Alpha to Omicron: Disease Severity and Clinical Outcomes of Major SARS-CoV-2 Variants.

BACKGROUND: Four severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants predominated in the United States since 2021. Understanding disease severity related to different SARS-CoV-2 variants remains limited. METHOD: Viral genome analysis was performed on SARS-CoV-2 clinical isolates circulating March 2021 through March 2022 in Cleveland, Ohio. Major variants were correlated with disease severity and patient outcomes. RESULTS: In total 2779 patients identified with either Alpha (n 1153), Gamma (n 122), Delta (n 808), or Omicron variants (n 696) were selected for analysis. No difference in frequency of hospitalization, intensive care unit (ICU) admission, and death were found among Alpha, Gamma, and Delta variants. However, patients with Omicron infection were significantly less likely to be admitted to the hospital, require oxygen, or admission to the ICU (2 12.8, P .001; 2 21.6, P .002; 2 9.6, P .01, respectively). In patients whose vaccination status was known, a substantial number had breakthrough infections with Delta or Omicron variants (218/808 [26.9] and 513/696 [73.7], respectively). In breakthrough infections, hospitalization rate was similar regardless of variant by multivariate analysis. No difference in disease severity was identified between Omicron subvariants BA.1 and BA.2. CONCLUSIONS: Disease severity associated with Alpha, Gamma, and Delta variants is comparable while Omicron infections are significantly less severe. Breakthrough disease is significantly more common in patients with Omicron infection.

Purinergic P2X7 receptor antagonist inhibits methamphetamine-induced reward, hyperlocomotion, and cortical IL-7A levels in mice: A role for P2X7/IL-17A crosstalk in methamphetamine behaviors?

P2X7 receptors are dysregulated during psychostimulant exposure. Furthermore, P2X7 receptors enhance endogenous systems (e.g., cytokines, dopamine, and glutamate) that facilitate psychostimulant addiction. Therefore, using mouse locomotor, conditioned place preference (CPP), and intracranial self-stimulation (ICSS) assays, we tested the hypothesis that methamphetamine (METH) reward and acute locomotor activation requires P2X7 receptor activity. We also investigated effects of P2X7 blockade on METH-induced changes in cytokine levels in brain reward regions. A438079 (5, 10, 50 mg/kg), a P2X7 antagonist, did not affect spontaneous locomotor activity but reduced hyperlocomotion caused by acute METH (1 mg/kg) exposure. A438079 (10 mg/kg) also prevented expression of METH CPP without causing aversive or rewarding effects. For ICSS experiments, METH (1 mg/kg) facilitated brain reward function as interpreted from reductions in baseline threshold. In the presence of A438079 (50 mg/kg), METH-induced facilitation of ICSS was reduced. Repeated METH exposure (1 mg/kg × 7 d) caused enhancement of IL-17A levels in the prefrontal cortex (PFC) that was normalized by A438070 (10 mg/kg × 7 d). The present data suggest that P2X7 receptor activity contributes to rewarding and locomotor-stimulant effects of METH through a potential mechanism involving IL-17A, which has recently been implicated in anxiety.

Suicide by sharp force associated with major self-mutilation and self-cannibalism.

Self-stabbing and self-cutting represents an uncommon method of suicide. We present a case of a 30-year-old man who was found dead in the forest. The body was naked and showed multiple cut and stab wounds on different parts of the body (face, neck, chest, abdomen, and extremities). A single-edged kitchen knife was found approximately 20 m from the body. Parts of both ears, the fifth toe of the right foot, and the scrotum were cut off. At the autopsy, two of the severed body parts-the toe and the part of the left ear-were found in the stomach. The cause of death was asphyxiation due to blood aspiration resulting from a cut throat injury. A police investigation uncovered a history of substance abuse and two previous suicidal attempts using a knife. Upon complex analysis of all the evidence, the manner of death was ruled a suicide, which was preceded by actions of major self-mutilation and self-cannibalism, both considered rare behavioral patterns.

Drug Delivery through the Psoriatic Epidermal Barrier-A "Skin-On-A-Chip" Permeability Study and Ex Vivo Optical Imaging.

Psoriasis is a chronic inflammatory disease with unmet medical needs. To clarify potential therapeutic targets, different animal models have been developed. In the current study, imiquimod-induced psoriasiform dermatitis was used for monitoring the changes in skin thickness, transepidermal water loss, body weight, blood perfusion and drug permeability for a topical cream formulation of caffeine, both in wild type and in knock out mice. Morphological characterization of control and diseased tissues was performed by scanning electron microscopy and two-photon microscopy. The chemically induced psoriatic group showed increased skin permeability for the model drug during disease progression. In wild type and TRPA1 KO mice, however, enhanced skin thickness and hyperkeratosis blocked further increase of drug penetration at the late phase (96 h). These results indicate that topical drug therapy can be more effective in early phases of plaque development, when skin thickness is lower. Although paracellular connections (tight junctions) are looser in the advanced phase, hyperkeratosis blocks drug delivery through the transappendageal routes. Novel drug formulations may have the potency for effective drug delivery across the epidermal barrier even in the advanced phase. For development of more effective topical drugs, further research is proposed to explore drug penetration both in healthy and diseased conditions.

EWSR1-SMAD3 rearranged fibroblastic tumor: Case series and review.

We report the largest series to date (N = 6) of EWSR1-SMAD3 rearranged fibroblastic tumor. Initially described in 2018, the tumor features a marked female predominance (F:M, 5:1, mean age 44-years, median age 45.5 years; range 27-57), with most cases (5/6, 83%) arising in acral locations (4 on foot/toe, 1 on hand). One case presented on the lower extremity. The lesions presented as nodules and were composed of short, variably cellular, intersecting fascicles of uniform spindled cells in a collagenous to myxoid stroma. In four cases, the tumor abutted the epidermis without a grenz zone. In one case, there was an abrupt transition to a central, acellular hyalinized area. Two other cases had admixed smaller collagenous areas, reminiscent of collagen rosettes. One had a concentric arrangement of tumor cells around blood vessels. Mitotic activity was low (<1/10 HPFs). All were positive for ERG by immunohistochemistry and negative for CD34 (6/6). An EWSR1-SMAD3 fusion was identified in three cases tested by next-generation sequencing (3/3). Rearrangement of EWSR1 by fluorescence in situ hybridization was showed in 1/1 case. Our series reaffirms prior findings and expands the known histopathologic spectrum of this emerging entity.

A Fatal Case of Cardiac Contusion After Blunt Chest Injury.

ABSTRACT: In this article, we report the autopsy findings of a 48-year-old man who sustained blunt trauma to the thorax. A medical record review revealed no history of cardiac disease. He presented to the hospital with a computed tomography-verified fracture of the left fourth and fifth ribs, and pulmonary and cardiac contusion. He was released from the hospital in stable condition at his own request 7 days later. Because of sudden deterioration, he was readmitted to the hospital the next day. Electrocardiogram detected cardiac arrhythmia on the 15th day after chest trauma. Electrocardiography detected pericardial effusion and severe mitral insufficiency resulting in left ventricular failure. Death was attributed to diffuse alveolar damage-complicating pneumonia due to cardiac contusion with mitral insufficiency occurring 25 days after hospital admission. Internal examination revealed diffuse fibrinous pericarditis, left atrial tear right above the anterior mitral valve leaflet with intrapericardial granulation tissue, and no sign of myocardial damage. Immunohistochemistry showed significantly more CD68-positive macrophages within tissue taken from the heart, a finding indicative of previous atrial and ventricular myocardial contusion. This case report demonstrates that routine hematoxylin and eosin staining may not always reveal significant myocardial damage.

Biomedical Applications of Translational Optical Imaging: From Molecules to Humans.

Light is a powerful investigational tool in biomedicine, at all levels of structural organization. Its multitude of features (intensity, wavelength, polarization, interference, coherence, timing, non-linear absorption, and even interactions with itself) able to create contrast, and thus images that detail the makeup and functioning of the living state can and should be combined for maximum effect, especially if one seeks simultaneously high spatiotemporal resolution and discrimination ability within a living organism. The resulting high relevance should be directed towards a better understanding, detection of abnormalities, and ultimately cogent, precise, and effective intervention. The new optical methods and their combinations needed to address modern surgery in the operating room of the future, and major diseases such as cancer and neurodegeneration are reviewed here, with emphasis on our own work and highlighting selected applications focusing on quantitation, early detection, treatment assessment, and clinical relevance, and more generally matching the quality of the optical detection approach to the complexity of the disease. This should provide guidance for future advanced theranostics, emphasizing a tighter coupling-spatially and temporally-between detection, diagnosis, and treatment, in the hope that technologic sophistication such as that of a Mars rover can be translationally deployed in the clinic, for saving and improving lives.

Undiagnosed cryptococcal meningoencephalitis with extensive hypoxic-ischemic brain injury mimicking grade 3 diffuse axonal injury.

In this article, we report the autopsy findings of a 50-year-old immunocompetent woman, who was hospitalized with an altered state of consciousness. Examinations, including cerebrospinal fluid analysis, carried out during hospitalization failed to identify the infectious agent causing progressive loss of consciousness and quadriparesis. The patient died within 8 days of admission to the hospital. Post-mortem microscopic and culture examination revealed Cryptococcus species. Death was attributed to cryptococcal meningoencephalitis. Histologic examination revealed accumulation of cryptococcus mimicking erythrocytes and extensive hemorrhage in hematoxylin and eosin-stained sections of the brain. Multifocal obliteration of the vascular bed by yeast was accompanied by hypoxic-ischemic brain injury mimicking traumatic diffuse axonal injury.

Secondary pulmonary hypoplasia associated with calcified Meckel´s diverticulum with osseous metaplasia.

In this paper, we report autopsy findings of a 1-day old full-term mature female neonate with pulmonary hypoplasia diagnosed postnatally. Death was attributed to acute respiratory failure due to hyaline membrane disease. We describe pathological features of calcified Meckels diverticulum with osseous metaplasia and inflammatory changes in adjacent peritoneum. As far as we know, this case report documents the youngest patient ever diagnosed with calcified Meckels diverticulum with osseous metaplasia.

The photoreceptor UVR8 mediates the perception of both UV-B and UV-A wavelengths up to 350 nm of sunlight with responsivity moderated by cryptochromes.

The photoreceptors UV RESISTANCE LOCUS 8 (UVR8) and CRYPTOCHROMES 1 and 2 (CRYs) play major roles in the perception of UV-B (280-315 nm) and UV-A/blue radiation (315-500 nm), respectively. However, it is poorly understood how they function in sunlight. The roles of UVR8 and CRYs were assessed in a factorial experiment with Arabidopsis thaliana wild-type and photoreceptor mutants exposed to sunlight for 6 or 12 hr under five types of filters with cut-offs in UV and blue-light regions. Transcriptome-wide responses triggered by UV-B and UV-A wavelengths shorter than 350 nm (UV-Asw ) required UVR8 whereas those induced by blue and UV-A wavelengths longer than 350 nm (UV-Alw ) required CRYs. UVR8 modulated gene expression in response to blue light while lack of CRYs drastically enhanced gene expression in response to UV-B and UV-Asw . These results agree with our estimates of photons absorbed by these photoreceptors in sunlight and with in vitro monomerization of UVR8 by wavelengths up to 335 nm. Motif enrichment analysis predicted complex signaling downstream of UVR8 and CRYs. Our results highlight that it is important to use UV waveband definitions specific to plants' photomorphogenesis as is routinely done in the visible region.

Targeted next generation sequencing (NGS) to classify melanocytic neoplasms.

This study piloted a pan-solid-tumor next generation sequence (NGS)-based laboratory developed test as a diagnostic aid in melanocytic tumors. 31 cases (4 "epithelioid" nevi, 5 blue nevi variants, 7 Spitz tumors [3 benign and 4 malignant] and 15 melanomas) were evaluated. All tumors [median diameter 7 mm (range 4-15 mm); median thickness 2.25 mm (range 0.25-12 mm)] yielded satisfactory results. The number of small nucleotide variants/tumor was significantly different between melanoma (median 18/tumor, range 4-71) and all other lesions (median 8/tumor, range 3-17) (P < 0.004) and malignant (median 16/tumor, range 4-71) vs benign lesions (median 7/tumor, range 3-14) (P = 0.01). BRAF, MET, NTRK1, and ROS fusions only occurred in benign Spitz tumors; EML4 fusion, BRAF, MAP2K1 and TERT mutations occurred in malignant Spitz tumors and/or melanoma. Amplifications and NRAS and NF1 mutations only occurred in melanoma. Most melanomas contained >1 pathogenic alteration. Developed NGS-based criteria correctly classified all malignant lesions in this series. 10/12 cases showed concordance with FISH; consensus diagnosis agreed with NGS classification in FISH-non-concordant cases. This pilot study suggests that NGS may be an effective diagnostic adjunct comparable to FISH, but further studies with larger numbers of cases are needed.

Superficial sarcomas with CIC rearrangement are aggressive neoplasms: A series of eight cases.

CIC rearranged sarcomas have significant overlap with Ewing sarcoma, are aggressive, and typically present in deep soft tissue. They most commonly have a t(4;19)(q35;q13) with CIC-DUX4 fusion. Superficial presentation is rare. We report eight (6F, 2M; median 45-years-old, range 14-65) superficial CIC-rearranged sarcomas, involving the extremities (n = 4), vulva (n = 2), and trunk (n = 2). The tumors were composed of nodules/sheets of round cells with necrosis and hemorrhage separated by dense hyaline bands. Tumor cells had vesicular chromatin, prominent nucleoli and frequent mitotic figures. One showed pagetoid spread. Targeted next-generation sequencing was positive for CIC-DUX4 fusion (6/6); fluorescence in situ hybridization (FISH) was positive for CIC rearrangement (2/3). Eight of eight had evidence of CIC-DUX4 fusion/rearrangement by molecular techniques. Immunohistochemistry was positive for CD99+ (8/8) and DUX4+ (4/4). FISH for EWSR1 rearrangement was negative (5/5). Of five patients with at least 6 months follow-up, three of five died of disease, all within 2 years of presentation. One is alive with disease at 48 months. One is disease free at 3 months. Superficial CIC-rearranged sarcomas should be considered in cases exhibiting features reminiscent of Ewing sarcoma, but with increased pleomorphism and/or geographic necrosis. In contrast to superficial Ewing sarcomas, superficial CIC-rearranged sarcomas are aggressive.

Arrhythmogenic Ventricular Cardiomyopathy Associated With Fibromuscular Dysplasia of Ostial Right Main Coronary Artery.

In this article, we report the autopsy findings of a 23-year-old woman, who was found unconscious at home by her relatives. During the transportation to the hospital, the woman was handed over to the ambulance personnel, who were the first to provide cardiopulmonary resuscitation. In the hospital, after an hour-lasting asystole, the heart activity was restored. Prolonged cardiac arrest led to hypoxic brain injury, which resulted in a persistent coma. Examinations carried out during hospitalization detected hypokinetic interventricular septum, frequent ventricular extrasystoles and ventricular fibrillation. The patient died within 35 hours of admission to the hospital. Gross findings of the heart included a noticeable increase of the adipose tissue in the right ventricular wall, where histologically focal myocardial atrophy with focal transmural lipomatosis reaching endocardium were detected. Death was attributed to arrhythmogenic ventricular cardiomyopathy. Pathogenic variants in JUP gene and KCNH2 gene confirmed the diagnosis. Other finding of note was fibromuscular dysplasia of ostial right main coronary artery causing a significant luminal narrowing.

Incidental idiopathic focal sclerosing mesenteritis in a 4-month-old child.

Sclerosing mesenteritis is a rare non-cancerous disease affecting the small bowel mesentery, which occurs predominantly in older age. The exact etiology is not known. Clinical symptoms are very variable and they include abdominal pain and distention, nausea, and vomiting. We present a case of a 4-month-old boy, who died suddenly at home. Based on the investigation of the circumstances of death, results of toxicology tests and histological examination the case was concluded as sudden infant death syndrome. During life, the child had repeated abdominal pain with distention. Secondary autopsy finding was a significant thickening of terminal ileum mesentery the length of 2,5 cm, with thickness reaching up to 1,5 cm and affecting almost half the circumference of the small intestine. According to the current literature, the case discussed in this article is the youngest recorded.

Chronic dissecting aneurysm of ascending aorta with a large intramural thrombus and isolated aortic defects.

We present macroscopic and microscopic findings in a case of chronic dissecting aneurysm of ascending aorta and aortic arch associated with isolated tears of aortic wall without its rupture in a 71-year-old female presenting with minimal clinical symptomatology. Aneurysmal dilation of the aorta was caused not only by the bridging of the vascular wall based on the presence of an organizing intramural thrombus in the false lumen between the separated layers, but also by a wide flat defect in the aortic intima and media with the preservation of the aortic wall integrity due to fibrotical alteration of tunica adventicia. Histologic examination of the thoracic aorta detected cystic medial degeneration with mild atherosclerosis.

Neuronal ceroid lipofuscinosis with cardiac involvement.

Neuronal ceroid lipofuscinoses (NCLs) are a group of inherited neurodegenerative disorders with clinical presentation predominantly in the childhood. The NCLs represent lysosomal storage disorders characterized by the accumulation of autofluorescent lipopigment storage material. The most common clinical features include development failure, psychomotor regression, seizures, and progressive loss of vision. We present a case of neuronal ceroid lipofuscinosis with cardiac involvement diagnosed post-mortem in a 9,5-year-old boy, whose clinical symptomatology comprised partial epilepsy, psychomotor decline and sinus bradycardia. In contrast to ventricular hypertrophy, being more frequently associated with NCLs, we discovered cardiac atrophy. Histologic examination of the heart revealed not only the lipofuscinosis affecting cardiac conducting cells and cardiomyocytes, but also basophilic degeneration of myocardium.

Incidental Detection of Maternal Neoplasia in Noninvasive Prenatal Testing.

BACKGROUND: Noninvasive prenatal testing (NIPT) uses cell-free DNA (cfDNA) as an analyte to detect copy-number alterations in the fetal genome. Because maternal and fetal cfDNA contributions are comingled, changes in the maternal genome can manifest as abnormal NIPT results. Circulating tumor DNA (ctDNA) present in cases of maternal neoplasia has the potential to distort the NIPT readout to a degree that prevents interpretation, resulting in a nonreportable test result for fetal aneuploidy. METHODS: NIPT cases that showed a distortion from normal euploid genomic representation were communicated to the caregiving physician as nonreportable for fetal aneuploidy. Follow-up information was subsequently collected for these cases. More than 450000 pregnant patients who submitted samples for clinical laboratory testing >3 years are summarized. Additionally, in-depth analysis was performed for >79000 research-consented samples. RESULTS: In total, 55 nonreportable NIPT cases with altered genomic profiles were cataloged. Of these, 43 had additional information available to enable follow-up. A maternal neoplasm was confirmed in 40 of these cases: 18 malignant, 20 benign uterine fibroids, and 2 with radiological confirmation but without pathological classification. CONCLUSIONS: In a population of pregnant women who submitted a blood sample for cfDNA testing, an abnormal genomic profile not consistent with fetal abnormalities was detected in about 10 out of 100000 cases. A subset of these observations (18 of 43; 41.9%) was attributed to maternal malignant neoplasms. These observational results suggest the need for a controlled trial to evaluate the potential of using cfDNA as an early biomarker of cancer.

Difference in the action spectra for UVR8 monomerisation and HY5 transcript accumulation in Arabidopsis.

The photoreceptor UV RESISTANCE LOCUS 8 (UVR8) activates photomorphogenic responses when plants are exposed to ultraviolet-B (UV-B) light. However, whereas the absorption spectrum of UVR8 peaks at 280 nm, action spectra for several photomorphogenic UV-B responses show maximal photon effectiveness at 290-300 nm. To investigate this apparent discrepancy we measured the effectiveness of UV wavelengths in initiating two responses in Arabidopsis: photoconversion of homodimeric UVR8 into the monomeric form, which is active in signaling, and accumulation of transcripts of the ELONGATED HYPOCOTYL 5 (HY5) transcription factor, which has a key role in UVR8-mediated responses. When purified UVR8 or Arabidopsis leaf extracts were exposed to UV light monomerisation was maximal at approximately 280 nm, which correlates with the UVR8 absorption spectrum. When intact plants were exposed to UV, monomerisation was most strongly initiated at approximately 290 nm, and this shift in maximal effectiveness could be explained by strong absorption or reflectance at 280 nm by leaf tissue. Notably, the action spectrum for accumulation of HY5 transcripts in the same leaf tissue samples used to assay UVR8 dimer/monomer status peaked at approximately 300 nm. Possible reasons for the difference in maximal photon effectiveness of UVR8 monomerisation and HY5 transcript accumulation in leaf tissue are discussed.

Sudden Death Due to Cystic Tumor of the Atrioventricular Node and Fibromuscular Dysplasia Involving Branches of the Coronary Arteries.

In this paper, we report the autopsy findings of a 42-year-old White male who was found deceased at his home by his brother in the early morning hours with a history of excessive alcohol consumption 1 day before his death. A medical record review revealed chronic alcohol use with alcohol dependence syndrome, hypertension, and cardiac arrhythmias by electrocardiogram 2 years prior. External examination revealed only a single bruise on the forehead. Internal examination revealed changes associated with chronic alcohol abuse and mild atherosclerosis. The lack of a cause of death at autopsy resulted in a dissection of the cardiac conduction system and the detection of a small cystic lesion at the atrioventricular node region. Microscopic examination revealed a cystic tumor of the atrioventricular node and fibromuscular dysplasia of the coronary artery branches near the sinoatrial and atrioventricular nodes. Based on the case history and autopsy findings, death was attributed to a fatal cardiac arrhythmia due to cystic tumor of the atrioventricular node with fibromuscular dysplasia of the coronary artery branches near the sinoatrial and atrioventricular nodes a possible contributing factor.