Authors' Reply "SegORG: Report Generation of Oral Potentially Malignant Disorders Image Based on Lesion Segmentation-Enhanced LLM".

Dear Editor, A 30-year-old male patient visited the Emergency Room (ER) on the 16th May 2022 complaining of a new-onset skin rash associated with systemic symptoms. He had not travelled abroad during the previous months. He was diagnosed with HIV infection 9 years prior and maintained a good immune-virologic control under antiretroviral therapy. He also presented past medical history of syphilis, hepatitis B and had been treated for hepatitis C virus. He recognized himself as MSM with high-risk sexual practices1 such as multiple sexual partners, use of recreational drugs and unprotected sexual intercourse 2 weeks prior his admission to the ER. The patient first presented with symptoms of proctitis (rectal bleeding, mucopurulent discharge and tenesmus). Four days later, he experienced a sudden onset of systemic symptoms with fever up to 39.3°C, headache, lymphadenopathy, generalized arthralgia and myalgia. The skin rash began 2 days later, on both arms and dorsum of hands and then spread to the trunk, legs, face and, lastly, genitalia, sparing palms and soles. Physical examination revealed a maculopapular pinkish exanthem associated with numerous flat-topped umbilicated pustules (Fig. 1a–c) with a necrotic centre and surrounded by an erythemato-edematous plaque (Fig. 2). In the genitalia, one single pustule in the penis body (Fig. 1d) and two isolated perianal ulcers were observed. Multiple enlarged painful lymph nodes were present in both inguinal and latero-cervical regions. A pustule exudate was collected and analysed using real-time polymerase chain reaction (RT-PCR) in the Spanish National Center for Microbiology, which resulted positive for monkeypox virus. Blood analysis showed a RPR titre of 1/4, which was stable compared with previous analytical determinations. Rectal, urethral and pharyngeal samples were tested for Chlamydia trachomatis and Neisseria gonorrhoeae, with negative results. Until a few years ago, most of the infections caused by monkeypox (MPX) virus had been detected in central and western Africa,2 mainly related to direct contact with animals.3 Moreover, sporadic cases have recently been described in other countries such as the USA4 or the United Kingdom.5 The disease is characterized by an onset of prodromal symptoms followed by a vesicular-pustular rash that begins on the head and spreads to the rest of the body.2, 6 On 14th May 2022, an alert was given for the appearance of MPX cases in several patients in Great Britain7 and Portugal.8 Two days later, cases began to be diagnosed in Madrid, Spain.8 This outbreak is being characterized by the appearance of lesions more limited to the genital area, with little or non-systemic symptoms and in general with a favourable outcome.9, 10 Most cases reported in our environment during this outbreak are associated with sexual practices,8 probably related to the prolonged proximity that intimate relationships entail. However, our case showed several distinctive features. First, general symptoms were preceded by a severe proctitis, which seems to be caused directly by monkeypox virus. In addition, typical lesions (umbilicated pustules with an ulcero-necrotic centre) often described alone in other publications were accompanied by a maculopapular rash similar to syphilitic roseola. Lastly, in contrast to what was already reported,10 the pustules in our patient began in arms and then extended to the rest of the body surface, affecting mostly to the trunk and proximal limbs. Herein, we present one of the first cases of autochthonous MPX disease detected in Madrid (Spain) with not known epidemiological contact with reservoir animals or travels to an endemic area. The rash with the appearance of vesicles and pustules is the most common manifestation of this disease along with fever and lymphadenopathy.9 However, we suggest that a maculopapular exanthem and proctitis could be considered as additional symptoms associated with MPX disease in some patients. The patient in this manuscript has given written informed consent to the publication of his case details. No funding was obtained for this study. None of the authors have any disclosure of conflict of interest for this work. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

In 2019, researchers from Asian countries gathered to discuss how to diagnose sarcopenia. The report from this meeting, the Asian Working Group for Sarcopenia 2019 (AWGS2019), suggested a 6-m walk <1.0 m/s as a criterion for sarcopenia diagnosis.1 In addition, the recently revised Japanese version of the Cardiovascular Health Study criteria (revised J-CHS criteria), which is used to diagnose frailty in Japanese older adults, also adopted a gait speed <1.0 m/s as a criterion to measure slowness for frailty.2 Although sarcopenia and frailty perform well in predicting some adverse health outcomes (e.g. dementia, disability and mortality), from the perspective of primary prevention, it is also important to explore a cut-off point of gait speed for clinical intervention and prevention of adverse health outcomes before older adults develop frailty or sarcopenia. We aimed to investigate the association between gait speed and incident disability in a long-term (up to 20 years) prospective cohort study of older Japanese community-dwellers. Data were collected as part of the National Institute for Longevity Sciences-Longitudinal Study of Aging (NILS-LSA) project.3 Participants were selected from the second (April 2000 to May 2002) to seventh (July 2010 to July 2012) waves of the NILS-LSA, because the Long-term Care Insurance information was available since April 2000. In this study, for each participant, their first participation after reaching old age (≥65 years) was used as the baseline (April 2000 to July 2012), and follow up started from the date of baseline participation and ended on 31 August 2020. Of the 1779 first-participated older individuals who had not been certified as having a disability (defined as requiring care level 1 or higher on the Long-term Care Insurance certificate) before/at the baseline survey, those whose gait speed and covariate data were incomplete at baseline were excluded. Thus, 1567 Japanese older individuals (767 men and 800 women, age 65–82 years, mean age 70.7 years [SD 4.8 years]) were analyzed in this study. The mean gait speed (m/s) was 1.30 (SD 0.19) for all participants, 1.32 (SD 0.19) for men and 1.27 (SD 0.19) for women. When gait speed was stratified into quintile groups, participants in the higher quintile groups (i.e. with faster gait speed) were younger, less likely to be women, to have a history of stroke or hypertension and to have depressive symptoms. Meanwhile, they were more likely to have a higher total physical activity level and to have a higher education level (data not shown). The median follow-up duration was 12.1 years (interquartile range 8.4–15.8 years). Compared with participants in the Q3 group (representing the average gait speed level of the participants), the multivariate-adjusted HR for participants in the Q1 (the lowest quintile) group was 1.57 (95% CI 1.23–2.00; P-value <0.001). The results did not change when stratified by sex. Additionally, the highest quintile (Q5) group of gait speed was associated with a lower risk of incident disability in men (Table 1). Our findings suggest that even a gait speed of >1 m/s might be associated with a higher risk of incident disability, and the cut-off of 1.1 m/s (the maximum value of the first quintile) can be used for the new cut-off, which almost equals 4 km/h and could be used for public health promotion. Although the use of quintiles based on the study population might not provide an accurate cut-off point for preventing disability for the whole older Japanese population, the average gait speed of our participants was comparable to previous studies, which indicates that our results are, to some extent, justified.4-6 However, further studies carried out in different settings are still warranted. Previous studies have reported that Japanese community-dwelling older individuals tend to walk faster than other older individuals of other ethnic backgrounds,7 and the gait speed for older Japanese adults has increased in the past 20 years.8, 9 The development of more appropriate standards for the primary prevention of adverse health outcomes among old Japanese community-dwellers is of great significance to the formulation of public health policies and the promotion of healthy aging in the future. The authors declare no conflict of interest. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

Homozygosity for the hyperunstable hemoglobin variant Hb Agrinio (HBA2:c.89T>C) leads to severe antenatal anemia: Eight new cases in three families.

An 8-year-old boy presented to our department with asymptomatic, whitish plaques on the glans for 6 months. He had experienced no other discomfort, urinary stream narrowing, or dysuria; however, his rash worsened. The patient was generally healthy and had no known underlying disease or relevant family history of similar skin lesions. The physical examination revealed a redundant prepuce and clearly demarcated porcelain-white atrophic plaques on the glans, coronal sulcus, and foreskin, without erosions (Figure 1a, b). Laboratory investigations revealed normal values of the complete blood count, urinalysis results, liver and renal functions, antinuclear antibody, immunoglobulin (Ig), anti-double-stranded DNA, thyroid function test, and hepatitis test. Based on the patient's clinical manifestation and progression, we suspected lichen sclerosus and performed noninvasive reflectance confocal microscopy (RCM). The findings were as follows (Figure 1c-e): Epidermal examination revealed a disorganized epidermal structure, significantly reducing the number of epidermal scanned layers, and round cyst-like structures containing medium-low-refractive substances. At the dermo-epidermal junction, the dermal papillary rings were destroyed and appeared nonrimmed. As the image depth increased, the superficial dermis was filled with medium refractivity, as well as coarse fibrous material, and some of the material was gathered in fascicular patterns. Numerous high-refractive uniformly round cells and larger irregular cellular structures were diffusely distributed and occasionally aggregated. A large number of dilated low-refractive grand or canalicular structures were vertically arranged on the confocal sections. Histopathological examination (Figure 1f) showed epidermal atrophy, liquefaction degeneration of basal cells, bands of homogenization of collagen and lymphocytes, and dense infiltration of melanophages. Based on the clinical and histological findings, the diagnosis of male genital lichen sclerosus (MGLSc) was made. MGLSc is a rare acquired, chronic inflammatory dermatosis in which persistent exposure of the susceptible epithelium to urinary occlusion is the most common pathological mechanism.1, 2 Clinically, the predominant symptoms of MGLSc are porcelain-white atrophic plaques on the glans, coronal sulcus, and foreskin. Most mature men have symptoms associated with spontaneous itching, burning, bleeding, and male dyspareunia; however, in pediatric patients, MGLSc is often asymptomatic and easily leads to an ignored and missed diagnosis. Since the disease has a progressive course and causes architectural changes in the genitalia, dysuria, scarring, architectural changes, and squamous cell carcinoma of the penis,1, 2 a seasonable and accurate diagnosis is urgently required. RCM can noninvasively observe changes in skin cell levels, and previous studies have suggested a high corresponding relationship between RCM images and histopathological features in the LS of females and male adults.3-5 However, few studies have investigated pediatric MGLSc. In our study, the RCM images of the boy revealed major key diagnostic features of LS, including a significantly reduced number of scanned layers, the destruction of dermal papillary rings, numerous cellular structures, coarse fibrous material, and the diffuse distribution of dilated canalicular structures in the upper dermis. This information and these clues confirmed that although the physiological structures of boys and girls differ greatly, the key points for diagnosing LS by RCM are unanimous, and this report further strengthens the evidence that RCM can be used to visualize major key diagnostic features of MGLSc. We recommend RCM as a useful adjuvant tool for diagnosis in children, but larger case series remain to be further studied. The authors declare no conflicts of interest. Approval for this study was obtained from the Ethics Committee of Tianjin Children's Hospital (Ref. No. KJRCPYXM2020-02). The parents signed an informed consent form to participate in the study. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

Since achieving herd immunity is an integral part of fighting a pandemic, the COVID-19 vaccination campaigns represent an essential step toward achieving this goal, thereby not only decreasing the mortality and morbidity of this virus, but possibly eliminating it.1 Nonetheless, growing evidence suggests that COVID-19 vaccines may be associated with a wide range of cutaneous reactions.2 Recently, these vaccines have also been linked to new onset and flare-up of pre-existing psoriasis, all of which attained complete clearance after the use of standard treatments.3, 4 Herein, we report the case of a 53-year-old man with severe plaque psoriasis since 2016, who had been previously but unsuccessfully treated with topical steroids, UV-therapy, methotrexate, adalimumab, secukinumab, guselkumab and apremilast. The patient, a heavy smoker, had been suffering from several comorbidities including hypertension, diabetes mellitus, thrombo-embolism and chronic obstructive lung disease complicated by several episodes of pulmonary infections. He presented to our outpatient department on March 2021 with extensive desquamative psoriatic lesions (PASI score of 31) and a body mass index of 24.84 kg/m2. Cyclosporine was started and PASI 100 was achieved after 1 month of treatment. In the following days, on April 22nd, he received the first dose of the Comirnaty® COVID-19 (BNT16B2b2 mRNA) vaccine (Pfizer-BioNTech). One week after the vaccination, the patient experienced a mild flare-up of psoriasis on his legs. However, 1 week following the second dose which was administered on May 27th, he developed generalized erythematous desquamative plaques and thoracic zona. Cyclosporine was thus interrupted, and acyclovir was started. Routine blood tests were normal, and the zona was successfully treated with acyclovir. Nevertheless, despite the reintroduction of cyclosporine, the use of topical steroids and the intake of acitretin, the patient's psoriasis remained uncontrolled. Consequently, oral corticosteroids were started on September 21st with ensuing clinical amelioration. To our knowledge, we report the first case of severe psoriasis flare-up following COVID-19 vaccine in a patient with significant comorbidities. And although the mechanisms underlying such exacerbations are poorly understood, they might be explained by the similar cytokine profiles of psoriasis and of the immune response induced by the COVID-19 vaccine. Psoriasis has long been proven to be a Th1-mediated chronic disorder whose pathogenesis is dominated by the IL-23/IL-17 axis.5 As for the BNT162b2 vaccine, it had been proven that in addition to inducing humoral immunity in humans, it can also stimulate Th1 cells.6 Moreover, animal models have recently demonstrated that COVID-19 mRNA vaccines can lead to production of IL-17.7 Yet, vaccinations remain a rare trigger of psoriasis and psoriasis-like eruptions, with other reported cases being linked to influenza, bacillus Calmette-Guerin, pneumococcal and tetanus-diphtheria vaccines.8 With respect to the temporal relationship of the Pfizer-BioNTech vaccine and the zoster, a possible explanation lies in the immunomodulation provoked by COVID-19 vaccination. Liu et al.9 demonstrated that even if this vaccine enhances the adaptive immunity against the novel coronavirus, it can decrease type I interferon responses reducing the host's ability to fight other viruses. This immune alteration can thereby explain the reactivation of varicella-zoster virus in our patient. Therefore, considering the importance of the COVID-19 vaccination campaigns in the fight against the pandemic, it is of major relevance that dermatologists be aware of the vaccines' possible role in inducing or exacerbating psoriasis and of the risk of severe relapses in patients suffering from several comorbidities. Thus, by increasing awareness and by managing psoriasis comorbidities, we can improve the care and the quality of life of patients suffering from this disease. None. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

IgM antibodies typically appear in the early stage of infection and have a short maintenance time, so IgM is frequently used as a diagnostic criterion for acute or recent disease [1]. However, unconventional IgM specific responses have been described in SARS-COV-2 infection, raising doubts about the use of IgM as a biomarker for COVID-19 and the role of this antibody in immunity to SARS-CoV-2 [1,2]. This article is protected by copyright. All rights reserved.

A 65-year-old man was referred to the dermatology clinic with blisters. The lesions started one week ago as multiple lesions with scaling on his chest, back and scalp (Figure 1). Oral mucosa was normal. One month ago, the patient had the BNT162b2 mRNA COVID-19 vaccine (Comirnaty, Biontech/Pfizer). He had hypertension for 10 years, and he has been using nebivolol 5 mg/day orally. A pill containing valsartan-hydrochlorothiazide combination was added to the treatment four months ago. Informed consent was obtained from the patient. Lesional biopsy with hematoxylin–eosin stain showed intraepidermal acantholytic blister formation. Abundant neutrophils and scarce eosinophils were present in the lumen of the blister. Direct immunofluorescence (DIF) showed intercellular deposition of IgG and C3 within the epidermis (Figure 1). In the patient's serum, antibodies against desmoglein-1 (1/100 [EUROIMMUN]) were detected with quantitative enzyme immunoassay. Anti-desmoglein-3 antibodies were not present. The patient was diagnosed with pemphigus foliaceus (PF) and treated with 48 mg/day oral prednisolone and azathioprine 100 mg/day. The response to treatment was evident with two weeks of therapy. Currently, the only mRNA vaccine available in Turkey is BNT162b2. Despite the possibility of exacerbation, the patient received the second dose of the BNT162b2 vaccine six weeks after the first vaccination. Two weeks after the second vaccine, multiple new lesions on the neck, back and gluteal region developed. Exacerbation subsided with topical treatments and the continuation of the therapy. Viral infections and vaccinations can provoke autoimmune disease processes. SARS-CoV-2 is associated with autoimmune diseases such as Kawasaki disease, Guillain Barre Syndrome, and Miller Fisher Syndrome.1 There are few COVID-19 triggered pemphigus vulgaris (PV) cases in the literature.2, 3 Molecular mimicry and bystander activation are proposed as the possible underlying mechanisms for the autoimmunity related to the SARS-CoV-2 virus.1 Cross-reactivity between SARS-CoV-2 spike protein antibody and human tissue proteins such as TGase2, TGase3, collagen and S100B was recently proposed as potential sources of autoimmunity.4 The bullous pemphigoid (BP) and PV was reported following SARS-CoV2 vaccinations.5 In a case series, five patients with existing autoimmune blistering diseases (AIBD) (3 BP [2 Moderna 1 Pfizer] and 2 PV [1 Moderna, 1 Pfizer]) had flare-ups after vaccination.5 All five patients were in remission at least for 6 months. One patient with BP vaccinated with Moderna COVID-19 had extensive oral mucosa involvement. The onset of lesions ranged between 3 days to 2 weeks after the vaccination. The transient bystander immune activation by the vaccine may have resulted in activation of previously existing subclinical inflammation in these cases. Subepidermal bullous dermatitis after receiving the first or second dose of SARS-CoV-2 mRNA vaccines (8 Pfizer, 4 Moderna) was reported in 12 patients without a history of BP or autoimmunity. All patients had severe pruritus. Histopathological examination showed subepidermal or subcorneal blisters with eosinophils. DIF from perilesional skin revealed IgG/IgA and C3 positivity in the dermo-epidermal junction.6 Currently, there are two reports of PV onset after the SARS-CoV2 vaccination. First is reported in a 40-year-old otherwise healthy female patient with painful erosions in oral mucosa 5 days following the mRNA vaccine BNT162b2, and worsening in her lesions after administration of 2nd dose.7 Second is a 38-year-old female patient who had painful oral lesions that appeared 1 week after administering the first AZD1222 vaccine.8 We cannot rule out the coincidental onset of PF and vaccination in our patient. There is one case of valsartan and hydrochlorothiazide induced PF in the literature, and we cannot confidently disregard the possible effect.9 However, the onset of the initial lesions after the first dose of vaccine and the exacerbation with new-onset generalized lesions after the second dose suggest the association with mRNA vaccine. In our case, disease course was controlled easily with the proper treatment regimen. Currently, the patient is under remission and is using azathioprine 100 mg/day. There is no consensus approach for further vaccination scheduling in such cases yet. If possible, switching to a different effective vaccine may be recommended. In our case, we recommended to continue with the mRNA vaccine BNT162b2 because of the emergence of new COVID-19 variants and the inefficacy of the alternative vaccine in our country. The authors declare that they have no conflict of interest. Şebnem Yıldırıcı: Wrote the draft of the paper; Seçil Vural: Primary physician of the patient, collected data, wrote, and revised the paper; Savaş Yaylı: Primary physician, revised the paper, contributed to revisions; Cüyan Demirkesen: Contributed to diagnosis by pathological examination. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

Dear Editor, The global burden of cancer is significant. The list of malignancies regarded as obesity-related continues to expand as evidence accumulates [1, 2]. Fueled by the ongoing obesity epidemic, obesity has emerged as one of the most important preventable causes of cancer worldwide [1, 3]. Given the long latency periods of many obesity-related adult cancers, risk factors with onset during early age and accumulation of risks during one's life course are likely to be of importance [4]. Early age overweight is a proposed risk factor for obesity-related cancer as isolated measurements of high body mass index (BMI) in both childhood and late adolescence have been reported to associate with certain obesity-related cancers [2, 5, 6]. However, obesity-related cancer as a composite group has so far only been studied in relation to adult BMI [7]. Studies of the relative contribution of overweight or obesity in childhood and young adulthood for the risk of adult cancer have been scarce [4]. In this present study, we tested our hypothesis that childhood overweight is associated with the risk of obesity-related adult cancer (Supplementary Table S1), independent of overweight status in young adulthood, using the BMI Epidemiology Study Gothenburg [8]. This population-based cohort was initiated with the overall objective to study the associations between developmental BMI and the risk of adult disease. A total of 36,566 men born in 1945-1961 with height and weight measurements from school health care records were investigated. Childhood body mass index (BMI) at age 8 years and young adult BMI at 20 years of age were calculated using the raw data of all paired height and weight measurements in the age period of 6.5-9.5 years for childhood BMI, and in the age period of 17.5-22.0 years for young adults. During the 1.5 million person-years of follow-up after 20 years of age (median follow-up 41.3 years, interquartile range 37.7-45.6 years), 1,562 (32% of all cancer diagnoses) obesity-related cancer diagnoses and 570 deaths (55% of all cancer deaths) due to cancer classified as obesity-related occurred. The cohort is detailed in Supplementary Table S2 and the inclusion process in Supplementary Figure S1. We found that boys with childhood overweight (BMI > 17.9 kg/m2; Supplementary Methods 1.2) had a markedly increased risk of obesity-related adult cancer and death due to obesity-related cancer, compared with their normal-weight peers (Table 1, Panel A). Overweight in young adulthood (BMI ≥ 25 kg/m2) was moderately associated with increased risk of obesity-related adult cancer, but not with obesity-related cancer death. In the model including both overweight status in childhood and young adulthood in the same analysis (Table 1, Panel A), the associations between childhood overweight and obesity-related cancer incidence and mortality were robust. The association between overweight in young adulthood and obesity-related cancer incidence did not reach statistical significance after adjustment for childhood overweight. Next, we evaluated the impact of change in overweight status from childhood to young adulthood on the risk of obesity-related adult cancer. Interestingly, men with childhood overweight that normalized during puberty had a 38% increased risk of obesity-related adult cancer, compared with men who had normal weight both in childhood and young adulthood (Table 1). In contrast, men with pubertal onset overweight did not have an increased risk of obesity-related adult cancer compared with men who had normal weight both in childhood and young adulthood (Table 1). The results were robust even after adjustments (Supplementary Table S3). Results from sensitivity analyses were coherent with our main analyses (Supplementary Results 2.1 and 2.2), including analyses where the first 10 years of follow-up were excluded to rule out undiagnosed disease-related weight loss (Supplementary Table S4), and using the less inclusive definition of obesity-related cancer by the International Agency for Research on Cancer (IARC) from 2016 (Supplementary Table S5). Further assessments did not indicate that mortality from causes other than obesity-related cancer had biased the observed increased risk of obesity-related cancer for boys with childhood overweight (Supplementary Figure S2). The absolute event rates of obesity-related cancer per 100,000 person-years were significantly higher for boys with childhood overweight than normal-weight boys (Supplementary Results 2.3). Thus, overweight in childhood was associated with an increased risk of obesity-related adult cancer, and this risk was not reversed if the childhood overweight status normalized before young adulthood. These findings establish childhood overweight as an independent risk factor for obesity-related adult cancer in men. Studies using BMI from the conscription examination in Israel and Sweden have reported that BMI in late adolescence was associated with the risk of some cancer diagnoses in men [2, 6]. However, these previous studies [2, 6, 9] had only one BMI measurement available and were therefore unable to evaluate the relative importance of childhood overweight and overweight in young adulthood for the risk of obesity-related adult cancer diagnosis. The results of this present study from analyses of overweight in young adulthood alone are in agreement with these studies. However, when childhood overweight was included in the same model, childhood overweight, but not overweight in young adulthood, was associated with the risk of adult obesity-related cancer. The present results suggest that being overweight, specifically during the childhood period, may initiate biological processes that eventually lead to an increased risk of cancer and that this effect initiated during childhood was not reversed by normalization of BMI during puberty. It is plausible that being overweight at sensitive developmental stages could stimulate long-term changes that promote cancer genesis. We propose that childhood might be a developmental period especially sensitive to the deleterious effects of overweight on cancer genesis. Possible mechanisms include epigenetic, endocrine, or metabolic programming through hyperinsulinemia, systemic inflammation, adipokine aberration, or excess stimulation by growth hormone/insulin-like growth factor-1 (IGF-1) [10]. For our main analyses, obesity-related cancer was defined according to the IARC report [1], with the addition of the cancer types (oral cancer, malignant melanoma, male breast cancer, lymphoma, and leukemia) where accumulated evidence, including the findings from the recent well-powered Israeli military study in adolescents [2], support a link with obesity in men. However, the main findings of this present study were unaltered when using the less inclusive, conservative IARC-definition of obesity-related cancer. The strengths of the present study include the large size of the cohort and the long and near-complete follow-up in high-quality national disease registers. The population-based nature of the cohort with BMI available both in childhood and young adulthood provides a unique possibility to study the relative contribution of the onset of overweight during childhood and puberty to adult disease. The limitations include that we were not able to include women. Further, adjustment for potential residual confounders such as overweight later in the adult period or for lifestyle habits such as smoking, diet, alcohol intake, or physical exercise was not possible. Prevalence of childhood obesity at the time of the present cohort was low, and hence, analyses of childhood obesity included too few cases. In conclusion, we identified childhood overweight as a risk factor for obesity-related adult cancer in men, which was independent of overweight status in young adulthood. Our findings suggest that weight control during childhood could prevent obesity-related adult cancer in men. Key issues for the future include finding effective strategies for the prevention and treatment of childhood overweight and obesity, and to define the associations between childhood overweight, adult overweight status and obesity-related cancer in women. Conceptualization: CO, JC, JMK. Data curation: JM, JMK, JC, MB. Formal analysis: JC, JM, JMK. Funding acquisition: CO, JC, JMK. Investigation: JC, JM. Methodology: CO, JK, JC. Project administration: JC, JMK. Resources: CO, JMK, MB. Software: JM. Supervision: JMK. Validation: CO, JC, JMK. Analyzed data: CO, JC, JMK. Writing - original draft: JC. Writing, review and editing: CO, JC, JM, MB, JMK. The Ethics Committee of the University of Gothenburg, Sweden, approved the study (protocol code DNR 013–10, 28-01-2010) and waived the need for informed consent due to the register-based nature of the study. The Ethics Committee waived consent for publication. This work was supported by the Swedish Research Council and by grants from the Swedish state under the agreement between the Swedish Government and the County Councils, the ALF-agreement (grant numbers 883541, 723791 and 238261), Swedish Heart-Lung Foundation, the Lundberg Foundation, the Torsten Söderberg Foundation, the Novo Nordisk Foundation and the Knut and Alice Wallenberg Foundation. None of the funders had any role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, or approval of the manuscript. This work is based on the previous work by Maria Nethander and Arvid Sondén, and was possible through the valuable support and collaboration from the former director of the Archives of Region Västra Götaland, the late Bo Thalén. None of the authors have any competing interests to declare. Research data is not publicly available due to privacy and ethical restrictions. However, anonymized data that are minimally required to reproduce results can be made available from the corresponding author upon reasonable request, upon approval from the University of Gothenburg, if the data can be made available according to mandatory national law. Research data is not publicly available due to privacy and ethical restrictions. However, anonymized data that are minimally required to reproduce results can be made available from the corresponding author upon reasonable request, upon approval from the University of Gothenburg, if the data can be made available according to mandatory national law. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Immune-mediated necrotizing myopathy after BNT162b2 vaccination in a patient with antibodies against receptor-binding domain of SARS-CoV-2 and signal recognition particle.

Double aortic arch with an aberrant left superior pulmonary vein in a young child presenting with pneumomediastinum.

Ruxolitinib in adult patients with secondary hemophagocytic lymphohistiocytosis.

Selumetinib has recently become available for the treatment of inoperable and symptomatic plexiform neurofibroma (NF) [1] with neurofibromatosis 1 (NF1). Here, we report a fatal case of aseptic pericarditis, massive pericardial effusion, and cardiopulmonary failure during 3 years of selumetinib treatment. A 19-year-old man with NF1 had plexiform neurofibromas in the left cervical region, pericardiac region, left side of the vertebral body, left back muscles, and left shoulder, along with severe scoliosis and thoracic cage deformity. Since there was a risk of serious functional impairment due to the future growth of plexiform neurofibromas particularly in the left cervical and pericardial regions, he had been treated with oral selumetinib (50 mg/day) for 3 years. Given a report of selumetinib-associated left ventricular dysfunction [2], the patient underwent routine surveillance echocardiography every 6 months. Echocardiographic findings were unremarkable until 1 month before admission, when a small, asymptomatic pericardial effusion was detected and managed conservatively. Several days before admission, he developed decreased responsiveness. At an outpatient visit, profound hypoxemia was noted, and he was emergently hospitalized. Contrast-enhanced computed tomography demonstrated a large pericardial effusion, and cardiac tamponade was diagnosed. Emergency pericardial drainage yielded exudative fluid; cytology showed reactive changes, and microbiological cultures were negative. Despite drainage, the effusion rapidly recurred, and his respiratory status progressively deteriorated. FDG positron emission tomography demonstrated an FDG-avid mass adjacent to the heart (Figure 1a). Although the maximal diameter was largely unchanged compared with imaging obtained 2 years earlier (29.6 to 30.9 mm), the mildly increased FDG uptake raised concern for malignant transformation at our institution. A pericardial window procedure was considered; however, it was deemed too high risk because intubation and positive-pressure ventilation were expected to further compromise his restricted cardiopulmonary function. His chronic type II respiratory failure worsened, and he died on hospital day 34. Autopsy revealed a well-circumscribed nodular mass extending from the outer surface into the parietal pericardium (Figure 1b). Histologically, the tumor consisted of wavy spindle cells without significant atypia (Figure 1c). The tumor cells were positive for S100 and SOX10, retained H3K27me3 expression, and showed a low Ki-67 index (~1%), consistent with a benign pericardial neurofibroma. A lymphocyte-predominant inflammatory infiltrate was observed in the surrounding pericardium, suggesting tumor-associated aseptic pericarditis (Figure 1d). We concluded that persistent exudative pericardial effusion secondary to aseptic pericarditis led to cardiac tamponade and progressive cardiorespiratory failure, which was exacerbated by NF1-related skeletal deformities and limited respiratory reserve. MEK inhibitors have been shown to induce activated CD8+ T cells [3] and to facilitate T-cell trafficking via fibroblast modulation [4], suggesting a potential to trigger inflammation in predisposed patients. In addition, the contribution of selumetinib to the acceleration of left ventricular dysfunction, particularly during cardiac tamponade, cannot be excluded in the present case. Clinicians should be particularly cautious when using selumetinib in patients who, as in the present case, are thought to have pulmonary congestion related to scoliosis, as selumetinib may accelerate the deterioration of left ventricular function. In addition, patients with multiple comorbidities require strict, multidisciplinary monitoring involving relevant specialties. This work was supported by Japan Society for the Promotion of Science (Grants 22K18392 and 23K15267) and Ministry of Health, Labour and Welfare Grant-in-Aid for Scientific Research (Grant 23FC1037a). The authors declare no conflicts of interest. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

Levodopa-induced dyskinesia (LID) is mainly classified into two forms: peak-dose dyskinesia and diphasic dyskinesia,1, 2 the former being mostly choreiform and prominent on the more affected side, while the latter typically appear in the lower limbs bilaterally and often present as dystonia.1 Atypical forms, including ocular, respiratory, and square-wave dyskinesia, have been described,1 but peak-dose LID with a tremor-like presentation has not been reported. This 53-year-old Caucasian man with a 10-year history of PD, was referred to us as he developed during the last year a troublesome “tremor” while holding his right upper limb (RUL) in a particular position as a result of his work as a painter, which was apparently treatment resistant. On examination, repetitive, low-frequency, high-amplitude tremor-like movements of his RUL were evident on holding a posture, especially in the wing-beating position (Video 1A). Given his otherwise controlled parkinsonism with the last Levodopa intake having occurred about 1 h before the examination, we wondered whether these movements could be Levodopa related, but he was unable to identify any temporal pattern. We therefore performed a Levodopa challenge: starting after 60 min from the intake of 150/50 mg Melevodopa/Carbidopa, he developed the tremor-like movements of his RUL, which were not present in the pragmatic OFF condition (Video 1B,C) and were hence interpreted as an atypical presentation of peak dose LID. Amantadine (50 mg tid) was added to his Levodopa treatment (100 mg qid), with resolution of this phenomenon. Collaterally, given the early age at onset, genetic analyses were performed disclosing the heterozygous variant c.1552 T>C (rs1557900457) of GBA1, which is reported to be very rare in Gnomad and classified as a “variant of unknown significance” according to the ACMG criteria. Sanger sequencing with targeted PCR was used to avoid amplifying the pseudo-gene. The GCase activity was found to be normal (eg, 4.9 nmol/h; pathological range <2.5 nmol/h), suggesting no functional impact on the enzymatic activity.2 Optimal PD management relies on careful examination as well as on correct interpretation of patients’ complaints in relation to the timing of pharmacological treatment. In this case, the atypical presentation and the patient's report of the phenomenon as a troublesome “tremor” led the treating physician to increase the dopaminergic stimulation, which was inefficacious. The phenomenology of his peak dose LID was in our view in keeping with low-frequency, high amplitude, repetitive, proximal and position-sensitive dystonic movements, bearing close resemblance with the “wing-beating” tremor reported in other dystonic syndromes.3 Notably, the parkinsonian tremor affecting his upper limbs in the OFF condition was phenomenologically very different and this might have been a clue to suspect a different pathophysiological mechanism, beyond the (missed) temporal pattern of occurrence with the Levodopa intakes. Accurate recognition of this rare phenomenology was crucial to ensure appropriate management. It is unknown whether his GBA1 status is related to this phenomenon. Atypical dyskinesia has been reported in GBA1 patients4 but dystonia is not more frequent in GBA1 carriers than in other genetic forms of early-onset PD.5 (1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the first draft, B. Review and Critique. C.S.: 1BC; 3A M.R.: 1C; 3B M.P.: 1C; 3B P.B.: 1C; 3B R.E.: 1A; 3B Ethical Compliance Statement: Institutional review board was not required for this work. Written informed consent was obtained from the patient for the publication of his clinical data and videos. Written informed consent was signed by the patient for the genetic analysis and for video collecting. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Funding Sources and Conflict of Interest: No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work.” Financial Disclosures for the Previous 12 Months: The authors declare that there are no additional disclosures to report. Author disclosures are available in the Supporting Information. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. Data S1.COI_disclosure. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Although rare, in several instances vaccines have been suggested as environmental factors triggering development of inflammatory myopathies, including dermatomyositis (DM)/polymyositis (PM).1, 2 We describe two cases in which DM became apparent after SARS-CoV-19 vaccination. Case 1; an 81-year-old female patient developed bilateral eyelid oedema and erythema on the dorsum of her hands and fingers approximately 2 weeks after her first SARS-CoV-19 vaccine (manufactured by Pfizer Inc., New York, NY, USA). Skin examination confirmed bilateral eyelid oedema and revealed e rythema with pruritus on both auricles and scaly erythema with pruritus from the posterior neck to the back of the head. In addition, periungual erythema on both fingers and erythema with slight hyperkeratosis at the bilateral metacarpophalangeal (MCP) joints, the extensor side of the right elbow joint, and the shoulder joint were noted (Fig. 1). Other than mild fatigue, no remarkable abnormalities were found upon physical examination, including the manual muscle strength test (MMT). She had no obvious respiratory symptoms or dysphagia. Laboratory examination revealed high values of the muscle deviation enzyme, creatine kinase (CK): 3119 U/L (normal range of female: 41–153), myoglobin: 583.42 ng/mL (normal range: 109>) and aldolase: 16.5 mg/dL (normal range: 5>). Concerning DM-specific antibodies, only anti-transcription intermediary factor 1-gamma (anti-TIF1-γ Ab) was positive. No obvious interstitial pneumonia was found by chest Xp. Histopathological findings of skin samples from erythema with slight hyperkeratosis at the extensor side of the right elbow joint revealed liquefaction degeneration in the basal layer and mild lymphocytic infiltration around small vessels at mid-dermis (Fig. 1). Histopathological findings of muscle (vastus lateralis muscle) were consistent with DM (not shown). Based on these results, she diagnosed as DM (anti-TIF1-γ Ab positive). A combination of prednisolone (PSL) 50 mg (1 mg/kg) and high-dose intravenous immunoglobulin therapy were administered. The general condition and myogenic enzyme level improved rapidly, and the skin findings gradually disappeared. In parallel, the patient’s faecal occult blood test was positive, and lower gastrointestinal endoscopy revealed findings suggestive of advanced sigmoid colon cancer. Case 2; an 87-year-old female patient experienced myalgia in both upper limbs and thighs approximately 1 week after her first SARS-CoV-19 vaccination (manufactured by Pfizer). Primary care doctor who found a high myoglobin value (401.8 ng/mL) referred her to our university hospital. Skin findings revealed oedema with slight erythema at bilateral eyelids and scaly erythema at a seborrheic lesion of the head and neck. Erythema with slight oedema and scratch marks were observed on her back (Fig. 2). There were no signs of Gottron papules or periungual erythema. General malaise and proximal muscle weakness (about MMT3) were observed predominantly in the upper arm. Histopathological examination of the erythema on her back was consistent with DM. Blood tests showed anti-TIF1-γ antibodies and a high level of carbohydrate antigen 19-9. A commuted topography scan revealed a mass lesion in the ascending colon, and the possibility of DM with malignant tumour of the colon was considered as a diagnosis. Treatment with PSL 30 mg/kg (1 mg/kg) was initiated, and myogenic enzyme levels and skin lesions improved. There have been several case reports of DM/PM in vaccinated patients, but the mechanisms are unclear and speculative.3 DM may occur when the immune response caused by receiving the vaccine occurs in a person with a particular genetic background; however, it is quite rare. In line with this, two cases in this present report were DM with anti-TIF1-γ Ab positive and colon cancer. Of course, our DM cases may be based on malignancy, without relationship to the vaccine. Various side effects have been reported following SARS-CoV-19 vaccination4 and determining whether the onset of these side effects is different from other vaccines is critical. Future data collection is crucial for us, dermatologists, to discover the connection between SARS-CoV-19 vaccinations and skin symptoms. The authors certify that they have obtained all appropriate patient consent forms. In the form, the patients have given their consent for the publication of their images and other clinical information in the journal. They understand that their name and initial will not be published, and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. None. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

Crohn's disease (CD) is a chronic inflammatory bowel disease that can affect any segment of the gastrointestinal tract, but most commonly affects the terminal ileum and colon. Appendiceal Crohn's disease (ACD) is rare, comprising 0.2%–2% of appendectomy specimens. Since its first description in 1953, ACD has been recognized as an uncommon subtype of CD that typically affects young adults [1, 2]. A 38-year-old previously healthy male presented with intermittent right lower quadrant pain that had persisted for 3 weeks. The patient denied systemic or other gastrointestinal symptoms. Examination revealed mild localized tenderness. A colonoscopy performed at a local clinic revealed a swollen lesion near the appendiceal orifice. Laboratory evaluations revealed leukocytosis with elevated C-reactive protein (CRP) levels. Additional studies, including routine stool culture and serologic tests for Epstein–Barr virus (EBV), cytomegalovirus (CMV), human immunodeficiency virus (HIV), amebiasis, and Clostridium difficile toxin, were all negative. Abdominal computed tomography revealed an appendiceal mass with peri-appendiceal fat stranding, cecal wall thickening, and regional lymphadenopathy (Figure 1A). A repeat colonoscopy revealed cecal inflammation without a discrete mass. The terminal ileum was intubated and showed no evidence of inflammation or malignancy (Figure 1B). Because of concerns about malignancy, a laparoscopic right hemicolectomy with resection of the terminal ileum and ileocolic lymph nodes was performed. Intraoperatively, a 2 × 1 cm ulcerative mass confined to the appendix, with partial involvement of the adjacent ileum and multiple enlarged ileocecal lymph nodes was observed (Figure 1C). Histopathology revealed acute and chronic transmural inflammation with fissures, lymphoid aggregates, and lymphoid follicles involving both the appendix and cecum, consistent with CD; no tuberculosis, parasitic infection or neoplasia was identified (Figure 1D–F). A diagnosis of ACD with cecal extension was established. The postoperative course was uneventful and a follow-up colonoscopy at 6 months revealed no evidence of disease recurrence throughout the colonic lumen up to the anastomotic site. Clinically, ACD often mimics acute appendicitis and, less frequently, appendiceal carcinoma. Radiological findings such as an appendiceal mass, fat stranding, and lymphadenopathy may be indistinguishable from malignancy [3, 4]. Colonoscopy may reveal cecal inflammation but is usually nondiagnostic. The definitive diagnosis relies on histopathology, with features such as transmural inflammation, lymphoid aggregates, and non-caseating granulomas (if present). Surgery is the primary treatment for this condition. Appendectomy alone is usually curative, though right hemicolectomy may be warranted when malignancy is suspected or when contiguous cecal or ileal involvement is evident. The role of long-term surveillance remains debatable; however, periodic follow-up is prudent to detect recurrence [5]. Our patient demonstrated no disease progression after 6 months. The authors declare no conflicts of interest. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.