Systematic analysis of proteome turnover in an organoid model of pancreatic cancer by dSILO.

The role of protein turnover in pancreatic ductal adenocarcinoma (PDA) metastasis has not been previously investigated. We introduce dynamic stable-isotope labeling of organoids (dSILO): a dynamic SILAC derivative that combines a pulse of isotopically labeled amino acids with isobaric tandem mass-tag (TMT) labeling to measure proteome-wide protein turnover rates in organoids. We applied it to a PDA model and discovered that metastatic organoids exhibit an accelerated global proteome turnover compared to primary tumor organoids. Globally, most turnover changes are not reflected at the level of protein abundance. Interestingly, the group of proteins that show the highest turnover increase in metastatic PDA compared to tumor is involved in mitochondrial respiration. This indicates that metastatic PDA may adopt alternative respiratory chain functionality that is controlled by the rate at which proteins are turned over. Collectively, our analysis of proteome turnover in PDA organoids offers insights into the mechanisms underlying PDA metastasis.

Clofarabine monotherapy in aggressive, relapsed and refractory Langerhans cell histiocytosis.

Over 50% of patients with systemic LCH are not cured with front-line therapies, and data to guide salvage options are limited. We describe 58 patients with LCH who were treated with clofarabine. Clofarabine monotherapy was active against LCH in this cohort, including heavily pretreated patients with a systemic objective response rate of 92.6%, higher in children (93.8%) than adults (83.3%). BRAFV600E+ variant allele frequency in peripheral blood is correlated with clinical responses. Prospective multicentre trials are warranted to determine optimal dosing, long-term efficacy, late toxicities, relative cost and patient-reported outcomes of clofarabine compared to alternative LCH salvage therapy strategies.

A locus coeruleus to dorsal hippocampus pathway mediates cue-induced reinstatement of opioid self-administration in male and female rats.

Opioid use disorder is a chronic relapsing disorder encompassing misuse, dependence, and addiction to opioid drugs. Long term maintenance of associations between the reinforcing effects of the drug and the cues associated with its intake are a leading cause of relapse. Indeed, exposure to the salient drug-associated cues can lead to drug cravings and drug seeking behavior. The dorsal hippocampus (dHPC) and locus coeruleus (LC) have emerged as important structures for linking the subjective rewarding effects of opioids with environmental cues. However, their role in cue-induced reinstatement of opioid use remains to be further elucidated. In this study, we showed that chemogenetic inhibition of excitatory dHPC neurons during re-exposure to drug-associated cues significantly attenuates cue-induced reinstatement of morphine-seeking behavior. In addition, the same manipulation reduced reinstatement of sucrose-seeking behavior but failed to alter memory recall in the object location task. Finally, intact activity of tyrosine hydroxylase (TH) LC-dHPCTh afferents is necessary to drive cue induced reinstatement of morphine-seeking as inhibition of this pathway blunts cue-induced drug-seeking behavior. Altogether, these studies show an important role of the dHPC and LC-dHPCTh pathway in mediating cue-induced reinstatement of opioid seeking.

Long-term outcomes of patients with large B-cell lymphoma treated with axicabtagene ciloleucel and prophylactic corticosteroids.

ZUMA-1 safety management cohort 6 investigated the impact of prophylactic corticosteroids and earlier corticosteroids and/or tocilizumab on the incidence and severity of cytokine release syndrome (CRS) and neurologic events (NEs) following axicabtagene ciloleucel (axi-cel) in patients with relapsed/refractory large B-cell lymphoma (R/R LBCL). Prior analyses of cohort 6 with limited follow-up demonstrated no Grade ≥3 CRS, a low rate of NEs, and high response rates, without negatively impacting axi-cel pharmacokinetics. Herein, long-term outcomes of cohort 6 (N = 40) are reported (median follow-up, 26.9 months). Since the 1-year analysis (Oluwole, et al. Blood. 2022;138[suppl 1]:2832), no new CRS was reported. Two new NEs occurred in two patients (Grade 2 dementia unrelated to axi-cel; Grade 5 axi-cel-related leukoencephalopathy). Six new infections and eight deaths (five progressive disease; one leukoencephalopathy; two COVID-19) occurred. Objective and complete response rates remained at 95% and 80%, respectively. Median duration of response and progression-free survival were reached at 25.9 and 26.8 months, respectively. Median overall survival has not yet been reached. Eighteen patients (45%) remained in ongoing response at data cutoff. With ≥2 years of follow-up, prophylactic corticosteroids and earlier corticosteroids and/or tocilizumab continued to demonstrate CRS improvement without compromising efficacy outcomes, which remained high and durable.

What are the best methods for rapid reviews of the research evidence? A systematic review of reviews and primary studies.

Rapid review methodology aims to facilitate faster conduct of systematic reviews to meet the needs of the decision-maker, while also maintaining quality and credibility. This systematic review aimed to determine the impact of different methodological shortcuts for undertaking rapid reviews on the risk of bias (RoB) of the results of the review. Review stages for which reviews and primary studies were sought included the preparation of a protocol, question formulation, inclusion criteria, searching, selection, data extraction, RoB assessment, synthesis, and reporting. We searched 11 electronic databases in April 2022, and conducted some supplementary searching. Reviewers worked in pairs to screen, select, extract data, and assess the RoB of included reviews and studies. We included 15 systematic reviews, 7 scoping reviews, and 65 primary studies. We found that several commonly used shortcuts in rapid reviews are likely to increase the RoB in the results. These include restrictions based on publication date, use of a single electronic database as a source of studies, and use of a single reviewer for screening titles and abstracts, selecting studies based on the full-text, and for extracting data. Authors of rapid reviews should be transparent in reporting their use of these shortcuts and acknowledge the possibility of them causing bias in the results. This review also highlights shortcuts that can save time without increasing the risk of bias. Further research is needed for both systematic and rapid reviews on faster methods for accurate data extraction and RoB assessment, and on development of more precise search strategies.

Effect of chair placement on physicians' behavior and patients' satisfaction: randomized deception trial.

OBJECTIVE: To evaluate the effect of chair placement on length of time physicians sit during a bedside consultation and patients' satisfaction. DESIGN: Single center, double blind, randomized controlled deception trial. SETTING: County hospital in Texas, USA. PARTICIPANTS: 51 hospitalist physicians providing direct care services, and 125 observed encounters of patients who could answer four orientation questions correctly before study entry, April 2022 to February 2023. INTERVENTION: Each patient encounter was randomized to either chair placement (≤3 feet (0.9 m) of patient's bedside and facing the bed) or usual chair location (control). MAIN OUTCOME MEASURES: The primary outcome was the binary decision of the physician to sit or not sit at any point during a patient encounter. Secondary outcomes included patient satisfaction, as assessed with the Tool to Assess Inpatient Satisfaction with Care from Hospitalists (TAISCH) and the Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) surveys, time in the room, and both physicians' and patients' perception of time in the room. RESULTS: 125 patient encounters were randomized (60 to chair placement and 65 to control). 38 of the 60 physicians in the chair placement group sat during the patient encounter compared with five of the 65 physicians in the control group (odds ratio 20.7, 95% confidence interval 7.2 to 59.4; P<0.001). The absolute risk difference between the intervention and control groups was 0.55 (95% confidence interval 0.42 to 0.69). Overall, 1.8 chairs needed to be placed for a physician to sit. Intervention was associated with 3.9% greater TAISCH scores (effect estimate 3.9, 95% confidence interval 0.9 to 7.0; P=0.01) and 5.1 greater odds of complete scores on HCAHPS (95% confidence interval 1.06 to 24.9, P=0.04). Chair placement was not associated with time spent in the room (10.6 minutes v control 10.6 minutes) nor perception of time in the room for physicians (9.4 minutes v 9.8 minutes) or patients (13.1 minutes v 13.5 minutes). CONCLUSION: Chair placement is a simple, no cost, low tech intervention that increases a physician's likelihood of sitting during a bedside consultation and resulted in higher patients' scores for both satisfaction and communication. TRIAL REGISTRATION: ClinicalTrials.gov NCT05250778.

Endogenous opioids gate the locus coeruleus pain generator.

The locus coeruleus (LC) plays a paradoxical role in chronic pain. Although largely known as a potent source of endogenous analgesia, increasing evidence suggests injury can transform the LC into a chronic pain generator. We sought to clarify the role of this system in pain. Here, we show optogenetic inhibition of LC activity is acutely antinociceptive. Following long-term spared nerve injury, the same LC inhibition is analgesic - further supporting its pain generator function. To identify inhibitory substrates that may naturally serve this function, we turned to endogenous LC mu opioid receptors (LC-MOR). These receptors provide powerful LC inhibition and exogenous activation of LC-MOR is antinociceptive. We therefore hypothesized that endogenous LC-MOR-mediated inhibition is critical to how the LC modulates pain. Using cell type-selective conditional knockout and rescue of LC-MOR receptor signaling, we show these receptors bidirectionally regulate thermal and mechanical hyperalgesia - providing a functional gate on the LC pain generator.

The Emmaus Project: Aging, Illness, and Dying Among Older Christians-A Qualitative Study.

Older patients have an increased risk of depression, neglect, and abuse. Studies demonstrate that spiritual and religious coping is important at times of personal crisis, but few studies explore the impact of religion on older persons' experiences of aging, illness, and impending death. This study set out to identify recurring spiritual and clinical themes shared by retirement home residents in the context of a Christian faith-based processing group. A qualitative cohort study of residents over the age of 65 was conducted at a retirement home in Chicago, Illinois. The study consisted of 8 hour-long Scripture-based processing group sessions co-led by a study researcher and the onsite chaplain. Questionnaires were administered to each group and handwritten responses were collected and analyzed to identify recurring clinical and spiritual themes. Ten participants enrolled in the group study. The questionnaire completion rate was 35% (49/140). The most recurring clinical themes included 1) events of death or terminal illness and 2) physical limitations. The most recurring spiritual themes included 1) God's presence and 2) prayer and worship. The most recurring coded theme overall was family. This study provided insight into the spiritual experiences of older Christians in one retirement home community. Increased awareness of the spiritual perspectives of the geriatric population may strengthen the doctor-patient relationship and lead to improvements in clinical care.

Poly-basic peptides and polymers as new drug candidate against Plasmodium falciparum.

Plasmodium falciparum, the malaria-causing parasite, is a leading cause of infection-induced deaths worldwide. The preferred treatment approach is artemisinin-combination therapy, which couples fast-acting artemisinin derivatives with longer-acting drugs like lumefantrine, mefloquine, and amodiaquine. However, the urgency for new treatments has risen due to the parasite's growing resistance to existing therapies. Our study shows that a common characteristic of the P. falciparum proteome - stretches of poly-lysine residues such as those found in proteins related to adhesion and pathogenicity - can serve as an effective peptide treatment for infected erythrocytes. A single dose of these poly-basic peptides can successfully diminish parasitemia in human erythrocytes in vitro with minimal toxicity. The effectiveness of the treatment correlates with the length of the poly-lysine peptide, with 30 lysine peptides supporting the eradication of erythrocytic parasites within 72 hours. PEG-ylation of the poly-lysine peptides or utilizing poly-lysine dendrimers and polymers further increases parasite clearance efficiency and bolsters the stability of these potential new therapeutics. Lastly, our affinity pull-downs and mass-spectrometry identify P. falciparum's outer membrane proteins as likely targets for polybasic peptide medications. Since poly-lysine dendrimers are already FDA-approved for drug delivery, their adaptation as antimalarial drugs presents a promising new therapeutic strategy.

A Multipathway Phosphopeptide Standard for Rapid Phosphoproteomics Assay Development.

Recent advances in methodology have made phosphopeptide analysis a tractable problem for many proteomics researchers. There are now a wide variety of robust and accessible enrichment strategies to generate phosphoproteomes while free or inexpensive software tools for quantitation and site localization have simplified phosphoproteome analysis workflow tremendously. As a research group under the Association for Biomolecular Resource Facilities umbrella, the Proteomics Standards Research Group has worked to develop a multipathway phosphopeptide standard based on a mixture of heavy-labeled phosphopeptides designed to enable researchers to rapidly develop assays. This mixture contains 131 mass spectrometry vetted phosphopeptides specifically chosen to cover as many known biologically interesting phosphosites as possible from seven different signaling networks: AMPK signaling, death and apoptosis signaling, ErbB signaling, insulin/insulin-like growth factor-1 signaling, mTOR signaling, PI3K/AKT signaling, and stress (p38/SAPK/JNK) signaling. Here, we describe a characterization of this mixture spiked into a HeLa tryptic digest stimulated with both epidermal growth factor and insulin-like growth factor-1 to activate the MAPK and PI3K/AKT/mTOR pathways. We further demonstrate a comparison of phosphoproteomic profiling of HeLa performed independently in five labs using this phosphopeptide mixture with data-independent acquisition. Despite different experimental and instrumentation processes, we found that labs could produce reproducible, harmonized datasets by reporting measurements as ratios to the standard, while intensity measurements showed lower consistency between labs even after normalization. Our results suggest that widely available, biologically relevant phosphopeptide standards can act as a quantitative "yardstick" across laboratories and sample preparations enabling experimental designs larger than a single laboratory can perform. Raw data files are publicly available in the MassIVE dataset MSV000090564.

Axicabtagene Ciloleucel in Combination with the 4-1BB Agonist Utomilumab in Patients with Relapsed/Refractory Large B-Cell Lymphoma: Phase 1 Results from ZUMA-11.

PURPOSE: Chimeric antigen receptor (CAR) T-cell therapies have shown clinical benefit for patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL), yet approximately 60% of patients do not respond or eventually relapse. We investigated the safety and feasibility of the CD19-directed CAR T-cell therapy axicabtagene ciloleucel (axi-cel) in combination with the 4-1BB agonist antibody utomilumab as an approach to improve efficacy of CAR T-cell therapy. PATIENTS AND METHODS: In phase 1 of the single-arm ZUMA-11 trial, patients with R/R LBCL received a single axi-cel infusion (target dose, 2 × 106 cells/kg) plus utomilumab 10 to 200 mg intravenously every 4 weeks for up to 6 months in a dose-escalation design. The primary endpoint was incidence of dose-limiting toxicities (DLT) with utomilumab. Key secondary endpoints were safety, antitumor activity, pharmacokinetics, and pharmacodynamics. RESULTS: No DLTs were observed among patients treated with axi-cel and utomilumab (n = 12). Grade ≥3 adverse events occurred in 10 patients (83%); none were Grade ≥3 cytokine release syndrome or neurologic events. The objective response rate was 75% and seven patients (58%) had a complete response. Peak CAR T-cell levels increased in a utomilumab dose-dependent manner up to 100 mg. Patients who received utomilumab 100 mg had persistently increased CAR T cells on days 57 to 168 compared with other dose levels. Utomilumab was associated with dose-dependent increases in IL2, IFNγ, and IL10. CONCLUSIONS: Utomilumab-mediated 4-1BB agonism combined with axi-cel therapy had a manageable safety profile. Dual 4-1BB and CD28 costimulation is a feasible therapeutic approach that may enhance CAR T-cell expansion in patients with LBCL.

Assessment of urinary 6-hydroxy-2,4-cyclohexadienyl mercapturic acid as a novel biomarker of benzene exposure.

Assessing benzene exposure is a public health priority due to its deleterious health effects and ubiquitous industrial and environmental sources of exposure. Phenyl mercapturic acid (PhMA) is a commonly used urinary biomarker to assess benzene exposure. However, recent work has identified significant interlaboratory variation in urinary PhMA concentrations related to methodological differences. In this study, we present urinary 6-hydroxy-2,4-cyclohexadienyl mercapturic acid (pre-PhMA), a metabolite that undergoes acid-catalyzed dehydration to form PhMA, as a novel and specific urinary biomarker for assessing benzene exposure. We developed and validated the first quantitative liquid chromatography-tandem mass spectrometry assay for measuring urinary concentrations of pre-PhMA. The pH effect on the method of ruggedness testing determined that pre-PhMA is stable across the normal human urine pH range and that neutral conditions must be maintained throughout quantification for robust and accurate measurement of urinary pre-PhMA concentrations. The method exhibited below 2 ng/mL sensitivity for pre-PhMA, linearity over three orders of magnitude, and precision and accuracy within 10%. Urinary pre-PhMA concentrations were assessed in 369 human urine samples. Smoking individuals exhibited elevated levels of pre-PhMA compared to non-smoking individuals. Furthermore, the relationship between benzene exposure and urinary pre-PhMA levels was explored by examining the correlation of pre-PhMA with 2-cyanoethyl mercapturic acid, a smoke exposure biomarker. The urinary biomarkers exhibited a positive correlation (r = 0.720), indicating that pre-PhMA levels increased with benzene exposure. The results of this study demonstrate that urinary pre-PhMA is a rugged and effective novel biomarker of benzene exposure that can be widely implemented for future biomonitoring studies.

Assessment of neighborhood-level disadvantage and pediatric obstructive sleep apnea severity.

Objectives: To examine the relationship between neighborhood-level advantage and severe obstructive sleep apnea (OSA) in children. Methods: A retrospective case-control study was conducted on 249 children who underwent adenotonsillectomy and had full-night polysomnography conducted within 6 months prior. Patients were divided into more or less socioeconomically disadvantaged groups using a validated measure, the area deprivation index (ADI). The primary outcomes were the relationship between the apnea-hypopnea index (AHI) and the presence of severe OSA, and the secondary outcome was residual moderate or greater OSA after tonsillectomy. Results: Of the 249 children included in the study, 175 (70.3%) were socially disadvantaged (ADI > 50). The median (interquartile range [IQR]) age was 9.4 (7.3-12.3) years, 129 (51.8%) were male, and the majority were White (151, 60.9%), Black (51, 20.6%), and/or of Hispanic (155, 62.5%) ethnicity. A total of 140 (56.2%) children were obese. The median (IQR) AHI was 8.9 (3.9-20.2). There was no significant difference in the median AHI or the presence of severe OSA between the more and less disadvantaged groups. Severe OSA was found to be associated with obesity (odds ratio [OR] = 3.13, 95% confidence interval [CI] = 1.83-5.34), and residual moderate or greater OSA was associated with older age (OR = 1.20, 95% CI = 1.05-1.38). Conclusions: The ADI was not significantly associated with severe OSA or residual OSA in this cohort of children. Although more neighborhood-level disadvantage may increase the risk of comorbidities associated with OSA, it was not an independent risk factor in this study. Level of Evidence: Level 4.

The impact of COVID-19 on the HIV continuum of care: challenges, innovations, and opportunities.

INTRODUCTION: In February 2019, the United States (US) launched the Ending the HIV Epidemic (EHE) initiative with emphasis on improving the various steps of the Human Immunodeficiency Virus (HIV) prevention and care continuum. However, in March 2020, the Coronavirus Disease 2019 (COVID-19) pandemic was declared, curtailing efforts to end the epidemic in the US. AREAS COVERED: To describe the impact of the pandemic on EHE in the US, the authors performed a comprehensive literature review focusing on outcomes at each step of the HIV care continuum. Simultaneously, they identified examples of pandemic-era innovations that may help EHE. EXPERT OPINION: Numerous studies demonstrated pandemic-related disruptions across the care continuum as well as the impact on preexisting barriers to care among People with HIV (PWH) at higher risk for poor outcomes. As the pandemic progressed, innovative approaches to delivering healthcare and providing essential services emerged, including widespread use of telemedicine, expansion of home-based care, self-collected sexually transmitted infection (STI) and HIV testing, and co-located testing for COVID-19 and HIV/STIs. While the COVID-19 pandemic initially hindered achieving EHE in the US, the ability to be agile, flexible, and creative led to innovation in HIV care delivery that may ultimately assist in meeting EHE goals as we transition into the post-pandemic era.

Severe Dystrophic Calcification of a Spinal Cord Stimulator Pulse Generator Pocket: A Case Report.

A spinal cord stimulator is an important long-term treatment modality for refractory chronic pain of multiple etiologies. Hardware-related complications remain known adverse events associated with this intervention. Understanding the risk factors for development of such complications is important for optimizing the efficacy and longevity of spinal cord stimulators. This case report highlights an uncommon case of implantable pulse generator site calcification that was discovered incidentally on spinal cord stimulator explant.

Large-scale map of RNA binding protein interactomes across the mRNA life-cycle.

Messenger RNAs (mRNAs) interact with RNA-binding proteins (RBPs) in diverse ribonucleoprotein complexes (RNPs) during distinct life-cycle stages for their processing and maturation. While substantial attention has focused on understanding RNA regulation by assigning proteins, particularly RBPs, to specific RNA substrates, there has been considerably less exploration leveraging protein-protein interaction (PPI) methodologies to identify and study the role of proteins in mRNA life-cycle stages. To address this gap, we generated an RNA-aware RBP-centric PPI map across the mRNA life-cycle by immunopurification (IP-MS) of ~100 endogenous RBPs across the life-cycle in the presence or absence of RNase, augmented by size exclusion chromatography (SEC-MS). Aside from confirming 8,700 known and discovering 20,359 novel interactions between 1125 proteins, we determined that 73% of our IP interactions are regulated by the presence of RNA. Our PPI data enables us to link proteins to life-cycle stage functions, highlighting that nearly half of the proteins participate in at least two distinct stages. We show that one of the most highly interconnected proteins, ERH, engages in multiple RNA processes, including via interactions with nuclear speckles and the mRNA export machinery. We also demonstrate that the spliceosomal protein SNRNP200 participates in distinct stress granule-associated RNPs and occupies different RNA target regions in the cytoplasm during stress. Our comprehensive RBP-focused PPI network is a novel resource for identifying multi-stage RBPs and exploring RBP complexes in RNA maturation.

Investigation of CRISPR-Independent Phage Resistance Mechanisms Reveals a Role for FtsH in Phage Adsorption to Streptococcus thermophilus.

Prokaryotes are under constant pressure from phage infection and thus have evolved multiple means of defense or evasion. While CRISPR-Cas constitutes a robust immune system and appears to be the predominant means of survival for Streptococcus thermophilus when facing lytic phage infection, other forms of phage resistance coexist in this species. Here, we show that S. thermophilus strains with deleted CRISPR-Cas loci can still give rise to phage-resistant clones following lytic phage challenge. Notably, non-CRISPR phage-resistant survivors had multiple mutations which would truncate or recode a membrane-anchored host protease, FtsH. Phage adsorption was dramatically reduced in FtsH mutants, implicating this protein in phage attachment. Phages were isolated which could bypass FtsH-based resistance through mutations predicted to alter tape measure protein translation. Together, these results identify key components in phage propagation that are subject to mutation in the molecular arms race between phage and host cell. IMPORTANCE Streptococcus thermophilus is an important organism for production of cultured dairy foods, but it is susceptible to lytic phages which can lead to failed products. Consequently, mechanisms for phage resistance are an active area of research. One such mechanism is CRISPR-Cas, and S. thermophilus is a model organism for the study of this form of adaptive immunity. Here, we expand on known mechanisms with our finding that spontaneous mutations in ftsH, a gene encoding a membrane-anchored protease, protected against phage infection by disrupting phage adsorption. In turn, mutations in phage tail protein genes allowed phages to overcome ftsH-based resistance. Our results identified components in phage propagation that are subject to mutation in the molecular arms race between phage and host.

Need a flu jab? Let's try pharmacy: patient characteristics and experiences with pharmacy immunisation services.

OBJECTIVES: New Zealand pharmacists have been providing immunisation services since 2011. Literature from other developed countries reports the positive experience of people with community pharmacy immunisation services resulting in expansion of the scope of pharmacy practice. However, there is a dearth of such data in a New Zealand context. Therefore, we aimed to understand patients' experiences with pharmacy immunisation services in New Zealand. METHODS: A self-administered questionnaire developed after considering the aims and objectives of the study, and previously published literature was delivered to 14 pharmacies covering a range of socio-economic areas across New Zealand. The survey assessed patients' experiences in a community pharmacy setting and measured their satisfaction using a 5-point Likert scale. KEY FINDINGS: Out of the 364 survey participants, 60.7% were female, 76.9% were of European ethnicity and 43.4% belonged to the age group of 45-64 years. Convenience (65.4%) and accessibility (44.8%) were cited as the most common reasons for choosing a community pharmacy to receive vaccinations. Over 90% of the respondents reported that they were satisfied with the pharmacy immunisation services, were vaccinated professionally, would choose a community pharmacy again next time for vaccination and would like to see pharmacists administering other vaccines. CONCLUSIONS: The pharmacy immunisation services were highly valued by patients because of the associated convenience and professionalism demonstrated by the pharmacists. A possible expansion of pharmacist-administered vaccination services to a wider range of vaccines will not only improve access to immunisation but will also potentially escalate immunisation rates.

Viral reactivations and co-infections in COVID-19 patients: a systematic review.

BACKGROUND: Viral reactivations and co-infections have been reported among COVID-19 patients. However, studies on the clinical outcomes of different viral reactivations and co-infections are currently in limit. Thus, the primary purpose of this review is to perform an overarching investigation on the cases of latent virus reactivation and co-infection in COVID-19 patients to build collective evidence contributing to improving patient health. The aim of the study was to conduct a literature review to compare the patient characteristics and outcomes of reactivations and co-infections of different viruses. METHODS: Our population of interest included confirmed COVID-19 patients who were diagnosed with a viral infection either concurrently or following their COVID-19 diagnosis. We extracted the relevant literature through a systematic search using the key terms in the online databases including the EMBASE, MEDLINE, Latin American Caribbean Health Sciences Literature (LILACS), from inception onwards up to June 2022. The authors independently extracted data from eligible studies and assessed the risk of bias using the Consensus-based Clinical Case Reporting (CARE) guidelines and the Newcastle-Ottawa Scale (NOS). Main patient characteristics, frequency of each manifestation, and diagnostic criteria used in studies were summarized in tables. RESULTS: In total, 53 articles were included in this review. We identified 40 reactivation studies, 8 coinfection studies, and 5 studies where concomitant infection in COVID-19 patients was not distinguished as either reactivation or coinfection. Data were extracted for 12 viruses including IAV, IBV, EBV, CMV, VZV, HHV-1, HHV-2, HHV-6, HHV-7, HHV-8, HBV, and Parvovirus B19. EBV, HHV-1, and CMV were most frequently observed within the reactivation cohort, whereas IAV and EBV within the coinfection cohort. In both reactivation and coinfection groups, patients reported cardiovascular disease, diabetes, and immunosuppression as comorbidities, acute kidney injury as complication, and lymphopenia and elevated D-dimer and CRP levels from blood tests. Common pharmaceutical interventions in two groups included steroids and antivirals. CONCLUSION: Overall, these findings expand our knowledge on the characteristics of COVID-19 patients with viral reactivations and co-infections. Our experience with current review indicates a need for further investigations on virus reactivation and coinfection among COVID-19 patients.