Several studies have investigated surgical residents' perceptions of family planning, and many have investigated medical students' perceptions of surgical specialties; however, there is limited ...research on medical students' perceptions of the impact of family planning on the decision to pursue surgical training. This study aims to investigate male and female medical students’ perceptions of family planning in residency.
A survey was distributed to all medical students at a single medical school in the Midwest between February 2023 and June 2023. The survey was adapted from a prior study investigating resident perceptions of family planning. It included questions about parental leave, having children, and perceived barriers to family planning.
One hundred students completed surveys. Seventy-four (74%) respondents identified as female and 57 (57%) were interested in surgery. Approximately half (55, 55%) of the respondents were strongly or definitely considering having children during residency. However, only eight (8%) students were aware of policies applicable to having children during residency. A majority (85, 85%) felt the decision to pursue surgical residency would prevent or delay having children at their preferred time. Most students felt they would be negatively perceived by peers (62, 62%) and faculty (87, 87%) if they had children during training. The highest perceived barriers to having children during training were work-time demands, childcare barriers, and time away from training.
Both men and women are interested in having children during residency but are unaware of the relevant parental leave policies and are concerned about how training will be impacted by taking time away or a lack of flexibility. Without transparency and flexibility in surgical residency, both men and women may forgo having children during training or choose a specialty they perceive to be more conducive to childbearing.
The CFTR (cystic fibrosis transmembrane conductance regulator) modulator combination elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to improve clinical outcomes and sweat chloride ...concentration in patients with cystic fibrosis (CF) and one or two
alleles. However, the effect of ELX/TEZ/IVA on CFTR function in the airways and intestine has not been studied.
To assess the effect of ELX/TEZ/IVA on CFTR function in airway and intestinal epithelia in patients with CF and one or two
alleles aged 12 years and older.
This prospective, observational, multicenter study assessed clinical outcomes including FEV
% predicted and body mass index and the CFTR biomarkers sweat chloride concentration, nasal potential difference, and intestinal current measurement before and 8-16 weeks after initiation of ELX/TEZ/IVA.
A total of 107 patients with CF including 55 patients with one
and a minimal function mutation and 52
homozygous patients were enrolled in this study. In patients with one
allele, nasal potential difference and intestinal current measurement showed that ELX/TEZ/IVA improved CFTR function in nasal epithelia to a level of 46.5% (interquartile range IQR, 27.5-72.4;
< 0.001) and in intestinal epithelia to 41.8% of normal (IQR, 25.1-57.6;
< 0.001). In
homozygous patients, ELX/TEZ/IVA exceeded improvement of CFTR function observed with TEZ/IVA and increased CFTR-mediated Cl
secretion to a level of 47.4% of normal (IQR, 19.3-69.2;
< 0.001) in nasal and 45.9% (IQR, 19.7-66.6;
< 0.001) in intestinal epithelia.
Treatment with ELX/TEZ/IVA results in effective improvement of CFTR function in airway and intestinal epithelia in patients with CF and one or two
alleles. Clinical trial registered with www.clinicaltrials.gov (NCT04732910).
How cytokine‐driven changes in chromatin topology are converted into gene regulatory circuits during inflammation still remains unclear. Here, we show that interleukin (IL)‐1α induces acute and ...widespread changes in chromatin accessibility via the TAK1 kinase and NF‐κB at regions that are highly enriched for inflammatory disease‐relevant SNPs. Two enhancers in the extended chemokine locus on human chromosome 4 regulate the IL‐1α‐inducible IL8 and CXCL1‐3 genes. Both enhancers engage in dynamic spatial interactions with gene promoters in an IL‐1α/TAK1‐inducible manner. Microdeletions of p65‐binding sites in either of the two enhancers impair NF‐κB recruitment, suppress activation and biallelic transcription of the IL8/CXCL2 genes, and reshuffle higher‐order chromatin interactions as judged by i4C interactome profiles. Notably, these findings support a dominant role of the IL8 “master” enhancer in the regulation of sustained IL‐1α signaling, as well as for IL‐8 and IL‐6 secretion. CRISPR‐guided transactivation of the IL8 locus or cross‐TAD regulation by TNFα‐responsive enhancers in a different model locus supports the existence of complex enhancer hierarchies in response to cytokine stimulation that prime and orchestrate proinflammatory chromatin responses downstream of NF‐κB.
Synopsis
ATAC‐seq, native 4C‐seq and CRISPR genome editing reveal functional hierarchies and chromatin looping dynamics of cytokine‐inducible “master” enhancers that govern gene regulation during the early proinflammatory response.
IL‐1α exposure remodels genome‐wide chromatin accessibility via TAK1 and NF‐κB.
Multiple dynamic and pre‐established 3D chromatin interactions facilitate the IL‐1α response.
Single‐enhancer deletion or activation reveal hierarchical control of the major human chemokine locus and inflammatory secretome.
Prelooped enhancers act across TADs to repress or activate TNFα‐regulated genes.
ATAC‐seq, native 4C‐seq and CRISPR genome editing reveal functional hierarchies and chromatin looping dynamics of cytokine‐inducible “master” enhancers that govern gene regulation during the early proinflammatory response.
We recently demonstrated that triple combination CFTR modulator therapy with elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) improves CFTR function in airway and intestinal epithelia to 40 to 50% of ...normal in patients with cystic fibrosis (CF) with one or two F508del alleles. In previous studies, this improvement of CFTR function was shown to improve clinical outcomes, however, effects on the lung clearance index (LCI) determined by multiple breath washout and abnormalities in lung morphology and perfusion detected by magnetic resonance imaging (MRI) have not been studied.
To examine the effect of ELX/TEZ/IVA on LCI and lung MRI scores in patients with CF and one or two F508del alleles aged 12 years and older.
This prospective, observational, multicenter, post-approval study assessed LCI and lung MRI scores before and 8-16 weeks after initiation of ELX/TEZ/IVA.
A total of 91 patients with CF including 45 heterozygous for F508del and a minimal function mutation (MF) and 46 homozygous for F508del were enrolled in this study. Treatment with ELX/TEZ/IVA improved LCI in F508del/MF (-2.4;IQR, -3.7 - -1.1;P<0.001) and F508del homozygous (-1.4;IQR, -2.4 - -0.4;P<0.001) patients. Further, ELX/TEZ/IVA improved the MRI global score in F508del/MF (-6.0;IQR, -11.0 - -1.3;P<0.001) and F508del homozygous (-6.5;IQR, -11.0 - -1.3;P<0.001) patients.
Our data demonstrate that improvement of CFTR function by ELX/TEZ/IVA improves lung ventilation and abnormalities in lung morphology including airway mucus plugging and wall thickening in adolescent and adult patients with CF and one or two F508del alleles in a real-world, post-approval setting.
Studies in human colonic cell lines and murine intestine suggest the presence of a Ca2+-activated anion channel, presumably TMEM16a. Is there a potential for fluid secretion in patients with severe ...cystic fibrosis transmembrane conductance regulator (CFTR) mutations by activating this alternative pathway? Two-dimensional nondifferentiated colonoid–myofibroblast cocultures resembling transit amplifying/progenitor (TA/PE) cells, as well as differentiated monolayer (DM) cultures resembling near-surface cells, were established from both healthy controls (HLs) and patients with severe functional defects in the CFTR gene (PwCF). F508del mutant and CFTR knockout (null) mice ileal and colonic mucosa was also studied. HL TA/PE monolayers displayed a robust short-circuit current response (ΔIeq) to UTP (100 µM), forskolin (Fsk, 10 µM) and carbachol (CCH, 100 µM), while ΔIeq was much smaller in differentiated monolayers. The selective TMEM16a inhibitor Ani9 (up to 30 µM) did not alter the response to luminal UTP, significantly decreased Fsk-induced ΔIeq, and significantly increased CCH-induced ΔIeq in HL TA/PE colonoid monolayers. The PwCF TA/PE and the PwCF differentiated monolayers displayed negligible agonist-induced ΔIeq, without a significant effect of Ani9. When TMEM16a was localized in intracellular structures, a staining in the apical membrane was not detected. TMEM16a is highly expressed in human colonoid monolayers resembling transit amplifying cells of the colonic cryptal neck zone, from both HL and PwCF. While it may play a role in modulating agonist-induced CFTR-mediated anion currents, it is not localized in the apical membrane, and it has no function as an apical anion channel in cystic fibrosis (CF) and healthy human colonic epithelium.
The introduction of mutation-specific combination therapy with the cystic fibrosis transmembrane conductance regulator (CFTR) modulators elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) has ...substantially improved lung function and quality of life of people with cystic fibrosis (CF). Collecting deep cough swabs and induced sputum, this postapproval study examined the effect of 14- and 50-week treatment with ELX/TEZ/IVA on the airway microbial metagenome of pancreatic- insufficient CF patients aged 12 years and older. Compared to pretreatment, the total bacterial load decreased, the individual species were more evenly distributed in the community, and the individual microbial metagenomes became more similar in their composition. However, the microbial network remained vulnerable to fragmentation. The initial shift of the CF metagenome was attributable to the ELX/TEZ/IVA-mediated gain of CFTR activity followed by a diversification driven by a group of commensals at the 1-year time point that are typical for healthy airways.
Shotgun metagenome sequencing of respiratory secretions with spike-in controls for normalization demonstrated that 1 year of high-efficient CFTR modulation with elexacaftor/tezacaftor/ivacaftor extensively reduced the bacterial load. Longer observation periods will be necessary to resolve whether the partial reversion of the basic defect that is achieved with ELX/TEZ/IVA is sufficient in the long run to render the CF lungs robust against the recolonization with common opportunistic pathogens.
Defects in expression, maturation or function of the epithelial membrane glycoprotein CFTR are causative for the progressive disease cystic fibrosis. Recently, molecular therapeutics that improve ...CFTR maturation and functional defects have been approved. We aimed to verify whether we could detect an improvement of CFTR protein expression and maturation by triple therapy with elexacaftor-tezacaftor-ivacaftor (ELX/TEZ/IVA).
Rectal suction biopsies of 21 p.Phe508del homozygous or compound heterozygous CF patients obtained pre- and during treatment with ELX/TEZ/IVA were analyzed by CFTR Western blot that was optimized to distinguish CFTR glycoisoforms.
CFTR western immunoblot analysis revealed that-compared to baseline-the levels of CFTR protein increased by at least twofold in eight out of 12 patients upon treatment with ELX/TEZ/IVA compared to baseline (
< 0.02). However, polydispersity of the mutant CFTR protein was lower than that of the fully glycosylated wild type CFTR Golgi isoform, indicating an incompletely glycosylated p.Phe508el CFTR protein isoform C* in patients with CF which persists after ELX/TEZ/IVA treatment.
Treatment with ELX/TEZ/IVA increased protein expression by facilitating the posttranslational processing of mutant CFTR but apparently did not succeed in generating the polydisperse spectrum of N-linked oligosaccharides that is characteristic for the wild type CFTR band C glycoisoform. Our results caution that the lower amounts or immature glycosylation of the C* glycoisoform observed in patients' biomaterial might not translate to fully restored function of mutant CFTR necessary for long-term provision of clinical benefit.
Evidence for the efficiency of highly-effective triple-CFTR-modulatory therapy with elexacaftor/tezacaftor/ivacaftor (ETI), either demonstrated in clinical trials or by
testing, is lacking for about ...10% of people with cystic fibrosis (pwCF) with rare mutations. Comprehensive assessment of CFTR function can provide critical information on the impact of ETI on CFTR function gains for such rare mutations, lending argument of the prescription of ETI. The mutation c.165-2A>G is a rare acceptor splice mutation that has not yet been functionally characterized. We here describe the functional changes induced by ETI in two brothers who are compound heterozygous for the splice mutations c.273+1G>C and c.165-2A>G.
We assessed the effects of ETI on CFTR function by quantitative pilocarpine iontophoresis (QPIT), nasal potential difference measurements (nPD), intestinal current measurements (ICM), β-adrenergic sweat secretion tests (SST) and multiple breath washout (MBW) prior to and 4 months after the initiation of ETI.
Functional CFTR analysis prior to ETI showed no CFTR function in the respiratory and intestinal epithelia and in the sweat gland reabsorptive duct in either brother. In contrast, β-adrenergic stimulated, CFTR-mediated sweat secretion was detectable in the CF range. Under ETI, both brothers continued to exhibit high sweat chloride concentration in QPIT, evidence of low residual CFTR function in the respiratory epithelia, but normalized β-adrenergically stimulated production of primary sweat.
Our results are the first to demonstrate that the c.165-2A>G/c.273+1G>C mutation genotype permits mutant CFTR protein expression. We showed organ-specific differences in the expression of CFTR and consecutive responses to ETI of the c.165-2A>G/c.273+1G>C CFTR mutants that are probably accomplished by non-canonical CFTR mRNA isoforms. This showcase tells us that the individual response of rare
mutations to highly-effective CFTR modulation cannot be predicted from assays in standard cell cultures, but requires the personalized multi-organ assessment by CFTR biomarkers.
Drinking water treatment residuals (WTR), a waste-derived product, are often recommended to use as an amendment in stormwater biofilters to enhance their capacity to remove phosphate and microbial ...pollutants. However, their efficacy has been assumed to remain high in the presence of compost, one of the most common amendments used in biofilters. This study tests the validity of that assumption by comparing the removal capacities of WTR-amended biofilters with and without the presence of compost. Our results show that amending sand with WTR increased E. coli removal by at least 1-log, but the addition of compost in the sand-WTR media lowered the removal capacity by 13 %. Similarly, the addition of WTR to sand improved phosphate removal to nearly 1177 %, but the removal decreased slightly by 8 % when adding compost to the media. The results confirmed that dissolved organic carbon (DOC) leached from the compost could compete for adsorption sites for bacteria and phosphate, thereby lowering WTR's adsorption capacity based on the amount of DOC adsorbed on WTR. Collectively, these results indicate that the stormwater treatment industry should avoid mixing compost with WTR to get the maximum benefits of WTR for bacterial removal and improve the performance lifetime of WTR-amended biofilters.
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•E. coli and phosphate removal increased with added water treatment residuals (WTR).•30 % and 10 % WTR fractions removed most E. coli and phosphate, respectively.•Compost significantly decreased WTR's ability to remove E. coli and phosphate.•Compost leachate increased in net negative surface charge of WTR and decreased removal.•WTR and compost did not affect the growth and the die-off of E. coli in biofilters.
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