RESUMO
After severe brain injury, it can be difficult to determine the state of consciousness of a patient, to determine whether the patient is unresponsive or perhaps minimally conscious1, and to predict whether they will recover. These diagnoses and prognoses are crucial, as they determine therapeutic strategies such as pain management, and can underlie end-of-life decisions2,3. Nevertheless, there is an error rate of up to 40% in determining the state of consciousness in patients with brain injuries4,5. Olfaction relies on brain structures that are involved in the basic mechanisms of arousal6, and we therefore hypothesized that it may serve as a biomarker for consciousness7. Here we use a non-verbal non-task-dependent measure known as the sniff response8-11 to determine consciousness in patients with brain injuries. By measuring odorant-dependent sniffing, we gain a sensitive measure of olfactory function10-15. We measured the sniff response repeatedly over time in patients with severe brain injuries and found that sniff responses significantly discriminated between unresponsive and minimally conscious states at the group level. Notably, at the single-patient level, if an unresponsive patient had a sniff response, this assured future regaining of consciousness. In addition, olfactory sniff responses were associated with long-term survival rates. These results highlight the importance of olfaction in human brain function, and provide an accessible tool that signals consciousness and recovery in patients with brain injuries.
Assuntos
Lesões Encefálicas/diagnóstico , Lesões Encefálicas/fisiopatologia , Estado de Consciência/fisiologia , Percepção Olfatória/fisiologia , Estado Vegetativo Persistente/diagnóstico , Estado Vegetativo Persistente/fisiopatologia , Olfato/fisiologia , Adulto , Nível de Alerta , Erros de Diagnóstico/prevenção & controle , Feminino , Humanos , Masculino , Odorantes/análise , Prognóstico , Recuperação de Função Fisiológica/fisiologia , Sensibilidade e Especificidade , Análise de SobrevidaRESUMO
PURPOSE: Comparing between the visual outcomes and post operative complications of two surgical treatments for sub macular hemorrhage, pars plana vitrectomy with tissue plasminogen activator (tPA) injection procedure, and pneumatic displacement of submacular hemorrhage with intravitreal tPA injection. METHODS: A retrospective chart review of patients with sub macular hemorrhage (SMH) was performed. Data was collected from 150 patients with sub macular hemorrhage. Patients were followed up from the day of admission and up to a year post surgery. Evaluation included visual acuity, optical coherence tomography (OCT), fundus examination and rates of complications. RESULTS: Pars plana vitrectomy procedure has showed a better visual outcome in small SMH. Comparing complications between the two treatment modalities, no significant difference has been found in the study. CONCLUSIONS: Pars plana vitrectomy and tPA showed a clear advantage with a trend of better visual acuity as well as a significant predictor to better visual acuity for small and medium sub macular hemorrhage.
Assuntos
Fibrinolíticos , Injeções Intravítreas , Hemorragia Retiniana , Ativador de Plasminogênio Tecidual , Tomografia de Coerência Óptica , Acuidade Visual , Vitrectomia , Humanos , Ativador de Plasminogênio Tecidual/administração & dosagem , Vitrectomia/métodos , Hemorragia Retiniana/terapia , Hemorragia Retiniana/diagnóstico , Hemorragia Retiniana/tratamento farmacológico , Estudos Retrospectivos , Masculino , Feminino , Idoso , Fibrinolíticos/administração & dosagem , Pessoa de Meia-Idade , Idoso de 80 Anos ou maisRESUMO
PURPOSE: This study evaluated age-related maternal outcomes of vacuum-assisted vaginal deliveries (VAD). METHODS: This retrospective cohort study included all nulliparous women with singleton VAD in one academic institution. Study group parturients were maternal age ≥ 35 years and controls < 35. Power analysis revealed that 225 women/group would be sufficient to detect a difference in the rate of third- and fourth-degree perineal tears (primary maternal outcome) and umbilical cord pH < 7.15 (primary neonatal outcome). Secondary outcomes were maternal blood loss, Apgar scores, cup detachment, and subgaleal hematoma. Outcomes were compared between groups. RESULTS: From 2014 to 2019, 13,967 nulliparas delivered at our institution. Overall, 8810 (63.1%) underwent normal vaginal delivery, 2432 (17.4%) instrumental, and 2725 (19.5%) cesarean. Among 11,242 vaginal deliveries, 10,116 (90%) involved women < 35, including 2067 (20.5%) successful VAD vs. 1126 (10%) women ≥ 35 years with 348 (30.9%) successful VAD (p < 0.001). Rates of third- and fourth-degree perineal lacerations were 6 (1.7%) with advanced maternal age and 57 (2.8%) among controls (p = 0.259). Cord pH < 7.15 was similar: 23 (6.6%) study group and 156 (7.5%) controls (p = 0.739). CONCLUSION: Advanced maternal age and VAD are not associated with higher risk for adverse outcomes. Older, nulliparous women are more likely to undergo vacuum delivery than younger parturients.
Assuntos
Parto Obstétrico , Vácuo-Extração , Gravidez , Recém-Nascido , Feminino , Humanos , Adulto , Pessoa de Meia-Idade , Masculino , Vácuo-Extração/efeitos adversos , Estudos Retrospectivos , Idade Materna , VaginaRESUMO
PURPOSE: To study the effect of decreased estimated fetal weight (EFW) percentiles in appropriate for gestational age fetuses. METHODS: This retrospective cohort study included women who had second and third trimester ultrasound examinations. Delivery and neonatal outcomes of pregnancies with decreased EFW of ≥ 30 percentiles in EFW between ultrasound examinations (decreased growth group) and those without such a decrease (control group) were compared. Deliveries with EFW or birthweight below the 10th percentile were excluded. RESULTS: Among 1610 deliveries, 57 were in the decreased growth group and 1553 in the control group. Maternal characteristics did not differ between the groups except for higher rate of nulliparity in the decreased growth group. We found similar rates of Category II/III monitoring, cesarean deliveries due to non-reassuring fetal heart rate and adverse neonatal outcomes. Neonatal birthweight was lower in the decreased growth group as compared to controls. CONCLUSIONS: This study did not find association between the group of appropriate for gestational age fetuses with decreased growth, with adverse outcomes.
RESUMO
PURPOSE: Meconium-stained amniotic fluid (MSAF) often signifies colonization of the amniotic sac by microorganisms. This study investigated additional adverse obstetric outcomes associated with MSAF in deliveries complicated by maternal intrapartum fever (IF). METHODS: This retrospective study included all singleton pregnancies from 2014 to 2020, with intrapartum maternal fever ≥ 38 °C during a trial of labor. In accordance with departmental protocol, all patients received intravenous antibiotic therapy consisting of ampicillin and gentamicin in the absence of allergies to these medications. Subsequent antibiotic therapy was adjusted based on the culture results. Antibiotic treatment was discontinued postpartum after 48 h without fever. Swab cultures were obtained immediately postpartum from both the maternal and fetal sides of the placenta. Maternal and fetal outcomes, along with positive placental cultures, were compared between participants with MSAF&IF and those with clear amniotic fluid &IF (control group). RESULTS: In comparison to the control group (n = 1089), the MSAF&IF group (n = 264) exhibited significantly higher rates of cesarean delivery (CD) (p = 0.001), CD due to non-reassuring fetal heart rate (p = 0.001), and cord pH ≤ 7.1 (p = 0.004). Positive swab cultures from the placental maternal and fetal sides were more prevalent among the MSAF&IF group (23.1% vs. 17.6%, p = 0.041 and 29.2% vs. 22.9%, p = 0.032, respectively). Placental cultures yielding gastrointestinal pathogens and extended spectrum beta-lactamase were notably more common in the MSAF&IF group compared to controls (p = 0.023). However, there was no significant difference between groups regarding the rate of group B streptococcus positive placental cultures. CONCLUSIONS: Women experiencing IF and MSAF during labor face an elevated risk of CD compared to those with IF alone. The presence of MSAF heightens the risk of positive placental cultures, particularly with gastrointestinal and extended spectrum beta-lactamase pathogens.
RESUMO
PURPOSE: This study's objective is to investigate disparities in the rates of gestational diabetes mellitus (GDM) diagnosis, influenced by the timing of the glucose challenge test GCT. METHODS: This retrospective cohort study included women with singleton or twin pregnancies exhibiting abnormal GCT result between 24 and 28 weeks of gestation, followed by an oral glucose tolerance test OGTT during the same period. Data regarding pregnancy follow-up from patients' deliveries at a singular tertiary medical from 2014 to 2022 were retrieved. The probability of GDM diagnosis was stratified based on the gestational week of the GCT and the definition of a positive OGTT, delineated by one or two abnormal values. RESULTS: The study included 636 women with abnormal GCT between 24 and 28 weeks of gestation. Of them, 157 unerwent the GCT between 24.0 and 24.6 weeks, 204 between 25.0 and 25.6 weeks, 147 between 26.0 and 26.6 weeks, and 128 between 27.0 and 28.6 weeks. We found that the highest incidence of GDM, defined by one or two pathological values of the OGTT, following the initial screening with a GCT, where abnormal results were defined as values exceeding 140 mg/dL, was diagnosed in patients who underwent GCT between 26.0 and 26.6 weeks of gestation. Conversely, the lowest rates were observed in patients screened between 24.0 and 24.6 weeks of gestation. CONCLUSION: The timing of screening for GDM using the GCT significantly affects the rate of diagnosis. Clinicians managing pregnancies should consider this data when formulating treatment plans.
RESUMO
BACKGROUND: Electronic nicotine delivery systems (ENDS) offer a promising approach to tobacco harm reduction, but many people use both ENDS and combustible cigarettes ("dual use"), which undermines potential risk reduction. To explore the role of ENDS nicotine delivery in promoting switching to ENDS, we conducted a study in which people who smoked cigarettes were offered an ENDS that had previously been shown to replicate the rapid nicotine pharmacokinetics of combustible cigarettes (BIDI® Stick). METHODS: Twenty-five cigarette smoking adults, not seeking smoking cessation treatment, but open to using ENDS as a cigarette substitute, were provided with a 12-week supply of BIDI® Stick in tobacco or menthol flavors, during a study that included seven biweekly sessions and a 6-month follow-up. Daily diaries assessed ENDS and cigarette use, and exhaled carbon monoxide (eCO) served as an objective marker of smoke intake. Subjective ratings were collected to assess the rewarding properties of ENDS and combustible cigarettes, and indices of nicotine dependence. RESULTS: Over 12 weeks, ENDS use increased to an average of 15.8 occasions per day (SD = 20.2) and self-reported cigarette consumption decreased by 82% from 16.7 cigarettes/day (SD = 6.0) at baseline to 3.0 cigarettes/day (SD = 4.1) at week 12. The eCO level decreased by 27% from an average of 20.0 ppm (SD = 9.8) at baseline to 14.5 ppm (SD = 9.9) at week 12. Four of 25 participants completely switched to ENDS and were smoking abstinent during weeks 9-12. At 6 months one participant was confirmed to be abstinent. Ratings of subjective reward for the ENDS were very similar to those of participants' usual brands of cigarettes. Dependence level was lower for the ENDS than for combustible cigarettes. CONCLUSIONS: In this study, the ENDS effectively replicated the subjective rewarding effects of participants' usual brands of cigarettes and led to a substantial reduction in reported cigarettes/day. Exhaled CO showed less of a decrease, possibly due to compensatory smoking behavior and/or the timing of eCO measurements that might not have reflected smoke intake throughout the day. The relatively low rate of sustained smoking abstinence at 6 months suggests that additional approaches continue to be needed for achieving higher rates of complete switching. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT05855343.
Assuntos
Sistemas Eletrônicos de Liberação de Nicotina , Nicotina , Redução do Consumo de Tabaco , Humanos , Feminino , Masculino , Adulto , Pessoa de Meia-Idade , Nicotina/administração & dosagem , Redução do Consumo de Tabaco/métodos , Monóxido de Carbono/análise , Monóxido de Carbono/metabolismo , Produtos do Tabaco , Adulto Jovem , Abandono do Hábito de Fumar/métodos , Redução do Dano , Testes Respiratórios , VapingRESUMO
Goal-directed behavior relies on maintaining relevant goals in working memory (WM) and updating them when required. Computational modeling, behavioral, and neuroimaging work has previously identified the processes and brain regions involved in selecting, updating, and maintaining declarative information, such as letters and pictures. However, the neural substrates that underlie the analogous processes that operate on procedural information, namely, task goals, are currently unknown. Forty-three participants were therefore scanned with fMRI while performing a procedural version of the reference-back paradigm that allowed for the decomposition of WM updating processes into gate-opening, gate-closing, task switching, and task cue conflict components. Significant behavioral costs were observed for each of these components, with interactions indicating facilitation between gate-opening and task switching, and a modulation of cue conflict by gate state. In neural terms, opening the gate to procedural WM was associated with activity in medial pFC, posterior parietal cortex (PPC), the basal ganglia (BG), thalamus, and midbrain, but only when the task set needed to be updated. Closing the gate to procedural WM was associated with frontoparietal and BG activity specifically in conditions where conflicting task cues had to be ignored. Task switching was associated with activity in the medial pFC/ACC, PPC, and BG, whereas cue conflict was associated with PPC and BG activity during gate closing but was abolished when the gate was already closed. These results are discussed in relation to declarative WM and to gating models of WM.
Assuntos
Encéfalo , Memória de Curto Prazo , Humanos , Encéfalo/diagnóstico por imagem , Gânglios da Base , Sinais (Psicologia) , Imageamento por Ressonância MagnéticaRESUMO
Epitranscriptomic changes in RNA catalyzed by the RNA-editing enzyme ADAR1 play an essential role in the regulation of diverse molecular and cellular processes, both under physiological conditions and in disease states, including cancer. Yet, despite a growing body of evidence pointing to ADAR1 as a potential therapeutic target, the mechanisms regulating its cellular abundance and activity, particularly of its constitutively expressed and ubiquitous form, ADAR1p110, are poorly understood. Here, we report the HECT-type E3 ubiquitin ligase SMURF2 as a pivotal regulator of ADAR1p110. We show that SMURF2, which is primarily known to promote the ubiquitin-mediated degradation of its protein substrates, protects ADAR1p110 from proteolysis and promotes its A-to-I editase activity in human and mouse cells and tissues. ADAR1p110's interactome analysis performed in human cells also showed a positive influence of SMURF2 on the stability and function of ADAR1p110. Mechanistically, we found that SMURF2 directly binds, ubiquitinates and stabilizes ADAR1p110 in an E3 ubiquitin ligase-dependent manner, through ADAR1p110 ubiquitination at lysine-744 (K744). Mutation of this residue to arginine (K744R), which is also associated with several human disorders, including dyschromatosis symmetrica hereditaria (DSH) and some types of cancer, abolished SMURF2-mediated protection of ADAR1p110 from both proteasomal and lysosomal degradation and inactivated ADAR1p110-mediated RNA editing. Our findings reveal a novel mechanism underlying the regulation of ADAR1 in mammalian cells and suggest SMURF2 as a key cellular factor influencing the protein abundance, interactions and functions of ADAR1p110.
Assuntos
RNA , Ubiquitina-Proteína Ligases , Adenosina/metabolismo , Animais , Inosina/metabolismo , Mamíferos/genética , Camundongos , Proteínas/metabolismo , RNA/metabolismo , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , UbiquitinaçãoRESUMO
STUDY OBJECTIVE: To create a decision support tool based on machine learning algorithms and natural language processing (NLP) technology, to augment clinicians' ability to predict cases of suspected adnexal torsion. DESIGN: Retrospective cohort study SETTING: Gynecology department, university-affiliated teaching medical center, 2014-2022. PATIENTS: This study assessed risk-factors for adnexal torsion among women managed surgically for suspected adnexal torsion based on clinical and sonographic data. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The dataset included demographic, clinical, sonographic, and surgical information obtained from electronic medical records. NLP was used to extract insights from unstructured free text and unlock them for automated reasoning. The machine learning model was a CatBoost classifier that utilizes gradient boosting on decision trees. The study cohort included 433 women who met inclusion criteria and underwent laparoscopy. Among them, 320 (74%) had adnexal torsion diagnosed during laparoscopy, and 113 (26%) did not. The model developed improved prediction of adnexal torsion to 84%, with a recall of 95%. The model ranked several parameters as important for prediction. Age, difference in size between ovaries, and the size of each ovary were the most significant. The precision for the "no torsion" class was 77%, with a recall of 45%. CONCLUSIONS: Using machine learning algorithms and NLP technology as a decision-support tool for the diagnosis of adnexal torsion is feasible. It improved true prediction of adnexal torsion to 84% and decreased cases of unnecessary laparoscopy.
Assuntos
Doenças dos Anexos , Torção Ovariana , Humanos , Feminino , Doenças dos Anexos/diagnóstico por imagem , Doenças dos Anexos/cirurgia , Estudos Retrospectivos , Processamento de Linguagem Natural , Anormalidade Torcional/diagnóstico por imagem , Anormalidade Torcional/cirurgiaRESUMO
Intestinal inflammation is mediated by a subset of cells populating the intestine, such as enteric glial cells (EGC) and macrophages. Different studies indicate that phytocannabinoids could play a possible role in the treatment of inflammatory bowel disease (IBD) by relieving the symptoms involved in the disease. Phytocannabinoids act through the endocannabinoid system, which is distributed throughout the mammalian body in the cells of the immune system and in the intestinal cells. Our in vitro study analyzed the putative anti-inflammatory effect of nine selected pure cannabinoids in J774A1 macrophage cells and EGCs triggered to undergo inflammation with lipopolysaccharide (LPS). The anti-inflammatory effect of several phytocannabinoids was measured by their ability to reduce TNFα transcription and translation in J774A1 macrophages and to diminish S100B and GFAP secretion and transcription in EGCs. Our results demonstrate that THC at the lower concentrations tested exerted the most effective anti-inflammatory effect in both J774A1 macrophages and EGCs compared to the other phytocannabinoids tested herein. We then performed RNA-seq analysis of EGCs exposed to LPS in the presence or absence of THC or THC-COOH. Transcriptomic analysis of these EGCs revealed 23 differentially expressed genes (DEG) compared to the treatment with only LPS. Pretreatment with THC resulted in 26 DEG, and pretreatment with THC-COOH resulted in 25 DEG. To evaluate which biological pathways were affected by the different phytocannabinoid treatments, we used the Ingenuity platform. We show that THC treatment affects the mTOR and RAR signaling pathway, while THC-COOH mainly affects the IL6 signaling pathway.
Assuntos
Inflamação , Lipopolissacarídeos , Animais , Lipopolissacarídeos/farmacologia , Lipopolissacarídeos/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Neuroglia/metabolismo , Macrófagos/metabolismo , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/metabolismo , MamíferosRESUMO
Poly(ADP-ribose) polymerase 1 (PARP1) is a key molecular stress sensor and response mediator implicated in multiple cellular functions in health and diseases. Despite its importance and intrinsic involvement in pivotal molecular and cellular processes, including DNA repair, transcription regulation, chromatin organization, and cell death, the regulatory mechanisms of PARP1 are poorly understood. In this study, we show that SMURF2, a HECT-type E3 ubiquitin ligase and suggested tumor suppressor, physically interacts with PARP1 in different cellular settings, directly ubiquitinates it in vitro and stimulates its PARylation activity in cells, the phenomenon that required SMURF2 E3 ubiquitin ligase function. Intriguingly, in the cellular environment SMURF2 was found to regulate the dynamic exchange of ubiquitin moieties on PARP1, mostly decreasing its monoubiquitination. Through the set of systematic mass spectrometry analyses conducted on SMURF2-modified cells, we identified on PARP1 18 lysine residues (out of 126 present in PARP1) as sites which ubiquitination was considerably affected by SMURF2. Subsequent site-directed mutagenesis coupled with in cellula ubiquitination and PARylation assays unveiled K222 as a critical site enabling a cross talk between SMURF2-modulated monoubiquitination of PARP1 and its activity, and pointed to K498, S507, and a KTR triad (K498/K521/K524) as the main auto-PARylation sites affected by SMURF2. The results also uncovered that SMURF2 controls PARP1 interactome, influencing its functions and expression in a context-dependent manner. Taken together, these findings suggest that SMURF2-mediated ubiquitin signaling plays an essential role in PARP1 regulation, beyond the regulation of its protein expression.
Assuntos
Regulação da Expressão Gênica/fisiologia , Poli(ADP-Ribose) Polimerase-1/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Sequência de Aminoácidos , Animais , Linhagem Celular Tumoral , Humanos , Camundongos , Camundongos Knockout , Poli(ADP-Ribose) Polimerase-1/genética , Interferência de RNA , Transdução de Sinais , Ubiquitina , Ubiquitina-Proteína Ligases/genética , UbiquitinaçãoRESUMO
OBJECTIVE: Large deletions and duplications account for 65%-80% of pathogenic Duchenne muscular dystrophy (DMD) variants. A nationwide carrier screening for DMD was initiated in Israel in 2020. We assessed the carrier rate and spectrum of variants detected in a cohort of women screened for DMD carrier status and analyzed screening efficacy and challenges related to DMD population screening. METHODS: A cohort of 12,362 women were tested at a single institute using multiplex ligation-dependent probe amplification based copy number analysis of the 79 DMD exons. Consecutive sequencing of the primer region was performed when a single exon deletion was suspected. RESULTS: Deletions involving multiple exons were detected in seven cases and duplications involving multiple exons were found in four. Of these, nine were pathogenic based on previous reports and familial segregation testing, translating to a carrier rate of 1:1374. A family history was reported in three cases. Single exon deletions were suspected in 81 cases; further sequencing detected a single nucleotide variant affecting probe hybridization. These cases clustered according to ethnic origin. DISCUSSION: Population screening for DMD has a significant yield. Most carriers did not report a family history of dystrophinopathies. Screening should be adjusted for methodological limitations. Some cases may require extensive genetic counseling and work-up.
Assuntos
Distrofia Muscular de Duchenne , Distrofina/genética , Éxons , Feminino , Deleção de Genes , Humanos , Reação em Cadeia da Polimerase Multiplex , Distrofia Muscular de Duchenne/diagnóstico , Distrofia Muscular de Duchenne/epidemiologia , Distrofia Muscular de Duchenne/genética , MutaçãoRESUMO
PURPOSE: To evaluate neonatal and maternal outcomes associated with detachment of non-metal vacuum cup during delivery and to identify risk factors for these detachments. METHODS: This retrospective cohort study included women with singleton pregnancy, who underwent vacuum-assisted vaginal delivery with a non-metal vacuum cup in a single academic institution, January 2014-August 2019. Failed vacuum deliveries were excluded. Primary outcomes were defined as subgaleal hematoma (SGH) and cord blood pH < 7.15. Secondary outcome included other neonatal complications and adverse maternal outcomes. Outcomes were compared between vacuum-assisted deliveries with and without cup detachment during the procedure. RESULTS: A total of 3246 women had successful VAD and met the inclusion criteria. During the procedure, the cup detached at least once in 665 (20.5%) deliveries and did not detach in 2581 (79.5%). The cup detachment group experienced higher rates of SGH (8.9% vs. 3.5%, p = 0.001) and cord blood pH < 7.15 (9.8% vs. 7.1%, p = 0.03). There were also more neonatal intensive care unit admissions (NICU) (4.4% vs. 2.7%, p = 0.03) and more fetuses with occiput posterior position (70.8% vs. 79.4%, p = 0.001), the vacuum duration was slightly longer (6 ± 3.7 vs. 5 ± 2.9 min) and more neonates had birth weights > 3700 g (14.1% vs, 10.3%, p = 0.006). Interestingly, there were more males in that group (60.6 vs. 54.6, p = 0.005). All these factors remained significant after controlling for potential confounders. CONCLUSIONS: Vacuum cup detachment has several predictive characteristics and is associated with adverse neonatal outcomes that should be incorporated into decisions made during the procedure.
Assuntos
Parto Obstétrico , Falha de Equipamento , Vácuo-Extração , Peso ao Nascer , Parto Obstétrico/efeitos adversos , Feminino , Sangue Fetal/química , Hematoma Subdural/etiologia , Humanos , Concentração de Íons de Hidrogênio , Recém-Nascido , Gravidez , Estudos Retrospectivos , Vácuo-Extração/efeitos adversos , Vácuo-Extração/métodosRESUMO
BACKGROUND: There is an increasing use of anti-protein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies (mAbs); however, real-world data is lacking. OBJECTIVES: To define the demographic and clinical characteristics of patients treated with anti-PCSK9 mAbs. To evaluate efficacy, tolerability, and differences between the approved agents. METHODS: A retrospective cohort study was conducted of patients treated at the lipid clinic at Rabin Medical Center (Beilinson Campus), Israel, from January 2016 to December 2019. Data from electronic records were evaluated for demographic and clinical characteristics, indication for use, response of lowering low-density lipoprotein cholesterol (LDL-C)/non-high-density lipoprotein cholesterol (non-HDL-C) levels and reaching target levels, side effects, tolerability, differences between the agents, and doses. RESULTS: The study cohort included 115 patients. Two-thirds (n=75) were at high cardiovascular risk, the rest at very high risk (n=40). The major indication for treatment was statin intolerance (n=97, 84%). Most patients (n=102, 88%) were treated by anti-PCSK9 mAbs agents only. LDL-C and non-HDL-C levels were decreased by 47% and 39%, respectively (156 + 49 to 81 + 39 and 192 + 53 to 116 + 42 mg/dl), within 6 months and remained stable. Two-thirds (n=76) of the patients reached their lipid target levels. No clinically significant differences were observed between the agents in efficacy or tolerability. CONCLUSIONS: In a real-world setting, anti-PCSK9 mAbs are used primarily as a single agent in high-risk and very high-risk cardiovascular populations with statin intolerance. They are well tolerated and effective in reduction of LDL-C levels. Further studies are needed to clarify comparisons between agents and doses.
Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases , Humanos , LDL-Colesterol , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Subtilisina , Pró-Proteína Convertase 9 , Estudos Retrospectivos , IsraelRESUMO
INTRODUCTION: Evidence suggests that cigarette smokers who switch to electronic nicotine delivery systems (ENDS) reduce their exposure to harmful toxicants and carcinogens. It is unclear if dual-use is associated with decreases in exposure to toxicants. METHODS: This parallel-group confinement study assessed changes in biomarkers of exposure (BOEs) over six days among healthy adult smokers who were randomized into 1 of 11 study groups: eight JUUL-brand System (JUUL) groups (4 JUUL flavors [Virginia Tobacco, Menthol, Mint, Mango] × 2 nicotine concentrations [5.0% or 3.0% by weight]); Dual-Use group used preferred JUUL flavor (5.0% nicotine) and ≤50% usual brand (UB) cigarettes/day; UB Cigarette group and one group abstained from all tobacco/nicotine product use (Abstinence group). Urine and blood analysis assessed changes in primary BOE endpoints (NNAL, 3-HPMA, MHBMA, S-PMA COHb) and secondary BOE endpoints (NNN, HMPMA, CEMA, 1-OHP, O-toluidine, 2-NA, 4-ABP) among 279 adult smokers. RESULTS: In JUUL groups, median percent reductions in primary BOEs (Day 6-Baseline) were 90%-≥100% of Abstinence; there were no significant differences between JUUL groups and Abstinence. All reductions in JUUL groups were substantially and statistically significantly greater than reductions in the UB Cigarette group (ps < 0.025). Median reductions in primary BOEs in the Dual-Use group were 43%-55% of Abstinence. Similar results were observed for secondary BOEs. CONCLUSION: This study suggests that the use of JUUL as a complete or partial substitute (i.e., dual-use with ≥50% reduction in cigarette consumption) for combustible cigarettes can substantially reduce exposure to multiple toxins associated with cigarette smoking. IMPLICATIONS: This study adds to the growing body of evidence supporting the utility of ENDS products as potentially reduced-harm alternatives to cigarettes for adult smokers. Adult smokers who switched completely from cigarette smoking to use of the JUUL System ("JUUL") in two nicotine concentrations (5.0% and 3.0%) and four flavors significantly reduced their exposure to multiple classes of cigarette-related toxicants. Additionally, smokers who used JUUL and continued smoking but reduced their daily cigarette consumption by ≥50% (dual users) also significantly reduced their toxicant exposure compared to cigarette smoking.
Assuntos
Sistemas Eletrônicos de Liberação de Nicotina , Produtos do Tabaco , Adulto , Biomarcadores , Humanos , Nicotina , Fumantes , FumarRESUMO
The C2-WW-HECT-domain E3 ubiquitin ligase SMURF2 emerges as an important regulator of diverse cellular processes. To date, SMURF2-specific modulators were not developed. Here, we generated and investigated a set of SMURF2-targeting synthetic peptides and peptidomimetics designed to stimulate SMURF2's autoubiquitination and turnover via a disruption of the inhibitory intramolecular interaction between its C2 and HECT domains. The results revealed the effects of these molecules both in vitro and in cellulo at the nanomolar concentration range. Moreover, the data showed that targeting of SMURF2 with either these modifiers or SMURF2-specific shRNAs could accelerate cell growth in a cell-context-dependent manner. Intriguingly, a concomitant cell treatment with a selected SMURF2-targeting compound and the DNA-damaging drug etoposide markedly increased the cytotoxicity produced by this drug in growing cells. Altogether, these findings demonstrate that SMURF2 can be druggable through its self-destructive autoubiquitination, and inactivation of SMURF2 might be used to affect cell sensitivity to certain anticancer drugs.
Assuntos
Antineoplásicos/farmacologia , Desenvolvimento de Medicamentos , Inibidores Enzimáticos/farmacologia , Ubiquitina-Proteína Ligases/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Ubiquitina-Proteína Ligases/metabolismoRESUMO
KEY MESSAGE: Among SARS-CoV-2-infected mothers, vaginal delivery rates were high and associated with favorable outcomes with no cases of neonatal COVID-19. PURPOSE: To investigate the mode of delivery and its impact on immediate neonatal outcome in SARS-CoV-2-infected women. METHODS: A prospective study following pregnant women diagnosed with COVID-19 who delivered between March 15th and July 4th in seven university affiliated hospitals in Israel. RESULTS: A total of 52 women with a confirmed diagnosis of COVID-19 delivered in the participating centers during the study period. The median gestational age at the time of delivery was 38 weeks, with 16 (30.8%) cases complicated by spontaneous preterm birth. Forty-three women (82.7%) underwent a trial of labor. The remaining 9 women underwent pre-labor cesarean delivery mostly due to obstetric indications, whereas one woman with a critical COVID-19 course underwent urgent cesarean delivery due to maternal deterioration. Among those who underwent a trial of labor (n = 43), 39 (90.7%) delivered vaginally, whereas 4 (9.3%) cases resulted in cesarean delivery. Neonatal RT-PCR nasopharyngeal swabs tested negative in all cases, and none of the infants developed pneumonia. No maternal and neonatal deaths were encountered. CONCLUSIONS: In this prospective study among SARS-CoV-2-infected mothers, vaginal delivery rates were high and associated with favorable outcomes with no cases of neonatal COVID-19. Our findings underscore that delivery management among SARS-CoV-2-infected mothers should be based on obstetric indications and may potentially reduce the high rates of cesarean delivery previously reported in this setting.
Assuntos
COVID-19/diagnóstico , Parto Obstétrico/efeitos adversos , Parto Obstétrico/métodos , Transmissão Vertical de Doenças Infecciosas/estatística & dados numéricos , Complicações Infecciosas na Gravidez/diagnóstico , Gestantes , SARS-CoV-2 , Adulto , COVID-19/epidemiologia , Cesárea/estatística & dados numéricos , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Israel/epidemiologia , Pandemias , Morte Perinatal , Gravidez , Complicações Infecciosas na Gravidez/virologia , Resultado da Gravidez , Nascimento Prematuro/epidemiologia , Nascimento Prematuro/virologia , Estudos Prospectivos , Vagina , Adulto JovemRESUMO
Working memory (WM) needs to protect current content from interference and simultaneously be amenable to rapid updating with newly relevant information. An influential model suggests these opposing requirements are met via a BG-thalamus gating mechanism that allows for selective updating of PFC WM representations. A large neuroimaging literature supports the general involvement of PFC, BG, and thalamus, as well as posterior parietal cortex, in WM. However, the specific functional contributions of these regions to key subprocesses of WM updating, namely, gate opening, content substitution, and gate closing, are still unknown, as common WM tasks conflate these processes. We therefore combined fMRI with the reference-back task, specifically designed to tease apart these subprocesses. Participants compared externally presented face stimuli to a reference face held in WM, while alternating between updating and maintaining this reference, resulting in opening versus closing the gate to WM. Gate opening and substitution processes were associated with strong BG, thalamic, and frontoparietal activation, but intriguingly, the same activity profile was observed for sensory cortex supporting task stimulus processing (i.e., the fusiform face area). In contrast, gate closing was not reliably associated with any of these regions. These findings provide new support for the involvement of the BG in gate opening, as suggested by the gating model, but qualify the model's assumptions by demonstrating that gate closing does not seem to depend on the BG and that gate opening also involves task-relevant sensory cortex.
Assuntos
Memória de Curto Prazo , Lobo Parietal , Cognição , Humanos , Imageamento por Ressonância MagnéticaRESUMO
INTRODUCTION: This study examined changes in biomarkers of exposure (BoE) after 5 days of nicotine-salt pod system (NSPS) use, compared with continuation of usual-cigarette smoking and cigarette abstinence, among adult combustible cigarette smokers. AIMS AND METHODS: A randomized, open-label, parallel-cohort, confinement study of healthy adult smokers, naive to NSPS use, was conducted. Participants (N = 90) were randomized to six cohorts (n = 15 each): exclusive ad libitum use of NSPS (four flavors: Virginia Tobacco, Mint, Mango, Creme), continuation of usual-brand cigarette smoking, or cigarette abstinence. Total nicotine equivalents and BoE (NNN, NNAL, 3-HPMA, MHBMA, S-PMA, HMPMA, CEMA, 1-OHP, and COHb) were measured. RESULTS: Eight non-nicotine BoEs, measured in urine, were reduced by an aggregate of 85.0% in the pooled NSPS cohort; increased by 14.4% in the cigarette cohort (p < .001 for pooled NSPS vs. cigarette); and reduced by 85.3% in the abstinence cohort (p > .05; 99.6% relative reduction between pooled NSPS vs. abstinence). Similar changes in individual BoEs were also observed (p < .001 for each BoE between pooled NSPS vs. cigarettes; and abstinence vs. pooled NSPS; p > .05 for each BoE between pooled NSPS vs. abstinence). Blood COHb decreased by 71.8% in the pooled NSPS cohort and 69.1% in the abstinence cohort (p > .05) and increased by 13.3% in the cigarette cohort (p < .001). Mean total urine nicotine equivalents increased in the pooled NSPS and cigarette cohorts by 9% and 26%, respectively, and did not significantly differ (p > .05). CONCLUSION: Complete switching from cigarettes to NSPS produced significant reductions in key non-nicotine BoEs associated with cigarette smoking. IMPLICATIONS: The results of this study concorded with evidence that complete switching from combustible cigarettes to tobacco and nontobacco-flavored vapor products may reduce exposure to key carcinogens and other toxicants known to be associated with tobacco-related diseases. Future research is needed to assess the long-term health effects of NSPS use. These results should not be interpreted to mean that the use of NSPS is without any risk, particularly for nonusers of tobacco products.