New Heterocyclic Compounds from Oxazol-5(4H)-one and 1,2,4-Triazin-6(5H)-one Classes: Synthesis, Characterization and Toxicity Evaluation.

This paper describes the synthesis of new heterocycles from oxazol-5(4H)-one and 1,2,4-triazin-6(5H)-one classes containing a phenyl-/4-bromophenylsulfonylphenyl moiety. The oxazol-5(4H)-ones were obtained via condensation of 2-(4-(4-X-phenylsulfonyl)benzamido)acetic acids with benzaldehyde/4-fluorobenzaldehyde in acetic anhydride and in the presence of sodium acetate. The reaction of oxazolones with phenylhydrazine, in acetic acid and sodium acetate, yielded the corresponding 1,2,4-triazin-6(5H)-ones. The structures of the compounds were confirmed using spectral (FT-IR, 1H-NMR, 13C-NMR, MS) and elemental analysis. The toxicity of the compounds was evaluated on Daphnia magna Straus crustaceans and on the budding yeast Saccharomyces cerevisiae. The results indicate that both the heterocyclic nucleus and halogen atoms significantly influenced the toxicity against D. magna, with the oxazolones being less toxic than triazinones. The halogen-free oxazolone had the lowest toxicity, and the fluorine-containing triazinone exhibited the highest toxicity. The compounds showed low toxicity against yeast cells, apparently due to the activity of plasma membrane multidrug transporters Pdr5 and Snq2. The predictive analyses indicated an antiproliferative effect as the most probable biological action. The PASS prediction and CHEMBL similarity studies show evidence that the compounds could inhibit certain relevant oncological protein kinases. These results correlated with toxicity assays suggest that halogen-free oxazolone could be a good candidate for future anticancer investigations.

Montreal cognitive assessment for evaluating cognitive impairment in Huntington's disease: a systematic review.

OBJECTIVE: This study aims to systematically review evidence of the accuracy of the Montreal Cognitive Assessment (MoCA) for evaluating the presence of cognitive impairment in patients with Huntington's disease (HD) and to outline the quality and quantity of research evidence available about the use of the MoCA in this population. METHODS: We conducted a systematic literature review, searching four databases from inception until April 2020. RESULTS: We identified 26 studies that met the inclusion criteria: two case-control studies comparing the MoCA to a battery of tests, three studies comparing MoCA to Mini-Mental State Examination, two studies estimating the prevalence of cognitive impairment in individuals with HD and 19 studies or clinical trials in which the MoCA was used as an instrument for the cognitive assessment of participants with HD. We found no cross-sectional studies in which participants received the index test (MoCA) and a reference standard diagnostic assessment composed of an extensive neuropsychological battery. The publication period ranged from 2010 to 2020. CONCLUSIONS: In patients with HD, the MoCA provides information about disturbances in general cognitive function. Even if the MoCA demonstrated good sensitivity and specificity when used at the recommended threshold score of 26, further cross-sectional studies are required to examine the optimum cutoff score for detecting cognitive impairments in patients with HD. Moreover, more studies are necessary to determine whether the MoCA adequately assesses cognitive status in individuals with HD.

Montreal Cognitive Assessment (MoCA) for HIV-Associated Neurocognitive Disorders.

This study aims to systematically review the evidence on the accuracy of the Montreal Cognitive Assessment (MoCA) test for diagnosing HIV-associated neurocognitive disorders (HAND) and to outline the quality and quantity of research evidence available about the accuracy of MoCA in populations infected with HIV. We conducted a systematic literature review, searching five databases from inception until January 2019. We extracted dichotomized positive and negative test results at various thresholds and calculated the sensitivity and specificity of MoCA. Quality assessment was performed according to the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) criteria. Eight cross-sectional studies met the inclusion criteria for meta-analysis. Overall, 1014 patients were included but most studies recruited small samples. Recruitment period ranged from 2009 to 2015. We assessed most studies as being applicable to the review question though we had concerns about the selection of participants in three studies. The accuracy of MoCA for diagnosing HAND was reported at six cut-off points (scores 22-27). The MoCA test provides information about general cognitive functioning disturbances that contribute to a diagnosis of HAND. A lower threshold than the original cut-off of 26 is probably more useful for optimal screening of HAND, as it lowers false positive rates and improves diagnostic accuracy. Nonetheless, the choice of cut-off always comes with a sensitivity-specificity trade-off, the preferred cut point depending on whether sensitivity or specificity is more valuable in a given context.

Thermosensitive, near-infrared-labeled nanoparticles for topotecan delivery to tumors.

Liposomal nanoparticles have proven to be versatile systems for drug delivery. However, the progress in clinic has been slower and less efficient than expected. This suggests a need for further development using carefully designed chemical components to improve usefulness under clinical conditions and maximize therapeutic effect. For cancer chemotherapy, PEGylated liposomes were the first nanomedicine to reach the market and have been used clinically for several years. Approaches toward targeted drug delivery using next generation "thermally triggered" nanoparticles are now in clinical trials. However, clinically tested thermosensitive liposomes (TSLs) lack the markers that allow tumor labeling and improved imaging for tissue specific applied hyperthermia. Here we describe the development of optically labeled TSLs for image guidance drug delivery and proof-of-concept results for their application in the treatment of murine xenograft tumors using the anticancer drug topotecan. These labeled TSLs also allow the simultaneous, real-time diagnostic imaging of nanoparticle biodistribution using a near-infrared (NIR; 750-950 nm) fluorophore coupled to a lipidic component of the lipid bilayer. When combined with multispectral fluorescence analysis, this allows for specific and high sensitivity tracking of the nanoparticles in vivo. The application of NIR fluorescence-labeled TSLs could have a transformative effect on future cancer chemotherapy.

Parsonage-Turner Syndrome following COVID-19 Vaccination: A Systematic Review.

BACKGROUND: Parsonage-Turner syndrome (PTS) is an inflammatory condition of the brachial plexus, with more than half of patients presenting a trigger, such as infection or vaccination. Our objective was to synthesize the clinical and paraclinical features, therapeutic responses, and outcomes of PTS post-COVID-19 vaccination. METHODS: We systematically reviewed two databases (LitCOVID and the WHO database on COVID-19) up to January 2024 following a published protocol (OSF registries). RESULTS: We included 59 cases. PTS occurred more frequently in males (61.1% mRNA group, 83.3% viral vector group). Patients in the mRNA group were younger (41.7% between 41 and 50 years vs. 38.9% between 61 and 70 years). Most cases had sudden pain within two weeks. Unilateral PTS was present in 94.4% of mRNA and all viral vector-vaccinated cases. Symptoms included pain (97.1% and 92.3%, respectively), usually followed within two weeks by motor deficits (97.2% and 94.1%, respectively), amyotrophy (30% and 81.8%, respectively), paresthesia (50% and 27.3%, respectively), and sensory loss (33.3% and 38.5%, respectively). Viral vector vaccine recipients had nerve involvement outside the brachial plexus. Ancillary investigations revealed CSF albuminocytological dissociation (33.3% and 100%, respectively) and ipsilateral axillary lymphadenopathy. Two PTS cases worsened after the second mRNA dose, and another recurred after influenza vaccination. One patient well tolerated the second dose of the viral vector vaccine, but symptoms reemerged in another. CONCLUSIONS: Current evidence suggests PTS may occur after all COVID-19 vaccine types, with some subgroup differences. Also, PTS might recur with subsequent similar or unrelated vaccines.

Synergy between a collagen IV mimetic peptide and a somatotropin-domain derived peptide as angiogenesis and lymphangiogenesis inhibitors.

Angiogenesis is central to many physiological and pathological processes. Here we show two potent bioinformatically-identified peptides, one derived from collagen IV and translationally optimized, and one from a somatotropin domain-containing protein, synergize in angiogenesis and lymphangiogenesis assays including cell adhesion, migration and in vivo Matrigel plugs. Peptide-peptide combination therapies have recently been applied to diseases such as human immunodeficiency virus (HIV), but remain uncommon thus far in cancer, age-related macular degeneration and other angiogenesis-dependent diseases. Previous work from our group has shown that the collagen IV-derived peptide primarily binds ß1 integrins, while the receptor for the somatotropin-derived peptide remains unknown. We investigate these peptides' mechanisms of action and find both peptides affect the vascular endothelial growth factor (VEGF) pathway as well as focal adhesion kinase (FAK) by changes in phosphorylation level and total protein content. Blocking of FAK both through binding of ß1 integrins and through inhibition of VEGFR2 accounts for the synergy we observe. Since resistance through activation of multiple signaling pathways is a central problem of anti-angiogenic therapies in diseases such as cancer, we suggest that peptide combinations such as these are an approach that should be considered as a means to sustain anti-angiogenic and anti-lymphangiogenic therapy and improve efficacy of treatment.

Chorea following SARS-CoV-2 infection and vaccination: a systematic review of reported cases.

OBJECTIVES: Chorea following SARS-CoV-2 infection and vaccination, has been increasingly recognized. We aimed to synthesize clinical and paraclinical characteristics, treatment responses, and outcomes of this neurologic complication. METHODS: We systematically reviewed LitCOVID, the World Health Organization database on COVID-19, and MedRxiv up to March 2023, following a published protocol. RESULTS: We included 14 chorea cases in patients with SARS-CoV-2 infection and eight following COVID-19 vaccination. Acute or subacute chorea preceded COVID-19 symptoms within 1-3 days or developed up to 3 months after infection. Frequently it was generalized (85.7%), with associated neurological manifestations (encephalopathy 35.7%; other movement disorders 7.1%). After vaccination, chorea had a sudden onset (87.5%) within 2 weeks (75%); 87.5% of cases presented hemichorea, with hemiballismus (37.5%) or other movement disorders; 12.5% presented additional neurological findings. Cerebrospinal fluid was normal in 50% of infected individuals but abnormal in all vaccinated cases. Brain magnetic resonance imaging detected normal basal ganglia in 51.7% of infection cases and 87.5% following vaccination. CONCLUSION: In SARS-CoV-2 infection, chorea may present several pathogenic mechanisms: autoimmune response to infection, direct infection-related injury, or an infection-related complication (i.e., acute disseminated encephalomyelitis, cerebral venous sinus thrombosis, hyperglycemia); also, previous Sydenham chorea may relapse. After COVID-19 vaccination, chorea could be due to an autoimmune reaction or other mechanisms (vaccine-induced hyperglycemia, stroke).

Assessment and Diagnosis of HIV-Associated Dementia.

The modern combined antiretroviral treatment (cART) for human immunodeficiency virus (HIV) infection has substantially lowered the incidence of HIV-associated dementia (HAD). The dominant clinical features include deficits in cognitive processing speed, concentration, attention, and memory. As people living with HIV become older, with high rates of comorbidities and concomitant treatments, the prevalence and complexity of cognitive impairment are expected to increase. Currently, the management of HAD and milder forms of HAND is grounded on the best clinical practice, as there is no specific, evidence-based, proven intervention for managing cognitive impairment. The present article acknowledges the multifactorial nature of the cognitive impairments found in HIV patients, outlining the current concepts in the field of HAD. Major areas of interest include neuropsychological testing and neuroimaging to evaluate CNS status, focusing on greater reliability in the exclusion of associated diseases and allowing for earlier diagnosis. Additionally, we considered the evidence for neurological involvement in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the impact of the coronavirus (COVID-19) pandemic, with wider consequences to population health than can be attributed to the virus itself. The indirect effects of COVID-19, including the increased adoption of telehealth, decreased access to community resources, and social isolation, represent a significant health burden, disproportionately affecting older adults with dementia who have limited social networks and increased functional dependence on the community and health system. This synopsis reviews these aspects in greater detail, identifying key gaps and opportunities for researchers and clinicians; we provide an overview of the current concepts in the field of HAD, with suggestions for diagnosing and managing this important neurological complication, which is intended to be applicable across diverse populations, in line with clinical observations, and closely representative of HIV brain pathology.

Parsonage-Turner Syndrome Following SARS-CoV-2 Infection: A Systematic Review.

Parsonage-Turner syndrome (PTS) is an inflammatory disorder of the brachial plexus. Hypothesized underlying causes focus on immune-mediated processes, as more than half of patients present some antecedent event or possible predisposing condition, such as infection, vaccination, exercise, or surgery. Recently, PTS was reported following the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We aimed to investigate data on PTS triggered by SARS-CoV-2 infection to provide an extensive perspective on this pathology and to reveal what other, more specific, research questions can be further addressed. In addition, we aimed to highlight research gaps requiring further attention. We systematically reviewed two databases (LitCOVID and the World Health Organization database on COVID-19) to January 2023. We found 26 cases of PTS in patients with previous SARS-CoV-2 infection. The clinical and paraclinical spectrum was heterogeneous, ranging from classical PTS to pure sensory neuropathy, extended neuropathy, spinal accessory nerve involvement, and diaphragmatic palsy. Also, two familial cases were reported. Among them, 93.8% of patients had severe pain, 80.8% were reported to present a motor deficit, and 53.8% of patients presented muscle wasting. Paresthesia was noted in 46.2% of PTS individuals and a sensory loss was reported in 34.6% of patients. The present systematic review highlights the necessity of having a high index of suspicion of PTS in patients with previous SARS-CoV-2 infection, as the clinical manifestations can be variable. Also, there is a need for a standardized approach to investigation and reporting on PTS. Future studies should aim for a comprehensive assessment of patients. Factors including the baseline characteristics of the patients, evolution, and treatments should be consistently assessed across studies. In addition, a thorough differential diagnosis should be employed.

Emerging Trends in Complications Associated with SARS-CoV-2 Infection.

The coronavirus disease 2019 (COVID-19) pandemic has presented a remarkable challenge to global health, sparking a surge in research aimed at understanding the multifaceted impacts of the virus [...].

Coinfection with Strongyloides and SARS-CoV-2: A Systematic Review.

BACKGROUND: Treatments for COVID-19, including steroids, might exacerbate Strongyloides disease in patients with coinfection. We aimed to systematically review clinical and laboratory features of SARS-CoV-2 and Strongyloides coinfection, investigate possible interventions, assess outcomes, and identify research gaps requiring further attention. METHODS: We searched two electronic databases, LitCOVID and WHO, up to August 2022, including SARS-CoV-2 and Strongyloides coinfection studies. We adapted the World Health Organization-Uppsala Monitoring Centre (WHO-UMC) system for standardized case causality assessment to evaluate if using corticosteroids or other immunosuppressive drugs in COVID-19 patients determined acute manifestations of strongyloidiasis. RESULTS: We included 16 studies reporting 25 cases of Strongyloides and SARS-CoV-2 coinfection: 4 with hyperinfection syndrome; 2 with disseminated strongyloidiasis; 3 with cutaneous reactivation of strongyloidiasis; 3 with isolated digestive symptoms; and 2 with solely eosinophilia, without clinical manifestations. Eleven patients were asymptomatic regarding strongyloidiasis. Eosinopenia or normal eosinophil count was reported in 58.3% of patients with Strongyloides reactivation. Steroids were given to 18/21 (85.7%) cases. A total of 4 patients (19.1%) received tocilizumab and/or Anakirna in addition to steroids. Moreover, 2 patients (9.5%) did not receive any COVID-19 treatment. The causal relationship between Strongyloides reactivation and COVID-19 treatments was considered certain (4% of cases), probable (20% of patients), and possible (20% of patients). For 8% of cases, it was considered unlikely that COVID-19 treatment was associated with strongyloidiasis reactivations; the relationship between the Strongyloides infection and administration of COVID-19 treatment was unassessable/unclassifiable in 48% of cases. Of 13 assessable cases, 11 (84.6%) were considered to be causally associated with Strongyloides, ranging from certain to possible. CONCLUSIONS: Further research is needed to assess the frequency and risk of Strongyloides reactivation in SARS-CoV-2 infection. Our limited data using causality assessment supports recommendations that clinicians should screen and treat for Strongyloides infection in patients with coinfection who receive immunosuppressive COVID-19 therapies. In addition, the male gender and older age (over 50 years) may be predisposing factors for Strongyloides reactivation. Standardized guidelines should be developed for reporting future research.

COVID19-associated new-onset movement disorders: a follow-up study.

BACKGROUND: Neurological symptoms are common manifestation in acute COVID-19. This includes hyper- and hypokinetic movement disorders. Data on their outcome, however, is limited. METHODS: Cases with new-onset COVID-19-associated movement disorders were identified by searching the literature. Authors were contacted for outcome data which were reviewed and analyzed. RESULTS: Movement disorders began 12.6 days on average after the initial onset of COVID-19. 92% of patients required hospital admission (mean duration 23 days). In a fraction of patients (6 of 27; 22%; 4 males/2 females, mean age 66.8 years) the movement disorder (ataxia, myoclonus, tremor, parkinsonism) was still present after a follow-up period of 7.5 ± 3 weeks. Severe COVID-19 in general and development of encephalopathy were risk factors, albeit not strong predictors, for the persistence. CONCLUSIONS: The prognosis of new-onset COVID-19-associated movement disorder appears to be generally good. The majority recovered without residual symptoms within several weeks or months. Permanent cases may be due to unmasking of a previous subclinical movement disorder or due to vascular/demyelinating damage. Given the relatively low response rate of one third only and the heterogeneity of mechanisms firm conclusions on the (long-term) outome cannot, however, be drawn.

Collagen IV and CXC chemokine-derived antiangiogenic peptides suppress glioma xenograft growth.

Peptides are receiving increasing attention as therapeutic agents due to their high binding specificity and versatility to be modified as targeting or carrier molecules. Particularly, peptides with antiangiogenic activity are of high interest because of their applicability to a wide range of cancers. In this study, we investigate the biological activity of two novel antiangiogenic peptides in preclinical glioma models. One peptide SP2000 is derived from collagen IV and the other peptide SP3019 belongs to the CXC family. We have previously characterized the capacity of SP2000 and SP3019 to inhibit multiple biological endpoints linked to angiogenesis in human endothelial cells in several assays. Here, we report additional studies using endothelial cells and focus on the activity of these peptides against human glioma cell growth, migration and adhesion in vitro, and growth as tumor xenografts in vivo. We found that SP2000 completely inhibits migration of the glioma cells at 50 µmol/l and SP3019 produced 50% inhibition at 100 µmol/l. Their relative antiadhesion activities were similar, with SP2000 and SP3019 generating 50% adhesion inhibition at 4.9 ± 0.82 and 21.3 ± 5.92 µmol/l, respectively. In-vivo glioma growth inhibition was 63% for SP2000 and 76% for SP3019 after 2 weeks of administration at daily doses of 10 and 20 mg/kg, respectively. The direct activity of these peptides against glioma cells in conjunction with their antiangiogenic activities warrants their further development as either stand-alone agents or in combination with standard cytotoxic or emerging targeted therapies in malignant brain tumors.

Montreal Cognitive Assessment for Evaluating Cognitive Impairment in Subarachnoid Hemorrhage: A Systematic Review.

Subarachnoid hemorrhage (SAH) is a severe condition with high mortality and extensive long-term morbidity. Although research has focused mainly on physical signs and disability for decades, in recent years, it has been increasingly recognized that cognitive and psychological impairments may be present in many patients with SAH, negatively impacting their quality of life. We performed a systematic review aiming to provide a comprehensive report on the diagnostic accuracy of the Montreal Cognitive Assessment (MoCA) test for evaluating the presence of cognitive impairment in patients with SAH. Using appropriate search terms, we searched five databases (PubMed, Scopus, PsychINFO, Web of Sciences, and Latin American and Caribbean Health Sciences Literature) up to January 2022. Two cross-sectional studies investigated the accuracy of MoCA in SAH patients in the subacute and chronic phase. We appraised the quality of the included studies using the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) criteria. The MoCA test provides information about general cognitive functioning disturbances. However, a lower threshold than the original cutoff might be needed as it improves diagnostic accuracy, lowering the false positive rates. Further research is necessary for an evidence-based decision to use the MoCA in SAH patients.

Subarachnoid Hemorrhage in Patients with SARS-CoV-2 Infection: Protocol for A Scoping Review.

Subarachnoid hemorrhage (SAH) is a life-threatening condition associated with high mortality and substantial long-term morbidity. The SARS-CoV-2 virus is a new pathogen that causes a disease with variable clinical manifestations. Although the Coronavirus disease 2019 (COVID-19) is associated with hypercoagulopathy, patients may also present with cerebral hemorrhage, including SAH. The present paper reports a protocol for a scoping review that is aimed to provide a comprehensive report on existing literature by examining data on SAH associated with SARS-CoV-2 infection. Our objective is to evaluate the epidemiology, clinical, laboratory, and neuroimaging features of SAH in patients with COVID-19 and to explore the etiology and possible interventions in this pathology. Using appropriate search terms, we will search LitCOVID, the WHO database on COVID-19, and MedRxiv. The inclusion criteria are pre-defined. We will extract the data of eligible studies in standardized forms and will report the results in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR). We will provide information for clinicians, healthcare providers, and public health specialists.

Wernicke Encephalopathy Presenting with Dysphagia: A Case Report and Systematic Literature Review.

Wernicke encephalopathy (WE) is a well-known neurological condition caused by thiamine (vitamin B1) deficiency that occurs in both alcoholic and non-alcoholic populations. We aimed to report a case of a patient with WE who presented with dysphagia and dysphonia and later developed typical symptoms of thiamine deficiency and to conduct a systematic review of the literature on this rare presentation of WE. We searched two databases (PubMed and Scopus) and included publications up to November 2022. We found 12 cases of WE and dysphagia, aged between 12 and 81 years; swallowing problems presented at the onset in nine patients (including the current case report). Our findings suggest that thiamine deficiency should be suspected in patients with dysphagia of unknown cause, even in the absence of alcohol abuse. In contrast to most WE patients, the majority of patients included in this review presented with dysphagia at the onset of their disease, even in the absence of the classic triad of cognitive impairment, ataxia, and oculomotor abnormalities, indicating that there could be varying susceptibilities to clinical manifestations of thiamine deficiency in different brain regions.

HIV-Associated Neurocognitive Disorder (HAND): Obstacles to Early Neuropsychological Diagnosis.

Despite the recent advances in HIV treatment, HIV-associated neurocognitive disorder (HAND) prevalence remains high, especially in the mild forms. Current recommendations endorse routine screening for HAND and early identification, but there are several obstacles in diagnosing and managing cognitive impairment in people living with HIV. The purpose of this review is to provide an overview of the concepts and diagnostic tools in the field of HAND and report on the strengths and limitations of currently available approaches.

Movement Disorders Induced by SARS-CoV-2 Infection: Protocol for a Scoping Review.

Infections are a significant cause of movement disorders. The clinical manifestations of SARS-CoV-2 infection are variable, with up to one-third of patients developing neurologic complications, including movement disorders. This scoping review will lay out a comprehensive understanding of movement disorders induced by SARS-CoV-2 infection. We aim to investigate the epidemiology, clinical and paraclinical features, interventions, and diagnostic challenges in patients with different types of movement disorders in the context of SARS-CoV-2 infection. We will search three databases applying appropriate search terms. Inclusion and exclusion criteria are pre-defined; the data of eligible studies will be extracted in standardized forms. We will report the results following Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR). We will present information for clinicians and other healthcare professionals, policymakers, and public health researchers. In addition, the results of the present review may assist in the development and confirmation of inclusion criteria and research questions for further systematic review or meta-analysis, with more precise, narrower questions.

Transmission of SARS-CoV-2 Associated with Cruise Ship Travel: A Systematic Review.

Background: Maritime and river travel may be associated with respiratory viral spread via infected passengers and/or crew and potentially through other transmission routes. The transmission models of SARS-CoV-2 associated with cruise ship travel are based on transmission dynamics of other respiratory viruses. We aimed to provide a summary and evaluation of relevant data on SARS-CoV-2 transmission aboard cruise ships, report policy implications, and highlight research gaps. Methods: We searched four electronic databases (up to 26 May 2022) and included studies on SARS-CoV-2 transmission aboard cruise ships. The quality of the studies was assessed based on five criteria, and relevant findings were reported. Results: We included 23 papers on onboard SARS-CoV-2 transmission (with 15 reports on different aspects of the outbreak on Diamond Princess and nine reports on other international cruises), 2 environmental studies, and 1 systematic review. Three articles presented data on both international cruises and the Diamond Princess. The quality of evidence from most studies was low to very low. Index case definitions were heterogeneous. The proportion of traced contacts ranged from 0.19 to 100%. Studies that followed up >80% of passengers and crew reported attack rates (AR) up to 59%. The presence of a distinct dose−response relationship was demonstrated by findings of increased ARs in multi-person cabins. Two studies performed viral cultures with eight positive results. Genomic sequencing and phylogenetic analyses were performed in individuals from three cruises. Two environmental studies reported PCR-positive samples (cycle threshold range 26.21−39.00). In one study, no infectious virus was isolated from any of the 76 environmental samples. Conclusion: Our review suggests that crowding and multiple persons per cabin were associated with an increased risk of transmission on cruise ships. Variations in design, methodology, and case ascertainment limit comparisons across studies and quantification of transmission risk. Standardized guidelines for conducting and reporting studies on cruise ships of acute respiratory infection transmission should be developed.

Transmission of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) from pre and asymptomatic infected individuals: a systematic review.

BACKGROUND: The role of SARS-Cov-2-infected persons who develop symptoms after testing (presymptomatics) or not at all (asymptomatics) in the pandemic spread is unknown. OBJECTIVES: To determine infectiousness and probable contribution of asymptomatic persons (at the time of testing) to pandemic SARS-CoV-2 spread. DATA SOURCES: LitCovid, medRxiv, Google Scholar, and WHO Covid-19 databases (to 31 March 2021) and references in included studies. STUDY ELIGIBILITY CRITERIA: Studies with a proven or hypothesized transmission chain based either on serial PCR cycle threshold readings and/or viral culture and/or gene sequencing, with adequate follow-up. PARTICIPANTS: People exposed to SARS-CoV-2 within 2-14 days to index asymptomatic (at time of observation) infected individuals. INTERVENTIONS: Reliability of symptom and signs was assessed within contemporary knowledge; transmission likelihood was assessed using adapted causality criteria. METHODS: Systematic review. We contacted all included studies' corresponding authors requesting further details. RESULTS: We included 18 studies from a diverse setting with substantial methodological variation (this field lacks standardized methodology). At initial testing, prevalence of asymptomatic cases was 12.5-100%. Of these, 6-100% were later determined to be presymptomatic, this proportion varying according to setting, methods of case ascertainment and population. Nursing/care home facilities reported high rates of presymptomatic: 50-100% (n = 3 studies). Fourteen studies were classified as high risk of, and four studies as at moderate risk of symptom ascertainment bias. High-risk studies may be less likely to distinguish between presymptomatic and asymptomatic cases. Six asymptomatic studies and four presymptomatic studies reported culturing infectious virus; data were too sparse to determine infectiousness duration. Three studies provided evidence of possible and three of probable/likely asymptomatic transmission; five studies provided possible and two probable/likely presymptomatic SARS-CoV-2 transmission. CONCLUSION: High-quality studies provide probable evidence of SARS-CoV-2 transmission from presymptomatic and asymptomatic individuals, with highly variable estimated transmission rates.