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Besides visual assessment of the intra-vascular appearance, intravascular optical coherence tomography (IVOCT) enables precise diameter measurements within the coronary arteries. The current study presents an upgraded test setup allowing the investigation of the elastic properties of porcine coronary arteries ex vivounder pulsatile flow conditions. IV-OCT imaging was performed within the left circumflex artery of a porcine heart applying a normotensive and a hypertensive pressure regime at different pulse rates. Radial compliance was derived from the luminal diameter as well as intra-arterial pressure measurements. Test results show a significant reduction of radial compliance under pulsatile conditions, when compared to reference measurements under steady flow. The mean radial compliance decreased with increasing pulse rate, which can be attributed to the viscoelastic properties of the arterial wall.

Our aim in this paper is twofold. Firstly, we develop a new asymptotic theory for Floquet exponents. We consider a linear system of differential equations with a time-periodic coefficient matrix. Assuming that the coefficient matrix depends analytically on a small parameter, we derive a full asymptotic expansion of its Floquet exponents. Based on this, we prove that only the constant order Floquet exponents of multiplicity higher than one will be perturbed linearly. The required multiplicity can be achieved via folding of the system through certain choices of the periodicity of the coefficient matrix. Secondly, we apply such an asymptotic theory for the analysis of Floquet metamaterials. We provide a characterization of asymptotic exceptional points for a pair of subwavelength resonators with time-dependent material parameters. We prove that asymptotic exceptional points are obtained if the frequency components of the perturbations fulfill a certain ratio, which is determined by the geometry of the dimer of subwavelength resonators., Journal of Differential Equations, 319, ISSN:0022-0396

Being driven by the goal of finding edge modes and of explaining the occurrenceof edge modes in the case of time-modulated metamaterials in the high-contrastand subwavelength regime, we analyse the topological properties of Floquet normal forms of periodically parameterized time-periodic linear ordinary differential equations {d/dtX=A alpha(t)X} (alpha is an element of Td). In fact, our main goal being the question whetheran analogous principle as the bulk-boundary correspondence of solid-state physicsis possible in the case of Floquet metamaterials, i.e., subwavelength high-contrasttime-modulated metamaterials. This paper is a first step in that direction. Since thebulk-boundary correspondence states that topological properties of the bulk materials characterize the occurrence of edge modes, we dedicate this paper to the topologica lanalysis of subwavelength solutions in Floquet metamaterials. This work should thusbe considered as a basis for further investigation on whether topological properties ofthe bulk materials are linked to the occurrence of edge modes. The subwavelength solu-tions being described by a periodically parameterized time-periodic linear ordinary differential equation{d/dtX=A alpha(t)X} (alpha is an element of Td), we put ourselves in the general settingof periodically parameterized time-periodic linear ordinary differential equations and introduce a way to (topologically) classify a Floquet normal formF,Pof the associated fundamental solution{X-alpha(t)=P(alpha,t)exp(tF(alpha))}(alpha is an element of Td). This is achieved by analysing the topological properties of the eigenvalues and eigenvectors of the monodromy matrix X-alpha(T)and the Lyapunov transformationP(alpha,t). The corresponding topological invariants can then be applied to the setting of Floquet metamaterials. In this paper these general results are considered in the case of a hexagonal struc-ture. We provide two interesting examples of topologically non-trivial time-modulated hexagonal structures, Mathematische Annalen, ISSN:1432-1807, ISSN:0025-5831

The aim of this article is to advance the field of metamaterials by proposing formulas for the design of high-contrast metamaterials with prescribed subwavelength defect mode eigenfrequencies. This is achieved in two settings: (i) design of non-hermitian static materials and (ii) design of instantly changing non-hermitian time-dependent materials. The design of static materials is achieved via characterizing equations for the defect mode eigenfrequencies in the setting of a defected dimer material. These characterizing equations are the basis for obtaining formulas for the material parameters of the defect which admit given defect mode eigenfrequencies. Explicit formulas are provided in the setting of one and two given defect mode eigenfrequencies in the setting of a defected chain of dimers. In the time-dependent case, we first analyze the influence of time-boundaries on the subwavelength solutions. We find that subwavelength solutions are preserved if and only if the material parameters satisfy a temporal Snell's law across the time boundary. The same result also identifies the change of the time-frequencies uniquely. Combining this result with those on the design of static materials, we obtain an explicit formula for the material design of instantly changing defected dimer materials which admit subwavelength modes with prescribed time-dependent defect mode eigenfrequency. Finally, we use this formula to create materials which admit spatio-temporally localized defect modes., Comment: v.2: Corrected metadata

The following article is one of the voices in the debate about the universality of priestly celibacy. It attempts to track the development of the theological and personalist arguments for celibacy contained in the most significant documents of the Magisterium of the Church. A special emphasis has been put on contemporary texts, issued after the Second Vatican Council. This choice has been caused by two major reasons. First, post-conciliar documents introduce a new quality to the argument of the universality of celibacy. Second, they have a far bigger impact on the discipline of the Church than previous texts.

Celem artykułu jest próba ukazania tego, w jaki sposób Duch Święty kształtuje osobowość chrześcijanina. Pojęcie „osobowości” zostało wybrane nieprzypadkowo, ponieważ posługuje się nim wiele współczesnych nauk o człowieku. Dlatego też bardzo dobrze nadaje się do multidyscyplinarnego dyskursu o osobie ludzkiej. Oczywiście fenomen osobowości ma nieco inne pole semantyczne w psychologii, socjologii, etyce czy pedagogice. W niniejszym opracowaniu terminy: „osobowość” oraz „osobowość chrześcijańska” będą rozumiane personalistycznie, zgodnie z intuicjami zaczerpniętymi od Wincentego Granata. Próba odpowiedzi na pytanie o to, w jaki sposób Duch Święty kształtuje osobowość człowieka, będzie prowadzona zgodnie z zaproponowaną przez Granata hermeneutyką osoby przez osobowość. Zdaniem lubelskiego personalisty można mówić o trzech płaszczyznach (rodzajach) osobowości ludzkiej: psychicznej, etycznej i społecznej. Jednakże należy pamiętać o tym, że za każdym razem chodzi o „osobę integralną”, ujmowaną wszakże w perspektywie pewnego wyodrębnionego spektrum jej bytowania i działania.

SummaryCortical circuits are composed predominantly of pyramidal-to-pyramidal neuron connections, yet their assembly during embryonic development is not well understood. We show that embryonic layer 5 pyramidal neurons, identified through single cell transcriptomics, display two phases of circuit assembly in vivo. At E14.5, a multi-layered circuit motif, composed of a single layer 5 cell type, forms. This motif is transient, switching to a second circuit motif, involving all three types, by E17.5. In vivo targeted single cell recordings and two-photon calcium imaging of embryonic layer 5 neurons reveal that, in both phases, neurons have active somas and neurites, tetrodotoxin-sensitive voltage-gated conductances, and functional glutamatergic synapses. Embryonic layer 5 neurons strongly express autism-associated genes, and perturbing these genes disrupts the switch between the two motifs. Hence, layer 5 pyramidal neurons form transient active pyramidal-to-pyramidal circuits, at the inception of neocortex, and studying these circuits could yield insights into the etiology of autism.

Bogoczłowieczeństwo jawi się jako wielka kategoria interpretacyjna, zdolna pomieścić w sobie zarówno namysł nad Bosko-ludzką rzeczywistością Chrystusa, jak i nad istotą człowieczeństwa w jego indywidualnym i społecznym charakterze. Dlatego też warto przyjrzeć się bliżej możliwościom, jakie daje ta kategoria w wydaniu teologii prawosławnej.

Człowiek od dawna próbował rozumieć siebie samego oraz otaczający go świat. Historia ludzkiej myśli obfituje w wielu uczonych, którzy przy użyciu rozmaitych systemów filozoficznych, etycznych, społecznych czy religijnych, a w czasach najnowszych także za pomocą wysoko rozwiniętej aparatury technicznej, próbowali i próbują wyjaśnić fenomen człowieka. Na tym tle niezwykle interesująca jawi się droga personalistyczna. Stara się ona wyjaśnić istotę bycia człowiekiem za pomocą kategorii ściśle związanych z tym, co prawdziwie ludzkie: z jego doświadczeniem; z jego egzystencją; z relacjami, w których żyje i działa. Współczesna polska myśl antropologiczna posiada co najmniej kilku wybitnych przedstawicieli tego prądu. Jednym z nich był znakomity lubelski personalista i teolog Wincenty Granat.

Artykuł poświęcony jest problematyce interpretacji nauczania papieża Franciszka na temat tzw. „sytuacji nieregularnych” zaprezentowanych w adhortacji Amoris laetitia. Jest to problem ważny, ponieważ ta część papieskiej teologii budzi największe kontrowersje. Przyglądając się dynamice rozwoju doktryny Kościoła, można bez trudu dostrzec jej nieustanny rozwój idący w kierunku coraz lepszego wyjaśniania prawd wiary, jak też nieustannej aktualizacji nauczania. Jednakże każda aktualizacja musi być zanurzona w Tradycji, ponieważ prawda pozostaje w swojej istocie niezmienna, a jedynie zmieniać się może pewna forma językowa jej przekazu. Przyjmując hermeneutykę ciągłości, jaka cechuje rozwój doktryny Kościoła, uprawnione jest poszukiwanie właściwego kontekstu hermeneutycznego dla „sytuacji nieregularnych” w świetle teologii i antropologii Jana Pawła II oraz na tle dokumentu Międzynarodowej Komisji Teologicznej poświęconego interpretacji dogmatów.

Introduction:Checkpoint inhibitor immunotherapy is associated with numerous adverse events, including eruptive keratoacanthomas and squamous cell carcinomas. However, no cases of immunotherapy-associated verrucous keratoses (VKs) have been reported. VKs are proliferative lesions generally considered benign, although they have been suggested to represent premalignant lesions.Cases:We present the first case series of three patients with immunotherapy-associated VKs. The patients were receiving nivolumab for renal cell carcinoma, combination ipilimumab/nivolumab for non-small cell lung carcinoma, and pembrolizumab for malignant melanoma. The VKs appeared 3-7 months after initiation of immunotherapy. Lesions were treated with shave removal or cryosurgery without recurrence. This report adds to the spectrum of cutaneous squamoproliferative lesions induced by checkpoint inhibitor immunotherapy.

We consider subsequences with gap constraints, i. e., length-k subsequences p that can be embedded into a string w such that the induced gaps (i. e., the factors of w between the positions to which p is mapped to) satisfy given gap constraints gc = (C_1, C_2, …, C_{k-1}); we call p a gc-subsequence of w. In the case where the gap constraints gc are defined by lower and upper length bounds C_i = (L^-_i, L^+_i) ∈ ℕ² and/or regular languages C_i ∈ REG, we prove tight (conditional on the orthogonal vectors (OV) hypothesis) complexity bounds for checking whether a given p is a gc-subsequence of a string w. We also consider the whole set of all gc-subsequences of a string, and investigate the complexity of the universality, equivalence and containment problems for these sets of gc-subsequences., LIPIcs, Vol. 248, 33rd International Symposium on Algorithms and Computation (ISAAC 2022), pages 64:1-64:18

In this paper, we consider a variant of the classical algorithmic problem of checking whether a given word $v$ is a subsequence of another word $w$. More precisely, we consider the problem of deciding, given a number $p$ (defining a range-bound) and two words $v$ and $w$, whether there exists a factor $w[i:i+p-1]$ (or, in other words, a range of length $p$) of $w$ having $v$ as subsequence (i.\,e., $v$ occurs as a subsequence in the bounded range $w[i:i+p-1]$). We give matching upper and lower quadratic bounds for the time complexity of this problem. Further, we consider a series of algorithmic problems in this setting, in which, for given integers $k$, $p$ and a word $w$, we analyse the set $p$-Subseq$_{k}(w)$ of all words of length $k$ which occur as subsequence of some factor of length $p$ of $w$. Among these, we consider the $k$-universality problem, the $k$-equivalence problem, as well as problems related to absent subsequences. Surprisingly, unlike the case of the classical model of subsequences in words where such problems have efficient solutions in general, we show that most of these problems become intractable in the new setting when subsequences in bounded ranges are considered. Finally, we provide an example of how some of our results can be applied to subsequence matching problems for circular words., Comment: Extended version of a paper which will appear in the proceedings of the 16th International Conference on Reachability Problems, RP 2022

Sclerodermatous graft versus host disease (sclGVHD) is a debilitating complication of hematopoietic stem cell transplant and is characterized by skin thickening and fibrosis that can result in severe contractures. While immunosuppressive therapy remains a mainstay of treatment, the disease course often progresses and, in severe cases, renders patients immobile and wheelchair-bound. Lasers that can target sclerotic lesions to improve tissue pliability and restore range of motion are a promising potential treatment for sclGVHD. Fractional CO2 lasers promote selective collagen remodeling by creating microcolumns of thermal injury that stimulate a wound healing response. Here, we present 2 patients with sclGVHD who underwent treatment with fractional ablative CO2 laser. In this pilot case series demonstrating the novel use of CO2 laser for severe, refractory sclGVHD, two patients were treated with fractional ablative CO2 laser to a focal area of sclerosis. One patient also received clobetasol ointment under occlusion in between treatments. Both patients reported marked subjective improvement in pain and mobility. Objective measurements were recorded for patient 2 who gained roughly 10 degrees of extension and 2 degrees of flexion, as well as a 10% reduction in skin thickness in the treated area. CO2 laser therapy with or without clobetasol ointment under occlusion is a promising treatment modality for sclGVHD.

Adult-onset Still’s disease classically presents with high fevers, arthralgias, leukocytosis, and an evanescent eruption. There are, however, a known subset of patients who develop an atypical eruption with persistent erythematous to violaceous papules and plaques. Here, we present the case of a white female in her 40s who presented with 2 years of spiking fevers, arthralgias, and a fixed pruritic eruption with erythematous plaques with overlying scale and linear accentuation. She was initially treated with oral prednisone, anakinra, and methotrexate. Due to persistent symptoms, she was switched to adalimumab with significant relief of symptoms. Prompt recognition of adult-onset Still’s disease with this atypical eruption may help prevent delayed or missed diagnosis and allow for early, appropriate intervention.

The paper studies the problem of the transcendence of the person suggested by Karol Wojtyla/John Paul II. It originates in the philosophical thought of this Polish personalist and is complemented in his theological works. According to Wojtyla transcendence can be described as “another name for the person” as it is closely related to the fulfilment of man as a personal being. The paper contains analyses of three dimensions of transcendence, and these are: 1) transcendence in action; 2) transcendence towards another “I”; and 3) transcendence towards personal God.

Reports of permanent chemotherapy-induced alopecia (PCIA) are increasing in the field of oncodermatology, but there is a dearth of information regarding how it is recognized and managed by health care providers (HCPs) across different medical specialties (dermatology, oncology, and internal medicine). A 25-question survey was designed to elicit general knowledge and awareness of PCIA, as well as attitudes about referral and treatment. Responses were collected via REDCap, a secure online application, and analyzed with descriptive statistics, chi-square, and ANOVA tests. There was a significant difference in the number of subjects who had heard of PCIA prior to starting the survey (Derm 79%, Onc 30%, IM 22%, p 6 months) than IM (42% and 45% vs. 17%) and significantly more had encountered patients with the condition (47% and 45% vs. 17%). More providers in dermatology and IM knew how to diagnose PCIA compared with oncology (84% and 83% vs. 70%). Dermatology HCPs were the only participants who had attempted to treat patients with PCIA, and most providers believed that patients would accept similar types of treatment for PCIA. Dermatology HCPs were more likely to report higher confidence in their abilities to diagnose and manage PCIA than other providers. The results of this survey identify knowledge gaps about PCIA among health care providers. Therefore, education and multidisciplinary engagement should be pursued in order to improve awareness, diagnosis, referral, and management of PCIA as part of survivorship care.

Sexual and gender minority (SGM) individuals, including lesbian, gay, bisexual, transgender/gender diverse, questioning/queer, intersex, and asexual (LGBTQIA) persons, represent a historically underserved population within the field of medicine, though their unique health needs are increasingly recognized. Part 2 of this two-part review will address unique concerns regarding acne, tanning behavior, sexually transmitted infections, and other health disparities among SGM adolescents. A more comprehensive understanding of the dermatologic needs of SGM youth will better allow pediatric dermatologists to actively and compassionately care for this health disparity population.

Biologic agents such as adalimumab, etanercept, golimumab, certolizumab, ustekinumab, brodalumab, secukinumab, ixekizumab, dupilumab, alefacept, rituximab, omalizumab, tildrakizumab, and guselkumab are now indicated in the treatment of dermatologic disorders. This review reports on current prevention, risk, and management of infection in patients receiving biologic therapy for dermatologic disorders. Although risk of infection in patients receiving biologic agents for management of a dermatologic disorder is well-known, it appears to continue to be a low risk. However, optimal prevention and management of some infection risks remain an unmet need. Although the overall risk for infection during biologic therapy for dermatologic disorders appears to remain low, there remains concern about the level of risk for reactivation of tuberculosis, as well as hepatitis B and C, and the risk for other, often uncommon, serious infection remains unknown. Continued pharmacovigilance serves to mitigate risk as well as promote optimal management of dermatologic disorders with biologic agents.

Background 68Gallium-DOTATATE positron emission tomography–computed tomography (PET CT) has shown superior accuracy in detecting grade 1 and 2 neuroendocrine tumors over previous imaging modalities and was recently included in National Comprehensive Cancer Network guidelines. It remains unclear which patients benefit most from this imaging modality. We therefore reviewed our initial experience with 68Gallium-DOTATATE PET CT to evaluate its usefulness in diagnosing, staging, and surveilling neuroendocrine tumors. Methods Records of patients who underwent 68Gallium-DOTATATE PET CT from March to December 2017 were prospectively evaluated. The primary endpoint was whether 68Gallium-DOTATATE PET CT changes treatment in patients with neuroendocrine tumors. Descriptive statistics, Fisher exact tests, and nested logistic regressions were conducted. Results A total of 50 consecutive patients were included. Of these, 41 patients (82%) had a biopsy-proven neuroendocrine tumor at the time of imaging. The remaining 9 patients (18%) had symptoms or biochemistry suggestive of a neuroendocrine tumor with negative cross-sectional imaging. 68Gallium-DOTATATE PET CT changed management in 33 patients (66%). There were 24 patients with intermodality changes in management and 9 patients with intramodality changes in management. Patients with scans performed for staging had a higher likelihood of a change in management (P = .006). Conclusion Performing 68Gallium-DOTATATE PET CT should be considered for staging and surveillance of neuroendocrine tumors because it is frequently associated with changes in management.

Semi-online algorithms that are allowed to perform a bounded amount of repacking achieve guaranteed good worst-case behaviour in a more realistic setting. Most of the previous works focused on minimization problems that aim to minimize some costs. In this work, we study maximization problems that aim to maximize their profit. We mostly focus on a class of problems that we call choosing problems, where a maximum profit subset of a set objects has to be maintained. Many known problems, such as Knapsack, MaximumIndependentSet and variations of these, are part of this class. We present a framework for choosing problems that allows us to transfer offline $\alpha$-approximation algorithms into $(\alpha-epsilon)$-competitive semi-online algorithms with amortized migration $O(1/\epsilon)$. Moreover we complement these positive results with lower bounds that show that our results are tight in the sense that no amortized migration of $o(1/\epsilon)$ is possible., Comment: CIE 2021

An absent factor of a string w is a string u which does not occur as a contiguous substring (a.k.a. factor) inside w. We extend this well-studied notion and define absent subsequences: a string u is an absent subsequence of a string w if u does not occur as subsequence (a.k.a. scattered factor) inside w. Of particular interest to us are minimal absent subsequences, i.e., absent subsequences whose every subsequence is not absent, and shortest absent subsequences, i.e., absent subsequences of minimal length. We show a series of combinatorial and algorithmic results regarding these two notions. For instance: we give combinatorial characterisations of the sets of minimal and, respectively, shortest absent subsequences in a word, as well as compact representations of these sets; we show how we can test efficiently if a string is a shortest or minimal absent subsequence in a word, and we give efficient algorithms computing the lexicographically smallest absent subsequence of each kind; also, we show how a data structure for answering shortest absent subsequence-queries for the factors of a given string can be efficiently computed.

Semi-online algorithms that are allowed to perform a bounded amount of repacking achieve guaranteed good worst-case behaviour in a more realistic setting. Most of the previous works focused on minimization problems that aim to minimize some costs. In this work, we study maximization problems that aim to maximize their profit.

Respect for human subjects serves as a foundation for the development and assessment of ethics in clinical research. In the past, however, significant violations of this principle have taken place. Responding to these atrocities, numerous guiding documents, including the Declaration of Helsinki and the Belmont Report, were created to establish a framework for the regulation of modern research design. These documents establish specific interpretations of respect for human subjects in clinical research and highlight the crucial role of voluntary participation and informed consent in this context. However, modern research design must still be subject to scrutiny and reevaluation. In this chapter, modern clinical research scenarios that exist in a sort of “ethical gray area” are explored in a case-based format. These include the role of placebo-controlled trials for diseases with well-accepted treatments, off-label clinical use of accepted treatments, and front-door consents. Because clinical research maintains a delicate balance between benefit for an individual and benefit for a population, the potential for harm to, or loss of respect for, research participants must be constantly considered.

An absent factor of a string $w$ is a string $u$ which does not occur as a contiguous substring (a.k.a. factor) inside $w$. We extend this well-studied notion and define absent subsequences: a string $u$ is an absent subsequence of a string $w$ if $u$ does not occur as subsequence (a.k.a. scattered factor) inside $w$. Of particular interest to us are minimal absent subsequences, i.e., absent subsequences whose every subsequence is not absent, and shortest absent subsequences, i.e., absent subsequences of minimal length. We show a series of combinatorial and algorithmic results regarding these two notions. For instance: we give combinatorial characterisations of the sets of minimal and, respectively, shortest absent subsequences in a word, as well as compact representations of these sets; we show how we can test efficiently if a string is a shortest or minimal absent subsequence in a word, and we give efficient algorithms computing the lexicographically smallest absent subsequence of each kind; also, we show how a data structure for answering shortest absent subsequence-queries for the factors of a given string can be efficiently computed., Comment: An extended abstract appeared in the proceedings of the 15th International Conference on Reachability Problems RP2021

General anesthetics induce loss of consciousness, a global change in behavior. However, a corresponding global change in activity in the context of defined cortical cell types has not been identified. Here, we show that spontaneous activity of mouse layer 5 pyramidal neurons, but of no other cortical cell type, becomes consistently synchronized in vivo by different general anesthetics. This heightened neuronal synchrony is aperiodic, present across large distances, and absent in cortical neurons presynaptic to layer 5 pyramidal neurons. During the transition to and from anesthesia, changes in synchrony in layer 5 coincide with the loss and recovery of consciousness. Activity within both apical and basal dendrites is synchronous, but only basal dendrites' activity is temporally locked to somatic activity. Given that layer 5 is a major cortical output, our results suggest that brain-wide synchrony in layer 5 pyramidal neurons may contribute to the loss of consciousness during general anesthesia.

Sclerodermatous graft versus host disease (sclGVHD) is a debilitating complication of hematopoietic stem cell transplant and is characterized by skin thickening and fibrosis that can result in severe contractures. While immunosuppressive therapy remains a mainstay of treatment, the disease course often progresses and, in severe cases, renders patients immobile and wheelchair-bound. Lasers that can target sclerotic lesions to improve tissue pliability and restore range of motion are a promising potential treatment for sclGVHD. Fractional CO2 lasers promote selective collagen remodeling by creating microcolumns of thermal injury that stimulate a wound healing response. Here, we present 2 patients with sclGVHD who underwent treatment with fractional ablative CO2 laser. In this pilot case series demonstrating the novel use of CO2 laser for severe, refractory sclGVHD, two patients were treated with fractional ablative CO2 laser to a focal area of sclerosis. One patient also received clobetasol ointment under occlusion in between treatments. Both patients reported marked subjective improvement in pain and mobility. Objective measurements were recorded for patient 2 who gained roughly 10 degrees of extension and 2 degrees of flexion, as well as a 10% reduction in skin thickness in the treated area. CO2 laser therapy with or without clobetasol ointment under occlusion is a promising treatment modality for sclGVHD.

A word $u$ is a subsequence of another word $w$ if $u$ can be obtained from $w$ by deleting some of its letters. The word $w$ with alph$(w)=\Sigma$ is called $k$-subsequence universal if the set of subsequences of length $k$ of $w$ contains all possible words of length $k$ over $\Sigma$. We propose a series of efficient algorithms computing the minimal number of edit operations (insertion, deletion, substitution) one needs to apply to a given word in order to reach the set of $k$-subsequence universal words.

Li-Fraumeni syndrome (LFS) is a rare genetic disorder that confers a high risk of developing certain malignancies at a young age. It is caused by germline mutations in the TP53 gene and is typically diagnosed by sequencing this gene in blood cells. The presence of a mutation in approximately half of the DNA reads (allelic fraction of 50%) is an indicator of a germline mutation, such as that in LFS. Clonal hematopoiesis (CH) is an expansion of a hematopoietic clone containing a somatic driver mutation with a low allelic fraction, usually not more than 10% to 20%. This report presents a patient with fallopian tube carcinoma who underwent multigene panel testing for cancer predisposition and was found to have a mutation in the TP53 gene, c.733G>T (p.Gly245Cys). Since the TP53 mutation had an allelic fraction of approximately 50%, it was interpreted as being germline, and the patient was diagnosed as having LFS. A year later, she developed acute myelogenous leukemia. Subsequent mutational analysis showed that the TP53 mutation was absent in her benign tissue sample but present in leukemic cells. Furthermore, sequencing of the fallopian tube tumor tissue revealed a different TP53 gene mutation, c.818G>T (p.Arg273Leu). These observations confirmed that the previously identified mutation in her blood was somatic rather than germline and that she had CH at the time of genetic testing. CH can occasionally lead to a misdiagnosis of a germline mutation and a cancer predisposition syndrome that has significant implications for patients and their families. Therefore, the abnormal result of genetic testing for hereditary cancer susceptibility should be carefully interpreted when the clinical presentation is atypical, when the patient is older, when the gene in question is known to have potential germline and somatic mutations such as the TP53 gene, and when the allelic fraction is approximately 50%.

Genetic engineering by viral infection of single cells is useful to study complex systems such as the brain. However, available methods for infecting single cells have drawbacks that limit their applications. Here we describe 'virus stamping', in which viruses are reversibly bound to a delivery vehicle - a functionalized glass pipette tip or magnetic nanoparticles in a pipette - that is brought into physical contact with the target cell on a surface or in tissue, using mechanical or magnetic forces. Different single cells in the same tissue can be infected with different viruses and an individual cell can be simultaneously infected with different viruses. We use rabies, lenti, herpes simplex, and adeno-associated viruses to drive expression of fluorescent markers or a calcium indicator in target cells in cell culture, mouse retina, human brain organoid, and the brains of live mice. Virus stamping provides a versatile solution for targeted single-cell infection of diverse cell types, both in vitro and in vivo.

Immune checkpoint inhibitors are used to treat numerous malignancies but may be associated with severe adverse events. Bullous dermatoses, chiefly bullous pemphigoid (BP), are potentially progressive adverse events that cause blistering skin lesions and may involve a significant body surface area. Herein, we report an 87-year-old man with urothelial cell carcinoma undergoing atezolizumab treatment who presented with an acute-onset blistering eruption. Biopsy revealed a subepidermal bulla, direct immunofluorescence revealed linear IgG and C3 deposits at the dermal-epidermal junction, and serum studies revealed elevated levels of antibodies to BP180 and BP230. Anti-PD-L1-induced BP was diagnosed, immunotherapy was withheld, and he was treated with oral doxycycline with niacinamide and clobetasol ointment. He restarted atezolizumab and has successfully received four cycles (every 3 weeks) while continuing this BP treatment regimen. A literature review revealed eight other cases of anti-PD-L1-induced bullous disorders. The incidence of bullous dermatoses with anti-PD-1/anti-PD-L1 agents combined is 1%, whereas the reported incidence for anti-PD-L1 agents alone ranges from 1.3-5%, raising concerns for a higher overall risk. In addition to our case, only one other case reported successful resumption of immunotherapy. Early control and management of immunotherapy-induced BP may reduce complications and prevent treatment discontinuation.

Checkpoint inhibitor immunotherapy, including ipilimumab and nivolumab, is associated with numerous immune-related adverse events including dermatitis, pruritus, hepatitis, diarrhea, and hypophysitis. As the number of patients undergoing immunotherapy treatment increases, however, rare and unusual immune-related adverse events are observed. Many of these resemble known autoimmune phenomenon, such as subacute lupus erythematosus and myositis. Herein, we report a patient with metastatic serous ovarian carcinoma undergoing treatment with combination ipilimumab and nivolumab who developed subacute cutaneous lupus erythematosus (SCLE). Recent case reports have documented SCLE as a novel immune-related adverse event. In our case, she was able to successfully restart immunotherapy after a course of oral corticosteroids and maintenance oral hydroxychloroquine and topical corticosteroid therapy.

Checkpoint inhibitor immunotherapy is a transformative treatment for advanced malignancies, but can be associated with numerous immune-related adverse events (irAEs). The majority of irAEs include those that closely resemble known cutaneous and neurocutaneous autoimmune or autoinflammatory diseases, such as scleroderma, psoriasis, and dermatomyositis. We present the case of a 63-year-old man with metastatic melanoma undergoing treatment with nivolumab who developed significant motor weakness, paresthesias of both hands, swollen fingers, and a pruritic rash over the face, chest, and upper back after two cycles. Creatine kinase was elevated. Electromyography revealed a myopathic pattern, muscle biopsy of the deltoid revealed an inflammatory myopathy, and skin biopsy showed interface dermatitis. There were no detectable autoantibodies except positive antinuclear antibody. He was diagnosed with immunotherapy-induced dermatomyositis, nivolumab was held, and he was treated with oral prednisone and intravenous immunoglobulin with overall improvement in myopathic and cutaneous symptoms. Dermatomyositis is an inflammatory myopathy with a characteristic dermatologic presentation that can occur spontaneously, as a paraneoplastic phenomenon, or as a drug reaction. This is the second known case of nivolumab-induced dermatomyositis. A review of the literature revealed seven total cases of immunotherapy-induced dermatomyositis. Functionally disabling autoimmune adverse effects of this severity would frequently persuade providers to discontinue immunotherapy in patients with metastatic disease.

Immune checkpoint inhibitors are used to treat numerous malignancies but may be associated with severe adverse events. Bullous dermatoses, chiefly bullous pemphigoid (BP), are potentially progressive adverse events that cause blistering skin lesions and may involve a significant body surface area. Herein, we report an 87-year-old man with urothelial cell carcinoma undergoing atezolizumab treatment who presented with an acute-onset blistering eruption. Biopsy revealed a subepidermal bulla, direct immunofluorescence revealed linear IgG and C3 deposits at the dermal-epidermal junction, and serum studies revealed elevated levels of antibodies to BP180 and BP230. Anti-PD-L1-induced BP was diagnosed, immunotherapy was withheld, and he was treated with oral doxycycline with niacinamide and clobetasol ointment. He restarted atezolizumab and has successfully received four cycles (every 3 weeks) while continuing this BP treatment regimen. A literature review revealed eight other cases of anti-PD-L1-induced bullous disorders. The incidence of bullous dermatoses with anti-PD-1/anti-PD-L1 agents combined is 1%, whereas the reported incidence for anti-PD-L1 agents alone ranges from 1.3-5%, raising concerns for a higher overall risk. In addition to our case, only one other case reported successful resumption of immunotherapy. Early control and management of immunotherapy-induced BP may reduce complications and prevent treatment discontinuation.

Checkpoint inhibitor immunotherapy, including ipilimumab and nivolumab, is associated with numerous immune-related adverse events including dermatitis, pruritus, hepatitis, diarrhea, and hypophysitis. As the number of patients undergoing immunotherapy treatment increases, however, rare and unusual immune-related adverse events are observed. Many of these resemble known autoimmune phenomenon, such as subacute lupus erythematosus and myositis. Herein, we report a patient with metastatic serous ovarian carcinoma undergoing treatment with combination ipilimumab and nivolumab who developed subacute cutaneous lupus erythematosus (SCLE). Recent case reports have documented SCLE as a novel immune-related adverse event. In our case, she was able to successfully restart immunotherapy after a course of oral corticosteroids and maintenance oral hydroxychloroquine and topical corticosteroid therapy.