determine whether the lower brain volumes in ketamine users were primarily due to ketamine use or to the use of these other substances. Users of alcohol, amphetamines, cannabis, cocaine and opiates have shown similar reductions in frontal, parietal and temporal cortices, as well as in cerebellum Below is the link to the electronic supplementary material.