Subarachnoid Blood Clearance and Aneurysmal Subarachnoid Hemorrhage Outcomes: A Retrospective Review.

BACKGROUND: Delayed cerebral ischemia (DCI) continues to be a significant contributor to morbidity and mortality following aneurysmal subarachnoid hemorrhage (aSAH). Subarachnoid blood and its degradation products have been implicated in DCI, and faster blood clearance has been hypothesized to confer better outcomes. This study evaluates the relationship between blood volume and its clearance on DCI (primary outcome) and location at 30 days (secondary outcome) after aSAH. METHODS: This is a retrospective review of adult patients presenting with aSAH. Hijdra sum scores (HSS) were assessed independently for each computed tomography (CT) scan of patients with available scans on post-bleed days 0-1 and 2-10. This cohort was used to evaluate the course of subarachnoid blood clearance (group 1). A subset of patients in the first cohort with available CT scans on both post-bleed days 0-1 and post-bleed days 3-4 composed the second cohort (group 2). This group was used to evaluate the association between initial subarachnoid blood (measured via HSS post-bleed days 0-1) and its clearance (measured via percentage reduction [HSS %Reduction] and absolute reduction [HSS-Abs-Reduction] in HSS between days 0-1 and 3-4) on outcomes. Univariable and multivariable logistic regression models were used to identify outcome predictors. RESULTS: One hundred fifty-six patients were in group 1, and 72 patients were in group 2. In this cohort, HSS %Reduction was associated with decreased risk of DCI in univariate (odds ratio [OR] = 0.700 [0.527-0.923], p = 0.011) and multivariable (OR = 0.700 [0.527-0.923], p = 0.012) analyses. Higher HSS %Reduction was significantly more likely to have better outcomes at 30 days in the multivariable analysis (OR = 0.703 [0.507-0.980], p = 0.036). Initial subarachnoid blood volume was associated with outcome location at 30 days (OR = 1.331 [1.040-1.701], p = 0.023) but not DCI (OR = 0.945 [0.780-1.145], p = 0.567). CONCLUSIONS: Early blood clearance after aSAH was associated with DCI (univariable and multivariable analyses) and outcome location at 30 days (multivariable analysis). Methods facilitating subarachnoid blood clearance warrant further investigation.

Imaging versus Intervention in Managing Small Unruptured Intracranial Aneurysms: A Cost-Effectiveness Analysis.

OBJECTIVE: Current guidelines recommend active surveillance with serial magnetic resonance angiography (MRA) for management of small, asymptomatic unruptured anterior circulation aneurysms (UIAs). We sought to determine the cost-effectiveness of active surveillance compared to immediate surgery. METHODS: We developed a Markov cost-effectiveness model simulating patients with small (<7 mm) UIAs managed by active surveillance via MRA, immediate surgery, or watchful waiting. Inputs for the model were abstracted from the literature and used to construct a comprehensive model following persons from diagnosis to death. Outcomes were quality-adjusted life-years (QALYs), lifetime medical costs (2015 USD), and incremental cost-effectiveness ratios (ICERs). Cost-effectiveness, deterministic, and probabilistic sensitivity analyses were performed. RESULTS: Immediate surgical treatment was the most cost-effective management strategy for small UIAs with ICER of USD 45,772 relative to active surveillance. Sensitivity analysis demonstrated immediate surgery was the preferred strategy, if rupture rate was >0.1%/year and if the diagnosis age was <70 years, while active surveillance was preferred if surgical complication risk was >11%. Probabilistic sensitivity analysis demonstrated that at a willingness-to-pay of USD 100,000/QALY, immediate surgical treatment was the most cost-effective strategy in 64% of iterations. CONCLUSION: Immediate surgical treatment is a cost-effective strategy for initial management of small UIAs in patients <70 years of age. While more costly than MRA, surgical treatment increased QALY. The cost-effectiveness of immediate surgery is highly sensitive to diagnosis age, rupture rate, and surgical complication risk. Though there are a wide range of rupture rates and complications associated with treatment, this analysis supports the treatment of small, unruptured anterior circulation intracranial aneurysms in patients <70 years of age.

A structural and spectroscopic investigation of octahedral platinum bis(dithiolene)phosphine complexes: platinum dithiolene internal redox chemistry induced by phosphine association.

The complexes [Pt(mdt)2] (4; mdt = methyldithiolene, [Me2C2S2](n-)), [Pt(adt)2] (5; adt = p-anisyldithiolene, [(MeO-p-C6H4)2C2S2](n-)), and [Pd(adt)2] (10) have been prepared in yields of ≥90% via transmetalation reactions with the corresponding [R2Sn(S2C2R'2)] complexes (R = (n)Bu, R' = Me; R = Me, R' = -C6H4-p-OMe, 3). Intraligand C-S and C-Cchelate bond lengths (~1.71 and ~1.40 Å, respectively) obtained by X-ray crystallography show these compounds to be comprised of radical monoanions mdt(•-) and adt(•-). The six-coordinate octahedral adducts [Pt(adt)2(dppe)] [6; dppe = 1,2-bis(diphenylphosphino)ethane], trans-[Pt(adt)2(PMe3)2] (8), and trans-[Pt(mdt)2(PMe3)2] (9) have also been prepared, and crystal structures reveal dithiolene ligands that are fully reduced ene-1,2-dithiolates (C-S and C-C(chelate) = ~1.77 and 1.35 Å, respectively). Reduction of the dithiolene ligand thus occurs to accommodate the +IV oxidation state typical of octahedral six-coordinate platinum. The cyclic voltammogram of 5 shows two fully reversible reductions at -0.11 and -0.84 V in CH2Cl2 (vs Ag/AgCl), attributed to successive (adt(•-) + e(-) → adt(2-)) processes, and a reversible oxidation at +1.01 V. The cyclic voltammogram of 9 shows two reversible oxidations at +0.38 and +0.86 V, which are assigned as successive (adt(2-) → adt(•-) + e(-)) oxidations. Consistent with their formulation as having fully reduced dithiolene ligands, the UV-vis spectra for 6, 8, and 9 show no low-energy absorptions below 700 nm, and the S K-edge XAS spectra of 6 and 8 show dithiolene sulfur that is reduced relative to that in 5. The introduction of PMe3 to 10 did not produce the palladium analogue of 8 but rather [Pd(adt)(PMe3)2] (11). The reaction of [PdCl2(PPh3)2] with Li2(mdt) produced a mixture of [Pd(mdt)(PPh3)2] (12, 20%) and [(Ph3P)Pd(µ-1,2-mdt-S,S':S)2Pd(PPh3)] (13, 28%), with the latter having C2 symmetry with a Pd2S2 core structure folded along the S···S axis.

The Effect of COVID-19 Vaccines on Stroke Outcomes: A Single-Center Study.

BACKGROUND: One of the defining narratives of the COVID-19 pandemic has been the acceptance and distribution of vaccine. To compare the outcomes of COVID-19 positive vaccinated and unvaccinated stroke patients. METHODS: This is a single-center retrospective study of COVID-19-vaccinated and unvaccinated stroke patients between April 2020 and March 2022. All patients presenting with stroke regardless of treatment modalities were included. National Institutes of Health Stroke Scale was used to assess stroke severity. The primary outcome was functional capacity of the patients at discharge. RESULTS: The study cohort comprised 203 COVID-19 positive stroke patients divided into 139 unvaccinated and 64 fully vaccinated patients. At discharge, the modified Rankin scale score was significantly lower in the vaccinated cohort (3[1-4] vs. 4[2-5], odds ratio = 0.508, P = 0.011). At 3 months of follow-up, the median modified Rankin scale score was comparable between both cohorts. CONCLUSIONS: Although vaccination did not show any significant difference in stroke patient outcomes on follow-up, vaccines were associated with lower rates of morbidity and mortality at discharge among stroke patients during the pandemic.

Clinical activity of PD-1 inhibition in the treatment of locally advanced or metastatic basal cell carcinoma.

BACKGROUND: Basal cell carcinoma (BCC) is the most common malignancy worldwide, yet the management of patients with advanced or metastatic disease is challenging, with limited treatment options. Recently, programmed death receptor 1 (PD-1) inhibition has demonstrated activity in BCC after prior Hedgehog inhibitor treatment. METHODS: We conducted a multicenter, retrospective analysis of BCC patients treated with PD-1 inhibitor therapy. We examined the efficacy and safety of PD-1 therapy, as well as clinical and pathological variables in association with outcomes. Progression-free survival (PFS), overall survival (OS) and duration of response (DOR) were calculated using Kaplan-Meier methodology. Toxicity was graded per Common Terminology Criteria for Adverse Events V.5.0. RESULTS: A total of 29 patients with BCC who were treated with PD-1 inhibition were included for analysis, including 20 (69.0%) with locally advanced and 9 (31.0%) with metastatic disease. The objective response rate was 31.0%, with five partial responses (17.2%), and four complete responses (13.8%). Nine patients had stable disease (31.0%), with a disease control rate of 62.1%. The median DOR was not reached. Median PFS was 12.2 months (95% CI 0.0 to 27.4). Median OS was 32.4 months (95% CI 18.1 to 46.7). Two patients (6.9%) developed grade 3 or higher toxicity, while four patients (13.8%) discontinued PD-1 inhibition because of toxicity. Higher platelets (p=0.022) and any grade toxicity (p=0.024) were significantly associated with disease control rate. CONCLUSIONS: The clinical efficacy of PD-1 inhibition among patients with advanced or metastatic BCC in this real-world cohort were comparable to published trial data. Further investigation of PD-1 inhibition is needed to define its optimal role for patients with this disease.

Presentation, diagnosis, and treatment of a cerebellar tuberculoma: illustrative case.

BACKGROUND: Central nervous system (CNS) tuberculomas are a feared complication of tuberculosis (TB) infection. These lesions can present in varying manners and are associated with significant morbidity and mortality. Prompt diagnosis and treatment of the lesion and the underlying infection are critical in the care of these patients. The authors presented a case of a 45-year-old Yemeni immigrant presenting with a 3-month history of severe right temporo-occipital headaches with photophobia and night sweats. Imaging showed a rim-enhancing lesion in the right cerebellar hemisphere. OBSERVATIONS: Laboratory tests were unremarkable and within normal limits. QuantiFERON testing was negative, ruling out latent TB infection. The patient received a suboccipital craniotomy, and resection of the cerebellar lesion showed caseating granuloma formation, which was positive for acid-fast bacilli and Fite stain. LESSONS: CNS tuberculomas are an important differential to consider in patients with a history of primary TB, regardless of active disease or immunocompetent status. Resection of these lesions remains a viable treatment option that is safe and effective.

Impact of COVID-19 infection among cancer patients treated at the Los Angeles County Medical Center.

We conducted a retrospective analysis of cancer patients who presented to the hospital with COVID-19 infection at a safety-net hospital in Los Angeles, California, from March 2020 to June 2020. From a list of 1,163 COVID-19+ adult patients, we selected the first 50 patients with malignancy for a preliminary analysis. There were 23 males (46.0%) and 27 females (54.0%); the median age was 60.5 years (IQR 47 - 72). Thirty-nine (78.0%) of the patients were Hispanic. The most prevalent cancers were genitourinary (14, 28.0%), hematologic (11, 22.0%), and gastrointestinal (10, 20.0%). Twenty-one (42.0%) patients had active disease at COVID-19 diagnosis, while 25 (50.0%) had no evidence of disease (NED), and 4 (8.0%) were unknown. Over 1 in 3 admitted patients experienced a "severe outcome," which was defined as critical level care (14, 34.1%), use of vasopressors (9, 22.0%), intubation (8, 19.5%), or death (5, 12.2%). Patients with severe outcomes were found to have statistically higher values of absolute neutrophil count (p = 0.005), aspartate aminotransferase (p = 0.049), high-sensitivity C-reactive protein, (p = 0.001) and lactate dehydrogenase (p = 0.040) on admission. Overall survival (OS) was not statistically different between those with hematologic versus solid malignancy nor between those with active disease versus remission (both p>0.05). Thirteen (81.3%) of the 16 patients who had cancer treatment in 2020 experienced delays in cancer therapy. Additional cases are being evaluated as the pandemic continues with the goal of identifying areas for potential intervention to improve outcomes in this at-risk population.

A Case Series of Multiple Primary Malignancies Among Patients With Advanced Melanoma.

Multiple primary malignancies (MPM) are described as two or more primary tumors within the same individual. The impact of MPM on the tumor microenvironment among patients with melanoma is poorly understood. Here, we describe this unique group of patients who have both advanced melanoma and at least one other primary malignancy and report their survival outcomes. In this study, patients with advanced melanoma and a second primary malignancy were identified. Medical records were reviewed for cancer treatment history. Kaplan-Meier methods were used to derive survival curves and estimate overall survival (OS), and log-rank tests were used to compare OS. Among 11 MPM patients, the most common non-melanoma cancers were breast (n = 3) and thyroid (n = 3). Median OS was 153.5 months for all patients. Median OS for synchronous MPM (sMPM) and metachronous MPM (mMPM) were 83.1 and 196.7 months, respectively (p= 0.10). Median OS was not reached when melanoma was diagnosed first, and 153.5 months when diagnosed second (p= 0.45). For six patients receiving immunotherapy for melanoma, there was a 100% complete response rate. In conclusion, patients with melanoma are at risk of secondary malignancies, including breast and thyroid cancer. The timing of secondary malignancies may impact prognosis. Further study of the impact of immunotherapy on MPM is warranted.

Pathogenesis, Symptomatology, and Transmission of SARS-CoV-2 through Analysis of Viral Genomics and Structure.

The novel coronavirus SARS-CoV-2, which emerged in late 2019, has since spread around the world and infected hundreds of millions of people with coronavirus disease 2019 (COVID-19). While this viral species was unknown prior to January 2020, its similarity to other coronaviruses that infect humans has allowed for rapid insight into the mechanisms that it uses to infect human hosts, as well as the ways in which the human immune system can respond. Here, we contextualize SARS-CoV-2 among other coronaviruses and identify what is known and what can be inferred about its behavior once inside a human host. Because the genomic content of coronaviruses, which specifies the virus's structure, is highly conserved, early genomic analysis provided a significant head start in predicting viral pathogenesis and in understanding potential differences among variants. The pathogenesis of the virus offers insights into symptomatology, transmission, and individual susceptibility. Additionally, prior research into interactions between the human immune system and coronaviruses has identified how these viruses can evade the immune system's protective mechanisms. We also explore systems-level research into the regulatory and proteomic effects of SARS-CoV-2 infection and the immune response. Understanding the structure and behavior of the virus serves to contextualize the many facets of the COVID-19 pandemic and can influence efforts to control the virus and treat the disease. IMPORTANCE COVID-19 involves a number of organ systems and can present with a wide range of symptoms. From how the virus infects cells to how it spreads between people, the available research suggests that these patterns are very similar to those seen in the closely related viruses SARS-CoV-1 and possibly Middle East respiratory syndrome-related CoV (MERS-CoV). Understanding the pathogenesis of the SARS-CoV-2 virus also contextualizes how the different biological systems affected by COVID-19 connect. Exploring the structure, phylogeny, and pathogenesis of the virus therefore helps to guide interpretation of the broader impacts of the virus on the human body and on human populations. For this reason, an in-depth exploration of viral mechanisms is critical to a robust understanding of SARS-CoV-2 and, potentially, future emergent human CoVs (HCoVs).

Pathogenesis, Symptomatology, and Transmission of SARS-CoV-2 through Analysis of Viral Genomics and Structure.

The novel coronavirus SARS-CoV-2, which emerged in late 2019, has since spread around the world and infected hundreds of millions of people with coronavirus disease 2019 (COVID-19). While this viral species was unknown prior to January 2020, its similarity to other coronaviruses that infect humans has allowed for rapid insight into the mechanisms that it uses to infect human hosts, as well as the ways in which the human immune system can respond. Here, we contextualize SARS-CoV-2 among other coronaviruses and identify what is known and what can be inferred about its behavior once inside a human host. Because the genomic content of coronaviruses, which specifies the virus's structure, is highly conserved, early genomic analysis provided a significant head start in predicting viral pathogenesis and in understanding potential differences among variants. The pathogenesis of the virus offers insights into symptomatology, transmission, and individual susceptibility. Additionally, prior research into interactions between the human immune system and coronaviruses has identified how these viruses can evade the immune system's protective mechanisms. We also explore systems-level research into the regulatory and proteomic effects of SARS-CoV-2 infection and the immune response. Understanding the structure and behavior of the virus serves to contextualize the many facets of the COVID-19 pandemic and can influence efforts to control the virus and treat the disease.

Characterization of Critically Ill COVID-19 Patients at a Brooklyn Safety-Net Hospital.

Background The novel coronavirus disease 2019 (COVID-19) pandemic continues to spread across the country with over 3 million cases and 150,000 deaths in the United States as of July 2020. Outcomes have been poor, with reported admission rates to the intensive care team of 5% in China and mortality among critically ill patients of 50% in Seattle. Here we explore the disease characteristics in a Brooklyn safety-net hospital affected by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. Methods A retrospective chart review of COVID-19 positive patients at The Brooklyn Hospital Center who were treated by the intensive care team prior to April 20, 2020. Data was extracted from the electronic health record, analyzed and correlated for outcome. Results Impact of various clinical treatments was assessed, showing no change in median overall survival (OS) of both hydroxychloroquine with azithromycin or vitamin C with zinc. Supplemental therapies were used in selected patients, and some were shown to increase median OS and patients requiring vasopressor support or invasive mechanical ventilation showed decreased OS. There was no statistically significant difference in overall survival based on ethnicity, healthcare status, or individual medical comorbidities, although a negative trend exists for diabetes. Despite this, there is a trend towards increasingly poor prognosis based on the number of comorbidities and Class 3 obesity.  Conclusions Despite the fact that we show no significant differences in mortality based on ethnicity, insurance status, or individual medical comorbidities, we show a high overall mortality. There is also a trend towards increased overall mortality in Class 3 obesity, which should be further investigated. We suggest that these findings may be attributed to both socioeconomic factors and an increased incidence of total medical comorbidities in our patient population.

A Fetal-type Variant Posterior Communicating Artery and its Clinical Significance.

The fetal posterior communicating artery is a well-established variant of the cerebral vasculature, occurring in 4-29% of the population. This variant can provide unique challenges in the identification and treatment of cerebrovascular disease or a cerebrovascular accident. Here we present a cadaveric case showing the presence of the fetal-type posterior communicating artery with a contralateral calcified internal carotid artery and discuss the importance of understanding this embryological variant. This case provides specific and unique clinical sequelae that require treatment to be initiated while understanding the various complications that may arise.

Publisher Correction: The molecular landscape of pediatric acute myeloid leukemia reveals recurrent structural alterations and age-specific mutational interactions.

In the version of this article originally published, the color key in Fig. 1a was wrong. In the Cytogenetics key, the box over t(8;21) originally was green. It should have been red, matching the color of the sections of the pie graphs below the key that were labeled with 15% and 19%.

Methylome of human senescent hematopoietic progenitors.

Senescence, a state of permanent cell cycle arrest, can be induced by DNA damage. This process, which was initially described in fibroblasts, is now recognized to occur in stem cells. It has been well characterized in cell lines, but there is currently very limited data available on human senescence in vivo. We recently reported that the expression of transposable elements (TE), including endogenous retroviruses, was up-regulated along with inflammatory genes in human senescent hematopoietic stem and progenitor cells (HSPCs) in vivo. The mechanism of regulation of TE expression is not completely understood, but changes in DNA methylation and chromatin modifications are known to alter their expression. In order to elucidate the molecular mechanisms for TE up-regulation after senescence of HSPCs, we employed whole-genome bisulfite sequencing in paired senescent and active human HSPCs in vivo from healthy subjects. We found that the senescent HSPCs exhibited hypomethylated regions in the genome, which were enriched for TEs. This is the first report characterizing the methylome of senescent human HSPCs.

Senescent human hematopoietic progenitors show elevated expression of transposable elements and inflammatory genes.

Genomic transposable elements (TEs) constitute the majority of the genome. Expression of TEs is known to activate the double-stranded RNA recognition pathway ("viral mimicry"), leading to the activation of interferon-stimulated genes, inflammation, and immune-mediated cell death. Recently, we showed that the expression of TEs is suppressed along with immune pathways in leukemic stem cells (LSCs) in acute myeloid leukemia, suggesting a potential mechanism for immune escape of LSCs. This indicated that, during oncogenesis, where there is escape from senescence, expression of TEs is suppressed. Senescence is known to activate the interferon response and inflammatory cytokines, known as the senescence-associated secretory phenotype (SASP). We characterized the transcriptome of senescent and active human hematopoietic stem and progenitor cells (HSPCs) in vivo and showed co-occurrence of overexpression of TEs, SASP genes, and gene pathways of inflammation in senescence. The percentage of circulating senescent HSPCs (s-HSPCs) did not increase with age, indicating active clearance. Induction of senescence in human HSPCs in vitro showed increased expression of TE and SASP genes. SASP is known to mediate clearance of senescent cells and active clearance of senescent cells has been shown to increase organismal fitness. We speculate that the expression of TEs in s-HSPCs could contribute to orderly clearance of the cells via activation of immune pathways, warranting further mechanistic studies. This is the first study to characterize the transcriptome of human s-HSPCs in vivo, revealing activated expression of TEs and inflammatory genes.

Understanding metabolic changes in aging bone marrow.

BACKGROUND: Aging is associated with complex molecular alterations at the cellular level. Bone marrow exhibits distinct phenotypic, genetic and epigenetic alterations with aging. Metabolic changes in the bone marrow related to aging have not been studied. METHODS: In this study, we characterized the metabolome and transcriptome of aging murine bone marrow and compared it with bone marrow from young healthy mice and chemotherapy treated mice; chemotherapy treatment is known to induce age-related changes in hematopoiesis. RESULTS: The metabolome of the aging bone marrow exhibited a signature of suppressed fatty-acid oxidation: accumulation of free fatty acids, reduced acyl-carnitines and low ß-hydroxy butyric acid. The aged bone marrow also exhibited a significant reduction in amino acid and nucleic acid pool. The transcriptome of the aging bone marrow revealed a signature of oxidative stress, known to be associated with mitochondrial dysfunction. Lastly, the metabolic and transcriptomic profiles of the bone marrow of chemotherapy treated mice did not show broad age-related changes but rather mostly resembled young healthy mice, suggestive of a lack of 'metabolic aging' with chemotherapy exposure. CONCLUSION: Our results revealed broad changes in lipids, amino acids, and nucleotides in aging marrow tissue. Together, these data provide a rich resource for the study of metabolic changes associated with aging in bone marrow.

The molecular landscape of pediatric acute myeloid leukemia reveals recurrent structural alterations and age-specific mutational interactions.

We present the molecular landscape of pediatric acute myeloid leukemia (AML) and characterize nearly 1,000 participants in Children's Oncology Group (COG) AML trials. The COG-National Cancer Institute (NCI) TARGET AML initiative assessed cases by whole-genome, targeted DNA, mRNA and microRNA sequencing and CpG methylation profiling. Validated DNA variants corresponded to diverse, infrequent mutations, with fewer than 40 genes mutated in >2% of cases. In contrast, somatic structural variants, including new gene fusions and focal deletions of MBNL1, ZEB2 and ELF1, were disproportionately prevalent in young individuals as compared to adults. Conversely, mutations in DNMT3A and TP53, which were common in adults, were conspicuously absent from virtually all pediatric cases. New mutations in GATA2, FLT3 and CBL and recurrent mutations in MYC-ITD, NRAS, KRAS and WT1 were frequent in pediatric AML. Deletions, mutations and promoter DNA hypermethylation convergently impacted Wnt signaling, Polycomb repression, innate immune cell interactions and a cluster of zinc finger-encoding genes associated with KMT2A rearrangements. These results highlight the need for and facilitate the development of age-tailored targeted therapies for the treatment of pediatric AML.

Erratum: The molecular landscape of pediatric acute myeloid leukemia reveals recurrent structural alterations and age-specific mutational interactions.

This corrects the article DOI: 10.1038/nm.4439.