The role of tocilizumab therapy in critically ill patients with severe acute respiratory syndrome coronavirus 2.

CONTEXT: Tocilizumab (TCZ), an interleukin-6 (IL-6) receptor antagonist, has been approved for use in rheumatoid arthritis and cytokine storm syndrome (CSS) associated with chimeric antigen receptor T cells treatment. Although TCZ is currently utilized in the treatment of critically ill coronavirus 2019 (COVID-19) patients, data on survival impact is minimal. OBJECTIVES: To assess the mortality rate of patients presenting with COVID-19 who received TCZ for suspected CSS. METHODS: This retrospective cohort study was conducted at Henry Ford Health System between March 10, 2020 and May 18, 2020. Data collection began in May 2020 and was completed in June 2020. Patients included in the study required hospital admission and had positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) polymerase chain reaction on nasopharyngeal swab. Eligibility criteria to receive TCZ, per hospital protocol, included any of the following: persistent fever, defined as 38.0 °C for at least 6 hours; a diagnosis of the acute respiratory distress syndrome (ARDS); serum ferritin ≥1,000 (ng/mL) or doubling within 24 hours; D-Dimer ≥ 5 (mg/L); serum lactate dehydrogenase ≥500 (IU/L); or interlukin-6 level ≥5 times the upper limit of normal. Dosing was initially determined by weight, then changed to a fixed 400 mg per hospital protocol. A comparator cohort was created from patients with COVID-19 and ARDS who did not receive TCZ. Patient survival was analyzed using the Kaplan-Meier method and compared by log rank test. A multivariable cox regression was applied to evaluate the association between TCZ and mortality. RESULTS: One hundred and thirty patients were evaluated in the study, 54 (41.5%) of whom received TCZ. Patients who received TCZ were younger (mean age, 63.8 vs. 69.4 years; p=0.0083) and had higher body mass indices (mean, 33.9 vs. 30.4; p=0.005). Of the comorbid conditions evaluated, heart disease was more common in the comparator group than the TCZ group (27 patients [35.5%] vs. 10 patients [18.5%]; p=0.034). A Kaplan-Meier survival curve demonstrated no difference in survival between TCZ and comparator patients (log rank p=0.495). In the multivariable Cox regression model for mortality at 30 days, treatment with TCZ was not associated with decreased mortality (hazard ratio, 1.1; 95% confidence interval, 0.53-2.3; p=0.77). Lower mean C-reactive protein (CRP) levels were demonstrated within 48 hours of disposition in the TCZ group (mean TCZ, 4.9 vs. mean comparator, 13.0; p=<0.0001). CONCLUSIONS: In this cohort study, no difference in survival was observed in critically ill patients treated with TCZ.

Diagnosing odontogenic sinusitis of endodontic origin: A multidisciplinary literature review.

PURPOSE: Endodontic disease is one of the most common causes of bacterial odontogenic sinusitis (ODS). Diagnosing ODS of endodontic origin involves otolaryngologists confirming sinusitis, and dental specialists confirming endodontic sources. The purpose of this study was to conduct a multidisciplinary literature review to highlight clinical and microbiological features of ODS, and the most optimal diagnostic modalities to confirm endodontic disease. METHODS: An extensive review of both medical and dental literature was performed by rhinologists, endodontists, and an infectious disease specialist. Frequencies of various clinical and microbiological features from ODS studies were collected, and averages were calculated. Different endodontic testing and imaging modalities were also evaluated on their abilities to confirm endodontic disease. RESULTS: ODS patients most often present with unilateral sinonasal symptoms for over 3 months, purulence on nasal endoscopy, and overt dental pathology on computed tomography (CT). Subjective foul smell, and maxillary sinus cultures demonstrating anaerobes and α-streptococci (viridans group) may be more specific to ODS. For endodontic evaluations, cold pulp testing and cone-beam CT imaging are most optimal for confirming pulpal and periapical disease. CONCLUSION: Diagnosing ODS requires collaboration between otolaryngologists and dental specialists. Clinicians should suspect ODS when patients present with unilateral sinonasal symptoms, especially foul smell. Patients will generally have purulent drainage on nasal endoscopy, and both sinus opacification and overt dental pathology on CT. However, some patients will have subtle or absent dental pathology on CT. For suspected endodontic disease, endodontists should be consulted for at least cold pulp testing, and ideally cone-beam CT.

Rapid Reorganization of an Academic Infectious Diseases Program During the Coronavirus Disease 2019 Pandemic in Detroit: A Novel Unit-based Group Rounding Model.

The surge of coronavirus disease 2019 (COVID-19) hospitalizations at our 877-bed quaternary care hospital in Detroit led to an emergent demand for Infectious Diseases (ID) consultations. The traditional 1-on-1 consultation model was untenable. Therefore, we rapidly restructured our ID division to provide effective consultative services. We implemented a novel unit-based group rounds model that focused on delivering key updates to teams and providing unit-wide consultations simultaneously to all team members. Effectiveness of the program was studied using Likert-scale survey data. The survey captured data from the first month of the Detroit COVID-19 pandemic. During this period there were approximately 950 patients hospitalized for treatment of COVID-19. The survey of trainees and faculty reported an overall 95% positive response to delivery of information, new knowledge acquisition, and provider confidence in the care of COVID-19 patients. This showed that the unit-based consult model is a sustainable effort to provide care during epidemics.

Comparison of bacterial maxillary sinus cultures between odontogenic sinusitis and chronic rhinosinusitis.

BACKGROUND: Bacterial odontogenic sinusitis (ODS) is distinct from other forms of rhinosinusitis. Diagnosing ODS can be challenging because of nonspecific clinical presentations and underrepresentation in the literature. The purpose of this study was to compare maxillary sinus bacterial cultures between patients with ODS and chronic rhinosinusitis (CRS), to determine whether certain bacteria are associated with ODS. METHODS: This was a retrospective case-control study of 276 consecutive patients from August 2015 to August 2019 who underwent endoscopic sinus surgery (ESS) for bacterial ODS, CRS without nasal polyps (CRSsNP), or CRS with nasal polyps (CRSwNP). When present, pus was sterilely cultured from maxillary sinuses after maxillary antrostomy, and aerobic and anaerobic cultures were immediately sent for processing. Demographics and culture results were compared between ODS and CRS patients, and then separately between ODS and CRSsNP, and ODS and CRSwNP. ODS culture results were also compared between different dental pathologies (endodontic vs oroantral fistula). RESULTS: The following bacteria were significantly more likely in ODS compared to CRS: mixed anaerobes, Fusobacterium spp., Eikenella corrodens, Streptococcus intermedius, Streptococcus anginosus, and Streptococcus constellatus. Staphylococcus aureus and Pseudomonas aeruginosa were inversely related to ODS. There were no significant differences in cultures between the different dental pathologies. CONCLUSION: Certain bacteria were more likely to be associated with ODS compared to CRS when purulence was cultured from the maxillary sinus. Physicians should evaluate for an odontogenic source of sinusitis when these ODS-associated bacteria are identified in maxillary sinus cultures.

Early Short-Course Corticosteroids in Hospitalized Patients With COVID-19.

BACKGROUND: There is no proven antiviral or immunomodulatory therapy for coronavirus disease 2019 (COVID-19). The disease progression associated with the proinflammatory host response prompted us to examine the role of early corticosteroid therapy in patients with moderate to severe COVID-19. METHODS: We conducted a single pretest, single posttest quasi-experiment in a multicenter health system in Michigan from 12 March to 27 March 2020. Adult patients with confirmed moderate to severe COVID were included. A protocol was implemented on 20 March 2020 using early, short-course, methylprednisolone 0.5 to 1 mg/kg/day divided in 2 intravenous doses for 3 days. Outcomes of standard of care (SOC) and early corticosteroid groups were evaluated, with a primary composite endpoint of escalation of care from ward to intensive care unit (ICU), new requirement for mechanical ventilation, and mortality. All patients had at least 14 days of follow-up. RESULTS: We analyzed 213 eligible subjects, 81 (38%) and 132 (62%) in SOC and early corticosteroid groups, respectively. The composite endpoint occurred at a significantly lower rate in the early corticosteroid group (34.9% vs 54.3%, P = .005). This treatment effect was observed within each individual component of the composite endpoint. Significant reduction in median hospital length of stay was also observed in the early corticosteroid group (5 vs 8 days, P < .001). Multivariate regression analysis demonstrated an independent reduction in the composite endpoint at 14-days controlling for other factors (adjusted odds ratio: 0.41; 95% confidence interval, .22 - .77). CONCLUSIONS: An early short course of methylprednisolone in patients with moderate to severe COVID-19 reduced escalation of care and improved clinical outcomes. CLINICAL TRIALS REGISTRATION: NCT04374071.

Cardiac Tamponade Secondary to COVID-19.

A 67-year-old woman presented with upper respiratory symptoms and was diagnosed with coronavirus disease-2019 (COVID-19). She was found to have a large hemorrhagic pericardial effusion with echocardiographic signs of tamponade and mild left ventricular impairment. Clinical course was complicated by development of takotsubo cardiomyopathy. She was treated with pericardiocentesis, colchicine, corticosteroids, and hydroxychloroquine, with improvement in symptoms. (Level of Difficulty: Intermediate.).

Elucidation of cGMP-dependent induction of mitochondrial biogenesis through PKG and p38 MAPK in the kidney.

Previous studies have shown that cGMP increases mitochondrial biogenesis (MB). Our laboratory has determined that formoterol and LY344864, agonists of the ß2-adrenergic receptor and 5-HT1F receptor, respectively, signal MB in a soluble guanylyl cyclase (sGC)-dependent manner. However, the pathway between cGMP and MB produced by these pharmacological agents in renal proximal tubule cells (RPTCs) and the kidney has not been determined. In the present study, we showed that treatment of RPTCs with formoterol, LY344864, or riociguat, a sGC stimulator, induces MB through protein kinase G (PKG), a target of cGMP, and p38, an associated downstream target of PKG and a regulator of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) expression in RPTCs. We also examined if p38 plays a role in PGC-1α phosphorylation in vivo. Administration of l-skepinone, a potent and specific inhibitor of p38α and p38ß, to naïve mice inhibited phosphorylated PGC-1α localization in the nuclear fraction of the renal cortex. Taken together, we demonstrated a pathway, sGC/cGMP/PKG/p38/PGC-1α, for pharmacological induction of MB and the importance of p38 in this pathway.

Mitochondrial energetics in the kidney.

The kidney requires a large number of mitochondria to remove waste from the blood and regulate fluid and electrolyte balance. Mitochondria provide the energy to drive these important functions and can adapt to different metabolic conditions through a number of signalling pathways (for example, mechanistic target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) pathways) that activate the transcriptional co-activator peroxisome proliferator-activated receptor-γ co-activator 1α (PGC1α), and by balancing mitochondrial dynamics and energetics to maintain mitochondrial homeostasis. Mitochondrial dysfunction leads to a decrease in ATP production, alterations in cellular functions and structure, and the loss of renal function. Persistent mitochondrial dysfunction has a role in the early stages and progression of renal diseases, such as acute kidney injury (AKI) and diabetic nephropathy, as it disrupts mitochondrial homeostasis and thus normal kidney function. Improving mitochondrial homeostasis and function has the potential to restore renal function, and administering compounds that stimulate mitochondrial biogenesis can restore mitochondrial and renal function in mouse models of AKI and diabetes mellitus. Furthermore, inhibiting the fission protein dynamin 1-like protein (DRP1) might ameliorate ischaemic renal injury by blocking mitochondrial fission.

Structural and Molecular Determinants of Membrane Binding by the HIV-1 Matrix Protein.

Assembly of HIV-1 particles is initiated by the trafficking of viral Gag polyproteins from the cytoplasm to the plasma membrane, where they co-localize and bud to form immature particles. Membrane targeting is mediated by the N-terminally myristoylated matrix (MA) domain of Gag and is dependent on the plasma membrane marker phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2]. Recent studies revealed that PI(4,5)P2 molecules containing truncated acyl chains [tr-PI(4,5)P2] are capable of binding MA in an "extended lipid" conformation and promoting myristoyl exposure. Here we report that tr-PI(4,5)P2 molecules also readily bind to non-membrane proteins, including HIV-1 capsid, which prompted us to re-examine MA-PI(4,5)P2 interactions using native lipids and membrane mimetic liposomes and bicelles. Liposome binding trends observed using a recently developed NMR approach paralleled results of flotation assays, although the affinities measured under the equilibrium conditions of NMR experiments were significantly higher. Native PI(4,5)P2 enhanced MA binding to liposomes designed to mimic non-raft-like regions of the membrane, suggesting the possibility that binding of the protein to disordered domains may precede Gag association with, or nucleation of, rafts. Studies with bicelles revealed a subset of surface and myr-associated MA residues that are sensitive to native PI(4,5)P2, but cleft residues that interact with the 2'-acyl chains of tr-PI(4,5)P2 molecules in aqueous solution were insensitive to native PI(4,5)P2 in bicelles. Our findings call to question extended-lipid MA:membrane binding models, and instead support a model put forward from coarse-grained simulations indicating that binding is mediated predominantly by dynamic, electrostatic interactions between conserved basic residues of MA and multiple PI(4,5)P2 and phosphatidylserine molecules.

Key differences in B cell activation patterns and immune correlates among treated HIV-infected patients versus healthy controls following influenza vaccination.

BACKGROUND: There is increasing recognition of the role of B cell dysfunction in HIV pathogenesis, but little is known about how these perturbations may influence responses to vaccinations. METHODS: Healthy controls (n=16) and antiretroviral therapy (ART)-treated aviremic HIV-infected subjects (n=26) receiving standard-of-care annual influenza vaccinations were enrolled in the present study. Total bacterial 16S rDNA levels were assessed by quantitative polymerase chain reactions in plasma. Serologic responses were characterized by ELISA, hemagglutination inhibition assay (HI), and microneutralization, and cell-mediated responses were assessed by ELISPOT (antigen-specific IgG+ antibody-secreting cells (ASCs)) and flow cytometry at pre-vaccination (D0), day 7-10 (D7) and day 14-21 (D14) post-vaccination. RESULTS: Decreased peripheral CD4+ T cell absolute counts and increased frequencies of cycling and apoptotic B cells were found at baseline in HIV-infected subjects relative to healthy controls. In healthy controls, post-vaccination neutralizing activities were related to the frequencies of vaccine-mediated apoptosis and cycling of B cells, but not to CD4+ T cell counts. In patients, both baseline and post-vaccination neutralizing activities were directly correlated with plasma level of bacterial 16S rDNA. However, overall vaccine responses including antibody titers and fold changes were comparable or greater in HIV-infected subjects relative to healthy controls. CONCLUSION: B cell function correlates with measures of recall humoral immunity in response to seasonal influenza vaccination in healthy controls but not in ART-treated patients.

Dual-acting stapled peptides target both HIV-1 entry and assembly.

BACKGROUND: Previously, we reported the conversion of the 12-mer linear and cell-impermeable peptide CAI to a cell-penetrating peptide NYAD-1 by using an i,i + 4 hydrocarbon stapling technique and confirmed its binding to the C-terminal domain (CTD) of the HIV-1 capsid (CA) protein with an improved affinity (K(d) ~ 1 µM) compared to CAI (K(d) ~ 15 µM). NYAD-1 disrupts the formation of both immature- and mature-like virus particles in in vitro and cell-based assembly assays. In addition, it displays potent anti-HIV-1 activity in cell culture against a range of laboratory-adapted and primary HIV-1 isolates. RESULTS: In this report, we expanded the study to i,i + 7 hydrocarbon-stapled peptides to delineate their mechanism of action and antiviral activity. We identified three potent inhibitors, NYAD-36, -66 and -67, which showed strong binding to CA in NMR and isothermal titration calorimetry (ITC) studies and disrupted the formation of mature-like particles. They showed typical α-helical structures and penetrated cells; however, the cell penetration was not as efficient as observed with the i,i + 4 peptides. Unlike NYAD-1, the i,i + 7 peptides did not have any effect on virus release; however, they impaired Gag precursor processing. HIV-1 particles produced in the presence of these peptides displayed impaired infectivity. Consistent with an effect on virus entry, selection for viral resistance led to the emergence of two mutations in the gp120 subunit of the viral envelope (Env) glycoprotein, V120Q and A327P, located in the conserved region 1 (C1) and the base of the V3 loop, respectively. CONCLUSION: The i,i + 7 stapled peptides derived from CAI unexpectedly target both CA and the V3 loop of gp120. This dual-targeted activity is dependent on their ability to penetrate cells as well as their net charge. This mechanistic revelation will be useful in further modifying these peptides as potent anti-HIV-1 agents.

Using the revised diagnostic criteria for frontotemporal dementia in India: evidence of an advanced and florid disease.

BACKGROUND: The International Consortium (FTDC) that revised the diagnostic criteria for behavioural variant frontotemporal dementia (bvFTD) did not have an Asian representation. Whether the revised criteria are equally useful in the early detection of Asian bvFTD patients therefore remains largely unexplored. Earlier studies have indicated differences in clinical manifestations in Indian and other Asian bvFTD patients when compared to western groups. There is an urgent need for clarification, given the projected exponential rise in dementia in these countries and the imminent clinical trials on bvFTD. OBJECTIVE: To assess how Indian bvFTD patients fulfil the FTDC criteria, hypothesizing that our patients might present differently early in the illness. METHOD: In a hospital-based retrospective observational study, we assessed 48 probable bvFTD patients, diagnosed according to the FTDC criteria, for the speed with which these criteria were fulfilled, the frequency of individual symptoms and their order of appearance during the illness. RESULTS: Most of our patients presented with moderate to severe dementia, in spite of having relatively short onset to diagnosis times. Patients on average took 1.4 years from onset to meet the FTDC criteria, with 90% of them presenting with four or more symptoms at diagnosis. Disinhibition was the commonest symptom and the first symptom in most patients. CONCLUSION: With most patients presenting with advanced and florid disease, the FTDC criteria have little additional impact in early identification of bvFTD in India. Modifying the criteria further could allow detection of Indian patients early enough for their inclusion in future clinical trials.

Environmental dependency behaviours in frontotemporal dementia: have we been underrating them?

Environmental dependency (ED) behaviours, such as imitation behaviour (IB) and incidental utilization behaviour (UB), are considered pathognomonic of a frontal lesion and can play a unique role in diagnosing behavioural variant frontotemporal dementia (bvFTD). However, with only few focused observations of ED behaviour reported in earlier studies, their roles in the diagnosis of bvFTD have so far remained supportive. In this observational study, conducted in the cognitive clinic of a tertiary-care hospital, we explored the hypotheses that a focused and systematic search could uncover more ED behaviours in patients with bvFTD, and that the presence of ED behaviours such as incidental UB and IB should allow us to cleanly differentiate bvFTD from AD. Forty-one bvFTD patients and 75 probable AD patients, all diagnosed using accepted criteria, were seen by a neurologist and a neuropsychologist. Information regarding ED behaviour was obtained from the caregiver's history, observations for spontaneous behaviour and induction of the behaviour in the clinic. All ED behaviours were significantly more frequent in bvFTD compared with AD. UB (78 %; 66 % incidental) and IB (59 %) occurred exclusively in bvFTD. Multi-pronged and focused clinical assessment contributed to the high frequency of ED behaviours. Nearly two-thirds of bvFTD patients, but none with AD, showed three or more ED behaviours. We concluded that ED behaviours are more common in bvFTD than is currently recognized. UB, IB or three ED behaviours, if present, could clearly differentiate bvFTD from AD. A focused search should consistently uncover ED behaviours in bvFTD patients.

Cytomegalovirus infection as a cause of cytopenia after chemotherapy for hematological malignancies.

OBJECTIVE: Unlike hematopoietic stem cell transplantation, there is very little information on cytomegalovirus (CMV) related cytopenias occurring in patients having acute lymphoblastic leukemia (ALL) or Non Hodgkin's lymphoma (NHL) receiving standard dose chemotherapy (SDCT). We studied the role of CMV infection in cytopenias after SDCT for childhood ALL or NHL. DESIGN: Retrospective study. SETTING: Pediatric Oncology Unit. METHODS: Between January 2007 and March 2010, we screened all children having ALL/NHL having prolonged cytopenia (ANC<1,000/cmm and/or platelets <1,00,000/cmm; >10 days beyond date for next chemotherapy; not explainable on basis of previously administered chemotherapy) for CMV infection. Testing for CMV infection was done by pp65 antigen assay, qualitative or quantitative RT-PCR. CMV positive episodes were analyzed for relationship to previous chemotherapy, clinical features and response to treatment. RESULTS: As defined, 24 episodes of cytopenia were identified. CMV infection was detected in 13/24 (54%) episodes in 9 patients. Duration of cytopenia in patients having CMV infection: 14-126 days (median 28 d). Neutropenia or thrombocytopenia were seen in 11/13 and 13/13 episodes, respectively. Fever (2-20 d) and loose motions (3-60 d) in 11/13 and 9/13 episodes, respectively. Eye examination records were available in 5 children; 3 had simultaneous or delayed chorioretinitis. Gancyclovir was used in all but 1 CMV-positive episode. In treated cases, counts recovered after a median of 8 days (3-56 d). CONCLUSION: Following chemotherapy for ALL/NHL, cytopenia that is prolonged or not explainable on the basis of chemotherapy toxicity should be evaluated for CMV infection.

Our experience with pectoralis major flap for management of sternal dehiscence: A review of 25 cases.

OBJECTIVE: To report our experience of the pectoralis major flap as the treatment modality for post coronary artery bypass sternal wound dehiscence. MATERIALS AND METHODS: A retrospective study of 25 open heart surgery cases, performed between January 2006 and December 2010 at Deenanath Mangeshkar Hospital, Pune, was carried out. Unilateral or bilateral pectoralis major muscle flap by the double breasting technique using rectus extension was used in the management of these patients. The outcome was assessed on the basis of efficacy of flap surgery in achieving wound healing and post-surgery shoulder joint movements to evaluate donor site morbidity. The follow-up ranged from 5 months to 3.5 years. RESULTS: Twenty-three (92%) patients were discharged with complete wound closure. One patient (4%) had wound dehiscence after flap surgery. One patient (4%) died in the hospital in the immediate postoperative period due to mediastinitis. No recurrent sternum infection has occurred till date in 24 patients (96%). For one patient (4%) who had wound dehiscence, daily dressing was done and wound healing was achieved with secondary intension. At follow-up, shoulder joint movements were normal in all the patients. CONCLUSIONS: The double breasting technique of the pectoralis major muscle flaps with rectus sheath extension is efficient in covering the entire length of the defect and can reduce the morbidity, without affecting the function of the shoulder joint.

Vaginitis due to Candida krusei: epidemiology, clinical aspects, and therapy.

Twelve women with vaginal Candida krusei infection were evaluated. In vitro antifungal susceptibility testing and molecular typing were performed. Patients infected with C. krusei frequently had refractory vulvovaginal signs and symptoms that were otherwise indistinguishable from vaginitis due to other yeasts. Patients were 32-63 years old and had previously received multiple courses of antimycotic agents, including fluconazole and miconazole. The most active azole in vitro was clotrimazole, with a 90% minimum inhibitory concentration of 0.25 microg/mL. Four of 6 patients treated with boric acid had clinical and mycological cure. Two dominant genotypes of C. krusei were identified via contour-clamped homogenous electrical field analysis. No major genotypic change was observed in successive isolates from the same patient in most cases, suggesting that these refractory cases were relapses. C. krusei is a rare but important cause of refractory vaginitis and is unique because of its intrinsic resistance to fluconazole.