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1.
Anal Bioanal Chem ; 2024 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-38656365

RESUMO

The masking of specific effects in in vitro assays by cytotoxicity is a commonly known phenomenon. This may result in a partial or complete loss of effect signals. For common in vitro assays, approaches for identifying and quantifying cytotoxic masking are partly available. However, a quantification of cytotoxicity-affected signals is not possible. As an alternative, planar bioassays that combine high-performance thin layer chromatography with in vitro assays, such as the planar yeast estrogen screen (p-YES), might allow for a quantification of cytotoxically affected signals. Affected signals form a typical ring structure with a supressed or completely lacking centre that results in a double peak chromatogram. This study investigates whether these double peaks can be used for fitting a peak function to extrapolate the theoretical, unaffected signals. The precision of the modelling was evaluated for four individual peak functions, using 42 ideal, undistorted peaks from estrogenic model compounds in the p-YES. Modelled ED50-values from bisphenol A (BPA) experiments with cytotoxically disturbed signals were 13 times higher than for the apparent data without compensation for cytotoxicity (320 ± 63 ng versus 24 ± 17 ng). This finding has a high relevance for the modelling of mixture effects according to concentration addition that requires unaffected, complete dose-response relationships. Finally, we applied the approach to results of a p-YES assay on leachate samples of an elastomer material used in water engineering. In summary, the fitting approach enables the quantitative evaluation of cytotoxically affected signals in planar in vitro assays and also has applications for other fields of chemical analysis like distorted chromatography signals.

2.
Curr Opin Microbiol ; 79: 102477, 2024 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-38663181

RESUMO

Apicomplexan and trypanosomatid parasites have evolved a wide range of post-transcriptional processes that allow them to replicate, differentiate, and transmit within and among multiple different tissue, host, and vector environments. In this review, we highlight the recent advances that point toward the regulatory potential of RNA modifications in mediating these processes on the coding and noncoding transcriptome throughout the life cycle of protozoan parasites. We discuss the recent technical advancements enabling the study of the 'epitranscriptome' and how parasites evolved RNA modification-mediated mechanisms adapted to their unique lifestyles.

3.
Transl Anim Sci ; 8: txae055, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38665215

RESUMO

Poor maternal nutrition of F0 ewes impairs F1 offspring growth, with minimal differences in glucose tolerance or select metabolic circulating factors, and independent of differences in residual feed intake (RFI). To determine if poor maternal nutrition in F0 ewes alters F2 offspring growth, circulating leptin, feed efficiency, or glucose tolerance, F0 ewes (n = 46) pregnant with twins were fed 100% (control), 60% (restricted), or 140% (over) of National Research Council requirements from days 30 ±â€…0.02 of gestation until parturition. At 16 to 19 mo of age, female F1 (n = 36) offspring were bred to generate F2 offspring [CON-F2 (n = 12 ewes; 6 rams), RES-F2 (n = 7 ewes; 13 rams), or OVER-F2 (n = 13 ewes; 9 rams) corresponding to diets of the granddam (F0)]. Lamb body weights (BW) and blood samples were collected weekly from days 0 to 28 and every 14 d until day 252 of age. Circulating leptin was measured in serum at days 0, 7, 14, 56, 210, and 252. An intravenous glucose tolerance test was performed at days 133 ±â€…0.28. At days 167 ±â€…0.33, individual daily intake was recorded over a 77-d feeding period to determine RFI. Rams were euthanized at days 285 ±â€…0.93, and body morphometrics, loin eye area (LEA), back fat thickness, and organ weights were collected and bone mineral density (BMD) and length were determined in the right hind leg. During gestation, OVER-F1 ewes tended to be 8.6% smaller than CON-F1 ewes (P ≤ 0.06). F2 offspring were of similar BW from birth to day 70 (P ≥ 0.20). However, from days 84 to 252, RES-F2 offspring tended to be 7.3% smaller than CON-F2 (P ≤ 0.10). Granddam diet did not influence F2 ram body morphometrics, organ or muscle weights, LEA, adipose deposition, or leg BMD (P ≥ 0.84). RES-F2 (-0.20) and CON-F2 (-0.45) rams tended to be more feed efficient than CON-F2 ewes (0.31; P ≤ 0.08). No effects of granddam diet were observed on glucose or insulin average or baseline concentrations, area under the curve, first-phase response, or ratio (P ≥ 0.52). However, CON-F2 rams (297 mg/dL ±â€…16.5) had a greater glucose peak compared with RES-F2 rams (239 mg/dL ±â€…11.2; P = 0.05). Peak insulin concentrations were not influenced by granddam diet (P = 0.75). At d 56, RES-F2 and OVER-F2 offspring had 53.5% and 61.8% less leptin compared with CON-F2 offspring, respectively (P ≤ 0.02). These data indicate that poor maternal nutrition impacts offspring growth into the second generation with minimal impacts on offspring RFI, glucose tolerance, and circulating leptin.

4.
J Sports Sci ; 42(5): 415-424, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38590213

RESUMO

This study explored the extent of menstrual manipulation and its associated impact on period-related symptoms and training disruptions in Australian Female Cyclists. 205 female cyclists, from recreational to elite level, participated in an online "Female Cyclist Questionnaire (FCQ)". The FCQ utilised a series of validated questionnaires to obtain demographic information and menstrual function of the respondents, and to investigate their menstrual manipulation habits and perceptions on how their period-related symptoms affected their well-being, mood, energy and training tolerance. More than 80% of the cyclists reported that their period-related symptoms impacted upon training and 41% made training adjustments based on these symptoms. Two-thirds of respondents thought their training should be phase-controlled yet only half discussed their hormonal cycles with their coaches. Menstrual manipulation was predicted by reduced "workout tolerance" in these cyclists (odds ratio = 0.632). Half of the respondents reported compromised ability to tolerate high-intensity interval training with period-related symptoms. Period pain, increased irritability, lower energy levels and more sugar cravings were commonly reported but did not predict menstrual manipulation. The data indicated that period-related symptoms are present in Australian female cyclists across all levels of participation. However, the perceived impact to training and subsequent behavioural changes varied among individuals.


Assuntos
Ciclismo , Humanos , Feminino , Ciclismo/fisiologia , Ciclismo/psicologia , Adulto , Austrália , Adulto Jovem , Inquéritos e Questionários , Adolescente , Afeto , Treinamento Intervalado de Alta Intensidade , Síndrome Pré-Menstrual , Humor Irritável , Ciclo Menstrual/fisiologia , Menstruação/fisiologia , Fissura/fisiologia
5.
Sci Rep ; 14(1): 8991, 2024 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-38637583

RESUMO

COVID-19 is a multisystemic disease caused by the SARS-CoV-2 airborne virus, a member of the Coronaviridae family. It has a positive sense single-stranded RNA genome and encodes two non-structural proteins through viral cysteine-proteases processing. Blocking this step is crucial to control virus replication. In this work, we reported the synthesis of 23 statine-based peptidomimetics to determine their ability to inhibit the main protease (Mpro) activity of SARS-CoV-2. Among the 23 peptidomimetics, 15 compounds effectively inhibited Mpro activity by 50% or more, while three compounds (7d, 8e, and 9g) exhibited maximum inhibition above 70% and IC50 < 1 µM. Compounds 7d, 8e, and 9g inhibited roughly 80% of SARS-CoV-2 replication and proved no cytotoxicity. Molecular docking simulations show putative hydrogen bond and hydrophobic interactions between specific amino acids and these inhibitors. Molecular dynamics simulations further confirmed the stability and persisting interactions in Mpro's subsites, exhibiting favorable free energy binding (ΔGbind) values. These findings suggest the statine-based peptidomimetics as potential therapeutic agents against SARS-CoV-2 by targeting Mpro.


Assuntos
COVID-19 , Proteases 3C de Coronavírus , Peptidomiméticos , Humanos , SARS-CoV-2/metabolismo , Peptidomiméticos/farmacologia , Simulação de Acoplamento Molecular , Inibidores de Proteases/química , Aminoácidos , Simulação de Dinâmica Molecular , Antivirais/farmacologia , Antivirais/química
6.
Cell Rep ; 43(4): 114012, 2024 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-38573856

RESUMO

Plasmodium falciparum is a human-adapted apicomplexan parasite that causes the most dangerous form of malaria. P. falciparum cysteine-rich protective antigen (PfCyRPA) is an invasion complex protein essential for erythrocyte invasion. The precise role of PfCyRPA in this process has not been resolved. Here, we show that PfCyRPA is a lectin targeting glycans terminating with α2-6-linked N-acetylneuraminic acid (Neu5Ac). PfCyRPA has a >50-fold binding preference for human, α2-6-linked Neu5Ac over non-human, α2-6-linked N-glycolylneuraminic acid. PfCyRPA lectin sites were predicted by molecular modeling and validated by mutagenesis studies. Transgenic parasite lines expressing endogenous PfCyRPA with single amino acid exchange mutants indicated that the lectin activity of PfCyRPA has an important role in parasite invasion. Blocking PfCyRPA lectin activity with small molecules or with lectin-site-specific monoclonal antibodies can inhibit blood-stage parasite multiplication. Therefore, targeting PfCyRPA lectin activity with drugs, immunotherapy, or a vaccine-primed immune response is a promising strategy to prevent and treat malaria.


Assuntos
Eritrócitos , Plasmodium falciparum , Polissacarídeos , Proteínas de Protozoários , Eritrócitos/parasitologia , Eritrócitos/metabolismo , Humanos , Proteínas de Protozoários/metabolismo , Proteínas de Protozoários/genética , Plasmodium falciparum/metabolismo , Polissacarídeos/metabolismo , Malária Falciparum/parasitologia , Animais , Lectinas/metabolismo , Lectinas/genética , Antígenos de Protozoários/metabolismo , Antígenos de Protozoários/imunologia , Antígenos de Protozoários/genética , Ligação Proteica
7.
Essays Biochem ; 2024 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-38639060

RESUMO

Sulfate is an important anion as sulfonation is essential in modulation of several compounds, such as exogens, polysaccharide chains of proteoglycans, cholesterol or cholesterol derivatives and tyrosine residues of several proteins. Sulfonation requires the presence of both the sulfate donor 3'-phosphoadenosine-5'-phosphosulfate (PAPS) and a sulfotransferase. Genetic disorders affecting sulfonation, associated with skeletal abnormalities, impaired neurological development and endocrinopathies, demonstrate the importance of sulfate. Yet sulfate is not measured in clinical practice. This review addresses sulfate metabolism and consequences of sulfonation defects, how to measure sulfate and why we should measure sulfate more often.

8.
Am J Otolaryngol ; 45(4): 104298, 2024 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-38640809

RESUMO

PURPOSE: To investigate glycoprotein nonmetastatic melanoma protein B (GPNMB) and vascular endothelial growth factor (VEGF) as potential fluorescent imaging markers by comparing their protein expression to epidermal growth factor receptor (EGFR). MATERIALS AND METHODS: Thirty-eight paired samples of untreated head and neck squamous cell carcinoma (HNSCC) primary tumours (PT) and corresponding synchronous lymph node metastases (LNM) were selected. After immunohistochemical staining, expression was assessed and compared by the percentage of positive tumour cells. Data were analysed using the Mann-Whitney test, effect sizes (ESr) and Spearman's correlation coefficient (r). RESULTS: GPNMB expression was observed in 100 % of PT, and median 80 % (range 5-100 %) of tumour cells, VEGF in 92 % and 60 % (0-100 %), EGFR in 87 % and 60 % (0-100 %) respectively. In corresponding LNM, GPNMB expression was observed in 100 % of LNM and median 90 % (20-100 %) of tumour cells, VEGF in 87 % and 65 % (0-100 %), and EGFR in 84 % and 35 % (0-100 %). A positive correlation was found between expression in PT and LNM for GPNMB (r = 0.548) and EGFR (r = 0.618) (p < 0.001), but not for VEGF (r = -0.020; p = 0.905). GPNMB expression was present in a higher percentage of tumour cells compared to EGFR in PT (p = 0.015, ESr = -0.320) and in LNM (p < 0.001, ESr = -0.478), while VEGF was not (p = 1.00, ESr = -0.109 and - 0.152, respectively). CONCLUSION: GPNMB expression is higher than EGFR in untreated HNSCC PT and corresponding LNM, while VEGF expression is comparable to EGFR. GPNMB is a promising target for fluorescent imaging in HNSCC.

9.
J Mech Behav Biomed Mater ; 154: 106534, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38581961

RESUMO

Articular cartilage exhibits site-specific tissue inhomogeneity, for which the tissue properties may continuously vary across the articular surface. To facilitate practical applications such as studying site-specific cartilage degeneration, the inhomogeneity may be approximated with several distinct region-wise variations, with one set of tissue properties for one region. A clustering method was previously developed to partition such regions using cartilage indentation-relaxation and thickness mapping instead of simply using surface geometry. In the present study, a quantitative parameter based on streaming potential measurement was introduced as an additional feature to assess the applicability of the methodology with independent datasets. Experimental data were collected from 24 sets of femoral condyles, extracted from fresh porcine stifle joints, through streaming potential mapping, automated indentation, and needle penetration tests. K-means clustering and Elbow method were used to find optimal region partitions. Consistent with previous findings, three regions were suggested for either lateral or medial condyle regardless of left or right joint. The region shapes were approximately triangular or trapezoidal, which was similar to what was found previously. Streaming potentials were confirmed to be region-dependent, but not significantly different among joints. The cartilage was significantly thicker in the medial than lateral condyles. The region areas were consistent among joints, and comparable to that found in a previous study. The present study demonstrated the capability of region partitioning methods with different variables, which may facilitate new applications whenever site-specific tissue properties must be considered.


Assuntos
Cartilagem Articular , Animais , Suínos , Articulação do Joelho , Fêmur
10.
Radiographics ; 44(5): e230137, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38635454

RESUMO

Nontraumatic pathologic conditions of the craniovertebral junction encompass a range of conditions affecting the complex anatomy of this region without direct physical injury. These conditions include congenital syndromes that predispose individuals to ligamentous laxity, potentially leading to instability. Additionally, rare but noteworthy cases such as Grisel syndrome, a cause of pediatric torticollis, may arise without a traumatic trigger. Inflammatory diseases, including rheumatoid arthritis, ankylosing spondylitis, and crystal deposition, can lead to cervical instability and spinal cord compression. Infections at the upper cervical spine are dominated by tuberculosis, typically transmitted through hematologic or lymphatic routes with characteristic imaging findings. On the other hand, purulent bacterial infections in this area are rare. Furthermore, although tumors involving the structures of the craniovertebral junction are infrequent, they can lead to significant complications, albeit less frequently through cord compression and more commonly via pathologic fractures or subluxation. The craniocervical junction is a complex anatomic region comprising ligaments, bones, joints, and muscles that support the head's weight and enable its wide range of motion. Accurate recognition and understanding of the complex anatomy and the various nontraumatic pathologic conditions at the craniovertebral junction are pivotal for initiating timely and appropriate treatment strategies. ©RSNA, 2024 Test Your Knowledge questions for this article are available in the supplemental material.


Assuntos
Luxações Articulares , Instabilidade Articular , Compressão da Medula Espinal , Humanos , Criança , Vértebras Cervicais , Instabilidade Articular/diagnóstico por imagem , Imageamento por Ressonância Magnética
11.
Front Pediatr ; 12: 1341762, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38571700

RESUMO

Background: Childhood cancer survivors (CCS) with chemotherapy induced sensorineural hearing loss (SNHL) are at risk for neurocognitive impairments. The purpose of this study was to determine the relationship between SNHL and cognitive function among CCS. Procedure: Inclusion: non-CNS solid tumor diagnosis; history of platinum chemotherapy (cisplatin and/or carboplatin); 8-17 years of age; off anti-cancer treatment for ≥6 months; and English speaking. Exclusion: history of intrathecal chemotherapy, cranial radiation, or baseline neurocognitive disorder. Participants completed the NIH Toolbox Cognition Battery at enrollment. T-tests were used to compare participants with normal hearing to those with hearing loss and the total sample with established Toolbox normative data (mean: 50; SD: 10). Results: Fifty-seven individuals enrolled; 52 completed full cognitive testing. Participants were on average 12.2 years of age and 7.0 years since treatment completion. Twenty-one participants (40%) received cisplatin, 27 (52%) carboplatin, and 4 (8%) received both. Fifteen participants (29%) demonstrated SNHL based on the better ear. CCS, regardless of the presence or absence of SNHL, demonstrated significantly lower mean cognitive skills compared to the normative sample in attention, executive function, language- vocabulary and oral reading, processing speed, and fluid, crystallized and total composite scores (all p < 0.01). Participants with SNHL had significantly lower crystallized composite (vocabulary, oral reading) than those with normal hearing (41.9 vs. 47.2, p < 0.05, Cohen's d = 0.62). Conclusions: CCS at risk for platinum induced hearing loss but without cranial radiation or intrathecal chemotherapy exposure demonstrate impaired cognitive skills and those with SNHL demonstrate lower crystallized composite scores.

12.
Ann R Coll Surg Engl ; 2024 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-38578035

RESUMO

INTRODUCTION: Acute right iliac fossa (RIF) pain is a common presenting symptom in surgical patients, with a wide range of differentials, particularly in premenopausal females. This study explores ultrasound usage in the management of women aged 16-55 years presenting with RIF pain. METHODS: A total of 1,082 patients who presented to a tertiary hospital over 12 months were included. Data were collected from patients' electronic records, including initial clinical impression, imaging, management, operative findings, histology and subsequent hospital attendances within 6 weeks and within 6 months. RESULTS: Following clinical assessment, 607 (56%) of patients underwent an ultrasound. Of these, 280 (25.9%) patients received no radiological imaging on initial presentation, and 252 (42%) had pathology identified on ultrasound. The most common finding was an ovarian cyst, closely followed by unexplained free pelvic fluid. Of the 607 patients scanned, 29 (4.8%) had an ultrasound diagnosis of appendicitis; 254 of 1,082 (23.5%) patients underwent operative management. Of the 254 patients who had surgery, 179 (70.5%) had preoperative imaging. Of the 29 (11.4%) cases where the intraoperative finding was gynaecological, 15 (51.7%) cases had not had any preoperative imaging. The negative appendicectomy rate was 21.3% (45/211). Of the 45 patients who had a histologically normal appendix, 22 (48.9%) had not had any previous imaging. Ultrasound had a specificity of 78% for diagnosing appendicitis. CONCLUSIONS: In patients who underwent operative management, a negative finding or finding not requiring surgical management was associated with no preoperative imaging. This supports the use of ultrasound scans as an adjunct in a multimodal approach to the assessment of women presenting with RIF pain.

13.
Sci Rep ; 14(1): 7880, 2024 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-38570593

RESUMO

Convergence of neural implants with artificial intelligence (AI) presents opportunities for the development of novel neural implants and improvement of existing neurotechnologies. While such technological innovation carries great promise for the restoration of neurological functions, they also raise ethical challenges. Developers of AI-driven neural implants possess valuable knowledge on the possibilities, limitations and challenges raised by these innovations; yet their perspectives are underrepresented in academic literature. This study aims to explore perspectives of developers of neurotechnology to outline ethical implications of three AI-driven neural implants: a cochlear implant, a visual neural implant, and a motor intention decoding speech-brain-computer-interface. We conducted semi-structured focus groups with developers (n = 19) of AI-driven neural implants. Respondents shared ethically relevant considerations about AI-driven neural implants that we clustered into three themes: (1) design aspects; (2) challenges in clinical trials; (3) impact on users and society. Developers considered accuracy and reliability of AI-driven neural implants conditional for users' safety, authenticity, and mental privacy. These needs were magnified by the convergence with AI. Yet, the need for accuracy and reliability may also conflict with potential benefits of AI in terms of efficiency and complex data interpretation. We discuss strategies to mitigate these challenges.


Assuntos
Inteligência Artificial , Implantes Cocleares , Reprodutibilidade dos Testes , Pesquisa Qualitativa , Grupos Focais
14.
bioRxiv ; 2024 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-38562766

RESUMO

Background and Aims: Chronic liver disease due to metabolic dysfunction-associated steatohepatitis (MASH) is a rapidly increasing global epidemic. MASH progression is a consequence of the complex interplay between inflammatory insults and dysregulated hepatic immune responses. T lymphocytes have been shown to accumulate in the liver during MASH, but the cause and consequence of T cell accumulation in the liver remain unclear. Our study aimed to define the phenotype and T cell receptor diversity of T cells from human cirrhotic livers and an animal model of MASH to begin resolving their function in disease. Approach and Results: In these studies, we evaluated differences in T cell phenotype in the context of liver disease we isolated liver resident T cell populations from individuals with cirrhosis and a murine model of MASH. Using both 5' single cell sequencing and flow cytometry we defined the phenotype and T cell receptor repertoire of liver resident T cells during health and disease. Conclusions: MASH-induced cirrhosis and diet-induced MASH in mice resulted in the accumulation of activated and clonally expanded T cells in the liver. The clonally expanded T cells in the liver expressed markers of chronic antigenic stimulation, including PD1 , TIGIT and TOX . Overall, this study establishes for the first time that T cells undergo antigen-dependent clonal expansion and functional differentiation during the progression of MASH. These studies could lead to the identification of potential antigenic targets that drive T cell activation, clonal expansion, and recruitment to the liver during MASH.

15.
Cell Rep ; 43(5): 114141, 2024 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-38656869

RESUMO

The cellular source of positive signals that reinvigorate T cells within the tumor microenvironment (TME) for the therapeutic efficacy of programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) blockade has not been clearly defined. We now show that Batf3-lineage dendritic cells (DCs) are essential in this process. Flow cytometric analysis, gene-targeted mice, and blocking antibody studies revealed that 4-1BBL is a major positive co-stimulatory signal provided by these DCs within the TME that translates to CD8+ T cell functional reinvigoration and tumor regression. Immunofluorescence and spatial transcriptomics on human tumor samples revealed clustering of Batf3+ DCs and CD8+ T cells, which correlates with anti-PD-1 efficacy. In addition, proximity to Batf3+ DCs within the TME is associated with CD8+ T cell transcriptional states linked to anti-PD-1 response. Our results demonstrate that Batf3+ DCs within the TME are critical for PD-1/PD-L1 blockade efficacy and indicate a major role for the 4-1BB/4-1BB ligand (4-1BBL) axis during this process.

17.
AIDS Care ; : 1-11, 2024 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-38648527

RESUMO

Despite success in achieving viral suppression during pregnancy in people living with HIV (PLWH), postpartum adherence remains a challenge. We aimed to describe rates of adherence at a Prevention of Mother-to-Child HIV Transmission (PMTCT) Center before and during the COVID-19 pandemic. This study was conducted from a cohort of PLWH who received prenatal care and were virally suppressed near delivery. We tracked combined antiretroviral therapy (cART) pickups for 12 months and HIV viral load (VL) from 2 to 12 months after delivery. We defined flexible adherence as a monthly pickup of cART and strict adherence as also having VL < 200 copies/mL and at least one maternal HIV VL between two and twelve months postpartum. Pre-pandemic was defined as delivery from March 2017-February 2019 and pandemic as March 2020-February 2022. During the study, 1119 PLWH were followed, and 965 (86%) were suppressed near delivery. There were 511 pre-pandemic and 290 pandemic participants. Adherence rates were 66/511 (13%) and 38/290 (13%), respectively. During the pandemic, more participants conceived using cART and were undetectable at the start of prenatal care; nevertheless, postpartum adherence was no better than pre-pandemic underscoring the need to improve strategies for adherence specific to this subset of PLWH in the postpartum period.

18.
Endocrinology ; 2024 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-38608138

RESUMO

Clomiphene citrate is a common treatment for ovulation induction in subfertile women, but its use is associated with elevated risk of adverse perinatal outcomes and birth defects. To investigate the biological plausibility of a causal relationship, this study investigated in mice the consequences for fetal development and pregnancy outcome of peri-conception clomiphene citrate administration at doses approximating human exposures. A dose-dependent adverse effect of clomiphene citrate given twice in the 36 h after mating was seen, with a moderate dose of 0.75 mg/kg sufficient to cause altered reproductive outcomes in three independent cohorts. Viable pregnancy was reduced by 30%, late gestation fetal weight was reduced by 16%, and ∼30% of fetuses exhibited delayed development and/or congenital abnormalities not seen in control dams, including defects of the lung, kidney, liver, eye, skin, limbs, and umbilicus. Clomiphene citrate also caused a 30 h average delay in time of birth, and elevated rate of pup death in the early postnatal phase. In surviving offspring, growth trajectory tracking and body morphometry analysis at 20 weeks of age showed post-weaning growth and development comparable to controls. A dysregulated inflammatory response in the endometrium was observed and may contribute to the underlying pathophysiological mechanism. These results demonstrate that in utero exposure to clomiphene citrate during early pregnancy can inhibit implantation and impact fetal growth and development, causing adverse perinatal outcomes. The findings raise the prospect of similar iatrogenic effects in women where clomiphene citrate may be present in the peri-conception phase unless its use is well-supervised.

19.
Scand J Gastroenterol ; : 1-11, 2024 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-38613245

RESUMO

BACKGROUND: Recurrences or persistent symptoms after an initial episode of diverticulitis are common, yet surgical treatment is rarely performed. Current guidelines lack clear recommendations on whether or not to operate, even though recent studies suggest an improved quality of life following surgery. The aim of this study is therefore to compare quality of life in patients with recurrent or ongoing diverticulitis treated conservatively versus surgically, giving a more definitive answer to the question of whether or not to operate on these patients. METHODS: A systematic literature search was conducted in EMBASE, MEDLINE and Cochrane. Only comparative studies reporting on quality of life were included. Statistical analysis included calculation of weighted mean differences and pooled odds ratios. RESULTS: Five studies were included; two RCT's and three retrospective observational studies. Compared to conservative treatment, the SF-36 scores were higher in the surgically treated group at each follow-up moment but only the difference in SF-36 physical scores at six months follow-up was statistically significant (MD 6.02, 95%CI 2.62-9.42). GIQLI scores were also higher in the surgical group with a MD of 14.01 (95%CI 8.15-19.87) at six months follow-up and 7.42 (95%CI 1.23-12.85) at last available follow-up. Also, at last available follow-up, significantly fewer recurrences occurred in the surgery group (OR 0.10, 95%CI 0.05-0.23, p < 0.001). CONCLUSION: Although surgery for recurrent diverticulitis is not without risk, it might improve long-term quality of life in patients suffering from recurrent- or ongoing diverticulitis when compared to conservative treatment. Therefore, it should be considered in this patient group.

20.
Artigo em Inglês | MEDLINE | ID: mdl-38632016

RESUMO

BACKGROUND: The calculation of body height in the intensive care unit is essential for obtaining the ideal body weight, which is used to program the tidal volume and establish objective and effective pulmonary ventilation. The objective of the study was to determine the interrater reliability of a tool for measuring body height in adult patients in an intensive care unit (ICU) in southwestern Colombia. METHODS: This cross-sectional observational study was conducted between January and May 2021, following the recommendations of the COSMIN protocol. Two physiotherapists in the roles of observer/evaluator measured the heights of 106 patients upon admission to the ICU with a previously designed. The sample size was calculated based on Pearson's correlation coefficient. For interrater reliability, the intraclass correlation coefficient (ICC) was used, and Bland-Altman analysis was used to assess concordance. The 95% confidence interval was established, and a P value <0.05 indicated statistical significance. RESULTS: A total of 106 individuals with a mean age of 59.3 years were included; the mean body height was 158.5 cm for women. The interrater reliability of the measurement of height was excellent (global ICC of 0.99, P = 0.000), and an almost perfect positive correlation was obtained between the raters for both women and men (R = 0.99). CONCLUSIONS: Excellent interrater/interobserver reliability was obtained for the measurement of body height in the ICU. This research highlights the importance of protocolizing the measurement of height in critical patients with valid and reliable instruments.

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