Prevalence of Aortic Root Pathologies in Platypnea-Orthodeoxia Syndrome Secondary to Intra-Cardiac Shunts.

Background: Atrial septal defects can allow right to left shunting of venous blood which presents clinically as platypnea-orthodeoxia syndrome. It is believed that concomitant presence of aortic root pathologies increases the likelihood of shunting. Methods: The study included a review of 510 articles listed in PubMed of patients with platypnea-orthodeoxia syndrome. Case reports of patients with extra-cardiac etiologies of platypnea-orthodeoxia were excluded. Results: We reviewed 191 case reports, and 98 cases (51.3%) had evidence of concomitant aortic root pathology. Furthermore, of the remaining 93 case reports, 69 ones excluded any mention of the nature of the aortic root altogether, further suggesting that this is an underreported number. Conclusions: There is a high prevalence of aortic root pathologies in patients with platypnea-orthodeoxia syndrome secondary to intra-cardiac shunts. In patients with unexplained hypoxemia and incidental finding of aortic root pathology, it may be worthwhile to obtain postural oxygen saturation measurements to exclude intra-cardiac shunts as the potential cause.

Profound metabolic acidosis in association with sodium thiosulfate therapy in a patient with calcific uremic arteriolopathy: a case report and literature review.

Calciphylaxis, also known as Calcific uremic arteriolopathy (CUA), is a serious disorder that presents with skin necrosis due to calcification of dermal and subcutaneous adipose tissue capillaries and arterioles. The condition occurs primarily in patients with end-stage renal disease (ESRD) on dialysis, and it carries high morbidity and mortality, primarily due to sepsis, with an estimated six-month survival of approximately 50%. Although there are no high-quality studies to guide the optimal treatment approach for patients with calciphylaxis, many retrospective studies and case series support treatment with sodium thiosulfate (STS). Despite the frequent use of STS as an off-label treatment, data regarding its safety and efficacy are limited. STS has generally been considered a safe drug with mild side effects. However, severe metabolic acidosis associated with STS is a rare and life-threatening complication of STS treatment and is often unpredictable. Herein, we report a 64-year-old female with ESRD on peritoneal dialysis (PD) who presented with a profound high anion gap metabolic acidosis and severe hyperkalemia while on STS treatment for CUA. No other etiology for her severe metabolic acidosis other than STS was identified. ESRD patients receiving STS should be monitored closely for this side effect. Dose reduction, increasing the duration of infusion, or even discontinuing STS treatment should be considered if severe metabolic acidosis develops.

A Trivalent HSV-2 gC2, gD2, gE2 Nucleoside-Modified mRNA-LNP Vaccine Provides Outstanding Protection in Mice against Genital and Non-Genital HSV-1 Infection, Comparable to the Same Antigens Derived from HSV-1.

HSV-1 disease is a significant public health burden causing orofacial, genital, cornea, and brain infection. We previously reported that a trivalent HSV-2 gC2, gD2, gE2 nucleoside-modified mRNA-lipid nanoparticle (LNP) vaccine provides excellent protection against vaginal HSV-1 infection in mice. Here, we evaluated whether this HSV-2 gC2, gD2, gE2 vaccine is as effective as a similar HSV-1 mRNA LNP vaccine containing gC1, gD1, and gE1 in the murine lip and genital infection models. Mice were immunized twice with a total mRNA dose of 1 or 10 µg. The two vaccines produced comparable HSV-1 neutralizing antibody titers, and surprisingly, the HSV-2 vaccine stimulated more potent CD8+ T-cell responses to gE1 peptides than the HSV-1 vaccine. Both vaccines provided complete protection from clinical disease in the lip model, while in the genital model, both vaccines prevented death and genital disease, but the HSV-1 vaccine reduced day two vaginal titers slightly better at the 1 µg dose. Both vaccines prevented HSV-1 DNA from reaching the trigeminal or dorsal root ganglia to a similar extent. We conclude that the trivalent HSV-2 mRNA vaccine provides outstanding protection against HSV-1 challenge at two sites and may serve as a universal prophylactic vaccine for HSV-1 and HSV-2.

Novel Adjuvant S-540956 Targets Lymph Nodes and Reduces Genital Recurrences and Vaginal Shedding of HSV-2 DNA When Administered with HSV-2 Glycoprotein D as a Therapeutic Vaccine in Guinea Pigs.

Herpes simplex virus type 2 (HSV-2) is a leading cause of genital ulcer disease and a major risk factor for acquisition and transmission of HIV. Frequent recurrent genital lesions and concerns about transmitting infection to intimate partners affect the quality of life of infected individuals. Therapeutic vaccines are urgently needed to reduce the frequency of genital lesions and transmission. S-540956 is a novel vaccine adjuvant that contains CpG oligonucleotide ODN2006 annealed to its complementary sequence and conjugated to a lipid that targets the adjuvant to lymph nodes. Our primary goal was to compare S-540956 administered with HSV-2 glycoprotein D (gD2) with no treatment in a guinea pig model of recurrent genital herpes (studies 1 and 2). Our secondary goals were to compare S-540956 with oligonucleotide ODN2006 (study1) or glucopyranosyl lipid A in a stable oil-in-water nano-emulsion (GLA-SE) (study 2). gD2/S-540956 reduced the number of days with recurrent genital lesions by 56%, vaginal shedding of HSV-2 DNA by 49%, and both combined by 54% compared to PBS, and was more efficacious than the two other adjuvants. Our results indicate that S-540956 has great potential as an adjuvant for a therapeutic vaccine for genital herpes, and merits further evaluation with the addition of potent T cell immunogens.

Persistent Norovirus infection in a young patient with renal transplant: The challenging cost of immunosuppression and the negative impact on patient's quality of life.

Norovirus (NoV) is one of the most common causes of acute infectious gastroenteritis in the United States (US). The infection is typically short-lasting and self-limiting in immunocompetent hosts. Renal transplant recipients on immunosuppressive therapy are more prone to infectious gastroenteritis that can be caused by various common and opportunistic organisms. NoV infection in renal transplant patients presents as an acute diarrheal illness that may progress to a chronic infection with frequent relapses leading to adverse short-term complications (acute renal injury (AKI) and acute graft rejection from the reduction of the dose of immunosuppressive medications) and possibly long-term morbidities (malabsorption syndrome, and a decline in graft survival). The management of chronic NoV infections in renal transplant patients may be quite challenging, as no specific antiviral treatment is presently approved, and frequent adjustments of immunosuppressive therapy may be required in the setting of reduced renal clearance and the attempts to decrease immunosuppressive effects to enhance the viral clearance.Herein, the authors present a case of persistent NoV in a young female patient with a renal transplant that was associated with recurrent admissions with AKI, gross electrolyte disturbances, and significant weight loss. The relapsing NoV infection has negatively impacted the patient's quality of life and socioeconomic performance.

A Case Series of Non-Tuberculous Mycobacterial Pulmonary Disease Masquerading as Malignancy From a Community-Based Hospital.

Non-tuberculous mycobacteria (NTM) are ubiquitous organisms in the environment that can potentially cause a range of pulmonary and extrapulmonary infections in humans. Epidemiological risk factors and the host's immune status determine the susceptibility to various clinical syndromes caused by different NTM species. Non-tuberculous mycobacteria pulmonary disease (NTM-PD) is primarily reported in patients with underlying lung disease. These infections often pose a significant disease burden on affected patients as they are often chronic, difficult to treat, and necessitate long-term multi-drug therapy. Mycobacterium avium complex (MAC) is the most common causative pathogen of NTM-PD in the USA, followed by Mycobacterium kansasii (M. kansasii). Less common species in the USA include Mycobacterium xenopi (M. xenopi), Mycobacterium abscessus, and others, largely depending upon the geographic location and exposure to species-specific predisposing risks. In this case series, the authors report on three elderly patients with chronic lung diseases who had pulmonary NTM disease caused by M. xenopi and MAC. The patients were encountered in both inpatient and outpatient settings from a community-based hospital in the midwestern USA. The clinical and radiological features of NTM-PD masqueraded as malignancy and posed a diagnostic dilemma. The epidemiology, clinical and radiological features, diagnosis, and management of NTM-PD are reviewed in this report.

Receptor Binding-Induced Conformational Changes in Herpes Simplex Virus Glycoprotein D Permit Interaction with the gH/gL Complex to Activate Fusion.

Herpes simplex virus (HSV) requires four essential virion glycoproteins-gD, gH, gL, and gB-for virus entry and cell fusion. To initiate fusion, the receptor binding protein gD interacts with one of two major cell receptors, HVEM or nectin-1. Once gD binds to a receptor, fusion is carried out by the gH/gL heterodimer and gB. A comparison of free and receptor-bound gD crystal structures revealed that receptor binding domains are located within residues in the N-terminus and core of gD. Problematically, the C-terminus lies across and occludes these binding sites. Consequentially, the C-terminus must relocate to allow for both receptor binding and the subsequent gD interaction with the regulatory complex gH/gL. We previously constructed a disulfide bonded (K190C/A277C) protein that locked the C-terminus to the gD core. Importantly, this mutant protein bound receptor but failed to trigger fusion, effectively separating receptor binding and gH/gL interaction. Here, we show that "unlocking" gD by reducing the disulfide bond restored not only gH/gL interaction but fusion activity as well, confirming the importance of C-terminal movement in triggering the fusion cascade. We characterize these changes, showing that the C-terminus region exposed by unlocking is: (1) a gH/gL binding site; (2) contains epitopes for a group (competition community) of monoclonal antibodies (Mabs) that block gH/gL binding to gD and cell-cell fusion. Here, we generated 14 mutations within the gD C-terminus to identify residues important for the interaction with gH/gL and the key conformational changes involved in fusion. As one example, we found that gD L268N was antigenically correct in that it bound most Mabs but was impaired in fusion, exhibited compromised binding of MC14 (a Mab that blocks both gD-gH/gL interaction and fusion), and failed to bind truncated gH/gL, all events that are associated with the inhibition of C-terminus movement. We conclude that, within the C-terminus, residue 268 is essential for gH/gL binding and induction of conformational changes and serves as a flexible inflection point in the critical movement of the gD C-terminus.

Some independence results related to finite trees.

We investigate some concrete independence results for systems of reverse mathematics which emerge from monotonicity properties of number-theoretic functions. Natural properties of the less than or equal to relation with respect to sums of natural numbers lead to independence results for first-order Peano arithmetic. Natural properties of the less than or equal to relation with respect to sums and products of natural numbers lead to independence results for arithmetical transfinite recursion. By considering number-theoretic functions of arbitrary arities, we obtain independence results for systems beyond arithmetical transfinite recursion. We discuss how these embeddability relations are related to tree embeddability relations and we consider variants where the tree embeddability relation is not assumed to preserve infima. The findings of this paper are complementary to results on Kruskal-like theorems proved earlier by the first author. This article is part of the theme issue 'Modern perspectives in Proof Theory'.

Rapid and accurate detection of herpes simplex virus type 2 using a low-cost electrochemical biosensor.

Herpes simplex virus type 2 (HSV-2) infection, which is almost exclusively sexually transmitted, causes genital herpes. Although this lifelong and incurable infection is extremely widespread, currently there is no readily available diagnostic device that accurately detects HSV-2 antigens to a satisfactory degree. Here, we report an ultrasensitive electrochemical device that detects HSV-2 antigens within 9 min and costs just $1 (USD) to manufacture. The electrochemical biosensor is biofunctionalized with the human cellular receptor nectin-1 and detects the glycoprotein gD2, which is present within the HSV-2 viral envelope. The performance of the device is tested in a guinea pig model that mimics human biofluids, yielding 88.9% sensitivity, 100.0% specificity, and 95.0% accuracy under these conditions, with a limit of detection of 0.019 fg mL-1 for gD2 protein and 0.057 PFU mL-1 for titered viral samples. Importantly, no cross-reactions with other viruses were detected, indicating the adequate robustness and selectivity of the sensor. Our low-cost technology could facilitate more frequent testing for HSV-2.

A Suspicious Hilar Mass Revealing an Uncommon Diagnosis of Pulmonary Actinomycosis in an Immunocompromised Young Female Patient: A Case Report and Literature Review.

 Actinomycosis is a chronic inflammatory infectious disease that can affect various organ systems. Pulmonary actinomycosis is an exceptionally uncommon clinical occurrence that yet deserves special attention, as it closely mimics a broad spectrum of infectious and neoplastic lung pathologies. The non-specific nature of its clinical features and radiological appearances makes early diagnosis quite challenging. The authors reported a 25-year-female with poorly controlled diabetes mellitus and morbid obesity who presented with a one-week history of unilateral, right-sided, pleuritic chest pain and shortness of breath. Chest imaging revealed a suspicious right hilar soft tissue mass encasing the right upper lobe bronchus with post-obstructive atelectasis. Transbronchial biopsy revealed suppurative granulomatous inflammation, and anaerobic cultures from the bronchial tissues grew Actinomyces species that were identified using the matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) technique. A long course of penicillin-based antibiotics was employed, and follow-up imaging revealed a satisfactory response to the antimicrobial therapy. This case demonstrates that microbiological examination is imperative to accurately diagnose the etiology of suspicious lung masses in young immunocompromised hosts. It also proves the diagnostic value of the MALDI-TOF technique in the early identification of Actinomyces species.

Clostridium tertium Bacteremia: A Marker of an Underlying Perforated Colonic Diverticular Disease in a Non-Neutropenic Patient With COVID-19.

Clostridium tertium (C. tertium) is an aero-tolerant, gram-positive, endospore-forming, and non-exotoxin-producing bacillus that has colonized the gastrointestinal tract of animals and humans. It is considered a rare pathogen of humans, possibly because of its low virulence. Most C. tertium infections in the reviewed literatures were predominately reported among neutropenic hosts with hematological malignancies. A 66-year-old female patient with a past medical history of type II diabetes mellitus and chronic obstructive pulmonary disease was admitted with coronavirus disease 2019 (COVID-19) that initially required non-invasive ventilation. The patient developed septic shock due to C. tertium bacteremia. Computed tomography of the abdomen depicted free intraperitoneal gas and sigmoid colon perforation. Exploratory laparotomy revealed perforated sigmoid diverticulitis, and Hartmann's procedure was performed. The patient received a prolonged course of susceptibility-guided antibiotics to clear C. tertium bacteremia. The authors described a rare case of C. tertium bacteremia as a marker of underlying perforated colonic diverticulitis in a non-neutropenic patient with COVID-19 that necessitated operative procedure intervention for primary source control and an extended course of targeted antibiotic therapy to treat the Clostridial infection. Our case reaffirmed the available literature that suggested the presence of C. tertium bacteremia in non-neutropenic patients raises suspicion of an associated gastrointestinal tract pathology that should warrant a diagnostic workup to identify the infection source culprit.

Clinical characteristics and outcomes of the first two waves of the COVID-19 pandemic in a community hospital: a retrospective cohort study.

Objective: To describe the clinical characteristics and outcomes of two waves of the COVID-19 pandemic. Methods: A de-identified dataset of patients with COVID-19 admitted to our community hospital in Evanston, Illinois, from March 1, 2020 to February 28, 2021 was retrospectively reviewed. Patients from the first wave were identified as those admitted during the initial peak of admissions observed at our hospital between March 1, 2020 and September 3, 2020. The second wave was defined as those admitted during the second peak of admissions observed between October 1, 2020 and February 28, 2021. Results: In total, 671 patients were included. Of these, 399 (59.46%) were identified as patients from the first wave and 272 (40.54%) as patients from the second wave. Significantly more patients received steroids (86.4% vs 47.9%, p < 0.001), remdesivir (59.6% vs 9.5%, p < 0.001), humidified high-flow nasal cannula (18% vs 6.5%, p < 0.001), and noninvasive ventilation (11.8% vs 3.3%, p < 0.001) during the second wave. Patients from the first wave had a greater hazard for death compared with patients from the second wave (hazard ratio [HR] 1.62, 95% CI 1.08-2.43; p = 0.019). Conclusion: Among patients hospitalized with COVID-19 in our community hospital, there was a decrease in case-fatality rate in the second surge of the COVID-19 pandemic compared with the first wave.

Community-Acquired Meningitis Complicated by Pyogenic Ventriculitis: A Case Report.

Ventriculitis is the inflammation of the ependymal lining of the ventricles in the brain which usually occurs as a complication of meningitis, intraventricular devices, intracranial surgery, or brain abscess. Common clinical features include fever, altered mental status, headache, and neck rigidity. Some commonly associated organisms are Streptococcus, gram-negative Bacillus, Staphylococcus, and Meningococcus. Here, we report the case of a 57-year-old female presenting with fever, headache, and altered mental status, along with positive physical examination findings of Kernig's and Brudzinski's signs without any focal neurological deficits. Cerebrospinal fluid analysis findings were consistent with bacterial infection with neutrophilic leukocytosis, high protein, and low glucose. The blood culture was positive for Streptococcus pneumoniae. Magnetic resonance imaging was negative for enhancement of the meninges but showed fluid-filled layering in the ventricles consistent with pyogenic ventriculitis. The patient improved clinically within three days of initiation of empiric antibiotics.

A Case of Campylobacter Fetus Subspecies Fetus Systemic Infection.

Campylobacter are gram-negative bacilli commonly known to cause gastro-intestinal infection; however, species like Campylobacter fetus subspecies fetus (C. fetus) have been documented to cause severe systemic illness, especially in immunocompromised hosts. It has been linked with severe sepsis, septic arthritis, endocarditis, and subdural abscess. We report a case of a 65-year-old male with a history of human immunodeficiency virus infection (HIV) and chronic hepatitis B presenting with high fevers, pain, and swelling in multiple joints. His blood cultures grew C. fetus. Synovial fluid analysis from the knee joint revealed leukocytes of 17,000 with 93% neutrophils, and gram stains and cultures from synovial fluid were negative. The patient improved with piperacillin-tazobactam and vancomycin which were transitioned to amoxicillin-clavulanic acid and azithromycin as the patient returned to baseline functional status.

Herpes Simplex Virus-2 Variation Contributes to Neurovirulence During Neonatal Infection.

Herpes simplex virus (HSV) infection of the neonatal brain causes severe encephalitis and permanent neurologic deficits. However, infants infected with HSV at the time of birth follow varied clinical courses, with approximately half of infants experiencing only external infection of the skin rather than invasive neurologic disease. Understanding the cause of these divergent outcomes is essential to developing neuroprotective strategies. To directly assess the contribution of viral variation to neurovirulence, independent of human host factors, we evaluated clinical HSV isolates from neonates with different neurologic outcomes in neurologically relevant in vitro and in vivo models. We found that isolates taken from neonates with encephalitis are more neurovirulent in human neuronal culture and mouse models of HSV encephalitis, as compared to isolates collected from neonates with skin-limited disease. These findings suggest that inherent characteristics of the infecting HSV strain contribute to disease outcome following neonatal infection.

Cardiac Arrest With Spontaneous Coronary Artery Dissection in a Young Female.

Spontaneous coronary artery dissection (SCAD) is a rare condition that has variable clinical presentations requiring a very high index of suspicion for diagnosis. We present here a case of a young female with SCAD who initially presented with chest pain and syncope, with progression to cardiac arrest.

Antibodies to Crucial Epitopes on HSV-2 Glycoprotein D as a Guide to Dosing an mRNA Genital Herpes Vaccine.

The toxicity of mRNA-lipid nanoparticle (LNP) vaccines depends on the total mRNA-LNP dose. We established that the maximum tolerated dose of our trivalent mRNA-LNP genital herpes vaccine was 10 µg/immunization in mice. We then evaluated one of the mRNAs, gD2 mRNA-LNP, to determine how much of the 10 µg total dose to assign to this immunogen. We immunized mice with 0.3, 1.0, 3.0, or 10 µg of gD2 mRNA-LNP and measured serum IgG ELISA, neutralizing antibodies, and antibodies to six crucial gD2 epitopes involved in virus entry and spread. Antibodies to crucial gD2 epitopes peaked at 1 µg, while ELISA and neutralizing titers continued to increase at higher doses. The epitope results suggested no immunologic benefit above 1 µg of gD2 mRNA-LNP, while ELISA and neutralizing titers indicated higher doses may be useful. We challenged the gD2 mRNA-immunized mice intravaginally with HSV-2. The 1-µg dose provided total protection, confirming the epitope studies, and supported assigning less than one-third of the trivalent vaccine maximum dose of 10 µg to gD2 mRNA-LNP. Epitope mapping as performed in mice can also be accomplished in phase 1 human trials to help select the optimum dose of each immunogen in a multivalent vaccine.

Abdominopelvic actinomycosis: An unexpected diagnosis in an elderly female with a destructive-appearing soft tissue mass.

We present the case of an elderly female who underwent a workup for acute blood loss anemia that incidentally led to the discovery of abdominopelvic actinomycosis. While esophagogastroduodenoscopy and colonoscopy were unremarkable, CT abdomen/pelvis displayed a soft tissue mass in the left sacral ala and presacral area that appeared suspicious for malignancy. MRI pelvis revealed a presacral abscess, and an IR-guided biopsy cemented the diagnosis. This case exemplifies how actinomycosis can mimic the presentation of cancer. Risk factors included a history of ischemic colitis and lumbar laminectomy, as mucosal tissue compromise and orthopedic hardware can be niduses for infection.

An mRNA vaccine to prevent genital herpes.

The rapid development of two nucleoside-modified mRNA vaccines that are safe and highly effective against coronavirus disease 2019 has transformed the vaccine field. The mRNA technology has the advantage of accelerated immunogen discovery, induction of robust immune responses, and rapid scale up of manufacturing. Efforts to develop genital herpes vaccines have been ongoing for 8 decades without success. The advent of mRNA technology has the potential to change that narrative. Developing a genital herpes vaccine is a high public health priority. A prophylactic genital herpes vaccine should prevent HSV-1 and HSV-2 genital lesions and infection of dorsal root ganglia, the site of latency. Vaccine immunity should be durable for decades, perhaps with the assistance of booster doses. While these goals have been elusive, new efforts with nucleoside-modified mRNA-lipid nanoparticle vaccines show great promise. We review past approaches to vaccine development that were unsuccessful or partially successful in large phase 3 trials, and describe lessons learned from these trials. We discuss our trivalent mRNA-lipid nanoparticle approach for a prophylactic genital herpes vaccine and the ability of the vaccine to induce higher titers of neutralizing antibodies and more durable CD4+ T follicular helper cell and memory B cell responses than protein-adjuvanted vaccines.

Guinea Pig and Mouse Models for Genital Herpes Infection.

This article describes procedures for two preclinical animal models for genital herpes infection. The guinea pig model shares many features of genital herpes in humans, including a natural route of inoculation, self-limiting primary vulvovaginitis, spontaneous recurrences, symptomatic and subclinical shedding of HSV-2, and latent infection of the associated sensory ganglia (lumbosacral dorsal root ganglia, DRG). Many humoral and cytokine responses to HSV-2 infection in the guinea pig have been characterized; however, due to the limited availability of immunological reagents, assessments of cellular immune responses are lacking. In contrast, the mouse model has been important in assessing cellular immune responses to herpes infection. Both the mouse and guinea pig models have been extremely useful for evaluating preventative and immunotherapeutic approaches for controlling HSV infection and recurrent disease. In this article, we describe procedures for infecting guinea pigs and mice with HSV-2, scoring subsequent genital disease, and measuring replicating virus to confirm infection. We also provide detailed protocols for dissecting and isolating DRG (the site of HSV-2 latency), quantifying HSV-2 genomic copies in DRG, and assessing symptomatic and subclinical shedding of HSV-2 in the vagina. © 2021 Wiley Periodicals LLC. Basic Protocol 1: Primary and recurrent genital herpes infection in the guinea pig model Support Protocol 1: Blood collection via lateral saphenous vein or by cardiac puncture after euthanasia Support Protocol 2: Dissection and isolation of dorsal root ganglia from guinea pigs Support Protocol 3: PCR amplification and quantification of HSV-2 genomic DNA from samples Basic Protocol 2: Primary genital herpes infection in the mouse model Alternate Protocol: Flank infection with HSV-2 in the mouse model Support Protocol 4: Dissection and isolation of mouse dorsal root ganglia.