Immunity and COVID-19 vaccines. Revisiting the bases.

The COVID-19 pandemic is one of the challenges of the 21st century; science and technology were put to the test for the development vaccines, diagnostic techniques and treatments in record time. However, misinformation and misinterpretation have made the safety and efficacy of COVID-19 vaccines a subject of debate. This review addresses concepts on immunization mechanisms and vaccination, as well as evidence supporting that COVID-19 vaccines are immunogenic, efficacious and safe.

La pandemia de COVID-19 es uno de los retos del siglo XXI; la ciencia y la tecnología se pusieron a prueba para desarrollar vacunas, técnicas diagnósticas y tratamientos en tiempo récord. No obstante, la desinformación y mala interpretación han hecho que la seguridad y eficacia de las vacunas contra COVID-19 sean un tema de debate. En esta revisión se abordan conceptos sobre los mecanismos de la inmunización y la vacunación; así como la evidencia que sostiene que las vacunas contra COVID-19 son inmunogénicas, eficaces y seguras.

Refined cut-off for TP53 immunohistochemistry improves prediction of TP53 mutation status in ovarian mucinous tumors: implications for outcome analyses.

TP53 mutations are implicated in the progression of mucinous borderline tumors (MBOT) to mucinous ovarian carcinomas (MOC). Optimized immunohistochemistry (IHC) for TP53 has been established as a proxy for the TP53 mutation status in other ovarian tumor types. We aimed to confirm the ability of TP53 IHC to predict TP53 mutation status in ovarian mucinous tumors and to evaluate the association of TP53 mutation status with survival among patients with MBOT and MOC. Tumor tissue from an initial cohort of 113 women with MBOT/MOC was stained with optimized IHC for TP53 using tissue microarrays (75.2%) or full sections (24.8%) and interpreted using established criteria as normal or abnormal (overexpression, complete absence, or cytoplasmic). Cases were considered concordant if abnormal IHC staining predicted deleterious TP53 mutations. Discordant tissue microarray cases were re-evaluated on full sections and interpretational criteria were refined. The initial cohort was expanded to a total of 165 MBOT and 424 MOC for the examination of the association of survival with TP53 mutation status, assessed either by TP53 IHC and/or sequencing. Initially, 82/113 (72.6%) cases were concordant using the established criteria. Refined criteria for overexpression to account for intratumoral heterogeneity and terminal differentiation improved concordance to 93.8% (106/113). In the expanded cohort, 19.4% (32/165) of MBOT showed evidence for TP53 mutation and this was associated with a higher risk of recurrence, disease-specific death, and all-cause mortality (overall survival: HR = 4.6, 95% CI 1.5-14.3, p = 0.0087). Within MOC, 61.1% (259/424) harbored a TP53 mutation, but this was not associated with survival (overall survival, p = 0.77). TP53 IHC is an accurate proxy for TP53 mutation status with refined interpretation criteria accounting for intratumoral heterogeneity and terminal differentiation in ovarian mucinous tumors. TP53 mutation status is an important biomarker to identify MBOT with a higher risk of mortality.

Analysis of DNA methylation in endometrial biopsies to predict risk of endometrial cancer.

OBJECTIVE: To determine whether analysis of methylated DNA in benign endometrial biopsy (EB) specimens is associated with risk of endometrial cancer (EC). METHODS: We identified 23 women with EBs performed at Mayo Clinic diagnosed as normal (n = 14) or hyperplasia (n = 9) and who later developed endometrial cancer after a median interval of 1 year. Cases were matched 1:1 with patients with benign EBs who did not develop EC (controls) by histology of benign EB (normal endometrium vs. endometrial hyperplasia without atypia), date of EB, age at EB, and length of post-biopsy follow-up. DNA extracted from formalin-fixed paraffin-embedded tissues underwent pyrosequencing to determine percent methylation of promoter region CpGs at 26 loci in 4 genes (ADCYAP1, HAND2, MME, RASSF1A) previously reported as methylated in EC. RESULTS: After pathologic review, 23 matched pairs of cases and controls were identified (14 normal, 9 hyperplasia without atypia per group). Among cases, median time from benign EB to EC was 1 year (range 2 days - 9.2 years). We evaluated 26 CpG sites within 4 genes and found a consistent trend of increasing percentage of methylation from control to case to EC for all CpGs. At the gene-level, mean methylation events of ADCYAP1 and HAND2 in cases were significantly higher than control (p = 0.015 and p = 0.021, respectively). Though the other genes did not reach statistical significance, we observed an increased methylation trend among all genes. Area-under-curve (AUC) calculations (predicting future development of EC in the setting of benign EB) for ADCYAP1 and HAND2 were 0.71 (95% CI 0.55-0.88) and 0.83 (95% CI 0.64-1, respectively). CONCLUSIONS: This proof-of-principle study provides evidence that specific methylation patterns in benign EB correlate with future development of EC.

Therapeutic options for mucinous ovarian carcinoma.

OBJECTIVE: Mucinous ovarian carcinoma (MOC) is an uncommon ovarian cancer histotype that responds poorly to conventional chemotherapy regimens. Although long overall survival outcomes can occur with early detection and optimal surgical resection, recurrent and advanced disease are associated with extremely poor survival. There are no current guidelines specifically for the systemic management of recurrent MOC. We analyzed data from a large cohort of women with MOC to evaluate the potential for clinical utility from a range of systemic agents. METHODS: We analyzed gene copy number (n = 191) and DNA sequencing data (n = 184) from primary MOC to evaluate signatures of mismatch repair deficiency and homologous recombination deficiency, and other genetic events. Immunohistochemistry data were collated for ER, CK7, CK20, CDX2, HER2, PAX8 and p16 (n = 117-166). RESULTS: Molecular aberrations noted in MOC that suggest a match with current targeted therapies include amplification of ERBB2 (26.7%) and BRAF mutation (9%). Observed genetic events that suggest potential efficacy for agents currently in clinical trials include: KRAS/NRAS mutations (66%), TP53 missense mutation (49%), RNF43 mutation (11%), ARID1A mutation (10%), and PIK3CA/PTEN mutation (9%). Therapies exploiting homologous recombination deficiency (HRD) may not be effective in MOC, as only 1/191 had a high HRD score. Mismatch repair deficiency was similarly rare (1/184). CONCLUSIONS: Although genetically diverse, MOC has several potential therapeutic targets. Importantly, the lack of response to platinum-based therapy observed clinically corresponds to the lack of a genomic signature associated with HRD, and MOC are thus also unlikely to respond to PARP inhibition.

Genes associated with bowel metastases in ovarian cancer.

OBJECTIVE: This study is designed to identify genes and pathways that could promote metastasis to the bowel in high-grade serous ovarian cancer (OC) and evaluate their associations with clinical outcomes. METHODS: We performed RNA sequencing of OC primary tumors (PTs) and their corresponding bowel metastases (n = 21 discovery set; n = 18 replication set). Differentially expressed genes (DEGs) were those expressed at least 2-fold higher in bowel metastases (BMets) than PTs in at least 30% of patients (P < .05) with no increased expression in paired benign bowel tissue and were validated with quantitative reverse transcription PCR. Using an independent OC cohort (n = 333), associations between DEGs in PTs and surgical and clinical outcomes were performed. Immunohistochemistry and mouse xenograft studies were performed to confirm the role of LRRC15 in promoting metastasis. RESULTS: Among 27 DEGs in the discovery set, 21 were confirmed in the replication set: SFRP2, Col11A1, LRRC15, ADAM12, ADAMTS12, MFAP5, LUM, PLPP4, FAP, POSTN, GRP, MMP11, MMP13, C1QTNF3, EPYC, DIO2, KCNA1, NETO1, NTM, MYH13, and PVALB. Higher expression of more than half of the genes in the PT was associated with an increased requirement for bowel resection at primary surgery and an inability to achieve complete cytoreduction. Increased expression of LRRC15 in BMets was confirmed by immunohistochemistry and knockdown of LRRC15 significantly inhibited tumor progression in mice. CONCLUSIONS: We identified 21 genes that are overexpressed in bowel metastases among patients with OC. Our findings will help select potential molecular targets for the prevention and treatment of malignant bowel obstruction in OC.

Fnip1 regulates skeletal muscle fiber type specification, fatigue resistance, and susceptibility to muscular dystrophy.

Mammalian skeletal muscle is broadly characterized by the presence of two distinct categories of muscle fibers called type I "red" slow twitch and type II "white" fast twitch, which display marked differences in contraction strength, metabolic strategies, and susceptibility to fatigue. The relative representation of each fiber type can have major influences on susceptibility to obesity, diabetes, and muscular dystrophies. However, the molecular factors controlling fiber type specification remain incompletely defined. In this study, we describe the control of fiber type specification and susceptibility to metabolic disease by folliculin interacting protein-1 (Fnip1). Using Fnip1 null mice, we found that loss of Fnip1 increased the representation of type I fibers characterized by increased myoglobin, slow twitch markers [myosin heavy chain 7 (MyH7), succinate dehydrogenase, troponin I 1, troponin C1, troponin T1], capillary density, and mitochondria number. Cultured Fnip1-null muscle fibers had higher oxidative capacity, and isolated Fnip1-null skeletal muscles were more resistant to postcontraction fatigue relative to WT skeletal muscles. Biochemical analyses revealed increased activation of the metabolic sensor AMP kinase (AMPK), and increased expression of the AMPK-target and transcriptional coactivator PGC1α in Fnip1 null skeletal muscle. Genetic disruption of PGC1α rescued normal levels of type I fiber markers MyH7 and myoglobin in Fnip1-null mice. Remarkably, loss of Fnip1 profoundly mitigated muscle damage in a murine model of Duchenne muscular dystrophy. These results indicate that Fnip1 controls skeletal muscle fiber type specification and warrant further study to determine whether inhibition of Fnip1 has therapeutic potential in muscular dystrophy diseases.

Three cases of bullous morphea: histopathologic findings with implications regarding pathogenesis.

Bullous morphea is a rare variant and is not frequently reported. We present three cases of bullous morphea. Although lymphangiectases have been suggested as the most likely mechanism for the development of the bullae in cases of morphea, none of the cases presented with lymphangiectases. To the contrary, all of our cases showed hemorrhagic content in the bullae, which suggests local trauma as a mechanism involved in bulla formation.

Morphological clues in the diagnosis of sclerodermiform dermatitis.

In this report, we review 5 sclerodermiform cutaneous conditions: eosinophilic fasciitis, systemic nephrogenic fibrosis, scleredema, scleromyxedema, and toxic oil syndrome. We emphasize the morphological differences between the conditions and some morphological clues that are important to differential diagnosis.

The use of CT findings to predict extent of tumor at primary surgery for ovarian cancer.

BACKGROUND: High tumor dissemination (HTD) is a major risk factor for serious morbidity after primary ovarian cancer (OC) surgery, particularly in medically compromised patients. We performed a pilot study of whether CT findings could predict extent of disease and surgical complexity necessary in advanced OC. METHODS: Preoperative CT images for patients with advanced OC from 1997-2003 were evaluated for rigorously defined disease-related findings and compared to both the findings at exploration and the required surgical procedures. Associations were assessed by the chi-square test. RESULTS: Forty-six cases met inclusion criteria. Mean age was 66.4y, and 76% had residual disease (RD) 1cm or less. CT and surgical findings correlated (sensitivity/specificity) as follows: diaphragm disease (48%/100%); surface liver (100%/93%); omental cake (72%/65%); any sigmoid involvement (54%/100%); ascites (44%/100%); extra-pelvic large bowel involvement (29%/91%). When diaphragm disease and omental cake were present, HTD was found in all cases (positive predictive value and specificity=100%, sensitivity 48%). For CT findings of liver, large bowel and spleen involvement there was a strong trend toward resection (P=0.001, P=0.06 and P=0.06, respectively). CONCLUSIONS: The findings of diaphragm disease and omental cake on CT scan are highly predictive for high tumor dissemination (HTD) and thus likelihood of extensive surgery required to achieve low residual disease. In addition, multiple CT findings correlate strongly with the need for higher surgical complexity which should facilitate preoperative planning and/or triage to specialized centers. These preliminary data suggest specific CT findings can be used to optimize treatment planning.

Nutritional status, CT body composition measures and survival in ovarian cancer.

OBJECTIVE: Body composition measures (BCMs) are an important predictor of nutritional status in patients with cancer. Poor nutritional status is common in ovarian cancer (OC) and is a well-known variable that influences cancer treatment and outcome. We aim to establish the role of BCMs measured by computed tomography (CT) in predicting outcomes in patients with OC. METHODS: We retrospectively searched our institutional database for patients with stage IIIC/IV OC who underwent surgery as primary treatment at Mayo Clinic between 1996 and 2005 and had adequate presurgical CT images available. For each patient, 1 axial CT image at the level of the 3rd lumbar vertebra was evaluated. Adipose and lean tissues were discriminated using commercially available software. Cox models were fit to evaluate the relationship between patient factors and overall survival (OS). Associations were summarized using hazard ratios (HRs) and corresponding 95% CIs. RESULTS: A total of 82 patients were identified, with a median age of 68.4 years. OS at 1 and 5 years was 84.1% and 24.1%, respectively. Older age (P=.01), stage IV disease (P<.001), and subcutaneous and muscular fat<77.21cm(2) (P<.001) were independently associated with poor OS. Longer hospital stay was independently predicted by albumin≤3g/dL (P=.03), suboptimal surgery (P=.02), and subcutaneous and muscular fat<77.21cm(2) (P<.001). Surgical complications were independently predicted only by albumin≤3g/dL (P<.01). CONCLUSIONS: CT BCMs, as indicators of nutritional status, are independent predictors of longer hospital stay and poor OS in patients with OC.

Subungual Keratoacanthoma: Typical and Atypical Presentations of an Uncommon Nail Tumor.

Introduction: Keratoacanthoma (KA) is a group of tumors of epidermal origin with controversial nature. Subungual keratoacanthoma (SUKA) is a rare and destructive variant with more aggressive behavior. SUKA appears as a rapidly growing, painful tumor beneath the nail plate that rapidly progresses to a mass that can measure up to 2 cm. The toe location is unusual. The diagnosis must be made based on the correlation of clinical, radiological, and histopathological findings. Case Presentation: We present two cases of patients diagnosed with SUKAs with different clinical presentations which ranged from very typical to uncommon one. Both cases were treated with simple excision without recurrences. Conclusion: SUKA is a rare subungual tumor. Nail bed location represents a more difficult diagnostic challenge. SUKA should be suspected in the context of persistent and progressive pain on a finger or toe, once more frequent painful tumors have been ruled out.

Trigeminal Trophic Syndrome as a Complication of Herpes Zoster Ophthalmicus.

Trigeminal trophic syndrome (TTS) is an unusual complication that occurs secondary to trigeminal nerve injury. The insult to the nerve can lead to anesthesia, hypoesthesia, and paresthesias producing sensations such as burning or itching. The combination of both leads to repeated self-inflicted skin trauma in an attempt to alleviate these sensations, eventually leading to ulceration of the skin. We report a case of a 71-year-old male patient with a scalp ulcer who had an episode of herpes zoster ophthalmicus four months prior to presentation.

Acne Necrotica in a Woman With Systemic Lupus Erythematosus and Systemic Sclerosis.

We report the case of a 25-year-old woman who presented to the outpatient dermatology clinic with a history of systemic lupus erythematosus, systemic sclerosis, and primary hypothyroidism. She complained of a one-year history of cutaneous lesions that were pruriginous and evolved into crusts and weeks later resolved with varioliform scarring. Clinicopathological correlation established a diagnosis of acne necrotica varioliformis. This report highlights the clues and pitfalls in its diagnosis and reviews associated systemic diseases.

An Uncommon Presentation of Pyogenic Granuloma.

Benign vascular neoplasms are common clinical problems encountered in the practice of primary care. Pyogenic granulomas are one of the most common benign vascular lesions in young adults. Although the physiopathological mechanism for the development of this condition is still not well understood, it has been commonly associated with several triggers such as treatment with retinoids, biological agents, invasive cutaneous therapies and trauma. The development of pyogenic granulomas on sites of vascular malformations like port wine stains has been described in the literature to occur rarely. Most of these types of cases have been studied to occur in the setting of pregnancy and after cryotherapy or pulsated laser therapy. The aim of this article is to present the case of a 21-year-old man with a recent appearance of a pyogenic granuloma within an underlying port wine stain in the posterior cervical region without any history of triggers or risk factors. Excision of the vascular lesion was done, and histopathological report confirmed the diagnosis. The objective of this manuscript is to discuss the possible mechanisms involved in the development of this uncommon presentation and to summarize the current literature related to this clinical scenario.

Painful nails: A practical approach to the diagnosis and management of painful nail conditions.

Because several nail disorders share similar clinical features, their diagnosis and management can be challenging to clinicians. The physical examination may disclose localized abnormalities or point to an underlying systemic disease, requiring additional workup. Furthermore, cosmetic distress and nail-related symptoms (e.g., tingling, stinging, numbness, and pain) are common factors that influence the patient's search for medical assistance. Nail pain (i.e., onychalgia) can accompany both localized and systemic pathology. Onychalgia can be acute or chronic according to the time of evolution; patients may describe it as intermittent or constant, and as a throbbing, burning, sharp, or shooting sensation denoting the nature of the pain. It may be exacerbated by colder temperatures, touch, and increased activity (e.g., manipulating objects, walking). We present four main groups of conditions that might cause nail pain: nail tumors, nail deformities, inflammatory or infectious diseases, and external or traumatic agents. Our article includes an overview of the clinical features, as well as diagnosis and management pearls for each entity. Physicians (dermatologists and nondermatologists) should be aware that abnormalities of the ungual and subungual space are not exclusive of dermatological disorders but may also be present in noncutaneous contexts.

Effects of heparinoid bridging in patients with mechanical heart valves.

BACKGROUND: Patients with mechanical heart valves (MHVs) require long-term oral anticoagulation therapy to protect against thromboembolisms. Invasive procedures with high bleeding risks require oral anticoagulation therapy cessation. Currently, guidelines recommend the use of either subcutaneous low-molecular-weight heparin or intravenous unfractionated heparin in the perioperative period. It is unclear whether the evidence supports the use of one heparinoid over the other. OBJECTIVES: To compare the effectiveness of low-molecular-weight heparin and unfractionated heparin bridging based on the adverse outcomes of thromboembolisms, major bleeding, and death during the perioperative period. DATE SOURCES: A literature search was conducted using PubMed, EMBASE, CINAHL, and the Cochrane Library. Five studies comparing the two bridging therapies in chronically anticoagulated MHV patients met the inclusion criteria. CONCLUSIONS: No statistical significance was found for the endpoints of thromboembolism and death. One study found a statistically significant higher occurrence of major bleeding in patients treated with unfractionated heparin. In all the studies, major bleeding occurred more often than thromboembolisms. Findings were limited by the study designs and methodologies. IMPLICATIONS FOR PRACTICE: Based on the available evidence, neither low-molecular-weight heparin nor intravenous heparin bridging was found to be more effective in reducing the occurrence of adverse events. This may be due in part to the study designs and lack of standardized bridging protocols used in the studies reviewed. Nurse practitioners should remain informed about bridging protocols and weigh the risk versus benefit of each bridging agent when caring for patients with MHVs.

Decision Process in Treatment of Reduced Periodontium: A Case Report.

The relationship between attachment loss and occlusal trauma has been debated for many years. When a patient presents with advanced periodontal disease, a decision has to be made on whether the teeth can be saved or extracted. In this treatment example, the decision process in therapeutic planning for a patient with stage IV periodontal disease is discussed. The main dilemma is whether the patient should receive a prosthodontic reconstruction supported by osseointegrated implants or by periodontally compromised natural teeth. It is assumed that implants do better than teeth over the long term based on firm documentation in the literature, but this article describes why a periodontal prosthesis is still a viable treatment option.

Apego Adulto y Soltería: Validación de una Escala / Adult Attachment and Singleness: Validation of a Scale

Resumen El apego es un vínculo afectivo que caracteriza y moldea las relaciones interpersonales cercanas. Los estilos de apego son el conjunto de conocimientos, expectativas e inseguridades que se sostienen sobre el sí mismo y los demás. El objetivo de la presente investigación fue elaborar una escala que evalúe el apego adulto no solo en el contexto romántico, sino con otros significativos, lo que permitirá el estudio de las personas sin pareja. Se realizaron tres estudios: en el estudio uno se realizó un análisis factorial exploratorio (n=400); en el estudio dos un análisis factorial confirmatorio (n=700). Se obtuvo una escala compuesta por 16 reactivos distribuidos en cuatro factores: preocupado, temeroso, evitante y seguro. La varianza explicada fue del 38.09%, con un índice de fiabilidad con un rango de 0.46 a 0.82 en los distintos factores. En el estudio tres se analizó la validez concurrente (n=201). En los tres estudios se encontraron diferencias entre las personas con pareja y sin pareja, puntuando más alto en seguridad las primeras y más alto en apego ansioso aquellas sin pareja. Se obtuvo una escala válida, confiable, culturalmente relevante que evalúa el apego adulto no solo en el ámbito romántico, sino con otros significativos.

Abstract The attachment is an affective bond that characterizes and shapes close interpersonal relationships. Attachment styles are the set of knowledge, expectations and insecurities about oneself and others. The aim of this research was to develop a scale with adequate psychometric properties, that allows to assess adult attachment not only in a romantic context, but with significant others in general. It will allow the study of groups such as single people. To address that aim, three studies were conducted in which men and women form Mexico City participated voluntarily. In study one an exploratory factor analysis was performed (n=400), in study two a confirmatory factor analysis was performed (n=700). As a result of these studies, it was obtained a scale compounded by 16 items distributed in four factors: preoccupied, fearful, dismissing, and secure. The explained variance was 38.09%, with a reliability index of 0.46 to 0.82 in the different factors. In study three concurrent validity was analyzed (n=201). Differences between people with a partner and single were found in the three studies, scoring higher in security the first and single people scoring higher in preoccupied attachment. It was obtained a valid, reliable, and culturally relevant scale to assess adult attachment not only in the romantic ambit, but also in relation to significant others like family and friends.