Diagnostic Yield, Radiation Exposure, and the Role of Clinical Decision Rules to Limit Computed Tomographic Pulmonary Angiography-Associated Complications.

OBJECTIVES: Computed tomographic pulmonary angiography (CT-PA) is associated with significant cost, contrast, and radiation exposure. Clinical decision rules (CDRs) reduce the need for diagnostic imaging; however, their utility in the medical intensive care unit (MICU) remains unknown. We explored the diagnostic yield and complications associated with CT-PA (radiation exposure and contrast-induced acute kidney injury [AKI]) while investigating the efficacy of CDRs to reduce unnecessary testing. METHODS: All CT-PAs performed in an academic MICU for 4 years were retrospectively reviewed. The Wells and revised Geneva scores (CDRs) and radiation dose per CT-PA were calculated, and the incidence of post-CT-PA AKI was recorded. RESULTS: A total of 439 studies were analyzed; the diagnostic yield was 11% (48 PEs). Positive CT-PAs were associated with a higher Wells score (5.8 versus 3.2, P < 0.001), but similar revised Geneva scores (6.4 versus 6.0, P = 0.32). A Wells score of ≥4 had a positive likelihood ratio of 2.1 with a negative predictive value of 98.2. More than half (88.9%) of patients with a Wells score of ≤4 developed an AKI, with 55.6% of those having recovery of renal function. CONCLUSIONS: There is overutilization of CT-PA in the MICU. The Wells score retains its negative predictive value in critically ill adult patients and may aid to limit radiation exposure and contrast-induced AKI in MICU.

Outcomes after cardiac arrest in Medical Intensive Care Unit: A propensity score matching analysis of COVID-19 MICU vs non COVID-19 MICU cardiac arrest.

AIM: To assess whether there were differences in resuscitation efforts and outcomes for medical intensive care unit (MICU) in-hospital cardiac arrest (IHCA) during the COVID-19 pandemic when compared to pre-pandemic. METHODS: Comparing COVID-19 MICU-IHCA patients (03/2020 to 10/2020) to non-COVID-19 MICU IHCA (01/2014 to 12/2018) at Clevleand Clinic Health System (CCHS) of NE Ohio. Propensity score matching analysis (PSMA) was used to create comparable groups. RESULTS: There were a total of 516 patients, 51 in COVID-19 MICU IHCA cohort and 465 in the non-COVID-19 MICU IHCA cohort. The mean (SD) age of the study population was 60.9 (16) years and 56% were males. In 92.1% (n = 475) patients, initial arrest rhythm was non-shockable. At the time of ICU admission, compared to the non-COVID-19 MICU-IHCA cohort, the COVID-19 MICU IHCA cohort had a lower mean APACHE III score (70 [32.9] vs 101.3 [39.6], P = <0.01). The COVID-19 cohort had a higher rate of survival to hospital discharge (12 [23.5%] vs 59 [12.7%], P = 0.03). Upon PSMA, the algorithm selected 40 COVID-19 patients and 200 non-COVID-19 patients. Imbalances in baseline characteristics, comorbidities, and APACHE III were well-balanced after matching. Survival rate after matching became non-significant; (10 [25%] vs 42 [21%], P = 0.67). Further, there were no significant differences in ICU or hospital length-of-stay or neurological outcomes at discharge for survivors in the two matched cohorts. CONCLUSION: It is imperative that COVID-19 patients receive unbiased and unrestricted resuscitation measures, without any discouragement.

Health Disparities: Interventions for Pulmonary Disease - A Narrative Review.

There is expansive literature documenting the presence of health disparities, but there are disproportionately few studies describing interventions to reduce disparity. In this narrative review, we categorize interventions to reduce health disparity in pulmonary disease within the US health care system to support future initiatives to reduce disparity. We identified 211 articles describing interventions to reduce disparity in pulmonary disease related to race, income, or sex. We grouped the studies into the following four categories: biologic, educational, behavioral, and structural. We identified the following five main themes: (1) there were few interventional trials compared with the breadth of studies describing health disparities, and trials involving patients with asthma who were Black, low income, and living in an urban setting were overrepresented; (2) race or socioeconomic status was not an effective marker of individual pharmacologic treatment response; (3) telehealth enabled scaling of care, but more work is needed to understand how to leverage telehealth to improve outcomes in marginalized communities; (4) future interventions must explicitly target societal drivers of disparity, rather than focusing on individual behavior alone; and (5) individual interventions will only be maximally effective when specifically tailored to local needs. Much work has been done to catalog health disparities in pulmonary disease. Notable gaps in the identified literature include few interventional trials, the need for research in diseases outside of asthma, the need for high quality effectiveness trials, and an understanding of how to implement proven interventions balancing fidelity to the original protocol and the need to adapt to local barriers to care.

Does veno-arterial carbon dioxide gradient provide an adequate estimation of cardiac index in pulmonary hypertension?

AIMS: Pulmonary hypertension (PH) management is dependent on cardiac output (CO) assessment. The gold standard Fick method for CO and cardiac index (CI) measurement is not widely available. An accessible and reliable method for CO/CI estimation is needed not only in catheterization labs but also in other environments such as the intensive care unit, where pulmonary artery catheters are less likely to be used. We hypothesized that veno-arterial carbon dioxide gradient (PvaCO2) is a reliable surrogate for Fick CI in patients with PH. METHODS AND RESULTS: A single-centre retrospective analysis of patients with PH who underwent direct Fick CI (DFCI) measurement during right heart catheterization. The primary outcome was correlation between PvaCO2 and DFCI. To assess the agreement between central and mixed venous CO2 values, a separate prospective cohort of patients was analysed. Data from 186 patients with all haemodynamic types of PH were analysed. PvaCO2 moderately correlated with Fick CI, R = -0.51 [95% confidence interval (CI): -0.61, -0.39]. A higher PvaCO2 was associated with an increased risk of CI < 2.5 L/min/m2 (odds ratio: 1.88, 95% CI: 1.55, 2.35). Low thermodilution CI with normal veno-arterial carbon dioxide gradient values was associated with a thermodilution underestimation of Fick CI. In the prospective analysis of 32 patients, central venous CO2 overestimated mixed venous values (mean difference 3.3, 95% CI: 2.5, 4.0) and there was poor agreement overall (limits of agreement -1.10, 7.59). CONCLUSION: Veno-arterial carbon dioxide gradient moderately correlates with Fick CI and may be useful to identify patients with low CI. Central and mixed venous CO2 values should not be used interchangeably in PH.

Comparison of risk scores for predicting outcomes after isolated tricuspid valve surgery.

BACKGROUND: Risk models play important roles in stratification and decision-making towards cardiac surgery. Isolated tricuspid valve surgery is a high risk but increasingly performed the operation, however, the performance of risk models has not been externally evaluated in these patients. We compared the prognostic utility of contemporary risk scores for isolated tricuspid valve surgery. METHODS: Consecutive patients undergoing isolated tricuspid valve surgery at Cleveland Clinic during 2004-2018 were evaluated in this cohort study. EuroSCORE II, Society of Thoracic Surgeon's tricuspid (STS-TVS) score, and the Model for End-stage Liver Disease (MELD) score were retrospectively calculated, and their performance for predicting operative mortality, postoperative complications, and mortality during follow-up was assessed. RESULTS: Amongst 207 patients studied, the mean age was 54.1 ± 17.9 years, 116 (56.0%) were female, 92 (44.4%) had secondary tricuspid regurgitation, and 151 (72.9%) had a surgical repair. Mean EuroSCORE II, STS-TVS, and MELD scores were 6.3 ± 6.6%, 5.5 ± 6.2%, and 9.8 ± 4.7, respectively. C-statistics (95% confidence intervals) for operative mortality were 0.83 (0.74-0.93) for EuroSCORE II, 0.60 (0.45-0.75) for STS-TVS score, and 0.74 (0.58-0.89) for MELD score, while observed/expected ratios were 0.78 and 0.89 for the first two scores. All three scores were associated with mortality during follow-up and discriminated most postoperative complications. CONCLUSION: EuroSCORE II was superior to STS-tricuspid score for isolated TVS risk assessment. Although surgical risk scores traditionally underestimated operative mortality after isolated tricuspid valve surgery, they did not in our cohort, reflecting the excellent surgical results. The simple MELD score performed similarly to the EuroSCORE II, especially for discriminating morbidities.

Effect of Tricuspid Valve Repair or Replacement on Survival in Patients With Isolated Severe Tricuspid Regurgitation.

Controversies remain in the management strategy for isolated tricuspid regurgitation (TR) because of adverse prognosis and uncertainties regarding the benefits of tricuspid valve surgery. We compared the characteristics and outcomes of a large cohort of patients with isolated TR, based on downstream tricuspid valve surgery versus medical management. Consecutive patients with isolated TR graded at least moderate-to-severe by echocardiography identified between January 2004 and December 2018 (n = 9,031, age 70 ± 15 years, 60% women) were retrospectively studied. The primary end point was time to all-cause mortality during follow-up. Outcomes were compared by management strategy using unadjusted and adjusted survival and multivariable regression analyses. Tricuspid valve surgery was performed in 632 of 9,031 of the cohort (7%), including 514 valve repairs and 118 valve replacements, with in-hospital mortality in 19 patients (2.9%). Overall, there were 3,985 all-cause deaths (44%) over mean follow-up of 2.6 ± 3.3 years. Tricuspid valve surgery was independently associated with lower mortality rate during follow-up, with hazard ratios (HRs) of 0.53 (95% confidence interval [CI] 0.45 to 0.64), and the association persisted in both primary and secondary TR subgroups. Tricuspid valve surgery also had a significantly higher rate of infective endocarditis and heart failure hospitalizations rates during follow-up, at HRs of 5.55 (95% CI 4.00 to 7.71) and 1.29 (95% CI 1.16 to 1.43), respectively. In conclusion, tricuspid valve surgery is rarely performed in isolated TR, but it is independently associated with greater survival for the overall cohort and both primary and secondary etiology subgroups. Increasing the utilization of this surgery at specialized centers is encouraged to try to improve the clinical outcomes for this challenging clinical entity.

Contemporary Etiologies, Outcomes, and Novel Risk Score for Isolated Tricuspid Regurgitation.

OBJECTIVES: The authors report etiologies and outcomes and devise a risk model in a large contemporary cohort of patients with isolated tricuspid regurgitation (TR). BACKGROUND: Isolated TR is a challenging clinical entity with heterogeneous etiology and often poor outcomes, with a paucity of recent research regarding the epidemiology of isolated TR. METHODS: Consecutive patients with isolated TR graded at least moderate to severe on echocardiography from January 2004 to December 2018 (n = 9,045, mean age 70.4 ± 15.4 years, 60.3% women) were studied. TR etiologies were individually adjudicated as secondary or primary, with subcategories. All-cause death during follow-up was the primary endpoint, with associations between etiology and outcomes analyzed and a risk model created. RESULTS: Primary and secondary TR etiologies were present in 470 (5.2%) and 8,575 (94.8%) patients, respectively. The main secondary etiologies were left heart disease in 4,664 (54.4%), atrial functional in 2,086 (24.3%), and pulmonary disease in 1,454 (17.0%), and the main primary etiologies were endocarditis in 222 (47.2%), degenerative or prolapse in 86 (18.3%), and prosthetic valve failure in 79 (16.8%). There were 3,987 deaths (44.0%) over a mean follow-up period of 2.6 ± 3.3 years. In unadjusted analyses, patients with secondary TR had worse survival than those with primary TR (HR: 1.56; 95% CI: 1.32-1.85), but this result was not statistically significant in multivariable analysis. The authors devised and internally validated a risk score for predicting 1-year mortality in these patients. CONCLUSIONS: Secondary TR constituted 95% of isolated significant TR and conferred worse survival than primary TR in unadjusted but not adjusted analyses. The present novel risk score stratifies the risk for 1-year death and may influence decision making for management in these high-risk patients.

A Kidney Transplant Recipient With Fulminant Progressive Multifocal Leukoencephalopathy-Immune Reconstitution Inflammatory Syndrome: A Rare Clinical Outcome and Review of the Literature.

Progressive multifocal leukoencephalopathy is a devastating disease affecting the central nervous system that may be seen in immunocompromised patients. We present a case of a kidney transplant recipient who received tacrolimus, mycophenolic acid, and prednisone and who developed motor deficits, altered cognition, and speech abnormalities, which culminated in a coma. The diagnosis was made by detecting John Cunningham polyomavirus DNA with polymerase chain reaction and observing characteristic findings on magnetic resonance imaging. Soon after immunosuppressive therapy was withdrawn, the patient's clinical status deteriorated due to immune reconstitution inflammatory syndrome, and prednisone was administered. Unfortunately, the patient died about 9 months after onset of symptoms. This case serves to illustrate the fulminant progression of progressive multifocal leukoencephalopathy and the possible complications that may arise when treating it.

Cutaneous Metastasis as a Presenting Feature of Renal Adenocarcinoma in a Renal Transplant Recipient: A Case Report.

Cutaneous metastases of urological malignancies are a rare phenomenon. We present a case of a renal transplant recipient who presented with skin nodule 12 years posttransplant. Pathohistologic evaluation revealed metastasis from the renal adenocarcinoma. The patient was treated with temsirolimus and later with sorafenib; however, he died 13 months after the initial presentation with a functional renal allograft.

Grover's Disease in a Kidney Transplant Recipient.

Dear Editor, It is not unusual for patients with renal insufficiency to develop skin pathologies. There are reports in the literature of increased incidence of calciphylaxis, pruritus, perforating dermatoses, and porphyria cutanea tarda in this patient population (1). Although it is quite rare, Grover's disease (GD) has been reported in several patients with renal insufficiency, but only once in a renal transplant recipient (2). The disease follows three patterns: persistently pruritic, transient eruptive, or a chronic asymptomatic course (3). Common risk factors concomitant with disease prevalence are immunosuppression, HIV, hemodialysis, viral and bacterial infections, malignancies, and other skin pathologies like contact and atopic dermatitis (4). A 60-year-old woman had a family history of polycystic kidney disease and was subsequently diagnosed in 1997. The patient had concomitant hepatic involvement and a stable aneurysm of the anterior cerebral artery. Consequently, the patient preemptively received a kidney transplant in 2015. The immunosuppressive therapy consisted of tacrolimus, mycophenolate mofetil, and prednisone with basiliximab induction. In 2017, a biopsy of the right thigh demonstrated squamous cell carcinoma in situ measuring 1×1cm in size. The lesion was treated with surgical excision. The patient also exhibited an erythematous brown macule with undefined borders on the left side of the nose with a size of 12 mm; it was later determined to be actinic keratosis. The lesion was treated successfully with cryotherapy. During this period, a fever prompted a PCR for BK virus DNA which showed a substantial amount of copies, measuring 28,850 copies/mL in urine and 98 copies/mL in blood. The mycophenolate dose was reduced, and tacrolimus trough concentration was maintained at between 3 and 5 µg/L. In 2018 the patient presented with multiple pruritic erythematous papules located on the trunk. Upon histological biopsy, there was dominant suprabasal acantholysis with numerous cells separating from the epithelium. Furthermore, there was a moderate amount of mononuclear infiltrate in the upper portion of the dermis and sparse suprabasal clefts (Figure 1). Clinical presentation and histologic examination were consistent with Grover's disease. The patient was treated topically with betamethasone cream twice daily for four weeks. The skin changes persisted for only a few weeks. The pathophysiological mechanism causing GD is still unknown. It is usually only a transient skin condition that lasts no more than a few weeks, but there have been more chronic cases lasting for years, particularly in patients on hemodialysis (5). The lesions commonly affect the chest area but may spread to diffusely envelope the body as erythematous papules, pustules, lichenoid lesions, or vesicles (2). Grover characterized 4 different subtypes based on the pathohistological findings as Darier-like (the most common), pemphigus vulgaris-like, Hailey-Hailey-like, or spongiotic subtype (3). The histological patterns are not exclusive to one patient and may even be found concomitantly in a single lesion. The condition is definitively diagnosed through histology, showing distinctive acantholysis along the epidermis with dyskeratosis that is described as "corps ronds" and "grains" (3). Grover's disease is more prevalent in middle-aged Caucasian men than any other group, with a 1.6-2.1 gender ratio (6). It was originally thought that the disease was caused by dysfunctional eccrine sweat glands, as the ailment was more common in patients that had increased perspiration either due to environmental heat, fever, or extensive bedrest. This idea was reinforced by histological evidence of atrophied sweat glands in uremic patients with renal insufficiency (7). Moreover, a case series and case report described remissions of GD in their patients on hemodialysis that received a renal transplant (5,8). However, subsequent studies have not supported an association with sweat dysfunction and disease development, while others have only managed to attribute sweat gland dysfunction as the primary trigger in 20-30% of cases (9). Conversely, cold dry air and xerosis cutis is thought to trigger the disease because it is four times more likely to be diagnosed in the winter months (10). Ultraviolet radiation has been identified as an exacerbating factor for GD, which could have been the trigger for onset of disease in our patient as demonstrated by her squamous cell carcinoma and actinic keratosis (11). Despite immunosuppression being a risk factor for GD, as shown by its association in patients with HIV, bone marrow transplantation, hemodialysis, and hematological malignancies, GD has been reported only once in the literature after a renal transplant (2,4). As our case, that patient developed GD a few years after transplant without an obvious trigger and the lesions appeared as red papules that were disseminated over the anterior thorax. Their patient's cutaneous lesion resolved spontaneously after 2 weeks and never returned in the 2.5-year follow-up period. Their patient has had two renal allografts over a 20 year timespan, while ours had had her graft for only two years. The immunosuppressive regimen was slightly different: cyclosporine, azathioprine, and methylprednisolone versus our combination of tacrolimus, mycophenolate mofetil, and prednisone. Grover's disease can be treated conservatively by avoiding risk factors such as UV light and sweating as well as and applying moisturizing emollients which may cause the lesion to resolve spontaneously. Medical therapy consists of topic corticosteroids, topical vitamin D analogues, oral retinoids, and oral corticosteroids, PUVA, and methotrexate for resistant cases (6,12). When a patient exhibits pruritic papules of the skin, GD should be considered in differential diagnosis, especially in kidney transplant patients and those on hemodialysis. While the condition is rare, increased recognition in this patient population will allow for studies to further characterize this poorly understood disease.

Molecular Mechanisms of Neurodegeneration Related to C9orf72 Hexanucleotide Repeat Expansion.

Two clinically distinct diseases, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), have recently been classified as two extremes of the FTD/ALS spectrum. The neuropathological correlate of FTD is frontotemporal lobar degeneration (FTLD), characterized by tau-, TDP-43-, and FUS-immunoreactive neuronal inclusions. An earlier discovery that a hexanucleotide repeat expansion mutation in chromosome 9 open reading frame 72 (C9orf72) gene causes ALS and FTD established a special subtype of ALS and FTLD with TDP-43 pathology (C9FTD/ALS). Normal individuals carry 2-10 hexanucleotide GGGGCC repeats in the C9orf72 gene, while more than a few hundred repeats represent a risk for ALS and FTD. The proposed molecular mechanisms by which C9orf72 repeat expansions induce neurodegenerative changes are C9orf72 loss-of-function through haploinsufficiency, RNA toxic gain-of-function, and gain-of-function through the accumulation of toxic dipeptide repeat proteins. However, many more cellular processes are affected by pathological processes in C9FTD/ALS, including nucleocytoplasmic transport, RNA processing, normal function of nucleolus, formation of membraneless organelles, translation, ubiquitin proteasome system, Notch signalling pathway, granule transport, and normal function of TAR DNA-binding protein 43 (TDP-43). Although the exact molecular mechanisms through which C9orf72 repeat expansions account for neurodegeneration have not been elucidated, some potential therapeutics, such as antisense oligonucleotides targeting hexanucleotide GGGGCC repeats in mRNA, were successful in preclinical trials and are awaiting phase 1 clinical trials. In this review, we critically discuss each proposed mechanism and provide insight into the most recent studies aiming to elucidate the molecular underpinnings of C9FTD/ALS.

A Comparison of Different Valgancyclovir Formulations in the Universal 6-Month Prophylaxis Against CMV Infection in Renal Transplant Recipients: A Randomized Single-Centre Study.

INTRODUCTION: Cytomegalovirus (CMV) is the most common opportunistic infective pathogen in kidney transplant recipients. Valganciclovir (VAL) is commonly used for prophylaxis, especially in high-risk recipients. Generic VAL formulations have become available, but the data about their safety and efficacy are lacking. METHODS: Consecutive de novo kidney transplant patients were randomized to generic VAL Valganciklovir Teva® (VT group)(24 patients) or Alvanocyte® (A group), Alvogen (19 patients) or to Valcyte® (V group), Roche (23 patients) in a 18-month open-label study. Universal prophylaxis was used for 6 months after the transplantation. CMV DNA levels were measured at 1,3,6,9,12 and 18 months after the transplantation. All positive measurements of CMV DNA were recorded. RESULTS: Groups did not differ regarding the clinical characteristics or the risk for developing CMV infection in the post-transplant period. CMV replications were most common at 9 months after the transplantation with rates of 9% for the V, 13% for the VT and 26% for the A group (p=0.26). At 12 months, positive CMV DNA was recorded in 22%, 8% and 11 % of patients taking V, VT and A, respectively (p=0.37). Rates of biopsy-proven acute rejection, adverse events, and serious adverse events were similar for all formulations. Lymphocele occurred most commonly in the V group (35%) compared to 17% in VT and 17% in the A group (p=0.23). One patient from each of the A and VT groups developed CMV disease. Additionally, they were the only two patients with CMV DNA copies above 656 IU/ml. Glomerular filtration rates were similar in all groups at all time points, while proteinuria was significantly higher at 12 months in patients who received V 0.32 g/day (0.18 - 0.42), compared to patients on VT 0.2 (0.1 - 0.2), or A 0.2 (0.2 - 0.3), p=0.04. CONCLUSION: Valgancyclovir efficacy and safety in this limited data set is similar with early administration of V, VT and A after kidney transplantation. Additional studies aimed at elucidating the effectiveness of this treatment regimen in patients who are at high risk for developing CMV infection are necessary to draw further conclusions.

Multiple Primary Malignancies in Renal Transplant Recipients: a Single Centre Retrospective Cohort Study.

BACKGROUND/AIMS: Renal transplant recipients are exposed to immunosuppressive treatment which may increase the risk for developing malignancies. Limited data exists concerning the occurrence of multiple primary malignancies (MPM) in renal transplant patients. METHODS: All the patients who received a renal allograft at our institution from 1973 to 2017 were included in this investigation. Data from patients with more MPM were obtained from the charts and medical records. Malignancies were categorized as synchronous if the interval between occurrences was less than or equal to 6 months and metachronous if the interval was more than 6 months. RESULTS: Out of the 1884 patients who received a renal allograft, 164 (8.7%) developed a malignant tumor. Twenty-two patients (13.4%; 6 females, 16 males) developed MPM, 7 synchronous (31.8%) and 15 metachronous types (68.2%). The most common initial primary tumors were skin cancers (8) and kidney cancers (3). Furthermore, skin cancers were the most common second primary malignancies (9). Log-rank analysis revealed significantly better survival in the synchronous group (113.3 months) than in the metachronous group (24.6 months) (p=0.04). CONCLUSION: MPM are more frequent in renal transplant recipients than in the general population. It is associated with a high mortality rate, especially in the metachronous group. An increased awareness and frequent screening tests are necessary when managing this condition.

Community Acquired Legionnaire's Disease in a Kidney Transplant Patient.

This case report details the clinical picture of a renal transplant recipient infected with community acquired Legionella pneumonia. While it is more commonly associated as a nosocomial infection due to pathogenic organisms in a hospital's water supply, this case serves as a reminder to consider the patient's impaired cellular immune function when trying to diagnose community acquired pneumonia.

Gene expression profiling of the dorsolateral and medial orbitofrontal cortex in schizophrenia.

Schizophrenia is a complex polygenic disorder of unknown etiology. Over 3,000 candidate genes associated with schizophrenia have been reported, most of which being mentioned only once. Alterations in cognitive processing - working memory, metacognition and mentalization - represent a core feature of schizophrenia, which indicates the involvement of the prefrontal cortex in the pathophysiology of this disorder. Hence we compared the gene expression in postmortem tissue from the left and right dorsolateral prefrontal cortex (DLPFC, Brodmann's area 46), and the medial part of the orbitofrontal cortex (MOFC, Brodmann's area 11/12), in six patients with schizophrenia and six control brains. Although in the past decade several studies performed transcriptome profiling in schizophrenia, this is the first study to investigate both hemispheres, providing new knowledge about possible brain asymmetry at the level of gene expression and its relation to schizophrenia. We found that in the left hemisphere, twelve genes from the DLPFC and eight genes from the MOFC were differentially expressed in patients with schizophrenia compared to controls. In the right hemisphere there was only one gene differentially expressed in the MOFC. We reproduce the involvement of previously reported genes TARDBP and HNRNPC in the pathogenesis of schizophrenia, and report seven novel genes: SART1, KAT7, C1D, NPM1, EVI2A, XGY2, and TTTY15. As the differentially expressed genes only partially overlap with previous studies that analyzed other brain regions, our findings indicate the importance of considering prefrontal cortical regions, especially those in the left hemisphere, for obtaining disease-relevant insights.

Radical O→C transposition: a metal-free process for conversion of phenols into benzoates and benzamides.

We report a metal-free procedure for transformation of phenols into esters and amides of benzoic acids via a new radical cascade. Diaryl thiocarbonates and thiocarbamates, available in a single high-yielding step from phenols, selectively add silyl radicals at the sulfur atom of the C═S moiety. This addition step, analogous to the first step of the Barton-McCombie reaction, produces a carbon radical which undergoes 1,2 O→C transposition through an O-neophyl rearrangement. The usually unfavorable equilibrium in the reversible rearrangement step is shifted forward via a highly exothermic C-S bond scission in the O-centered radical, which furnishes the final benzoic ester or benzamide product. The metal-free preparation of benzoic acid derivatives from phenols provides a potentially useful alternative to metal-catalyzed carbonylation of aryl triflates.