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1.
J Hosp Infect ; 2024 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-38492645

RESUMO

OBJECTIVES: There is limited data on the effects of discontinuing single-room isolation while maintaining contact precautions, such as the use of gowns and gloves. In April 2021, our hospital ceased single-room isolation for patients with VRE because of single-room unavailability. This study assessed the impact of this policy by examining the incidence of hospital-acquired VRE bloodstream infections (HA-VRE BSI). METHODS: This retrospective quasi-experimental study was conducted at a tertiary care hospital in Seoul, South Korea. Time-series analysis was used to evaluate HA-VRE BSI incidence at the hospital level and in the hematology unit before (phase 1) and after (phase 2) the policy change. RESULTS: At the hospital level, HA-VRE BSI incidence level (VRE BSI per 1000 patient-days per month) and trend did not change significantly between phase 1 and phase 2 (coefficient -0.015, 95% confidence interval [CI]: -0.053 - 0.023, P = 0.45 and 0.000, 95% CI: -0.002 - 0.002, P = 0.84, respectively). Similarly, HA-VRE BSI incidence level and trend in the hematology unit (-0.285, 95% CI: -0.618 - 0.048, P = 0.09 and -0.018, 95% CI: -0.036 - 0.000, P = 0.054, respectively) did not change significantly across the two phases. CONCLUSIONS: Discontinuing single-room isolation of VRE-colonized or infected patients was not associated with an increase in the incidence of VRE BSI at the hospital level or among high-risk patients in the hematology unit. Horizontal intervention for multidrug-resistant organisms, including measures like enhanced hand hygiene and environmental cleaning, may be more effective at preventing VRE transmission.

2.
Commun Biol ; 7(1): 162, 2024 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-38332126

RESUMO

Modulation of cell death is a powerful strategy employed by pathogenic bacteria to evade host immune clearance and occupy profitable replication niches during infection. Intracellular pathogens employ the type III secretion system (T3SS) to deliver effectors, which interfere with regulated cell death pathways to evade immune defenses. Here, we reveal that poly(ADP-ribose) polymerase-1 (PARP1)-dependent cell death restrains Edwardsiella piscicida's proliferation in mouse monocyte macrophages J774A.1, of which PARP1 activation results in the accumulation of poly(ADP-ribose) (PAR) and enhanced inflammatory response. Moreover, E. piscicida, an important intracellular pathogen, leverages a T3SS effector YfiD to impair PARP1's activity and inhibit PAR accumulation. Once translocated into the host nucleus, YfiD binds to the ADP-ribosyl transferase (ART) domain of PARP1 to suppress its PARylation ability as the pharmacological inhibitor of PARP1 behaves. Furthermore, the interaction between YfiD and ART mainly relies on the complete unfolding of the helical domain, which releases the inhibitory effect on ART. In addition, YfiD impairs the inflammatory response and cell death in macrophages and promotes in vivo colonization and virulence of E. piscicida. Collectively, our results establish the functional mechanism of YfiD as a potential PARP1 inhibitor and provide more insights into host defense against bacterial infection.


Assuntos
Edwardsiella , Infecções por Enterobacteriaceae , Animais , Camundongos , Sistemas de Secreção Tipo III/metabolismo , Poli Adenosina Difosfato Ribose , Virulência , Edwardsiella/metabolismo
3.
Cell Rep Methods ; 4(2): 100709, 2024 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-38359822

RESUMO

We establish a reliable method for selectively delivering adeno-associated viral vectors (AAVs) across the blood-brain barrier (BBB) in the marmoset without the need for neurosurgical injection. We focally perturbed the BBB (∼1 × 2 mm) in area 8aD of the frontal cortex in four adult marmoset monkeys using low-intensity transcranial focused ultrasound aided by microbubbles. Within an hour of opening the BBB, either AAV2 or AAV9 was delivered systemically via tail-vein injection. In all four marmosets, fluorescence-encoded neurons were observed at the site of BBB perturbation, with AAV2 showing a sparse distribution of transduced neurons when compared to AAV9. The results are compared to direct intracortical injections of anterograde tracers into area 8aD and similar (albeit sparser) long-range connectivity was observed. With evidence of transduced neurons specific to the region of BBB opening as well as long-distance tracing, we establish a framework for focal noninvasive transgene delivery to the marmoset brain.


Assuntos
Encéfalo , Callithrix , Animais , Encéfalo/fisiologia , Barreira Hematoencefálica , Transgenes , Neurônios
4.
Artigo em Inglês | MEDLINE | ID: mdl-38411778

RESUMO

PURPOSE: Distinguishing between complicated and uncomplicated Staphylococcus aureus bacteraemia (SAB) is therapeutically essential. However, this distinction has limitations in reflecting the heterogeneity of SAB and encouraging targeted diagnostics. Recently, a new risk stratification system for SAB metastatic infection, involving stepwise approaches to diagnosis and treatment, has been suggested. We assessed its applicability in methicillin-resistant SAB (MRSAB) patients. METHODS: We retrospectively analysed data of a 3-year multicentre, prospective cohort of hospitalised patients with MRSAB. We classified the patients into three risk groups: low, indeterminate, and high, based on the new system and compared between-group management and outcomes. RESULTS: Of 380 patients with MRSAB, 6.3% were classified as low-, 7.6% as indeterminate-, and 86.1% as high-risk for metastatic infection. No metastatic infection occurred in the low-, 6.9% in the indeterminate-, and 19.6% in the high-risk groups (P < 0.001). After an in-depth diagnostic work-up, patients were finally diagnosed as 'without metastatic infection (6.3%)', 'with metastatic infection (17.4%)', and 'uncertain for metastatic infection (76.3%)'. 30-day mortality increased as the severity of diagnosis shifted from 'without metastatic infection' to 'uncertain for metastatic infection' and 'with metastatic infection' (P = 0.09). In multivariable analysis, independent factors associated with metastatic complications were suspicion of endocarditis in transthoracic echocardiography, clinical signs of metastatic infection, Pitt bacteraemia score ≥ 4, and persistent bacteraemia. CONCLUSIONS: The new risk stratification system shows promise in predicting metastatic complications and guiding work-up and management of MRSAB. However, reducing the number of cases labelled as 'high-risk' and 'uncertain for metastatic infection' remains an area for improvement.

5.
Data Brief ; 52: 110002, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38226039

RESUMO

Pistacia chinensis and Pistacia weinmannifolia are small trees and are distributed in East Asia, in particular China. The data on P. chinensis presented in this article is associated with the research article, "DOI: 10.5010/JPB.2019.46.4.274" [1]. Both P. chinensis and P. weinmannifolia have long been used as ethnobotanical plants to treat various illnesses, including dysentery, inflammatory swelling, rheumatism, liver diseases, influenza, lung cancer, etc. Many studies have been carried out to delve into the pharmaceutical properties of these Pistacia species using plant extracts, but genomic studies are very rarely performed to date. To enrich the genetic information of these two species, RNA sequencing was conducted using a pair-end Illumina HiSeq2500 sequencing system, resulting in 2.6 G of raw data from P. chinensis (Accession no: SRR10136265) and 2.7 G bases from P. weinmannifolia (Accession no: SRR10136264). Transcriptome shotgun assembly using three different assembly tools generated a total of 18,524 non-redundant contigs (N50, 1104 bp) from P. chinensis and 18,956 from P. weinmannifolia (N50, 1137 bp). The data is accessible at NCBI BioProject: PRJNA566127. These data would be crucial for the identification of genes associated with the compounds exerting pharmaceutical properties and also for molecular marker development.

7.
J Infect Chemother ; 30(4): 300-305, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37890528

RESUMO

INTRODUCTION: We investigated the prevalence of fusidic acid (FA) resistance in MSSA and MRSA stratified by sequence (ST) and spa types, and determined the prevalence of FA resistance mechanisms. METHODS: From August 2014 to April 2020, S. aureus blood isolates were collected in Asan Medical Center, Seoul, South Korea. Antimicrobial susceptibility tests were performed using broth microdilution and interpreted according to EUCAST's FA criteria. We performed spa typing for fusA mutation presence and acquired FA resistance determinants (fusB, fusC, and fusD) by PCR. RESULTS: Of the 590 MRSA isolates, 372 were FA resistant, and among 425 MSSA isolates, 136 were resistant. Of the 380 ST5-MRSA isolates, 350 were FA resistant, whereas only 1 of 14 ST5-MSSA isolates was FA resistant. Conversely, of the 163 ST72-MRSA isolates, only 8 were resistant, whereas 37 of 42 ST72-MSSA were resistant. The fusA mutation (80%) was the most common determinant. The one FA resistant ST5-MSSA isolate belonged to the t2460 spa type, the most common spa type (24 of 35 isolates) of FA resistant ST5-MRSA. In addition, t324 and t148, which are minor spa types of ST72-MSSA, were susceptible to FA, in contrast to other ST72-MSSA spa types, and the major spa type of ST72-MRSA (110 of 163 isolates). CONCLUSIONS: FA resistance was common in ST5-MRSA and ST72-MSSA, and rare in ST5-MSSA and ST72-MRSA. Our findings suggest that minor clones of ST5-MSSA isolates, with the fusA mutation and minor clones of ST72-MSSA susceptible to FA, may have evolved to harbor the mecA gene.


Assuntos
Staphylococcus aureus Resistente à Meticilina , Infecções Estafilocócicas , Humanos , Staphylococcus aureus Resistente à Meticilina/genética , Ácido Fusídico/farmacologia , Ácido Fusídico/uso terapêutico , Staphylococcus aureus , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/epidemiologia , República da Coreia/epidemiologia
8.
Cereb Cortex ; 34(1)2024 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-37950874

RESUMO

Cortical neurons of eutherian mammals project to the contralateral hemisphere, crossing the midline primarily via the corpus callosum and the anterior, posterior, and hippocampal commissures. We recently reported and named the thalamic commissures (TCs) as an additional interhemispheric axonal fiber pathway connecting the cortex to the contralateral thalamus in the rodent brain. Here, we demonstrate that TCs also exist in primates and characterize the connectivity of these pathways with high-resolution diffusion-weighted MRI, viral axonal tracing, and fMRI. We present evidence of TCs in both New World (Callithrix jacchus and Cebus apella) and Old World primates (Macaca mulatta). Further, like rodents, we show that the TCs in primates develop during the embryonic period, forming anatomical and functionally active connections of the cortex with the contralateral thalamus. We also searched for TCs in the human brain, showing their presence in humans with brain malformations, although we could not identify TCs in healthy subjects. These results pose the TCs as a vital fiber pathway in the primate brain, allowing for more robust interhemispheric connectivity and synchrony and serving as an alternative commissural route in developmental brain malformations.


Assuntos
Substância Branca , Animais , Humanos , Substância Branca/diagnóstico por imagem , Encéfalo , Corpo Caloso/diagnóstico por imagem , Corpo Caloso/fisiologia , Tálamo/diagnóstico por imagem , Macaca mulatta , Mamíferos
9.
J Infect Chemother ; 30(4): 366-370, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37935348

RESUMO

Though remdesivir benefits COVID-19 patients, its use in those with renal dysfunction is currently limited due to concerns about possible toxic effects of accumulated sulfobutylether-ß-cyclodextrin (SBECD) on liver and kidney. We examined renal and hepatic function for a month in renally-impaired COVID-19 patients who were treated or not treated with remdesivir to assess the safety of the drug. A retrospective study was performed in adult COVID-19 patients with glomerular filtration rates of <30 ml/min/1.73 m2 at admission to a tertiary care hospital between November 2020 and March 2022. Data on serum creatinine and liver chemistry were collected serially. A total of 101 patients with impaired renal function were analyzed, comprising 64 remdesivir-treated patients and 37 who did not receive any antiviral agent. Although remdesivir-treated patients were more likely to be infected with the Omicron variant (79.7% vs. 48.6%), baseline characteristics did not differ significantly between the two groups. Among patients who initially did not require dialysis, 18.4% (7/38) of remdesivir-treated patients developed acute kidney injury (AKI) at days 4-6, compared with 51.7% (15/29) of non-remdesivir-treated patients. Liver injury severity worsened in 3.1% (2/64) of remdesivir-treated patients and 5.4% (2/37) of non-remdesivir-treated patients at days 4-6. In addition, there was no significant increase in AKI and liver injury over time in remdesivir-treated patients, and there were no cases of discontinuation of remdesivir due to adverse reactions. Concerns regarding the safety of SBECD should not lead to hasty withholding of remdesivir treatment in renally-impaired COVID-19 patients.


Assuntos
Injúria Renal Aguda , Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , COVID-19 , Adulto , Humanos , SARS-CoV-2 , Estudos Retrospectivos , Tratamento Farmacológico da COVID-19 , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/epidemiologia
10.
Antibiotics (Basel) ; 12(10)2023 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-37887212

RESUMO

Rifampin resistance (RIF-R) in Staphylococcus aureus (S. aureus) with rpoB mutations as one of its resistance mechanisms has raised concern about clinical treatment and infection prevention strategies. Data on the prevalence and molecular epidemiology of RIF-R S. aureus blood isolates in South Korea are scarce. We used broth microdilution to investigate RIF-R prevalence and analyzed the rpoB gene mutation in 1615 S. aureus blood isolates (772 methicillin-susceptible and 843 methicillin-resistant S. aureus (MRSA)) from patients with bacteremia, between 2008 and 2017. RIF-R prevalence and antimicrobial susceptibility were determined. Multilocus sequence typing was used to characterize the isolate's molecular epidemiology; Staphylococcus protein A (spa), staphylococcal cassette chromosome mec (SCCmec), and rpoB gene mutations were detected by PCR. Among 52 RIF-R MRSA isolates out of 57 RIF-R S. aureus blood isolates (57/1615, 0.4%; 5 methicillin-susceptible and 52 MRSA), ST5 (44/52, 84.6%), SCCmec IIb (40/52, 76.9%), and spa t2460 (27/52, 51.9%) were predominant. rpoB gene mutations with amino acid substitutions showed that A477D (17/48, 35.4%) frequently conferred high-level RIF resistance (MIC > 128 mg/L), followed by H481Y (4/48, 8.3%). RIF-R S. aureus blood isolates in South Korea have unique molecular characteristics and are closely associated with rpoB gene mutations. RIF-R surveillance through S. aureus-blood isolate epidemiology could enable effective therapeutic management.

11.
Eur J Clin Microbiol Infect Dis ; 42(12): 1439-1447, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37851178

RESUMO

PURPOSE: Increasing evidence has suggested that metformin may play positive roles in a wide range of infectious diseases. This study aimed to investigate the clinical impact of metformin exposure during Staphylococcus aureus bacteremia (SAB) in patients with diabetes. METHODS: A 3-year observational cohort study of 452 patients (aged ≥ 16 years) with SAB was performed at a tertiary care hospital. Metformin exposure was defined as receiving metformin during SAB, regardless of metformin use before the onset of bacteremia. RESULTS: Of 452 patients, 51 (11.3%) were classified in Group A (diabetes with metformin exposure), 115 (25.4%) in Group B (diabetes without metformin exposure), and 286 (63.3%) in Group C (no diabetes). The 30-day mortality rate in Group A was significantly lower than that in Group B (3.9% [2/51] versus 14.8% [17/115]; p = 0.04) and lower than that in Group C (3.9% [2/51] versus 17.1% [49/286]; p = 0.02). The mortality rates did not differ between Group B and Group C (14.8% [17/115] versus 17.1% [49/286]; p = 0.57). The rates of persistent and recurrent bacteremia were comparable among the three groups. Multivariate analysis indicated that metformin exposure was significantly associated with reduced mortality (adjusted odds ratio, 0.20; 95% confidence interval, 0.04-0.88; p = 0.03). CONCLUSIONS: Metformin exposure during SAB appears to be an independent predictor of survival in patients with diabetes.


Assuntos
Bacteriemia , Doenças Transmissíveis , Diabetes Mellitus , Infecções Estafilocócicas , Adolescente , Humanos , Bacteriemia/tratamento farmacológico , Bacteriemia/epidemiologia , Bacteriemia/microbiologia , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/epidemiologia , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus , Adulto
12.
Antimicrob Agents Chemother ; 67(11): e0082223, 2023 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-37874294

RESUMO

Klebsiella pneumoniae bacteremia is known to present a virulent clinical course, including multiple metastatic infections, which is not uncommon in Asia. However, there are limited data on the incidence and risk factors for ocular involvement in K. pneumoniae bacteremia. We retrospectively reviewed the medical records of all patients with K. pneumoniae bacteremia who underwent ophthalmologic examination in a tertiary center in Seoul, Korea, from February 2012 to December 2020. Two retinal specialists reviewed the findings of the ophthalmologic examinations and classified them as endophthalmitis, chorioretinitis, and no ocular involvement. Of 689 patients, 56 [8.1%; 95% confidence interval (CI) 6.2-10.4] had ocular involvement, and 9 (1.3%; 95% CI 0.6-2.5) were diagnosed with endophthalmitis. Of 47 patients with chorioretinitis, 45 (95.7%) improved with systemic antibiotic therapy alone. Community-onset bacteremia (100% vs 62.1% vs 57.4%, P = 0.04), cryptogenic liver abscess (55.6% vs 11.8% vs 8.5%, P = 0.003), and metastatic infection (66.7% vs 5.8% vs 10.6%, P < 0.001) were more common in endophthalmitis than in no ocular involvement or chorioretinitis. In the multivariable analysis, cryptogenic liver abscess [adjusted odds ratio (aOR), 6.63; 95% CI 1.44-35.20] and metastatic infection (aOR, 17.52; 95% CI 3.69-96.93) were independent risk factors for endophthalmitis. Endophthalmitis was not associated with 30-day mortality. Endophthalmitis is rare in Asian patients with K. pneumoniae bacteremia. Targeted ophthalmologic examination in those with cryptogenic liver abscess, metastatic infection, or ocular symptoms may be more appropriate than routine examination of all patients.


Assuntos
Bacteriemia , Coriorretinite , Endoftalmite , Infecções por Klebsiella , Abscesso Hepático , Humanos , Klebsiella pneumoniae , Incidência , Estudos Retrospectivos , Infecções por Klebsiella/tratamento farmacológico , Infecções por Klebsiella/epidemiologia , Antibacterianos/uso terapêutico , Abscesso Hepático/tratamento farmacológico , Endoftalmite/tratamento farmacológico , Endoftalmite/epidemiologia , Coriorretinite/complicações , Coriorretinite/tratamento farmacológico , Bacteriemia/epidemiologia , Fatores de Risco
13.
Med Mycol ; 61(9)2023 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-37656877

RESUMO

In September 2022, the proportion of clinically false positive results with high index values for the galactomannan (GM) assay increased dramatically in our hospital and remained high until November 2022. We aimed to identify the possible causative agent that led to the dramatic increase in false positivity in GM assay. A case-control-control study was conducted, and patients admitted to two intensive care units between September and November 2022 were included. We defined each time point at which the GM assay was conducted in a patient as an episode and classified episodes into strong-positive (≥10.0 index; case), positive (control), and negative (<0.5 index; control) groups. We compared the medications administered in three groups and measured GM levels in relevant medications, including parenteral nutrition (PN). In total, 118 episodes in 33 patients were classified into three groups. There were 46 negative, 23 positive, and 49 strong-positive episodes, and there was a significant difference in the use of Winuf® PNs (P < .001) between the three groups. Forty episodes (82%) in the strong-positive group received Winuf®, compared with three (6.5%) in the negative group and one (4.3%) in the positive group (P < .001). All samples of Winuf® PNs used in the five patients whose GM results were repeatedly strong-positive were strongly positive for GM. False positivity in GM assay can be caused by the administration of specific PNs. A thorough investigation of prescribed medications should be considered when there is an abrupt increase in the proportion of strong-positive or positive GM results.


Assuntos
Aspergillus , Galactose , Humanos , Estudos de Casos e Controles , Nutrição Parenteral/veterinária
14.
Infect Chemother ; 55(3): 388-393, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37674337

RESUMO

BACKGROUND: Sporadic measles outbreaks have continued to occur in Korea, mainly in adults in their 20s and 30s, most notably in 2014 and 2019. We here evaluated the possible causes of a low seroprevalance of measles by testing young healthcare workers (HCWs). MATERIALS AND METHODS: This study was conducted in a 2,743-bed tertiary-care hospital in Seoul between 2020 and 2021. We performed a measles antibody test (chemiluminescence immunoassay), measured the IgM/IgG index ratio, and conducted an avidity test at 1-month after Measles-Mumps-Rubella (MMR) vaccination in HCWs who had been seronegative for measles. Measles vaccination histories were obtained from the national vaccine registry. RESULTS: Of the 3,173 HCWs newly employed in our hospital during the study period, 54 with a negative measles IgG at commencement were enrolled. Thirty six (67%) of these subjects were female, and the median age was 25 years (interquartile range [IQR]: 24 - 27). Fourty nine (91%) showed seroconversion at 1 month after the first vaccination. Of these individuals, 38 received both measles IgM and IgG test, and all had an IgM/IgG index <1. Of the 49 seroconverters, all HCWs showed a high avidity index. According to the national immunization registry, 45 (83%) received at least 2 doses of an MMR vaccination. CONCLUSION: Secondary vaccine failure may underlie vaccine failure in young Korean adults. HCWs born after 1985 with a negative measles antibody may need only a single dose booster vaccination rather than a 2-dose vaccination regimen.

15.
J Infect ; 87(6): 490-497, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37757919

RESUMO

INTRODUCTION: The impact of different doses of dexamethasone on outcomes from acute COVID-19 pneumonia is unknown. METHODS: We performed a systematic review and meta-analysis of randomised control trials comparing different doses of dexamethasone in adult patients with COVID-19. High dose dexamethasone treatment was defined as 12-24 mg daily, whereas low-dose treatment was 6-8 mg daily. Primary outcome was 28-day mortality. RESULTS: Eight trials including 3469 patients were identified, with 1775 patients receiving high dose dexamethasone. There was no difference in mortality between patients receiving high dose or low-dose dexamethasone (22.0% vs. 20.2%; odds ratio 1.20 [95% confidence interval 0.86-1.67]; p = 0.29; I2 = 63%; TSA-adjusted CI [0.31-4.66]; very low QoE). Meta-regression did not demonstrate a dose-dependent effect of steroids on mortality. High dose dexamethasone was associated with an increased risk of hyperglycaemia (23.6% vs. 17.2%; 1.51 [1.19-1.92]; p = 0.0008; I2 = 0%; TSA-adjusted CI [0.90-2.54]; low QoE) but not secondary infections (14.3% vs. 15.0%; 0.87 [0.56-1.37]; p = 0.56; I2 = 72%; very low QoE). Risk of bias was low for seven of the eight studies. CONCLUSIONS: The mortality of patients with acute COVID-19 receiving high-dose dexamethasone is similar to patients receiving low-dose dexamethasone, although high-dose dexamethasone is associated with an increased risk of hyperglycaemia.


Assuntos
COVID-19 , Hiperglicemia , Adulto , Humanos , Dexametasona/efeitos adversos , Tratamento Farmacológico da COVID-19 , Hiperglicemia/tratamento farmacológico
16.
Medicine (Baltimore) ; 102(39): e35094, 2023 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-37773854

RESUMO

The clinical characteristics of the rebound phenomenon after antiviral therapy in patients with Coronavirus disease-2019 (COVID-19) are largely unknown. There are few data comparing the rebound phenomenon after molnupiravir therapy to that after nirmatrelvir-ritonavir therapy. We investigated the incidence and risk factors associated with COVID-19 rebound after nirmatrelvir-ritonavir or molnupiravir therapy during the Omicron era. This prospective cohort study enrolled patients with mild-to-moderate COVID-19 who received nirmatrelvir-ritonavir or molnupiravir. We conducted weekly questionnaires of symptom scores from day 0 to day 28, with an additional day when patients experienced reappearing symptoms. We defined COVID-19 rebound as when patients experienced a 50% increase in symptom scores compared to the lowest symptom score between days 0 and 14. Among the 150 patients, 93 (62%) and 57 (38%) received nirmatrelvir-ritonavir therapy and molnupiravir, respectively. Of these, 11 patients (7.3%; 95% CI, 3.1-11.5) experienced COVID-19 rebound. The median duration from antiviral therapy to rebound was 12 days. Patients with clinical rebound had a higher symptom score at antiviral therapy initiation than those without (median, 5 vs 4; P = .02). There was no significant difference in the clinical rebounds associated with nirmatrelvir-ritonavir and molnupiravir therapy (5.4% vs 10.5%; P = .39). Approximately one-tenth of patients with mild-to-moderate COVID-19 who received antiviral therapy experienced rebound phenomena after treatment. Regardless of antiviral therapy type, high initial symptom scores were associated with a more frequent rebound phenomenon.


Assuntos
COVID-19 , Ritonavir , Humanos , Estudos Prospectivos , Ritonavir/uso terapêutico , Tratamento Farmacológico da COVID-19 , Antivirais/uso terapêutico
17.
Int J Antimicrob Agents ; 62(5): 106959, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37633425

RESUMO

BACKGROUND: Due to high mortality and limited treatment options, the rise in carbapenemase-producing Enterobacterales (CPE) has become a major concern. This study aimed to evaluate the incidence and characteristics of subsequent CPE bacteraemia in rectal CPE carriers and investigate the risk factors for CPE bacteraemia compared with non-carbapenemase-producing (non-CP) Enterobacterales bacteraemia. METHODS: A retrospective analysis was conducted on adult patients who were confirmed to have CPE colonisation by stool surveillance culture at a tertiary hospital from January 2018 to February 2022. All episodes of Enterobacterales bacteraemia up to 6 months after CPE colonisation were identified. RESULTS: Of 1174 patients identified as rectal CPE carriers, 69 (5.8%; 95% CI 4.6-7.3%) experienced subsequent CPE bacteraemia during the 6 months after the diagnosis of CPE colonisation. Colonisation by a Klebsiella pneumoniae carbapenemase (KPC) producer (or CP-K. pneumoniae), colonisation by multiple CPE species, chronic kidney disease and haematological malignancy were independently associated with CPE bacteraemia in CPE carriers. When CPE carriers developed Enterobacterales bacteraemia, the causative agent was more frequently non-CP Enterobacterales than CPE (63.6% vs. 36.4%). Among these patients, colonisation with a KPC producer, CPE colonisation at multiple sites, shorter duration from colonisation to bacteraemia (< 30 days) and recent intraabdominal surgery were independent risk factors for CPE bacteraemia rather than non-CP Enterobacterales bacteraemia. CONCLUSIONS: In CPE carriers, non-CP Enterobacterales were more often responsible for bacteraemia than CPE. Empirical antibiotic therapy for CPE should be considered when sepsis is suspected in a CPE carrier with risk factors for CPE bacteraemia.


Assuntos
Bacteriemia , Infecções por Enterobacteriaceae , Adulto , Humanos , Estudos Retrospectivos , Proteínas de Bactérias , beta-Lactamases , Bacteriemia/epidemiologia , Klebsiella pneumoniae , Fatores de Risco , Infecções por Enterobacteriaceae/epidemiologia
18.
Alzheimers Dement (N Y) ; 9(3): e12417, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37614242

RESUMO

Introduction: Our limited understanding of the mechanisms that trigger the emergence of Alzheimer's disease (AD) has contributed to the lack of interventions that stop, prevent, or fully treat this disease. We believe that the development of a non-human primate model of AD will be an essential step toward overcoming limitations of other model systems and is crucial for investigating primate-specific mechanisms underlying the cellular and molecular root causes of the pathogenesis and progression of AD. Methods: A new consortium has been established with funding support from the National Institute on Aging aimed at the generation, characterization, and validation of Marmosets As Research Models of AD (MARMO-AD). This consortium will study gene-edited marmoset models carrying genetic risk for AD and wild-type genetically diverse aging marmosets from birth throughout their lifespan, using non-invasive longitudinal assessments. These include characterizing the genetic, molecular, functional, behavioral, cognitive, and pathological features of aging and AD. Results: The consortium successfully generated viable founders carrying PSEN1 mutations in C410Y and A426P using CRISPR/Cas9 approaches, with germline transmission demonstrated in the C410Y line. Longitudinal characterization of these models, their germline offspring, and normal aging outbred marmosets is ongoing. All data and resources from this consortium will be shared with the greater AD research community. Discussion: By establishing marmoset models of AD, we will be able to investigate primate-specific cellular and molecular root causes that underlie the pathogenesis and progression of AD, overcome limitations of other model organisms, and support future translational studies to accelerate the pace of bringing therapies to patients.

19.
Sleep ; 46(10)2023 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-37531589

RESUMO

STUDY OBJECTIVES: This study investigated alterations in resting-state functional connectivity (RSFC) and hyperarousal biomarkers in patients with chronic insomnia disorder (CID), compared with good sleepers (GS). We also examined the relationships between altered RSFC and hyperarousal biomarkers. METHODS: Fifty patients with CID and 52 GS completed self-reporting questionnaires, and then underwent polysomnography and resting-state functional magnetic resonance imaging. We analyzed RSFC in the amygdala (AMG) and anterior insula (aINS), which are core regions of the salience network that are likely to be involved in hyperarousal. We also analyzed electroencephalography (EEG) relative beta power and heart rate variability (HRV) parameters (e.g. low and high frequency) during sleep. We then tested between-group differences in the RSFC and hyperarousal biomarkers; we examined correlations of RSFC with EEG beta power and HRV. RESULTS: Compared with GS, patients with CID showed more negative RSFC between the right amygdala (R.AMG) and left supramarginal gyrus (L.SMG), but less positive RSFC between the left aINS and bilateral lateral prefrontal cortex. The R.AMG-L.SMG RSFC was negatively correlated with EEG beta power in central regions (C3: r = -0.336, p = 0.012; C4: r = -0.314, p = 0.024). CONCLUSIONS: Decreased RSFC between the R.AMG and L.SMG in patients with insomnia may reflect the difficulty in cortical top-down regulation of the AMG, indicating daytime hyperarousal. Individuals who experience hyperarousal during the daytime may also exhibit cortical hyperarousal during sleep, as indicated by increased EEG beta power.


Assuntos
Distúrbios do Início e da Manutenção do Sono , Humanos , Distúrbios do Início e da Manutenção do Sono/diagnóstico por imagem , Sono , Eletroencefalografia , Tonsila do Cerebelo/diagnóstico por imagem , Biomarcadores , Imageamento por Ressonância Magnética
20.
Commun Biol ; 6(1): 806, 2023 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-37532791

RESUMO

The common marmoset monkey (Callithrix jacchus) is a species of rising prominence in the neurosciences due to its small size, ease of handling, fast breeding, and its shared functional and structural brain characteristics with Old World primates. With increasing attention on modeling human brain diseases in marmosets, understanding how to deliver therapeutic or neurotropic agents to the marmoset brain noninvasively is of great preclinical importance. In other species, including humans, transcranial focused ultrasound (tFUS) aided by intravenously injected microbubbles has proven to be a transient, reliable, and safe method for disrupting the blood-brain barrier (BBB), allowing the focal passage of therapeutic agents that do not otherwise readily traverse the tight endothelial junctions of the BBB. The critical gap that we address here is to document parameters to disrupt the BBB reliably and safely in marmosets using tFUS. By integrating our marmoset brain atlases and the use of a marmoset-specific stereotactic targeting system, we conduct a series of systematic transcranial sonication experiments in nine marmosets. We demonstrate the effects of center frequency, acoustic pressure, burst period, and duration, establish a minimum microbubble dose, estimate microbubble clearance time, and estimate the duration that the BBB remains open to passage. Successful BBB disruption is reported in vivo with MRI-based contrast agents, as well as Evans blue staining assessed ex vivo. Histology (Hematoxylin and Eosin staining) and immunohistochemistry indicate that the BBB can be safely and reliably opened with the parameters derived from these experiments. The series of experiments presented here establish methods for safely, reproducibly, and focally perturbing the BBB using tFUS in the common marmoset monkey that can serve as a basis for noninvasive delivery of therapeutic or neurotropic agents.


Assuntos
Barreira Hematoencefálica , Callithrix , Animais , Humanos , Encéfalo , Imageamento por Ressonância Magnética
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