Impact of COVID-19 on gestational diabetes pregnancy outcomes in the UK: A multicentre retrospective cohort study.

OBJECTIVE: To determine the impact of implementing emergency care pathway(s) for screening, diagnosing and managing women with gestational diabetes (GDM) during COVID-19. DESIGN: Retrospective multicentre cohort. SETTING: Nine National Health Service (NHS) Hospital Trusts/Health boards in England and Scotland. POPULATION: 4915 women with GDM pre-pandemic (1 April 2018 to 31 March 2020), and 3467 women with GDM during the pandemic (1 May 2020 to 31 March 2021). METHODS: We examined clinical outcomes for women with GDM prior to and during the pandemic following changes in screening methods, diagnostic testing, glucose thresholds and introduction of virtual care for monitoring of antenatal glycaemia. MAIN OUTCOME MEASURES: Intervention at birth, perinatal mortality, large-for-gestational-age infants and neonatal unit admission. RESULTS: The new diagnostic criteria more often identified GDM women who were multiparous, had higher body mass index (BMI) and greater deprivation, and less frequently had previous GDM (all p < 0.05). During COVID, these women had no differences in the key outcome measures. Of the women, 3% were identified with pre-existing diabetes at antenatal booking. Where OGTT continued during COVID, but virtual care was introduced, outcomes were also similar pre- and during the pandemic. CONCLUSIONS: Using HbA1c and fasting glucose identified a higher risk GDM population during the pandemic but this had minimal impact on pregnancy outcomes. The high prevalence of undiagnosed pre-existing diabetes suggests that women with GDM risk factors should be offered HbA1c screening in early pregnancy.

Listening to Women: Experiences of Using Closed-Loop in Type 1 Diabetes Pregnancy.

Introduction: Recent high-profile calls have emphasized that women's experiences should be considered in maternity care provisioning. We explored women's experiences of using closed-loop during type 1 diabetes (T1D) pregnancy to inform decision-making about antenatal rollout and guidance and support given to future users. Methods: We interviewed 23 closed-loop participants in the Automated insulin Delivery Among Pregnant women with T1D (AiDAPT) trial after randomization to closed-loop and ∼20 weeks later. Data were analyzed thematically. Results: Women described how closed-loop lessened the physical and mental demands of diabetes management, enabling them to feel more normal and sleep better. By virtue of spending increased time-in-range, women also worried less about risks to their baby and being judged negatively by health care professionals. Most noted that intensive input and support during early pregnancy had been crucial to adjusting to, and developing confidence in, the technology. Women emphasized that attaining pregnancy glucose targets still required ongoing effort from themselves and the health care team. Women described needing education to help them determine when, and how, to intervene and when to allow the closed-loop to operate without interference. All women reported more enjoyable pregnancy experiences as a result of using closed-loop; some also noted being able to remain longer in paid employment. Conclusions: Study findings endorse closed-loop use in T1D pregnancy by highlighting how the technology can facilitate positive pregnancy experiences. To realize fully the benefits of closed-loop, pregnant women would benefit from initial intensive oversight and support together with closed-loop specific education and training. Clinical Trial Registration number: NCT04938557.

Automated Insulin Delivery in Women with Pregnancy Complicated by Type 1 Diabetes.

BACKGROUND: Hybrid closed-loop insulin therapy has shown promise for management of type 1 diabetes during pregnancy; however, its efficacy is unclear. METHODS: In this multicenter, controlled trial, we randomly assigned pregnant women with type 1 diabetes and a glycated hemoglobin level of at least 6.5% at nine sites in the United Kingdom to receive standard insulin therapy or hybrid closed-loop therapy, with both groups using continuous glucose monitoring. The primary outcome was the percentage of time in the pregnancy-specific target glucose range (63 to 140 mg per deciliter [3.5 to 7.8 mmol per liter]) as measured by continuous glucose monitoring from 16 weeks' gestation until delivery. Analyses were performed according to the intention-to-treat principle. Key secondary outcomes were the percentage of time spent in a hyperglycemic state (glucose level >140 mg per deciliter), overnight time in the target range, the glycated hemoglobin level, and safety events. RESULTS: A total of 124 participants with a mean (±SD) age of 31.1±5.3 years and a mean baseline glycated hemoglobin level of 7.7±1.2% underwent randomization. The mean percentage of time that the maternal glucose level was in the target range was 68.2±10.5% in the closed-loop group and 55.6±12.5% in the standard-care group (mean adjusted difference, 10.5 percentage points; 95% confidence interval [CI], 7.0 to 14.0; P<0.001). Results for the secondary outcomes were consistent with those of the primary outcome; participants in the closed-loop group spent less time in a hyperglycemic state than those in the standard-care group (difference, -10.2 percentage points; 95% CI, -13.8 to -6.6); had more overnight time in the target range (difference, 12.3 percentage points; 95% CI, 8.3 to 16.2), and had lower glycated hemoglobin levels (difference, -0.31 percentage points; 95% CI, -0.50 to -0.12). Little time was spent in a hypoglycemic state. No unanticipated safety problems associated with the use of closed-loop therapy during pregnancy occurred (6 instances of severe hypoglycemia, vs. 5 in the standard-care group; 1 instance of diabetic ketoacidosis in each group; and 12 device-related adverse events in the closed-loop group, 7 related to closed-loop therapy). CONCLUSIONS: Hybrid closed-loop therapy significantly improved maternal glycemic control during pregnancy complicated by type 1 diabetes. (Funded by the Efficacy and Mechanism Evaluation Program; AiDAPT ISRCTN Registry number, ISRCTN56898625.).

Electronic Vaporization of Nicotine Salt or Freebase produces differential effects on metabolism, neuronal activity and behavior in male and female C57BL/6J mice.

The use of Electronic Nicotine Delivery Systems (ENDS) is increasing in prevalence and popularity. ENDS are a rapidly evolving technology as devices and e-liquid formulations adapt to policy restrictions and market demand To identify the impacts of nicotine formulation and concentration, we exposed female and male C57BL/6J mice to passive electronic vaporization of different nicotine formulations (freebase or salt) and concentrations (1% or 3%) and measured serum nicotine metabolite levels, brain activity by cFos expression, and anxiety-like and motivated behavior using the novelty suppressed feeding test. We found that the 3% freebase nicotine vapor group displayed significantly higher serum nicotine levels than either 1% or 3% nicotine salt formulations, and female mice displayed higher serum nicotine and cotinine levels compared to males. Central amygdala (CeA) activity was significantly elevated in male mice following nicotine vapor exposure, but the increase was not significantly different between nicotine vapor groups. CeA activity in female mice was unaffected. In contrast increased activity in the ventral tegmental area (VTA) was only observed in female mice exposed to 3% nicotine freebase and specifically in the dopaminergic population. Anxiety-like behavior in female mice was relatively unaffected by nicotine vapor exposure, however male mice displayed increased anxiety-like behavior and reduced motivation to feed after vapor exposure, specifically in the 3% freebase group. These results identify important sex differences in the impact of nicotine formulation and concentration on nicotine metabolism, brain region-specific activity and anxiety-like behavior, which may have significant relevance for different consequences of vaping in men and women.

Healthcare professionals' views about how pregnant women can benefit from using a closed-loop system: Qualitative study.

BACKGROUND: Interest is growing in how closed-loop systems can support attainment of within-target glucose levels amongst pregnant women with type 1 diabetes. We explored healthcare professionals' views about how, and why, pregnant women benefitted from using the CamAPS FX system during the AiDAPT trial. METHODS: We interviewed 19 healthcare professionals who supported women using closed-loop during the trial. Our analysis focused on identifying descriptive and analytical themes relevant to clinical practice. RESULTS: Healthcare professionals highlighted clinical and quality-of-life benefits to using closed-loop in pregnancy; albeit, they attributed some of these to the continuous glucose monitoring component. They emphasised that the closed-loop was not a panacea and that, to gain maximum benefit, an effective collaboration between themselves, the woman and the closed-loop was needed. Optimal performance of the technology, as they further noted, also required women to interact with the system sufficiently, but not excessively; a requirement that they felt some women had found challenging. Even where healthcare professionals felt that this balance was not achieved, they suggested that women had still benefitted from using the system. Healthcare professionals reported difficulties predicting how specific women would engage with the technology. In light of their trial experiences, healthcare professionals favoured an inclusive approach to closed-loop rollout in routine clinical care. CONCLUSIONS: Healthcare professionals recommended that closed-loop systems be offered to all pregnant women with type 1 diabetes in the future. Presenting closed-loop systems to pregnant women and healthcare teams as one pillar of a three-party collaboration may help promote optimal use.

Rollout of Closed-Loop Technology to Pregnant Women with Type 1 Diabetes: Healthcare Professionals' Views About Potential Challenges and Solutions.

Aims: To explore healthcare professionals' views about the training and support needed to rollout closed-loop technology to pregnant women with type 1 diabetes. Methods: We interviewed (n = 19) healthcare professionals who supported pregnant women using CamAPS FX closed-loop during the Automated insulin Delivery Amongst Pregnant women with Type 1 diabetes (AiDAPT) trial. Data were analyzed descriptively. An online workshop involving (n = 15) trial team members was used to inform recommendations. Ethics approvals were obtained in conjunction with those for the wider trial. Results: Interviewees expressed enthusiasm for a national rollout of closed-loop, but anticipated various challenges, some specific to use during pregnancy. These included variations in insulin pump and continuous glucose monitoring expertise and difficulties embedding and retaining key skills, due to the relatively small numbers of pregnant women using closed-loop. Inexperienced staff also highlighted difficulties interpreting data downloads. To support rollout, interviewees recommended providing expert initial advice training, delivered by device manufacturers together with online training resources and specific checklists for different systems. They also highlighted a need for 24 h technical support, especially when supporting technology naive women after first transitioning onto closed-loop in early pregnancy. They further recommended providing case-based meetings and mentorship for inexperienced colleagues, including support interpreting data downloads. Interviewees were optimistic that if healthcare professionals received training and support, their long-term workloads could be reduced because closed-loop lessened women's need for glycemic management input, especially in later pregnancy. Conclusions: Interviewees identified challenges and opportunities to rolling-out closed-loop and provided practical suggestions to upskill inexperienced staff supporting pregnant women using closed-loop. A key priority will be to determine how best to develop mentorship services to support inexperienced staff delivering closed-loop. Clinical Trials Registration: NCT04938557.

The value of admissions characteristics for predicting the practice location of University of Saskatchewan College of Medicine graduates.

Background: The physician workforce in Saskatchewan depends upon the retention of locally trained physicians. Characteristics collected at the time of medical school application may predict future practice location, but these associations have not been explored. Methods: We identified the current practice location of University of Saskatchewan College of Medicine graduates who matriculated between 2000 and 2013 and extracted data from their admission applications including gender, age, high school, previous university, and current location at the time of application. We then conducted univariate and multivariate analyses to evaluate associations between these characteristics and rural- and Saskatchewan-based practice. Results: We identified the current practice location of 1,001 (98.9%) of the graduates of the included cohorts. Attending a Saskatchewan high school (p < 0.001), a high school in a smaller population center (p < 0.01), and a Saskatchewan university (p < 0.001) were predictive of Saskatchewan-based practice. Attending a high school outside of Saskatchewan (p < 0.05), a high school in a smaller population center (p < 0.001), and living in a small population centre at the time of application (p < 0.05) were predictive of rural-based practice within or outside of Saskatchewan. Conclusion: Demographic characteristics collected at time of medical school application are associated with future Saskatchewan- and rural-based practice. These findings will guide admissions policies in Saskatchewan and may inform admission practices of other medical schools.

Contexte: La main-d'œuvre médicale en Saskatchewan dépend de la rétention des médecins formés dans la province. Les informations recueillies au moment de la demande d'admission à la faculté de médecine peuvent permettre de prédire le lieu de pratique futur, mais ces liens n'ont pas été explorés. Méthodes: Nous avons trouvé le lieu de pratique actuel des diplômés de la faculté de médecine de l'Université de la Saskatchewan qui se sont inscrits entre 2000 et 2013 et avons extrait de leurs demandes d'admission les données concernant le sexe, l'âge, l'école secondaire et l'université précédente fréquentées, et le lieu de résidence au moment de la demande. Nous avons ensuite effectué des analyses univariées et multivariées pour évaluer les liens entre ces éléments et la pratique en milieu rural et en Saskatchewan. Résultats: Nous avons trouvé le lieu de pratique actuel de 1001 (98,9 %) des diplômés des cohortes incluses. La fréquentation d'une école secondaire de la Saskatchewan (p<0,001), d'une école secondaire dans une petite agglomération (p<0,01) et d'une université de la Saskatchewan (p<0,001) étaient des facteurs prédictifs de la pratique en Saskatchewan. La fréquentation d'une école secondaire à l'extérieur de la Saskatchewan (p < 0,05), d'une école secondaire dans une petite agglomération (p < 0,001) et le fait de vivre dans une petite agglomération au moment de la demande d'admission (p < 0,05) étaient des facteurs prédictifs d'une pratique en milieu rural à l'intérieur ou à l'extérieur de la Saskatchewan. Conclusion: Les caractéristiques démographiques recueillies au moment de la demande d'admission à la faculté de médecine sont corrélées à la pratique future en Saskatchewan et en milieu rural. Ces résultats guideront les politiques d'admission en Saskatchewan et pourraient éclairer les pratiques d'admission d'autres facultés de médecine.

AiDAPT: automated insulin delivery amongst pregnant women with type 1 diabetes: a multicentre randomized controlled trial - study protocol.

BACKGROUND: Pregnant women with type 1 diabetes strive for tight glucose targets (3.5-7.8 mmol/L) to minimise the risks of obstetric and neonatal complications. Despite using diabetes technologies including continuous glucose monitoring (CGM), insulin pumps and contemporary insulin analogues, most women struggle to achieve and maintain the recommended pregnancy glucose targets. This study aims to evaluate whether the use of automated closed-loop insulin delivery improves antenatal glucose levels in pregnant women with type 1 diabetes. METHODS/DESIGN: A multicentre, open label, randomized, controlled trial of pregnant women with type 1 diabetes and a HbA1c of ≥48 mmol/mol (6.5%) at pregnancy confirmation and ≤ 86 mmol/mol (10%) at randomization. Participants who provide written informed consent before 13 weeks 6 days gestation will be entered into a run-in phase to collect 96 h (24 h overnight) of CGM glucose values. Eligible participants will be randomized on a 1:1 basis to CGM (Dexcom G6) with usual insulin delivery (control) or closed-loop (intervention). The closed-loop system includes a model predictive control algorithm (CamAPS FX application), hosted on an android smartphone that communicates wirelessly with the insulin pump (Dana Diabecare RS) and CGM transmitter. Research visits and device training will be provided virtually or face-to-face in conjunction with 4-weekly antenatal clinic visits where possible. Randomization will stratify for clinic site. One hundred twenty-four participants will be recruited. This takes into account 10% attrition and 10% who experience miscarriage or pregnancy loss. Analyses will be performed according to intention to treat. The primary analysis will evaluate the change in the time spent in the target glucose range (3.5-7.8 mmol/l) between the intervention and control group from 16 weeks gestation until delivery. Secondary outcomes include overnight time in target, time above target (> 7.8 mmol/l), standard CGM metrics, HbA1c and psychosocial functioning and health economic measures. Safety outcomes include the number and severity of ketoacidosis, severe hypoglycaemia and adverse device events. DISCUSSION: This will be the largest randomized controlled trial to evaluate the impact of closed-loop insulin delivery during type 1 diabetes pregnancy. TRIAL REGISTRATION: ISRCTN 56898625 Registration Date: 10 April, 2018.

Circulating endocannabinoids and genetic polymorphisms as predictors of posttraumatic stress disorder symptom severity: heterogeneity in a community-based cohort.

The endocannabinoid signaling system (ECSS) regulates fear and anxiety. While ECSS hypoactivity can contribute to symptoms of established post-traumatic stress disorder (PTSD), the role of the ECSS in PTSD development following trauma is unknown. A prospective, longitudinal cohort study of 170 individuals (47% non-Hispanic Caucasian and 70% male) treated at a level 1 trauma center for traumatic injury was carried out. PTSD symptom assessments and blood were obtained during hospitalization and at follow-up (6-8 months post injury). Serum concentrations of the endocannabinoids N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG) were determined at both time points and selected genetic polymorphisms in endocannabinoid genes, including rs324420 in fatty acid amide hydrolase, were assessed. For the entire sample, serum concentrations of AEA at hospitalization were significantly higher in those diagnosed with PTSD at follow-up (p = 0.030). Serum concentrations of 2-AG were significantly, positively correlated with PTSD symptom severity at follow-up only in minorities (p = 0.014). Minority participants (mostly Black/African American) also demonstrated significant, negative correlations between serum AEA concentrations and PTSD symptom severity both measured at hospitalization (p = 0.015). The A/A genotype at rs324420 was associated with significantly higher PTSD symptom severity (p = 0.025) and occurred exclusively in the Black participants. Collectively, these results are contrary to our hypothesis and find positive associations between circulating endocannabinoids and risk for PTSD. Minority status is an important modulator of the association between endocannabinoids and risk for PTSD, suggesting that the ECSS contributes to risk most significantly in these individuals and the contextual factors related to these findings should be further explored.

Patient reported experiences and treatment outcomes of orthodontic patients treated within secondary care settings in the South West of England during the COVID-19 pandemic.

OBJECTIVE: To assess the impact of the temporary cessation of orthodontic services on patients undergoing treatment during the COVID-19 pandemic. DESIGN: Two-phase multicentre service evaluation. SETTING: Secondary care orthodontic departments in the South West of England. MATERIALS AND METHODS: Phase 1 - Patient-Reported Experience Measure questionnaire (PREM). The questionnaire was distributed to patients who had undergone orthodontic treatment during the COVID-19 pandemic once services had resumed. Phase 2 - assessment of treatment outcomes, specifically with the Peer Assessment Rating (PAR) Index. A total of 280 PAR scores were obtained from a cohort of patients treated before and during the pandemic. RESULTS: A total of 711 PREM questionnaires were completed. Participants generally felt relaxed when visiting secondary care settings, orthodontic departments and whilst wearing orthodontic appliances during the pandemic. Nearly 40% of participants were concerned that the pandemic would impact on their treatment, particularly treatment length. Treatment outcomes revealed that patients treated before and during the pandemic experienced percentage PAR score reductions of 83.9% and 80.6%, respectively. Patients receiving treatment during the pandemic experienced longer treatment durations of 126 days. CONCLUSION: During the pandemic, low levels of anxiety were reported with respect to receiving orthodontic treatment in secondary care settings. Irrespective of the pandemic, a high standard of orthodontic treatment was provided. However, patient concerns regarding treatment length were justified.

What's new in the management of type 1 diabetes in pregnancy?

Type 1 diabetes in pregnancy is associated with an increased risk of complications for both mother and fetus. However, managing glycaemia during pregnancy to reduce these risks is challenging, owing to changes in insulin resistance with advancing gestation, as well as increased daily variation in insulin pharmacokinetics. These factors can add significant psychological and daily self-care burden to mothers during what may already be an anxious time. Increasingly, diabetes technologies are being used during pregnancy to improve and facilitate diabetes self-care. While these can be empowering for people with type 1 diabetes, careful consideration is required in relation to how and when these can be continued safely in the inpatient setting (including acute antenatal admissions, labour and delivery) and when extra support is required from adequately trained healthcare professionals. This article describes current forms of diabetes technologies used and the latest national guidance relating to the care of type 1 diabetes in pregnancy.

Collaboration Between Child Play Therapy and Speech-Language Pathology: Case Reports of a Novel Language and Behavior Intervention.

Purpose It has been well documented that a significant number of children with developmental language disorders (DLDs) also exhibit challenging behaviors. In this study, a new intervention (Play and Language [PAL]) was developed through a research collaboration between a speech-language pathologist and a play therapist. The purpose of this clinical focus article is to describe child play therapy techniques and how these, along with early language intervention techniques, may positively impact preschool children's general communication and behavior. Method Students in a communication sciences and disorders program were trained to use a combination of child therapy techniques and language facilitation procedures in the PAL approach. Five preschool children, who displayed DLD and challenging behaviors, participated in a 2-week daily intensive intervention. Pre- and postintervention data for general communication and behavior skills were collected through parent report and language sample data. Student clinician and parent surveys were collected to assess the feasibility of conducting the new intervention and the parent-observed outcomes and satisfaction. Results A majority of the children who participated in the study increased their intelligibility and number of different words. Fewer than half increased their sentence length. These same children decreased their challenging behaviors, with 11 of 14 behaviors being reduced to normal levels. All parents reported satisfaction with their child's results. In addition, students trained to provide the intervention reported high levels of satisfaction with the training to implement PAL and that they were confident in providing the intervention techniques. Conclusion Together, our exploratory data provide preliminary and limited evidence that combining play therapy and language facilitation techniques may improve general communication skills and decrease challenging behaviors within the same intervention. Supplemental Material https://doi.org/10.23641/asha.16840459.

Airway Epithelial Inflammation In Vitro Augments the Rescue of Mutant CFTR by Current CFTR Modulator Therapies.

In cystic fibrosis (CF), defective biogenesis and activity of the cystic fibrosis transmembrane conductance regulator (CFTR) leads to airway dehydration and impaired mucociliary clearance, resulting in chronic airway infection and inflammation. The most common CFTR mutation, F508del, results in a processing defect in which the protein is retained in the endoplasmic reticulum and does not reach the apical surface. CFTR corrector compounds address this processing defect to promote mutant CFTR transfer to the apical membrane. When coupled with potentiators to increase CFTR channel activity, these drugs yield significant clinical benefits in CF patients carrying the F508del mutation. However, processing of CFTR and other proteins can be influenced by environmental factors such as inflammation, and the impact of airway inflammation on pharmacological activity of CFTR correctors is not established. The present study evaluated CFTR-rescuing therapies in inflamed CF airway epithelial cultures, utilizing models that mimic the inflammatory environment of CF airways. Primary bronchial epithelial cultures from F508del/F508del CF patients were inflamed by mucosal exposure to one of two inflammatory stimuli: 1) supernatant from mucopurulent material from CF airways with advanced lung disease, or 2) bronchoalveolar lavage fluid from pediatric CF patients. Cultures inflamed with either stimulus exhibited augmented F508del responses following therapy with correctors VX-809 or VX-661, and overcame the detrimental effects of chronic exposure to the CFTR potentiator VX-770. Remarkably, even the improved CFTR rescue responses resulting from a clinically effective triple therapy (VX-659/VX-661/VX-770) were enhanced by epithelial inflammation. Thus, the airway inflammatory milieu from late- and early-stage CF lung disease improves the efficacy of CFTR modulators, regardless of the combination therapy used. Our findings suggest that pre-clinical evaluation of CFTR corrector therapies should be performed under conditions mimicking the native inflammatory status of CF airways, and altering the inflammatory status of CF airways may change the efficacy of CFTR modulator therapies.

Circulating endocannabinoids and prospective risk for depression in trauma-injury survivors.

Biological mechanisms associated with response to trauma may impact risk for depression. One such mechanism is endocannabinoid signaling (eCB), a neuromodulatory system comprised of the CB1 subtype of cannabinoid receptors (CB1R), encoded by the CNR1 gene, and two primary endogenous ligands: 2-arachidonoylglycerol (2-AG) and N-arachidonylethanolamine (AEA), hydrolyzed by monoacylglycerol lipase (gene name MGLL) and fatty acid amide hydrolase (gene name FAAH). Preclinical data suggest that eCB/CB1R signaling acts as a stress buffer and its loss or suppression increases depression-like behaviors. We examined circulating concentrations of the eCBs (2-AG and AEA) days and six months after a traumatic injury as a marker of eCB/CB1R signaling and as predictors of Center for Epidemiologic Studies of Depression Scale-Revised [CESD-R] scores as a measure of depression severity six months after injury. We also explored associations of CNR1, FAAH, and MGLL genetic variance with depression severity at six months. Results from hierarchical multiple linear regressions showed that higher 2-AG serum concentrations after trauma predicted greater depression at six months (ß = 0.23, p = 0.007); neither AEA after trauma, nor 2-AG and AEA at six months were significant predictors (p's > 0.305). Carriers of minor allele for the putative single nucleotide polymorphism in the CNR1 gene rs806371 (ß = 0.19, p = 0.024) experienced greater depression at six months. These data suggest that the eCB signaling system is highly activated following trauma and that eCB/CB1R activity contributes to long-term depression risk.

Accumulation and persistence of ivacaftor in airway epithelia with prolonged treatment.

BACKGROUND: Current dosing strategies of CFTR modulators are based on serum pharmacokinetics, but drug concentrations in target tissues such as airway epithelia are not known. Previous data suggest that CFTR modulators may accumulate in airway epithelia, and serum pharmacokinetics may not accurately predict effects of chronic treatment. METHODS: CF (F508del homozygous) primary human bronchial epithelial (HBE) cells grown at air-liquid interface were treated for 14 days with ivacaftor plus lumacaftor or ivacaftor plus tezacaftor, followed by a 14-day washout period. At various intervals during treatment and washout phases, drug concentrations were measured via mass spectrometry, electrophysiological function was assessed in Ussing chambers, and mature CFTR protein was quantified by Western blotting. RESULTS: During treatment, ivacaftor accumulated in CF-HBEs to a much greater extent than either lumacaftor or tezacaftor and remained persistently elevated even after 14 days of washout. CFTR activity peaked at 7 days of treatment but diminished with further ivacaftor accumulation, though remained above baseline even after washout. CONCLUSIONS: Intracellular accrual and persistence of CFTR modulators during and after chronic treatment suggest complex pharmacokinetic and pharmacodynamic properties within airway epithelia that are not predicted by serum pharmacokinetics. Direct measurement of drugs in target tissues may be needed to optimize dosing strategies, and the persistence of CFTR modulators after treatment cessation has implications for personalized medicine approaches.

Human Fetal Tissue from Elective Abortions in Research and Medicine: Science, Ethics, and the Law.

Since the U.S. Supreme Court issued its landmark decision in 1973 to legalize abortion, over 60 million preborn have been killed by elective abortion. While alive in the womb, these preborn are abandoned and not protected under current law. But once aborted, their body parts are a highly esteemed and prized commodity amongst certain members of the scientific community. Moral discourse is disregarded for the sake of science. The public have been lulled and lured into believing that this practice must continue in order to understand and develop cures for some of the most debilitating diseases of our day. But they are mistaken. This practice is not necessary, especially in light of numerous noncontroversial alternatives. Here, we expose and consider the false and misleading claims regarding human fetal tissue (HFT) in research from scientific, legal, and ethical points of view. We endeavor deeply to understand the depth of the injustice in this practice and what forces promote and maintain it; and by revealing and understanding these forces, we set forth how these inhumane practices can be ended. An accurate portrayal of the history of HFT use in research is provided, along with a close examination of the current state of this practice under existing laws. The serious societal implications are also discussed, which will worsen beyond comprehension if these practices are allowed to continue. The timeliness of this information cannot be overstated, and a thorough understanding is paramount for anyone who desires to know the facts about HFT in research and medicine and its detrimental impact for humanity.

Is There a Correlation Between Nasolabial Appearance and Dentoalveolar Relationships in Patients With Repaired Unilateral Cleft Lip and Palate?

OBJECTIVE: To determine whether a relationship exists between the aesthetic scores given to photographic records of the nasolabial region of patients with repaired unilateral cleft lip and palate (UCLP) and the 5-Year Olds' Index scores of study models for the same participants. DESIGN: Retrospective study. SETTING: University of Bristol Dental Hospital, United Kingdom. PARTICIPANTS: Patients with nonsyndromic UCLP previously enrolled in the Cleft Care UK (CCUK) Study. METHODS: The CCUK participants, who had both study models and photographs (frontal and worm's eye view), were identified and their records retrieved. These were rated by 2 consultants and 2 senior registrars in orthodontics. The 5-Year Olds' Index was used to score the study models, and at a separate sitting, a 5-point Likert scale was used to score the cropped frontal and worm's eye view photographs of the same children. The results were analyzed using intraclass correlation coefficients and Cohen κ. MAIN OUTCOME MEASURES: Correlation between the aesthetic scores of the photographic views and the concordant 5-Year Olds' Index scores of the study models. RESULTS: The intraclass correlation coefficient scores showed very poor agreement between the photographic views and their concordant study models. The level of inter- and intra-rater reliability was strongest when scoring the study models. CONCLUSIONS: There was no agreement between the scores given to various photographic views and their corresponding study models. Scoring the study models using the 5-Year Olds' Index was the most reliable outcome measure for this age-group.

Antimicrobial Irrigation and Technique during Breast Augmentation: Survey of Current Practice.

Breast augmentation is among the most common procedures performed in the United States. Though bacterial contamination of breast prostheses is associated with adverse sequelae, there are no universally accepted guidelines and limited best practice recommendations for antimicrobial breast pocket irrigation. We designed a survey to identify pocket irrigation preferences and antimicrobial techniques during implant-based breast augmentation among American Society of Plastic Surgeons (ASPS) members. METHODS: In January 2018, a random cohort of 2,488 ASPS members was surveyed. Questions queried breast pocket irrigation methods and surgical techniques including implant placement, incision location, and implant soaking agents. An extensive literature review of breast pocket irrigation practices was completed and used as a basis for the survey. RESULTS: The survey response rate was above the ASPS average at 16% (n = 407). Respondents preferred an inframammary incision (90%) and submuscular implant placement (92%). Triple antibiotic solution (TAS) and TAS + Betadine ± Bacitracin were preferred by 61% and Betadine variants by 11%. Preferred dwell times stratified to 30 seconds (39%), 1 minute (18%), 2-5 minutes (21%), and >5 minutes (22%). Among those employing a TAS variant, 53% preferred a suboptimal dwell time of ≤1 minute. Prostheses were soaked in TAS (42%), TAS + Betadine ± Bacitracin (15%), a Betadine variant (12%), or other (31%). CONCLUSIONS: Periprosthetic bacterial contamination leads to comorbidity following breast augmentation. Our results reveal significant variability regarding breast pocket irrigation techniques among ASPS members during cosmetic breast augmentation. These data suggest the need for best practice guidelines regarding breast pocket irrigation and implant soaking agents.

Haemolytic disease of the fetus and newborn diagnosed after delivery of a baby to a mother with low anti-E antibody titres.

The authors report a term male neonate who was born in unexpectedly poor condition with low Apgar scores and low venous cord gas pH. He required admission to the neonatal unit and was found to have developed haemolytic anaemia with associated hydrops, following a presumed severe antenatal insult. Antenatally, low levels of anti-E antibodies (titre 8) had been detected at 28 weeks' gestation. Following the British Society for Haematology and local neonatal team guidance, advice was given for cord direct antiglobulin test, full blood count and bilirubin at delivery. This case highlights the rare case of haemolytic disease of the fetus and newborn on a background of maternal low titre anti-E antibodies.