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SUV420H1 di- and tri-methylates histone H4 lysine 20 (H4K20me2/H4K20me3) and plays crucial roles in DNA replication, repair, and heterochromatin formation. It is dysregulated in several cancers. Many of these processes were linked to its catalytic activity. However, deletion and inhibition of SUV420H1 have shown distinct phenotypes, suggesting that the enzyme likely has uncharacterized non-catalytic activities. Our cryoelectron microscopy (cryo-EM), biochemical, biophysical, and cellular analyses reveal how SUV420H1 recognizes its nucleosome substrates, and how histone variant H2A.Z stimulates its catalytic activity. SUV420H1 binding to nucleosomes causes a dramatic detachment of nucleosomal DNA from the histone octamer, which is a non-catalytic activity. We hypothesize that this regulates the accessibility of large macromolecular complexes to chromatin. We show that SUV420H1 can promote chromatin condensation, another non-catalytic activity that we speculate is needed for its heterochromatin functions. Together, our studies uncover and characterize the catalytic and non-catalytic mechanisms of SUV420H1, a key histone methyltransferase that plays an essential role in genomic stability.
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Histona-Lisina N-Metiltransferase , Histonas , Cromatina/genética , Microscopia Crioeletrônica , Heterocromatina/genética , Histona-Lisina N-Metiltransferase/genética , Histonas/genética , Lisina , Nucleossomos/genética , HumanosRESUMO
The two doublet histones of Marseillevirus are distantly related to the four eukaryotic core histones and wrap 121 base pairs of DNA to form remarkably similar nucleosomes. By permeabilizing Marseillevirus virions and performing genome-wide nuclease digestion, chemical cleavage, and mass spectrometry assays, we find that the higher-order organization of Marseillevirus chromatin fundamentally differs from that of eukaryotes. Marseillevirus nucleosomes fully protect DNA within virions as closely abutted 121-bp DNA-wrapped cores without linker DNA or phasing along genes. Likewise, we observed that nucleosomes reconstituted onto multi-copy tandem repeats of a nucleosome-positioning sequence are tightly packed. Dense promiscuous packing of fully wrapped nucleosomes rather than "beads on a string" with genic punctuation represents a distinct mode of DNA packaging by histones. We suggest that doublet histones have evolved for viral genome protection and may resemble an early stage of histone differentiation leading to the eukaryotic octameric nucleosome.
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Vírus Gigantes , Nucleossomos , Nucleossomos/genética , Histonas/genética , Vírus Gigantes/genética , DNA/genética , Vírion/genética , Genoma ViralRESUMO
PIEZOs are mechanosensitive ion channels that convert force into chemoelectric signals1,2 and have essential roles in diverse physiological settings3. In vitro studies have proposed that PIEZO channels transduce mechanical force through the deformation of extensive blades of transmembrane domains emanating from a central ion-conducting pore4-8. However, little is known about how these channels interact with their native environment and which molecular movements underlie activation. Here we directly observe the conformational dynamics of the blades of individual PIEZO1 molecules in a cell using nanoscopic fluorescence imaging. Compared with previous structural models of PIEZO1, we show that the blades are significantly expanded at rest by the bending stress exerted by the plasma membrane. The degree of expansion varies dramatically along the length of the blade, where decreased binding strength between subdomains can explain increased flexibility of the distal blade. Using chemical and mechanical modulators of PIEZO1, we show that blade expansion and channel activation are correlated. Our findings begin to uncover how PIEZO1 is activated in a native environment. More generally, as we reliably detect conformational shifts of single nanometres from populations of channels, we expect that this approach will serve as a framework for the structural analysis of membrane proteins through nanoscopic imaging.
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Canais Iônicos , Membrana Celular/metabolismo , Fluorescência , Canais Iônicos/química , Canais Iônicos/metabolismo , Modelos Moleculares , Movimento , Conformação Proteica , Análise de Célula ÚnicaRESUMO
The visual allure of microscopy makes it an intuitively powerful research tool. Intuition, however, can easily obscure or distort the reality of the information contained in an image. Common cognitive biases, combined with institutional pressures that reward positive research results, can quickly skew a microscopy project towards upholding, rather than rigorously challenging, a hypothesis. The impact of these biases on a variety of research topics is well known. What might be less appreciated are the many forms in which bias can permeate a microscopy experiment. Even well-intentioned researchers are susceptible to bias, which must therefore be actively recognized to be mitigated. Importantly, although image quantification has increasingly become an expectation, ostensibly to confront subtle biases, it is not a guarantee against bias and cannot alone shield an experiment from cognitive distortions. Here, we provide illustrative examples of the insidiously pervasive nature of bias in microscopy experiments - from initial experimental design to image acquisition, analysis and data interpretation. We then provide suggestions that can serve as guard rails against bias.
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Microscopia , Pesquisadores , Humanos , ViésRESUMO
BACKGROUND: Central Michigan University (CMU) participated in a state-wide SARS-CoV-2 wastewater monitoring program since 2021. Wastewater samples were collected from on-campus sites and nine off-campus wastewater treatment plants servicing small metropolitan and rural communities. SARS-CoV-2 genome copies were quantified using droplet digital PCR and results were reported to the health department. RESULTS: One rural, off-campus site consistently produced higher concentrations of SARS-CoV-2 genome copies. Samples from this site were sequenced and contained predominately a derivative of Alpha variant lineage B.1.1.7, detected from fall 2021 through summer 2023. Mutational analysis of reconstructed genes revealed divergence from the Alpha variant lineage sequence over time, including numerous mutations in the Spike RBD and NTD. CONCLUSIONS: We discuss the possibility that a chronic SARS-CoV-2 infection accumulated adaptive mutations that promoted long-term infection. This study reveals that small wastewater treatment plants can enhance resolution of rare events and facilitate reconstruction of viral genomes due to the relative lack of contaminating sequences.
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COVID-19 , SARS-CoV-2 , Humanos , SARS-CoV-2/genética , COVID-19/epidemiologia , Águas Residuárias , Genoma Viral , RNA ViralRESUMO
Fluorescence microscopy images should not be treated as perfect representations of biology. Many factors within the biospecimen itself can drastically affect quantitative microscopy data. Whereas some sample-specific considerations, such as photobleaching and autofluorescence, are more commonly discussed, a holistic discussion of sample-related issues (which includes less-routine topics such as quenching, scattering and biological anisotropy) is required to appropriately guide life scientists through the subtleties inherent to bioimaging. Here, we consider how the interplay between light and a sample can cause common experimental pitfalls and unanticipated errors when drawing biological conclusions. Although some of these discrepancies can be minimized or controlled for, others require more pragmatic considerations when interpreting image data. Ultimately, the power lies in the hands of the experimenter. The goal of this Review is therefore to survey how biological samples can skew quantification and interpretation of microscopy data. Furthermore, we offer a perspective on how to manage many of these potential pitfalls.
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Biologia , Luz , Anisotropia , Microscopia de Fluorescência/métodos , FotodegradaçãoRESUMO
BACKGROUND: Cardiovascular disease is a major cause of maternal mortality, but the extent to which infertility treatment is implicated in heart disease remains unclear. OBJECTIVE: To evaluate the association between infertility treatment and postpartum heart disease. METHODS: We designed a retrospective cohort study of patients who delivered in the United States between 2010 and 2018. The primary outcome was hospitalization within 12-month post-delivery due to heart disease (including ischemic heart disease, atherosclerotic heart disease, cardiomyopathy, hypertensive disease, heart failure, and cardiac dysrhythmias). We estimated the rate difference (RD) of hospitalizations among patients who conceived with infertility treatment and those who conceived spontaneously. Associations were expressed as hazard ratios (HRs) and 95% confidence intervals (CIs), derived from Cox proportional hazards regression after adjustment for potential confounders. RESULTS: Infertility treatment was recorded in 0.9% (n = 287,813) of 31,339,991 deliveries. Rates of heart disease hospitalizations with infertility treatment and with spontaneous conception were 550 and 355 per 100,000, respectively (RD 195, 95% CI: 143-247; adjusted HR 1.99, 95% CI: 1.80-2.20). The most important increase in risk was observed for hypertensive disease (adjusted HR 2.16, 95% CI: 1.92-2.42). This increased risk was apparent as early as 30-day post-delivery (HR 1.61, 95% CI: 1.39-1.86), with progressively increasing risk up to a year. CONCLUSIONS: Although the absolute risk of postpartum heart disease hospitalization is low, infertility treatment is associated with an increased risk, especially for hypertensive disease. These findings highlight the importance of timely postpartum follow-ups in patients who received infertility treatment.
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Insuficiência Cardíaca , Hipertensão , Infertilidade , Feminino , Humanos , Estados Unidos/epidemiologia , Estudos Retrospectivos , Hospitalização , Período Pós-Parto , Insuficiência Cardíaca/epidemiologiaRESUMO
OBJECTIVE: We used a polygenic risk score (PRS) to identify high-risk groups for primary open-angle glaucoma (POAG) within population-based cohorts. DESIGN: Secondary analysis of four prospective population-based studies. PARTICIPANTS: We included four European-ancestry cohorts: the United States (US) based Nurses' Health Study (NHS), NHS2, and the Health Professionals Follow-up Study, and the Rotterdam Study (RS) in the Netherlands. The US cohorts included female nurses and male health professionals aged 55+ years. The RS included residents aged 45 years or older living in Rotterdam, the Netherlands. METHODS: PRS weights were estimated by applying the Lassosum method on imputed genotype and phenotype data from the UK-Biobank. This resulted in 144,020 variants, single nucleotide polymorphism (SNPs) and indels, with non-zero betas that we used to calculate a PRS in the target populations. Using multivariable Cox proportional hazard models, we estimated the relationship between the standardized PRS and relative risk for POAG. Additionally, POAG prediction was tested by calculating these models' concordance (Harrell's C-statistic). Finally, we assessed the association between PRS tertiles and glaucoma-related traits. MAIN OUTCOME MEASURES: The relative risk for POAG and Harrell's C-statistic (the equivalent of an area-under-the-curve for longitudinal models). RESULTS: Among 1,046 cases and 38,809⬠controls, the relative risk (95% confidence interval) for POAG for participants in the highest PRS quintile was 3.99 (3.08, 5.18) in the US cohorts, and 4.89 (2.93, 8.17) in the Rotterdam Study, compared with participants with median genetic risk (3rd quintile). In restricted cubic spline analyses, the relation between continuous PRS and POAG risk increased exponentially in the US and Rotterdam cohorts (Pspline<0.05). Combining age, sex, intraocular pressure >25 mmHg, and family history resulted in a meta-analyzed concordance of 0.75 (0.73, 0.75). Adding the PRS to this model improved the concordance to 0.82 (0.80, 0.84). In a meta-analysis of all cohorts, cases in the highest tertile had a larger cup-disc ratio at diagnosis, by 0.11 (0.07, 0.15), and a 2.07-fold increased risk of requiring glaucoma surgery (1.19, 3.60). CONCLUSIONS: Incorporating a PRS into a POAG predictive model improves identification concordance from 0.75 up to 0.82, supporting its potential for guiding more cost-effective screening strategies.
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PURPOSE OF REVIEW: Lung cancer is the leading cause of cancer-related death in the United States. Pulmonary resection, in addition to perioperative systemic therapies, is a cornerstone of treatment for operable patients with early-stage and locoregional disease. In recent years, increased emphasis has been placed on surgical quality metrics: specific and evidence-based structural, process, and outcome measures that aim to decrease variation in lung cancer care and improve long term outcomes. These metrics can be divided into potential areas of intervention or improvement in the preoperative, intraoperative, and postoperative phases of care and form the basis of guidelines issued by organizations including the National Cancer Center Network (NCCN) and Society of Thoracic Surgeons (STS). This review focuses on established quality metrics associated with lung cancer surgery with an emphasis on the most recent research and guidelines. RECENT FINDINGS: Over the past 18âmonths, quality metrics across the peri-operative care period were explored, including optimal invasive mediastinal staging preoperatively, the extent of intraoperative lymphadenectomy, surgical approaches related to minimally invasive resection, and enhanced recovery pathways that facilitate early discharge following pulmonary resection. SUMMARY: Quality metrics in lung cancer surgery is an exciting and important area of research. Adherence to quality metrics has been shown to improve overall survival and guidelines supporting their use allows targeted quality improvement efforts at a local level to facilitate more consistent, less variable oncologic outcomes across centers.
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Neoplasias Pulmonares , Pneumonectomia , Melhoria de Qualidade , Humanos , Neoplasias Pulmonares/cirurgia , Pneumonectomia/normas , Guias de Prática Clínica como Assunto , Estados Unidos , Estadiamento de Neoplasias , Excisão de Linfonodo/normas , Assistência Perioperatória/normas , Assistência Perioperatória/métodosRESUMO
BACKGROUND AND OBJECTIVES: Early detection of hepatocellular carcinoma (HCC) is associated with improved survival. However, a greater proportion of patients treated at safety net hospitals (SNHs) present with late-stage disease compared to those at academic medical centers (AMCs). This study aims to identify barriers to diagnosis of HCC, highlighting differences between SNHs and AMCs. METHODS: The US Safety Net Collaborative-HCC database was queried. Patients were stratified by facility of diagnosis (SNH or AMC). Patient demographics and HCC screening rates were examined. The primary outcome was stage at diagnosis (AJCC I/II-"early"; AJCC III/IV-"late"). RESULTS: 1290 patients were included; 50.2% diagnosed at SNHs and 49.8% at AMCs. At SNHs, 44.4% of patients were diagnosed late, compared to 27.6% at AMCs. On multivariable regression, Black race was associated with late diagnosis in both facilities (SNH: odds ratio 1.96, p = 0.03; AMC: 2.27, <0.01). Screening was associated with decreased odds of late diagnosis (SNH: 0.46, p = 0.04; AMC: 0.37, p < 0.01). CONCLUSIONS: Black race was associated with late diagnosis of HCC, while screening was associated with early diagnosis across institutional types. These results suggest socially constructed racial bias in screening and diagnosis of HCC. Screening efforts targeting SNH patients and Black patients at all facilities are essential to reduce disparities.
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BACKGROUND: Reported rates of maternal mortality in the United States have been staggeringly high and increasing, and cardiovascular disease (CVD) is a chief contributor to such deaths. However, the impact of hypertensive disorders of pregnancy (HDP) on the short-term risk of cardiovascular death is not well understood. OBJECTIVES: To evaluate the association between HDP (chronic hypertension, gestational hypertension, preeclampsia, eclampsia, and superimposed preeclampsia) and pregnancy-associated mortality rates (PMR) from all causes, CVD-related causes both at delivery and within 1 year following delivery. METHODS: We used the Nationwide Readmissions Database (2010-2018) to examine PMRs for females 15-54 years old. International Classification of Disease 9 and 10 diagnosis codes were used to identify pregnancy-associated deaths due to HDP and CVD. Discrete-time Cox proportional hazards regression models were used to calculate adjusted hazard ratios (HR) and 95% confidence intervals (CI) for mortality at delivery (0 days) and at <30, <60, <90, <180, and <365 days after delivery in relation to HDP. RESULTS: Of 33,417,736 hospital deliveries, the rate of HDP was 11.0% (n = 3,688,967), and the PMR from CVD was 6.4 per 100,000 delivery hospitalisations (n = 2141). Compared with normotensive patients, HRs for CVD-related PMRs increased with HDP severity, reaching over 58-fold for eclampsia patients. HRs were higher for stroke-related (1.2 to 170.9) than heart disease (HD)-related (0.99 to 39.8) mortality across all HDPs. Except for gestational hypertension, the increased risks of CVD mortality were evident at delivery and persisted 1 year postpartum for all HDPs. CONCLUSIONS: HDPs are strong risk factors for pregnancy-associated mortality due to CVD at delivery and within 1 year postpartum; the risks are stronger for stroke than HD-related PMR. While absolute PMRs are low, this study supports the importance of extending postpartum care beyond the traditional 42-day postpartum visit for people whose pregnancies are complicated by hypertension.
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Doenças Cardiovasculares , Eclampsia , Hipertensão Induzida pela Gravidez , Pré-Eclâmpsia , Acidente Vascular Cerebral , Gravidez , Feminino , Humanos , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Obstetrical complications impact the health of mothers and offspring along the life course, resulting in an increased burden of chronic diseases. One specific complication is abruption, a life-threatening condition with consequences for cardiovascular health that remains poorly studied. OBJECTIVES: To describe the design and data linkage algorithms for the Placental Abruption and Cardiovascular Event Risk (PACER) cohort. POPULATION: All subjects who delivered in New Jersey, USA, between 1993 and 2020. DESIGN: Retrospective, population-based, birth cohort study. METHODS: We linked the vital records data of foetal deaths and live births to delivery and all subsequent hospitalisations along the life course for birthing persons and newborns. The linkage was based on a probabilistic record-matching algorithm. PRELIMINARY RESULTS: Over the 28 years of follow-up, we identified 1,877,824 birthing persons with 3,093,241 deliveries (1.1%, n = 33,058 abruption prevalence). The linkage rates for live births-hospitalisations and foetal deaths-hospitalisations were 92.4% (n = 2,842,012) and 70.7% (n = 13,796), respectively, for the maternal cohort. The corresponding linkage rate for the live births-hospitalisations for the offspring cohort was 70.3% (n = 2,160,736). The median (interquartile range) follow-up for the maternal and offspring cohorts was 15.4 (8.1, 22.4) and 14.4 (7.4, 21.0) years, respectively. We will undertake multiple imputations for missing data and develop inverse probability weights to account for selection bias owing to unlinked records. CONCLUSIONS: Pregnancy offers a unique window to study chronic diseases along the life course and efforts to identify the aetiology of abruption may provide important insights into the causes of future CVD. This project presents an unprecedented opportunity to understand how abruption may predispose women and their offspring to develop CVD complications and chronic conditions later in life.
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Descolamento Prematuro da Placenta , Complicações Cardiovasculares na Gravidez , Gravidez , Feminino , Recém-Nascido , Humanos , Descolamento Prematuro da Placenta/epidemiologia , Estudos de Coortes , Estudos Retrospectivos , Placenta , Fatores de Risco , Complicações Cardiovasculares na Gravidez/epidemiologia , Morte Fetal , Doença CrônicaRESUMO
PURPOSE: Breast cancer is the most common form of cancer among Canadian women. Survivorship challenges include fatigue, sleep disturbance, and cognitive impairment. This study examined (1) symptom trajectory from diagnosis to 3 years; (2) whether symptom change in the first 4 months was associated with prolonged difficulties after 3 years; and (3) which factors were associated with deterioration in symptoms during the first 4 months. METHODS: This prospective observational cohort study examined 53 women (Mage = 58.6, 96.2% White, 67.9% stage I) with newly diagnosed breast cancer over 3 years. Women completed assessments before starting treatment, 4 months, and 3 years after diagnosis. Three-way repeated-measures ANOVAs evaluated symptom trajectories. A repeated-measures mediation analysis was performed to determine if change from pre-treatment to 4 months accounted for change from pre-treatment to 3 years. A series of between-subjects ANOVAs were used to determine what variables significantly differed by deterioration status. RESULTS: Perceived cognitive impairment and fatigue increased linearly from diagnosis to 3 years. Change in fatigue in the first 4 months fully accounted for its change over 3 years. Insomnia severity and sleep quality deteriorated from diagnosis to 4 months, but returned to pre-treatment levels at 3 years. Those whose fatigue and cognitive ability deteriorated during the first 4 months were younger. CONCLUSION: Efforts to identify those who are at risk of experiencing fatigue, sleep disturbance, and cognitive impairment; monitor patients early after receiving a diagnosis; and provide targeted interventions may prevent long-term deterioration and improve well-being.
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Neoplasias da Mama , Sobreviventes de Câncer , Disfunção Cognitiva , Distúrbios do Início e da Manutenção do Sono , Humanos , Feminino , Distúrbios do Início e da Manutenção do Sono/etiologia , Distúrbios do Início e da Manutenção do Sono/complicações , Sobreviventes de Câncer/psicologia , Neoplasias da Mama/complicações , Neoplasias da Mama/terapia , Neoplasias da Mama/psicologia , Estudos Prospectivos , Canadá , Disfunção Cognitiva/epidemiologia , Disfunção Cognitiva/etiologia , Fadiga/epidemiologia , Fadiga/etiologiaRESUMO
OBJECTIVES: Poor sleep is a common side effect of cancer. Cannabis is increasingly used to manage cancer treatment-related symptoms, including sleep. This study investigated factors related to cannabis use for sleep among Canadian cancer survivors. METHOD: Adult Canadian cancer survivors (N = 940) were recruited via the Angus Reid Institute and completed an online, cross-sectional survey. Univariate and multiple binomial logistic regression models identified factors associated with cannabis use for sleep. RESULTS: Of the participants (Mage = 64.5 yrs; Women = 51.1%; White = 92.9%), 25.1% (n = 236) currently use cannabis for sleep. Participants were at greater odds of using cannabis for sleep if they identified as a gender other than man or woman (AOR = 11.132), were diagnosed with multiple medical conditions (2:AOR = 1.988; 3+:AOR = 1.902), two psychological conditions (AOR = 2.171), multiple sleep disorders (AOR = 2.338), insomnia (AOR = 1.942), bone (AOR = 6.535), gastrointestinal (AOR = 4.307), genitourinary (AOR = 2.586), hematological (AOR = 4.739), or an unlisted cancer (AOR = 3.470), received hormone therapy only (AOR = 3.054), drink heavily (AOR = 2.748), or had mild insomnia (AOR = 1.828). Older participants (AOR=.972) and those with sleep apnea were less likely to use cannabis for sleep (AOR=.560). CONCLUSION: Given its prevalence, research is needed to understand how factors associated with cannabis use as a sleep aid among Canadian cancer survivors may influence its use and effectiveness and whether these factors are barriers to accessing evidence-based treatments.
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Sobreviventes de Câncer , Humanos , Feminino , Masculino , Estudos Transversais , Pessoa de Meia-Idade , Sobreviventes de Câncer/estatística & dados numéricos , Canadá , Idoso , Distúrbios do Início e da Manutenção do Sono/epidemiologia , Inquéritos e Questionários , Transtornos do Sono-Vigília/epidemiologia , Adulto , Neoplasias/complicações , Medicamentos Indutores do Sono/uso terapêutico , Maconha Medicinal/administração & dosagemRESUMO
Vital signs monitoring is a fundamental component of ensuring the health and safety of women and newborns during pregnancy, labor, and childbirth. This monitoring is often the first step in early detection of pregnancy abnormalities, providing an opportunity for prompt, effective intervention to prevent maternal and neonatal morbidity and mortality. Contemporary pregnancy monitoring systems require numerous devices wired to large base units; at least five separate devices with distinct user interfaces are commonly used to detect uterine contractility, maternal blood oxygenation, temperature, heart rate, blood pressure, and fetal heart rate. Current monitoring technologies are expensive and complex with implementation challenges in low-resource settings where maternal morbidity and mortality is the greatest. We present an integrated monitoring platform leveraging advanced flexible electronics, wireless connectivity, and compatibility with a wide range of low-cost mobile devices. Three flexible, soft, and low-profile sensors offer comprehensive vital signs monitoring for both women and fetuses with time-synchronized operation, including advanced parameters such as continuous cuffless blood pressure, electrohysterography-derived uterine monitoring, and automated body position classification. Successful field trials of pregnant women between 25 and 41 wk of gestation in both high-resource settings (n = 91) and low-resource settings (n = 485) demonstrate the system's performance, usability, and safety.
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Monitorização Fisiológica/instrumentação , Gravidez/fisiologia , Dispositivos Eletrônicos Vestíveis , Tecnologia sem Fio/instrumentação , Feminino , Recursos em Saúde , Frequência Cardíaca Fetal , Humanos , Contração Uterina , Sinais VitaisRESUMO
Abnormal uterine bleeding is a common and bothersome symptom in people using hormonal contraception, and it can lead to discontinuation of reliable methods of contraception and unintended pregnancies. Clinicians should counsel individuals about the potential for abnormal bleeding at initiation of the contraceptive method. After considering and excluding other potential causes of abnormal uterine bleeding, clinicians can offer treatment options specific to each hormonal contraceptive method. This article includes algorithms to help clinicians treat abnormal uterine bleeding in people using levonorgestrel intrauterine devices, depo-medroxyprogesterone acetate, progestin implant, progestin-only pills, and combined hormonal contraception. For patients with levonorgestrel intrauterine devices, physicians should first ensure that the device is correctly placed within the uterus, then consider nonsteroidal anti-inflammatory drugs as a first-line treatment for abnormal uterine bleeding; estradiol can be used if nonsteroidal anti-inflammatory drugs are ineffective. For depo-medroxyprogesterone acetate or progestin implant users, combined oral contraceptives or nonsteroidal anti-inflammatory drugs may be considered. For patients using norethindrone progestin-only pills, changing to drospirenone progesterone-only pills may help reduce the bleeding. In people using combined hormonal contraception, it may be helpful to increase estrogen content from 20 mcg to 35 mcg per day, decrease the hormone-free interval (from seven to four or five days) in people using cyclic contraception, or start a trial of low-dose doxycycline. For continuous combined contraception users, adding a hormone-free interval of four or five days can help regulate bleeding patterns.
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Levanogestrel , Progestinas , Gravidez , Feminino , Humanos , Levanogestrel/efeitos adversos , Progestinas/efeitos adversos , Acetato de Medroxiprogesterona/efeitos adversos , Contracepção Hormonal , Anticoncepção , Hemorragia Uterina/induzido quimicamente , Anti-Inflamatórios/uso terapêutico , Anticoncepcionais Orais Hormonais/efeitos adversosRESUMO
PURPOSE: In vitro fertilization (IVF) is associated with abnormal trophoblast invasion and resultant decreased levels of circulating placental biomarkers such as placental growth factor (PlGF). Our objective was to evaluate maternal serum levels of second/third trimester PlGF, sonographic placental parameters, and clinical outcomes among IVF frozen embryo transfer (FET) pregnancies with and without embryo trophectoderm biopsy. METHODS: This was a retrospective study of pregnant patients who conceived using a single frozen embryo transfer (FET) and gave birth between 30 January 2018 and 31 May 2021. We compared PlGF levels, sonographic placental parameters, and clinical outcomes between FET with biopsy and FET without biopsy groups. RESULTS: The median PlGF level was 614.5 pg/mL (IQR 406-1020) for FET pregnancies with biopsy, and 717.0 pg/mL (IQR 552-1215) for FET pregnancies without biopsy. The adjusted mean difference was 190.9 pg/mL lower in the FET biopsy group (95% CI, -410.6, 28.8; p = 0.088). There were no statistically significant differences in placental parameters or clinical pregnancy outcomes. CONCLUSION: This exploratory study demonstrated a possible trend toward lower maternal serum PlGF in the pregnancies conceived with FET using a biopsied embryo. Further investigation is warranted into the potential placental health effects of trophectoderm biopsy.
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BACKGROUND: Sudden gains occur in a range of disorders and treatments and are of clinical and theoretical significance if they can shed light on therapeutic change processes. This study investigated the relationship between sudden gains in panic symptoms and preceding cognitive change during cognitive behavioural therapy (CBT) for panic disorder. METHOD: Participants with panic disorder completed in session measures of panic symptoms and catastrophic cognitions. Independent samples t-tests were used to compare the post-treatment score of those who met criteria for one or more sudden gain during treatment with those who did not, and to compare within-session cognitive change between pre-sudden gain sessions and the previous (control) session. RESULTS: Twenty-two (42%) of 53 participants experienced a sudden gain during treatment. Participants demonstrating a sudden gain showed more improvement in panic symptoms from pre- to post-treatment than those without a sudden gain. The within-session cognitive change score in the pre-gain session was significantly greater than in the control session. CONCLUSIONS: Sudden gains occurred in individual CBT for panic disorder and within-session cognitive change was associated with sudden gains. This is consistent with the cognitive model of panic disorder and highlights how sudden gains can help to identify key change processes.
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Terapia Cognitivo-Comportamental , Transtorno de Pânico , Humanos , Transtorno de Pânico/terapia , Transtorno de Pânico/psicologia , Resultado do Tratamento , CogniçãoRESUMO
Sensory loss leads to widespread cross-modal plasticity across brain areas to allow the remaining senses to guide behavior. While multimodal sensory interactions are often attributed to higher-order sensory areas, cross-modal plasticity has been observed at the level of synaptic changes even across primary sensory cortices. In particular, vision loss leads to widespread circuit adaptation in the primary auditory cortex (A1) even in adults. Here we report using mice of both sexes in which cross-modal plasticity occurs even earlier in the sensory-processing pathway at the level of the thalamus in a modality-selective manner. A week of visual deprivation reduced inhibitory synaptic transmission from the thalamic reticular nucleus (TRN) to the primary auditory thalamus (MGBv) without changes to the primary visual thalamus (dLGN). The plasticity of TRN inhibition to MGBv was observed as a reduction in postsynaptic gain and short-term depression. There was no observable plasticity of the cortical feedback excitatory synaptic transmission from the primary visual cortex to dLGN or TRN and A1 to MGBv, which suggests that the visual deprivation-induced plasticity occurs predominantly at the level of thalamic inhibition. We provide evidence that visual deprivation-induced change in the short-term depression of TRN inhibition to MGBv involves endocannabinoid CB1 receptors. TRN inhibition is considered critical for sensory gating, selective attention, and multimodal performances; hence, its plasticity has implications for sensory processing. Our results suggest that selective disinhibition and altered short-term dynamics of TRN inhibition in the spared thalamic nucleus support cross-modal plasticity in the adult brain.SIGNIFICANCE STATEMENT Losing vision triggers adaptation of the brain to enhance the processing of the remaining senses, which can be observed as better auditory performance in blind subjects. We previously found that depriving vision of adult rodents produces widespread circuit reorganization in the primary auditory cortex and enhances auditory processing at a neural level. Here we report that visual deprivation-induced plasticity in adults occurs much earlier in the auditory pathway, at the level of thalamic inhibition. Sensory processing is largely gated at the level of the thalamus via strong cortical feedback inhibition mediated through the thalamic reticular nucleus (TRN). We found that TRN inhibition of the auditory thalamus is selectively reduced by visual deprivation, thus playing a role in adult cross-modal plasticity.
Assuntos
Endocanabinoides , Núcleos Talâmicos , Masculino , Feminino , Camundongos , Animais , Núcleos Talâmicos/fisiologia , Tálamo/fisiologia , Vias Auditivas/fisiologia , Transmissão Sináptica/fisiologiaRESUMO
BACKGROUND: Between May and November, 2022, global outbreaks of human monkeypox virus infection have been reported in more than 78 000 people worldwide, predominantly in men who have sex with men. We describe the epidemiological and clinical characteristics of monkeypox virus infection in cisgender (cis) and transgender (trans) women and non-binary individuals assigned female sex at birth to improve identification and understanding of risk factors. METHODS: International collaborators in geographical locations with high numbers of diagnoses of monkeypox virus infection were approached and invited to contribute data on women and non-binary individuals with confirmed monkeypox virus infection. Contributing centres completed deidentified structured case-report spreadsheets, adapted and developed by participating clinicians, to include variables of interest relevant to women and non-binary individuals assigned female at birth. We describe the epidemiology and clinical course observed in the reported infections. FINDINGS: Collaborators reported data for a total of 136 individuals with monkeypox virus infection who presented between May 11 and Oct 4, 2022, across 15 countries. Overall median age was 34 years (IQR 28-40; range 19-84). The cohort comprised 62 trans women, 69 cis women, and five non-binary individuals (who were, because of small numbers, grouped with cis women to form a category of people assigned female at birth for the purpose of comparison). 121 (89%) of 136 individuals reported sex with men. 37 (27%) of all individuals were living with HIV, with a higher proportion among trans women (31 [50%] of 62) than among cis women and non-binary individuals (six [8%] of 74). Sexual transmission was suspected in 55 (89%) trans women (with the remainder having an unknown route of transmission) and 45 (61%) cis women and non-binary individuals; non-sexual routes of transmission (including household and occupational exposures) were reported only in cis women and non-binary individuals. 25 (34%) of 74 cis women and non-binary individuals submitted to the case series were initially misdiagnosed. Overall, among individuals with available data, rash was described in 124 (93%) of 134 individuals and described as anogenital in 95 (74%) of 129 and as vesiculopustular in 105 (87%) of 121. Median number of lesions was ten (IQR 5-24; range 1-200). Mucosal lesions involving the vagina, anus, or oropharynx or eye occurred in 65 (55%) of 119 individuals with available data. Vaginal and anal sex were associated with lesions at those sites. Monkeypox virus DNA was detected by PCR from vaginal swab samples in all 14 samples tested. 17 (13%) individuals were hospitalised, predominantly for bacterial superinfection of lesions and pain management. 33 (24%) individuals were treated with tecovirimat and six (4%) received post-exposure vaccinations. No deaths were reported. INTERPRETATION: The clinical features of monkeypox in women and non-binary individuals were similar to those described in men, including the presence of anal and genital lesions with prominent mucosal involvement. Anatomically, anogenital lesions were reflective of sexual practices: vulvovaginal lesions predominated in cis women and non-binary individuals and anorectal features predominated in trans women. The prevalence of HIV co-infection in the cohort was high. FUNDING: None.