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An ongoing pandemic of coronavirus disease (COVID-19) is caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Characterization of the histopathology and cellular localization of SARS-CoV-2 in the tissues of patients with fatal COVID-19 is critical to further understand its pathogenesis and transmission and for public health prevention measures. We report clinicopathologic, immunohistochemical, and electron microscopic findings in tissues from 8 fatal laboratory-confirmed cases of SARS-CoV-2 infection in the United States. All cases except 1 were in residents of long-term care facilities. In these patients, SARS-CoV-2 infected epithelium of the upper and lower airways with diffuse alveolar damage as the predominant pulmonary pathology. SARS-CoV-2 was detectable by immunohistochemistry and electron microscopy in conducting airways, pneumocytes, alveolar macrophages, and a hilar lymph node but was not identified in other extrapulmonary tissues. Respiratory viral co-infections were identified in 3 cases; 3 cases had evidence of bacterial co-infection.

On April 20, 2018, the Kween District Health Office in Kween District, Uganda reported 7 suspected cases of human anthrax. A team from the Uganda Ministry of Health and partners investigated and identified 49 cases, 3 confirmed and 46 suspected; no deaths were reported. Multiple exposures from handling the carcass of a cow that had died suddenly were significantly associated with cutaneous anthrax, whereas eating meat from that cow was associated with gastrointestinal anthrax. Eating undercooked meat was significantly associated with gastrointestinal anthrax, but boiling the meat for >60 minutes was protective. We recommended providing postexposure antimicrobial prophylaxis for all exposed persons, vaccinating healthy livestock in the area, educating farmers to safely dispose of animal carcasses, and avoiding handling or eating meat from livestock that died of unknown causes.

Lassa virus (LASV) causes Lassa fever; mortality rates are higher in pregnant women, and fetal infection and death are possible. Sexual transmission after recovery from Lassa fever has occurred. Using virus strains that are lethal (Josiah) or nonlethal (NJ2015) in guinea pigs, we characterized LASV-associated pathology and reproductive tissue tropism in male and female animals. Uterus, ovary, and epididymis were the earliest and most affected tissues; perivascular lymphocytic inflammation was prominent at lethal timepoints and persisted in survivors after clinical disease. LASV-Josiah RNA was detected in reproductive tissues by 4 days postinfection (dpi). Virus localized by immunohistochemistry and in situ hybridization predominantly within vascular smooth muscle and interstitial mesenchymal cells and was widespread in reproductive tissues in lethal infections (12-25 dpi) but not detected in survivors (41-42 dpi). Using a physiologically relevant model, we describe reproductive tissue targets to further elucidate LASV infection and effects on reproductive health and virus transmission.

The prevention of HIV and unintended pregnancies is a public health priority. Multi-purpose prevention technologies capable of long-acting HIV and pregnancy prevention are desirable for women. Here, we utilized a preclinical macaque model to evaluate the pharmacokinetics of biodegradable ε-polycaprolactone implants delivering the antiretroviral islatravir (ISL) and the contraceptive etonogestrel (ENG). Three implants were tested: ISL-62 mg, ISL-98 mg, and ENG-33 mg. Animals received one or two ISL-eluting implants, with doses of 42, 66, or 108 µg of ISL/day with or without an additional ENG-33 mg implant (31 µg/day). Drug release increased linearly with dose with median [range] plasma ISL levels of 1.3 [1.0–2.5], 1.9 [1.2–6.3] and 2.8 [2.3–11.6], respectively. The ISL-62 and 98 mg implants demonstrated stable drug release over three months with ISL-triphosphate (ISL-TP) concentr54ations in PBMCs above levels predicted to be efficacious for PrEP. Similarly, ENG implants demonstrated sustained drug release with median [range] plasma ENG levels of 495 [229–1110] pg/mL, which suppressed progesterone within two weeks and showed no evidence of altering ISL pharmacokinetics. Two of the six ISL-98 mg implants broke during the study and induced implant-site reactions, whereas no reactions were observed with intact implants. We show that ISL and ENG biodegradable implants are safe and yield sufficient drug levels to achieve prevention targets. The evaluation of optimized implants with increased mechanical robustness is underway for improved durability and vaginal efficacy in a SHIV challenge model.

Granulomatous amoebic encephalitis (GAE) caused by Balamuthia mandrillaris is a rare subacute infection with exceptionally high mortality. Diagnosis is typically made by brain biopsy or at autopsy. Detection of Balamuthia mandrillaris cell-free DNA by next-generation sequencing of plasma enabled rapid, noninvasive diagnosis in a case of amoebic encephalitis.

A man in his 70s with a complex medical history, including cadaveric renal transplant, presented with recurrent urinary tract infections. Investigation revealed recurrent urinary pathogens, including Enterobacter cloacae and persistent BK viruria. Cystoscopy revealed a pedunculated mass in the right posterior–lateral wall, inferior to the transplant urethral orifice, and biopsy of this mass showed invasive small cell carcinoma with a prominent adenocarcinoma component. The tumour was treated with complete transurethral resection followed by carboplatin, etoposide and radiation. Laboratory analysis of biopsied samples showed immunostaining and molecular evidence of BK virus DNA in the cancer cells. Follow-up cystoscopies have shown no recurrence of the cancer.

Zika virus is an arthropod-borne virus that is a member of the family Flaviviridae transmitted mainly by mosquitoes of the genus Aedes. Although usually asymptomatic, infection can result in a mild and self-limiting illness characterised by fever, rash, arthralgia, and conjunctivitis. An increase in the number of children born with microcephaly was noted in 2015 in regions of Brazil with high transmission of Zika virus. More recently, evidence has been accumulating supporting a link between Zika virus and microcephaly. Here, we describe findings from three fatal cases and two spontaneous abortions associated with Zika virus infection. In this case series, formalin-fixed paraffin-embedded tissue samples from five cases, including two newborn babies with microcephaly and severe arthrogryposis who died shortly after birth, one 2-month-old baby, and two placentas from spontaneous abortions, from Brazil were submitted to the Infectious Diseases Pathology Branch at the US Centers for Disease Control and Prevention (Atlanta, GA, USA) between December, 2015, and March, 2016. Specimens were assessed by histopathological examination, immunohistochemical assays using a mouse anti-Zika virus antibody, and RT-PCR assays targeting the NS5 and envelope genes. Amplicons of RT-PCR positive cases were sequenced for characterisation of strains. Viral antigens were localised to glial cells and neurons and associated with microcalcifications in all three fatal cases with microcephaly. Antigens were also seen in chorionic villi of one of the first trimester placentas. Tissues from all five cases were positive for Zika virus RNA by RT-PCR, and sequence analyses showed highest identities with Zika virus strains isolated from Brazil during 2015. These findings provide strong evidence of a link between Zika virus infection and different congenital central nervous system malformations, including microcephaly as well as arthrogryposis and spontaneous abortions. None.

This manuscript describes the Child Health and Mortality Prevention Surveillance (CHAMPS) network approach to pathologic evaluation of minimally invasive tissue sampling (MITS) specimens, including guidelines for histopathologic examination and further diagnostics with special stains, immunohistochemistry, and molecular testing, as performed at the CHAMPS Central Pathology Laboratory (CPL) at the Centers for Disease Control and Prevention, as well as techniques for virtual discussion of these cases (telepathology) with CHAMPS surveillance locations. Based on review of MITS from the early phase of CHAMPS, the CPL has developed standardized histopathology-based algorithms for achieving diagnoses from MITS and telepathology procedures in conjunction with the CHAMPS sites, with the use of whole slide scanners and digital image archives, for maximizing concurrence and knowledge sharing between site and CPL pathologists. These algorithms and procedures, along with lessons learned from initial implementation of these approaches, guide pathologists at the CPL and CHAMPS sites through standardized diagnostics of MITS cases, and allow for productive, real-time case discussions and consultations.

Zika virus is a mosquito-borne flavivirus that is related to dengue virus and transmitted primarily by Aedes aegypti mosquitoes, with humans acting as the principal amplifying host during outbreaks. Zika virus was first reported in Brazil in May 2015. Here, Martines et al describe evidence of a link between Zika virus infection and microcephaly and fetal demise through detection of viral RNA and antigens in brain tissues from two congenitally infected newborns and two fetal losses reported in the country in 2015.

mTOR is a serine/threonine kinase at the hub of multiple signaling pathways, with roles in proliferation, translation, and growth. The PI3K/AKT/mTOR pathway is frequently hyperactivated in cancers and can be targeted pharmacologically. To better understand the role of mTOR in cancer treatment and in response to cell stressors, mouse models of decreased mTOR and of a single nucleotide polymorphism (SNP) in Mtor were evaluated. Specifically, mice with T-cell-specific, constitutively-active AKT (Lck-MyrAkt) that develop spontaneous thymic lymphomas were crossed to mice with genetically reduced mTOR expression (knock down, KD). Genetic mTOR reduction was associated with prolonged survival (24 weeks in KD mice versus 14 weeks in WT mice), though both eventually developed pre-T lymphoblastic leukemia/lymphoma (pre-T LBL). Transcriptional profiling of the murine pre-T LBL revealed that mTOR KD was associated with decreased expression of Cdk6, a critical proliferative control node in T-cell development and oncogenic transformation. The combination of a mTOR inhibitor (rapamycin) and a CDK4/6 inhibitor (PD-0332991, palbociclib) cooperatively decreased viability and signaling downstream of drug targets in murine thymic lymphoma cells and human T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) cell lines. In addition, the role of mTOR in response to cell stressors was examined in the context of inflammatory, genotoxic, and oncogenic stress. In this study, a rare SNP in Mtor (C1977T, leading to the amino acid substitution R628C), found in BALB/c mice, was linked to decreased DNA damage response (DDR) through gene expression profiling in an inflammatory environment. Mice with the SNP (628C KI) had significantly decreased survival post total body irradiation (TBI) compared to WT and heterozygous mice. Mouse embryonic fibroblasts (MEFs) and bone marrow from 628C KI mice were more sensitive to DNA damage and the DNA damage proteins FANCD2 and ATM were decreased in KI MEFs. Downstream targets of mTOR, most notably those phosphorylated by mTORC2, were also decreased in KI MEFs, especially the target PKCα. Proliferation was decreased by irradiation in WT MEFs, and was minimally affected by irradiation in KI MEFs. KI mice exposed to fractionated irradiation over several weeks developed thymic lymphomas more rapidly and had decreased survival compared to WT mice. Finally, to evaluate oncogenic stress, keratinocytes from KI mice were Ras-transformed and grafted onto nude mice, resulting in a higher rate of papilloma development than seen with keratinocytes from WT mice. The mTOR KD mouse model confirmed the importance of mTOR in T-cell leukemia/lymphoma, while the KI model highlighted the role of mTOR in response to cell stressors that put selective pressure on cancer cells. These findings emphasize the continued importance of research into therapies targeting mTOR and mTOR’s role in cancer progression.