The Impact of the Seasonal and Geographical Distribution of Tuberculosis in Sicily: A 6-Year Retrospective Study (2018-2023).

Background: Tuberculosis (TB) continues to be a major public health issue, with high mortality rates reported worldwide. It is worth noting that most of the hospitalizations for tuberculosis in the Sicilian region involve Italian-born individuals, underscoring the need to address this problem. Recent research on the geographic area and seasonality of infectious diseases, including tuberculosis, may aid in developing effective preventive measures. Objectives: This study aimed to evaluate the impact of the season and geographical area on tuberculosis disease prevalence in the Sicilian region. Methods: A retrospective study from January 2018 to May 2023 was conducted on patients with tuberculosis in the Sicilian region by analyzing computerized records on the Infectious Diseases Information System, currently named the Italian National Notification System (NSIS), of the Epidemiology Unit at Policlinico Paolo Giaccone University Hospital of Palermo and the Regional Reference Laboratory for Tuberculosis Surveillance and Control. Results: Eastern and Western Sicily were the geographical Sicilian areas with the highest frequency of patients with tuberculosis (52.2% and 42.6%, respectively). In comparison, Central Sicily had a significantly lower frequency of patients with tuberculosis (5.2%). Regarding the season, autumn was the season with the highest number of notification cases (28.9%), while spring was the season with the lowest frequency of patients with tuberculosis (19.7%). In autumn, we found significantly fewer patients with tuberculosis from Eastern Sicily (39.3%) and Central Sicily (1.5%), while Western Sicily had more patients with tuberculosis (59.3%). In spring, we found significantly more patients with tuberculosis from Eastern Sicily (64.1%), while Western and Central Sicily had significantly fewer patients with tuberculosis (23.9% and 12%, respectively). The presence of patients with tuberculosis did not significantly differ between geographical regions in summer and winter. Conclusions: Geographical area and seasonality significantly impact the distribution of tuberculosis cases in Sicily. These factors may be linked to different climatic conditions across the various geographical areas considered. Our findings suggest that climate can play a critical role in the spread of airborne infectious diseases, such as tuberculosis.

Lymphocyte profile in peripheral blood of patients with multiple myeloma.

Multiple myeloma (MM) is a disease which remains incurable. One of the main reasons is a weakened immune system that allows MM cells to survive. Therefore, the current research is focused on the study of immune system imbalance in MM to find the most effective immunotherapy strategies. Aiming to identify the key points of immune failure in MM patients, we analysed peripheral lymphocytes subsets from MM patients (n = 57) at various stages of the disease course and healthy individuals (HI, n = 15) focusing on T, NK, iNKT, B cells and NK-cell cytokines. Our analysis revealed that MM patients exhibited immune alterations in all studied immune subsets. Compared to HI, MM patients had a significantly lower proportion of CD4 + T cells (19.55% vs. 40.85%; p < 0.001) and CD4 + iNKT cells (18.8% vs. 40%; p < 0.001), within B cells an increased proportion of CD21LCD38L subset (4.5% vs. 0.4%; p < 0.01) and decreased level of memory cells (unswitched 6.1% vs. 14.7%; p < 0.001 and switched 7.8% vs. 11.2%; NS), NK cells displaying signs of activation and exhaustion characterised by a more than 2-fold increase in SLAMF7 MFI (p < 0.001), decreased expression of NKG2D (MFI) and NKp46 (%) on CD16 + 56 + and CD16 + 56- subset respectively (p < 0.05), Effective immunotherapy needs to consider these immune defects and monitoring of the immune status of MM patients is essential to define better interventions in the future.

Blaschkoid melanotic cutaneous lupus erythematosus with "melanocytic nests".

Melanotic cutaneous lupus erythematosus (LE) is a newly described clinical variant of chronic cutaneous LE, presenting with localized or diffuse brownish or grayish macular and reticulated pigmentation in the absence of erythema, scaling, atrophy, scarring, or telangiectasia. The diagnosis is based upon histopathology, which demonstrates the characteristic features of LE with an interface vacuolar dermatitis with melanophages, and a superficial and deep, perivascular and periadnexal lymphocytic infiltrate with mucin deposition. Herein, we describe a case of a 61-year-old White male presenting with melanotic cutaneous LE with a blaschkoid distribution on his face in which the histopathological phenomenon of "true melanocytic nests" in the setting of a lichenoid pattern was seen. We want to highlight how nests of cellular aggregates at the dermoepidermal junction labeling with melanocytic markers may occur in the setting of an interface tissue reaction. This benign reactional pattern may mimic atypical melanocytic proliferations, especially on sun-damaged skin. Clinicopathological correlation and careful microscopic examination using a panel of multiple melanocytic markers is crucial for making an accurate final diagnosis. All the cases of melanotic cutaneous LE reported in the literature are also reviewed.

Stevens-Johnson syndrome and toxic epidermal necrolysis: 11-year retrospective experience in a high-complexity tertiary hospital in Milan, Italy.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe drug-induced hypersensitivity reactions characterized by widespread epidermal necrosis, mucous membrane erosions, and systemic findings. We have provided our 11-year experience from a Milan, Italy tertiary hospital managing SJS/TEN, evaluating the clinical and histopathologic features plus the impact on mortality. We retrospectively analyzed 28 patients diagnosed with SJS/TEN based on the clinical and histopathologic findings, according to the classification criteria of multiple studies. We assessed the dermatographics, comorbidities, drug history, lesion characteristics, clinical findings, treatments, blood tests, and outcomes. Severity scores (SCORTEN, Re-SCORTEN, ABCD-10) were used for treatment evaluation and mortality prediction. Data were statistically analyzed, and significant factors associated with mortality were identified. We found that among the 28 patients, 89.2% had comorbidities, mainly cardiovascular diseases, and 21.4% had autoimmune disorders. All patients had received systemic therapy (46.6% monotherapy, 53.6% combination therapy), with systemic steroids (71.4%) and intravenous immunoglobulins (67.8%) being common treatments. There were complications, including systemic infections (67.9%) and septic shock (10.7%). The overall mortality rate was 17.8%. The statistical analysis indicated that malignancy, a high ABCD-10 score, and a high neutrophil-to-lymphocyte ratio were significantly associated with mortality. The extent of affected body surface area did not correlate significantly with mortality. This study provides insights into SJS/TEN management, revealing factors influencing mortality in a high-complexity tertiary hospital setting.

Unraveling the complexities of drug reaction with eosinophilia and systemic symptoms (DRESS): Insights into clinical, laboratory, and histopathologic features of a case series from an Italian tertiary center.

Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe and potentially life-threatening drug hypersensitivity reaction. The diagnosis and management of DRESS are complicated due to its heterogeneous clinical and pathologic presentations, delayed onset of signs and symptoms, and unpredictable outcome. This retrospective study aimed to analyze cases of DRESS from a single Italian referring tertiary hospital center (Grande Ospedale Metropolitano Niguarda, Milan, Italy) with a focus on clinical features, causative drugs, histopathologic findings, and treatment. We have included 18 of 32 patients with a probable or definite diagnosis of DRESS. The study observed a slight predominance of women, with antimicrobials and allopurinol identified as the main causative drugs. Clinical manifestations varied, with a monomorphic maculopapular eruption being the most common, whereas facial edema and mucosal involvement were less frequently observed. Multiple organs were commonly affected, with liver and kidney involvement being prominent. Cardiac involvement was associated with the severity of eosinophilia. Laboratory evaluations showed elevated eosinophil levels and increased eosinophil cationic protein levels, supporting the role of eosinophils in DRESS pathogenesis. Histopathologic analysis revealed various patterns often coexisting in the same biopsy in 83% of cases, with interface dermatitis being the most frequent, followed by the perivascular pattern and the spongiotic/eczematous pattern. We observed eosinophils in the biopsy samples in about 50% of patients, and the relationship between peripheral eosinophilia and eosinophils in skin biopsies was not significant. In addition to the RegiSCAR score, age may play a role in predicting disease severity, as older patients with lower scores had poorer outcomes. The prognosis of DRESS depended on early identification, discontinuation of the causative agent, and appropriate therapy. Systemic corticosteroids were the primary treatment option.

Lichen Planus Pigmentosus with True Melanocytic Nests: A Case Report with a Comprehensive Literature Review.

Lichen Planus Pigmentosus (LPP) is an uncommon variant of lichen planus characterized by the development of dark greyish-brown macules and patches primarily affecting sun-exposed areas. Histologically, it presents with lichenoid interface dermatitis with many melanophages. In select cases, the presence of melanocytic nests or pseudomelanocytic nests within LPP lesions has been documented, posing a diagnostic challenge. We present a detailed case report of a 32-year-old Eritrean woman with a longstanding history of hyperpigmented macules, alongside an in-depth review of the existing literature on lichenoid dermatoses featuring melanocytic or pseudomelanocytic nests. This paper delves into the clinical presentation, histopathological features, differential diagnosis, and potential mechanisms underlying this intriguing phenomenon.

MAF functions as a pioneer transcription factor that initiates and sustains myelomagenesis.

Deregulated expression of lineage-affiliated transcription factors (TFs) is a major mechanism of oncogenesis. However, how the deregulation of nonlineage affiliated TF affects chromatin to initiate oncogenic transcriptional programs is not well-known. To address this, we studied the chromatin effects imposed by oncogenic MAF as the cancer-initiating driver in the plasma cell cancer multiple myeloma. We found that the ectopically expressed MAF endows myeloma plasma cells with migratory and proliferative transcriptional potential. This potential is regulated by the activation of enhancers and superenhancers, previously inactive in healthy B cells and plasma cells, and the cooperation of MAF with the plasma cell-defining TF IRF4. Forced ectopic MAF expression confirms the de novo ability of oncogenic MAF to convert transcriptionally inert chromatin to active chromatin with the features of superenhancers, leading to the activation of the MAF-specific oncogenic transcriptome and the acquisition of cancer-related cellular phenotypes such as CCR1-dependent cell migration. These findings establish oncogenic MAF as a pioneer transcription factor that can initiate as well as sustain oncogenic transcriptomes and cancer phenotypes. However, despite its pioneer function, myeloma cells remain MAF-dependent, thus validating oncogenic MAF as a therapeutic target that would be able to circumvent the challenges of subsequent genetic diversification driving disease relapse and drug resistance.

SARS-CoV-2 Detection by Digital Polymerase Chain Reaction and Immunohistochemistry in Skin Biopsies from 52 Patients with Different COVID-19-Associated Cutaneous Phenotypes.

BACKGROUND: COronaVIrus Disease 19 (COVID-19) is associated with a wide spectrum of skin manifestations, but SARS-CoV-2 RNA in lesional skin has been demonstrated only in few cases. OBJECTIVE: The objective of this study was to demonstrate SARS-CoV-2 presence in skin samples from patients with different COVID-19-related cutaneous phenotypes. METHODS: Demographic and clinical data from 52 patients with COVID-19-associated cutaneous manifestations were collected. Immunohistochemistry and digital PCR (dPCR) were performed in all skin samples. RNA in situ hybridization (ISH) was used to confirm the presence of SARS-CoV-2 RNA. RESULTS: Twenty out of 52 (38%) patients presented SARS-CoV-2 positivity in the skin. Among these, 10/52 (19%) patients tested positive for spike protein on immunohistochemistry, five of whom had also positive testing on dPCR. Of the latter, one tested positive both for ISH and ACE-2 on immunohistochemistry while another one tested positive for nucleocapsid protein. Twelve patients showed positivity only for nucleocapsid protein on immunohistochemistry. CONCLUSIONS: SARS-CoV-2 was detected only in 38% of patients, without any association with a specific cutaneous phenotype, suggesting that the pathophysiology of cutaneous lesions mostly depends on the activation of the immune system. The combination of spike and nucleocapsid immunohistochemistry has higher diagnostic yield than dPCR. Skin persistence of SARS-CoV-2 may depend on timing of skin lesions, viral load, and immune response.

The clinical and pathologic spectrum of mucocutaneous reactions after COVID-19 vaccinations in three tertiary referral centers of northern Italy.

Adverse cutaneous reactions after COVID-19 vaccinations have increased, highlighting not only how SARS-CoV-2 infection but also COVID-19 vaccines may induce adverse cutaneous manifestations. We evaluated the clinical and pathologic spectrum of mucocutaneous reactions after COVID-19 vaccinations, observed consecutively within three large tertiary centers of the Metropolitan City of Milan (Lombardy), comparing our results with the currently available literature. We retrospectively reviewed medical records and skin biopsies of patients diagnosed with mucocutaneous adverse events after COVID-19 vaccinations and followed at three Italian tertiary referral centers in the Metropolitan City of Milan. One hundred twelve patients (77 women and 35 men (112 total); median age, 60 years) have been included in the present study; a cutaneous biopsy was performed in 41 cases (36%). The trunk and arms were the most involved anatomic areas. Autoimmune reactions after COVID-19 vaccinations, urticaria, morbilliform eruptions, and eczematous dermatitis have been the most commonly diagnosed disorders. Compared to the currently available literature, we performed many more histologic examinations, allowing us to make more precise diagnoses. Most of the cutaneous reactions were self-healing and/or responded to topical and systemic steroids and systemic antihistamines, thus not discouraging the general population from carrying out vaccinations, which currently have a good safety profile.

The challenge of Morgellons disease: A patient with clinicopathologic correlation.

Morgellons disease is a rare condition characterized by patient-reported multicolored fibers and other nonorganic particles or organic particles embedded in and protruding from diffuse skin ulcerations. Although the scientific community is prone to believe that Morgellons disease is a psychiatric disorder, an infectious pathogenesis associated with Borrelia burgdorferi in the setting of Lyme disease has also been proposed. The histopathology is usually considered as nonspecific. To illustrate this condition, we present the case of an adult woman with significant ulcerative skin lesions and cicatricial changes on the face, trunk, and arms. After multiple biopsies and successful microscopic visualization of the fibers, she received a diagnosis of Morgellons disease in the setting of delusional infestation. No evidence of Borrelia infection was found. Treatment with antipsychotics was initiated, but the patient was lost to follow-up, as is often the case with patients with Morgellons disease.

Rickettsiosis with Pleural Effusion: A Systematic Review with a Focus on Rickettsiosis in Italy.

BACKGROUND: Motivated by a case finding of Mediterranean spotted fever (MSF) associated with atypical pneumonia and pleural effusion in which Rickettsia conorii subsp. israelensis was identified by molecular methods in the pleural fluid, we wanted to summarize the clinical presentations of rickettsiosis in Italy by systematic research and to make a systematic review of all the global cases of rickettsiosis associated with pleural effusion. METHODS: For the literature search, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology was followed. We chose to select only the studies published in last 25 years and confirmed both with serological and molecular assays. RESULTS: Human cases of rickettsiosis in Italy were reported in 48 papers describing 2831 patients with very different clinical presentations; the majority was MSF accounted to R. conorii and was reported in Sicily. Pleural effusion associated with infection with microorganisms belonging to Rickettsiales was described in 487 patients. It was rarely associated with microorganisms different from O. tsutsugamushi; also rarely, cases of scrub typhus were reported outside Southeast Asia and in the largest majority, the diagnosis was achieved with serology. CONCLUSIONS: MSF, especially when caused by R. conorii subsp. israelensis, may be a severe disease. A high index of suspicion is required to promptly start life-saving therapy. Pleural effusion and interstitial pneumonia may be part of the clinical picture of severe rickettsial disease and should not lead the physician away from this diagnosis.

Systems medicine dissection of chr1q-amp reveals a novel PBX1-FOXM1 axis for targeted therapy in multiple myeloma.

Understanding the biological and clinical impact of copy number aberrations (CNAs) on the development of precision therapies in cancer remains an unmet challenge. Genetic amplification of chromosome 1q (chr1q-amp) is a major CNA conferring an adverse prognosis in several types of cancer, including in the blood cancer multiple myeloma (MM). Although several genes across chromosome 1 (chr1q) portend high-risk MM disease, the underpinning molecular etiology remains elusive. Here, with reference to the 3-dimensional (3D) chromatin structure, we integrate multi-omics data sets from patients with MM with genetic variables to obtain an associated clinical risk map across chr1q and to identify 103 adverse prognosis genes in chr1q-amp MM. Prominent among these genes, the transcription factor PBX1 is ectopically expressed by genetic amplification and epigenetic activation of its own preserved 3D regulatory domain. By binding to reprogrammed superenhancers, PBX1 directly regulates critical oncogenic pathways and a FOXM1-dependent transcriptional program. Together, PBX1 and FOXM1 activate a proliferative gene signature that predicts adverse prognosis across multiple types of cancer. Notably, pharmacological disruption of the PBX1-FOXM1 axis with existing agents (thiostrepton) and a novel PBX1 small molecule inhibitor (T417) is selectively toxic against chr1q-amp myeloma and solid tumor cells. Overall, our systems medicine approach successfully identifies CNA-driven oncogenic circuitries, links them to clinical phenotypes, and proposes novel CNA-targeted therapy strategies in MM and other types of cancer.

The innate sensor ZBP1-IRF3 axis regulates cell proliferation in multiple myeloma.

Multiple myeloma is a malignancy of plasma cells initiated and driven by primary and secondary genetic events. However, myeloma plasma cell survival and proliferation might be sustained by non-genetic drivers. Z-DNA-binding protein 1 (ZBP1; also known as DAI) is an interferon-inducible, Z-nucleic acid sensor that triggers RIPK3-MLKL-mediated necroptosis in mice. ZBP1 also interacts with TBK1 and the transcription factor IRF3 but the function of this interaction is unclear, and the role of the ZBP1-IRF3 axis in cancer is not known. Here we show that ZBP1 is selectively expressed in late B-cell development in both human and murine cells and it is required for optimal T-cell-dependent humoral immune responses. In myeloma plasma cells, the interaction of constitutively expressed ZBP1 with TBK1 and IRF3 results in IRF3 phosphorylation. IRF3 directly binds and activates cell cycle genes, in part through co-operation with the plasma cell lineage-defining transcription factor IRF4, thereby promoting myeloma cell proliferation. This generates a novel, potentially therapeutically targetable and relatively selective myeloma cell addiction to the ZBP1-IRF3 axis. Our data also show a noncanonical function of constitutive ZBP1 in human cells and expand our knowledge of the role of cellular immune sensors in cancer biology.

A severe case of Israeli spotted fever with pleural effusion in Italy.

BACKGROUND: The most common Italian rickettsiosis is Mediterranean Spotted Fever (MSF). MSF is commonly associated with a symptom triad consisting of fever, cutaneous rash, and inoculation eschar. The rash is usually maculopapular but, especially in severe presentations, may be petechial. Other typical findings are arthromyalgia and headache. Herein, we describe for the first time an unusual case of Israeli spotted fever (ISF) associated with interstitial pneumonia and pleural effusion in which R. conorii subsp. israelensis was identified by molecular methods in the blood, as well as in the pleural fluid. CASE PRESENTATION: A 72-year-old male presented with a 10-day history of remittent fever. On admission, the patient's general condition appeared poor with confusion and drowsiness; the first assessment revealed a temperature of 38.7°, blood pressure of 110/70 mmHg, a blood oxygen saturation level of 80% with rapid, frequent, and superficial breathing using accessory muscles (28 breaths per minute), and an arrhythmia with a heart rate of 90 beats per minute. qSOFA score was 3/3. Chest CT revealed ground-glass pneumonia with massive pleural effusion. Petechial exanthema was present diffusely, including on the palms and soles, and a very little eschar surrounded by a violaceous halo was noted on the dorsum of the right foot. Awaiting the results of blood cultures, broad-spectrum antibiotic therapy with meropenem 1 g q8h, ciprofloxacin 400 mg q12h, and doxycycline 100 mg q12h was initiated. Doxycycline was included in the therapy because of the presence of petechial rash and fever, making us consider a diagnosis of rickettsiosis. This suspicion was confirmed by the positivity of polymerase chain reaction on whole blood for R. conorii subsp. israelensis. Thoracentesis was performed to improve alveolar ventilation. R. conorii subsp. israelensis was again identified in the pleural fluid by PCR technique. On day 4 the clinical condition worsened. Blood exams showed values suggestive of secondary hemophagocytic lymphohistiocytosis; 4 out of 8 diagnostic criteria were present and empirical treatment with prednisone was started resulting in a gradual improvement in general condition. CONCLUSIONS: Israeli spotted fever may be a severe disease. A high index of suspicion is required to promptly start life-saving therapy. Pleural effusion and interstitial pneumonia may be part of the clinical picture of severe rickettsial disease and should not lead the physician away from this diagnosis.

New Candidates for Autism/Intellectual Disability Identified by Whole-Exome Sequencing.

Intellectual disability (ID) is characterized by impairments in the cognitive processes and in the tasks of daily life. It encompasses a clinically and genetically heterogeneous group of neurodevelopmental disorders often associated with autism spectrum disorder (ASD). Social and communication abilities are strongly compromised in ASD. The prevalence of ID/ASD is 1-3%, and approximately 30% of the patients remain without a molecular diagnosis. Considering the extreme genetic locus heterogeneity, next-generation sequencing approaches have provided powerful tools for candidate gene identification. Molecular diagnosis is crucial to improve outcome, prevent complications, and hopefully start a therapeutic approach. Here, we performed parent-offspring trio whole-exome sequencing (WES) in a cohort of 60 mostly syndromic ID/ASD patients and we detected 8 pathogenic variants in genes already known to be associated with ID/ASD (SYNGAP1, SMAD6, PACS1, SHANK3, KMT2A, KCNQ2, ACTB, and POGZ). We found four de novo disruptive variants of four novel candidate ASD/ID genes: MBP, PCDHA1, PCDH15, PDPR. We additionally selected via bioinformatic tools many variants in unknown genes that alone or in combination can contribute to the phenotype. In conclusion, our data confirm the efficacy of WES in detecting pathogenic variants of known and novel ID/ASD genes.