Fecal dysbiosis and inflammation in intestinal-specific Cftr knockout mice on regimens preventing intestinal obstruction.

Chronic intestinal inflammation is a poorly understood manifestation of cystic fibrosis (CF), which may be refractory to ion channel CF transmembrane conductance regulator (CFTR) modulator therapy. People with CF exhibit intestinal dysbiosis, which has the potential for stimulating intestinal and systemic inflammation. CFTR is expressed in organ epithelia, leukocytes, and other tissues. Here, we investigate the contribution of intestinal epithelium-specific loss of Cftr [iCftr knockout (KO)] to dysbiosis and inflammation in mice treated with either of two antiobstructive dietary regimens necessary to maintain CF mouse models [polyethylene glycol (PEG) laxative or a liquid diet (LiqD)]. Feces collected from iCftr KO mice and their wild-type (WT) sex-matched littermates were used to measure fecal calprotectin to evaluate inflammation and to perform 16S rRNA sequencing to characterize the gut microbiome. Fecal calprotectin was elevated in iCftr KO relative to WT mice that consumed either PEG or LiqD. PEG iCftr KO mice did not show a change in α diversity versus WT mice but demonstrated a significant difference in microbial composition (ß diversity) with included increases in the phylum Proteobacteria, the family Peptostreptococcaceae, four genera of Clostridia including C. innocuum, and the mucolytic genus Akkermansia. Fecal microbiome analysis of LiqD-fed iCftr KO mice showed both decreased α diversity and differences in microbial composition with increases in the Proteobacteria family Enterobacteriaceae, Firmicutes families Clostridiaceae and Peptostreptococcaceae, and enrichment of Clostridium perfringens, C. innocuum, C. difficile, mucolytic Ruminococcus gnavus, and reduction of Akkermansia. It was concluded that epithelium-specific loss of Cftr is a major driver of CF intestinal dysbiosis and inflammation with significant similarities to previous studies of pan Cftr KO mice.NEW & NOTEWORTHY Chronic intestinal inflammation is a manifestation of cystic fibrosis (CF), a disease caused by loss of the anion channel CF transmembrane conductance regulator (CFTR) that is expressed in many tissues. This study shows that intestinal epithelial cell-specific loss of CFTR [inducible Cftr knockout (KO)] in mice is sufficient to induce intestinal dysbiosis and inflammation. Experiments were performed on mice consuming two dietary regimens routinely used to prevent obstruction in CF mice.

Fecal Dysbiosis and Inflammation in Intestinal-Specific Cftr Knockout Mice on Regimens Preventing Intestinal Obstruction.

Chronic intestinal inflammation is a poorly understood manifestation of Cystic Fibrosis (CF), which may be refractory to ion channel CFTR modulator therapy. People with CF exhibit intestinal dysbiosis which has potential for stimulating intestinal and systemic inflammation. CFTR is expressed in organ epithelia and in the leukocyte population. Here, we investigate the contribution of intestinal epithelial-specific loss of Cftr (iCftr KO) to dysbiosis and inflammation in mice treated with either of two anti-obstructive dietary regimens necessary to maintain CF mouse models (PEG laxative or a liquid diet, LiqD). Feces collected from iCftr KO mice and their wildtype (WT) sex-matched littermates were used to measure fecal calprotectin and to perform 16S rRNA sequencing to characterize the gut microbiome. Fecal calprotectin was elevated in iCftr KO relative to WT samples of mice consuming either PEG or LiqD. PEG iCftr KO mice did not show a change in α-diversity versus WT but demonstrated a significant difference in microbial composition (ß-diversity) with increases in phylum Proteobacteria , family Peptostreptococcaceae , four genera of Clostridia including C. innocuum , and mucolytic genus Akkermansia . Fecal microbiome analysis of LiqD iCftr KO mice showed both decreased α-diversity and differences in microbial composition with increases in Proteobacteria family Enterobacteriaceae , Firmicutes families Clostridiaceae and Peptostreptococcaceae , and enrichment of Clostridium perfringens , C. innocuum , C. difficile , mucolytic Ruminococcus gnavus , and reduction of Akkermansia . It was concluded that epithelial-specific loss of Cftr is a major driver of CF intestinal dysbiosis and inflammation with significant similarities to previous studies of global Cftr KO mice. New and noteworthy: Chronic intestinal inflammation is a manifestation of cystic fibrosis (CF), a disease caused by loss of the anion channel CFTR that is expressed in many tissues. This study shows that intestinal epithelial cell-specific loss of CFTR (iCftr KO) in mice is sufficient to induce intestinal dysbiosis and inflammation. Studies were performed on mice consuming either dietary regimen (PEG laxative or liquid diet) routinely used to prevent obstruction in CF mice.

Impact evaluation of the family expectations program and moderation by sociodemographic disadvantage.

The federal government, through the Administration for Children and Families (ACF), has funded community-based relationship education programs for couples, individuals, and families, with a strong focus on serving economically disadvantaged and racially diverse families. This study evaluated the impact of a 36-hour, workshop-based couple relationship education program that was funded by ACF using a randomized controlled trial (RCT) design and intent-to-treat (ITT) analyses. Participants were 1320 couples who were either expecting a baby or had a baby within the past 3 months, at the time of enrollment. Follow-up surveys were administered 12 months later. Analyses evaluated program impacts on relationship stability, constructive communication, and destructive conflict compared to a no-treatment control group. Analyses showed a statistically significant impact of the program on destructive conflict (d = 0.10) but not on constructive communication (d = 0.06) or stability (dCox  = 0.10). Based on findings from previous evaluations, we also examined whether participants' levels of sociodemographic disadvantage moderated these effects. There was significant moderation by sociodemographic disadvantage on constructive communication and destructive conflict, but not on stability. Effects were observed for those at higher levels of sociodemographic disadvantage.

Synthesis and Evaluation of Pseudomonas aeruginosa ATP Synthase Inhibitors.

New antibiotics with unique biological targets are desperately needed to combat the growing number of resistant bacterial pathogens. ATP synthase, a critical protein found in all life, has recently become a target of interest for antibiotic development due to the success of the anti-tuberculosis drug bedaquiline, and while many groups have worked on developing drugs to target bacterial ATP synthase, few have been successful at inhibiting Pseudomonas aeruginosa (PA) ATP synthase specifically. PA is one of the leading causes of resistant nosocomial infections across the world and is extremely challenging to treat due to its various antibiotic resistance mechanisms for most commonly used antibiotics. Herein, we detail the synthesis and evaluation of a series of C1/C2 quinoline analogues for their ability to inhibit PA ATP synthase and act as antibiotics against wild-type PA. From this survey, we found six compounds capable of inhibiting PA ATP synthase in vitro showing that bulky/hydrophobic C1/C2 substitutions are preferred. The strongest inhibitor showed an IC50 of 10 µg/mL and decreased activity of PA ATP synthase to 24% relative to the control. While none of the compounds were able to inhibit wild-type PA in cell culture, two showed improved inhibition of PA growth when permeability of the outer membrane was increased or efflux was knocked out, thus demonstrating that these compounds could be further developed into efficacious antibiotics.

Laparoscopic Appendectomy and Cholecystectomy Timing Predicts Hand-Offs but Not Miscounts.

INTRODUCTION: Intraoperative hand-offs are poorly coordinated and associated with risk of surgical miscount. We evaluated hand-off patterns for nursing staff during two common operations hypothesizing that hand-off patterns would be associated with increased surgical miscounts and vary during operations performed standard versus nonstandard operating hours. METHODS: We retrospectively analyzed laparoscopic cholecystectomy (N = 3888) and appendectomy (N = 1768) from 2012 to 2021 at a single institution using electronic medical records. We evaluated intraoperative hand-off patterns and the presence of miscounts for operations performed during standard versus nonstandard hours. Standard operating hours were defined as M-F 7:30 am to 5:00 pm. RESULTS: Across 5656 operations, 10 cases had surgical miscounts and were significantly longer than those without (156.5 versus 101 min P = 0.0178). More than half (51.3%) of cases had no identified hand-offs, and 42.9% of cases occurred during nonstandard hours. Cases during standard versus nonstandard hours were more likely to have hand-offs (56.0% versus 38.9%), P < 0.0001 and had shorter interval between hand-offs (64 versus 75 min), P < 0.0001. The period between patient entry to the room and intubation, which includes initial counts, had a disproportionately high percentage of hand-offs (P < 0.0001). CONCLUSIONS: Variability in hand-off occurrence and frequency in operations performed during standard and nonstandard hours suggest that hand-offs are influenced by staffing patterns. Few surgical miscounts occurred but were associated with longer cases. Hand-offs disproportionately occurred between patient entry and intubation, with a potential for disruption of initial instrument counts. Future work optimizing hand-off coordination is an opportunity to mitigate risk to patients.

Goblet cell hyperplasia is not epithelial-autonomous in the Cftr knockout intestine.

Goblet cell hyperplasia is an important manifestation of cystic fibrosis (CF) disease in epithelial-lined organs. Explants of CF airway epithelium show normalization of goblet cell numbers; therefore, we hypothesized that small intestinal enteroids from Cftr knockout (KO) mice would not exhibit goblet cell hyperplasia. Toll-like receptors 2 and 4 (Tlr2 and Tlr4) were investigated as markers of inflammation and influence on goblet cell differentiation. Ex vivo studies found goblet cell hyperplasia in Cftr KO jejunum compared with wild-type (WT) mice. IL-13, SAM pointed domain-containing ETS transcription factor (Spdef), Tlr2, and Tlr4 protein expression were increased in Cftr KO intestine relative to WT. In contrast, WT and Cftr KO enteroids did not exhibit differences in basal or IL-13-stimulated goblet cell numbers, or differences in expression of Tlr2, Tlr4, and Spdef. Ileal goblet cell numbers in Cftr KO/Tlr4 KO and Cftr KO/Tlr2 KO mice were not different from Cftr KO mice, but enumeration was confounded by altered mucosal morphology. Treatment with Tlr4 agonist LPS did not affect goblet cell numbers in WT or Cftr KO enteroids, whereas the Tlr2 agonist Pam3Csk4 stimulated goblet cell hyperplasia in both genotypes. Pam3Csk4 stimulation of goblet cell numbers was associated with suppression of Notch1 and Neurog3 expression and upregulated determinants of goblet cell differentiation. We conclude that goblet cell hyperplasia and inflammation of the Cftr KO small intestine are not exhibited by enteroids, indicating that this manifestation of CF intestinal disease is not epithelial-automatous but secondary to the altered CF intestinal environment.NEW & NOTEWORTHY Studies of small intestinal organoids from cystic fibrosis (CF) mice show that goblet cell hyperplasia and increased Toll-like receptor 2/4 expression are not primary manifestations of the CF intestine. Intestinal goblet cell hyperplasia in the CF mice was not strongly altered by genetic ablation of Tlr2 and Tlr 4, but could be induced in both wild-type and CF intestinal organoids by a Tlr2-dependent suppression of Notch signaling.

Modeling Performance of Open Surgical Cases.

INTRODUCTION: Previous efforts used digital video to develop computer-generated assessments of surgical hand motion economy and fluidity of motion. This study tests how well previously trained assessment models match expert ratings of suturing and tying video clips recorded in a new operating room (OR) setting. METHODS: Enabled through computer vision of the hands, this study tests the applicability of assessments born out of benchtop simulations to in vivo suturing and tying tasks recorded in the OR. RESULTS: Compared with expert ratings, computer-generated assessments for fluidity of motion (slope = 0.83, intercept = 1.77, R2 = 0.55) performed better than motion economy (slope = 0.73, intercept = 2.04, R2 = 0.49), although 85% of ratings for both models were within ±2 of the expert response. Neither assessment performed as well in the OR as they did on the training data. Assessments were sensitive to changing hand postures, dropped ligatures, and poor tissue contact-features typically missing from training data. Computer-generated assessment of OR tasks was contingent on a clear, consistent view of both surgeon's hands. CONCLUSIONS: Computer-generated assessment may help provide formative feedback during deliberate practice, albeit with greater variability in the OR compared with benchtop simulations. Future work will benefit from expanded available bimanual video records.

Zn-based physiometacomposite nanoparticles: distribution, tolerance, imaging, and antiviral and anticancer activity.

The aim of this study was to investigate the distribution, tolerance, and anticancer and antiviral activity of Zn-based physiometacomposites (PMCs). Manganese, iron, nickel and cobalt-doped ZnO, ZnS or ZnSe were synthesized. Cell uptake, distribution into 3D culture and mice, and biochemical and chemotherapeutic activity were studied by fluorescence/bioluminescence, confocal microscopy, flow cytometry, viability, antitumor and virus titer assays. Luminescence and inductively coupled plasma mass spectrometry analysis showed that nanoparticle distribution was liver >spleen >kidney >lung >brain, without tissue or blood pathology. Photophysical characterization as ex vivo tissue probes and LL37 peptide, antisense oligomer or aptamer delivery targeting RAS/Ras binding domain (RBD) was investigated. Treatment at 25 µg/ml for 48 h showed ≥98-99% cell viability, 3D organoid uptake, 3-log inhibition of ß-Galactosidase and porcine reproductive respiratory virus infection. Data support the preclinical development of PMCs for imaging and delivery targeting cancer and infectious disease.

Evaluation of Intraoperative Hand-Off Frequency, Duration, and Context: A Mixed Methods Analysis.

BACKGROUND: Hand-offs in the operating room contribute to poor communication, reduced team function, and may be poorly coordinated with other activities. Conversely, they may represent a missed opportunity for improved communication. We sought to better understand the coordination and impact of intraoperative hand-offs. METHODS: We prospectively audio-video (AV) recorded 10 operations and evaluated intraoperative hand-offs. Data collected included percentage of time team members were absent due to breaks, relationships between hand-offs and intraoperative events (incision, surgical counts), and occurrences of simultaneous hand-offs. We also identified announcement that a hand-off had occurred and anchoring, in which team members not involved in the hand-off participated and provided information. RESULTS: Spanning 2919 min of audio-video data, there were 74 hand-offs (range, 4-14 per case) totaling 225.2 min, representing 7.7% of time recorded. Thirty-two (45.1%) hand-offs were interrupted or delayed because of competing activities; eight hand-offs occurred during an instrument or laparotomy pad count. Six cases had simultaneous hand-offs; two cases had two episodes of simultaneous hand-offs. Eight hand-offs included an announcement. Seven included anchoring. Evaluating both temporary and permanent hand-offs, one or more original team members was absent for 40.7% of time recorded and >one team member was absent for 20.5% of time recorded. CONCLUSIONS: Intraoperative hand-offs are frequent and not well coordinated with intraoperative events including counts and other hand-offs. Anchoring and announced hand-offs occurred in a small proportion of cases. Future work must focus on optimizing timing, content, and participation in intraoperative hand-offs.

A BAC Transgene Expressing Human CFTR under Control of Its Regulatory Elements Rescues Cftr Knockout Mice.

Small-molecule modulators of cystic fibrosis transmembrane conductance regulator (CFTR) biology show promise in the treatment of cystic fibrosis (CF). A Cftr knockout (Cftr KO) mouse expressing mutants of human CFTR would advance in vivo testing of new modulators. A bacterial artificial chromosome (BAC) carrying the complete hCFTR gene including regulatory elements within 40.1 kb of DNA 5' and 25 kb of DNA 3' to the gene was used to generate founder mice expressing hCFTR. Whole genome sequencing indicated a single integration site on mouse chromosome 8 (8qB2) with ~6 gene copies. hCFTR+ offspring were bred to murine Cftr KO mice, producing hCFTR+/mCftr- (H+/m-) mice, which had normal survival, growth and goblet cell function as compared to wild-type (WT) mice. Expression studies showed hCFTR protein and transcripts in tissues typically expressing mCftr. Functionally, nasal potential difference and large intestinal short-circuit (Isc) responses to cAMP stimulation were similar in magnitude to WT mice, whereas small intestinal cAMP ΔIsc responses were reduced. A BAC transgenic mouse with functional hCFTR under control of its regulatory elements has been developed to enable the generation of mouse models of hCFTR mutations by gene editing for in vivo testing of new CF therapies.

Familiarity and Communication in the Operating Room.

BACKGROUND: Poor communication is implicated in many adverse events in the operating room (OR); however, many hospitals' scheduling practices permit unfamiliar operative teams. The relationship between unfamiliarity, team communication and effectiveness of communication is poorly understood. We sought to evaluate the relationship between familiarity, communication rates, and communication ineffectiveness of health care providers in the OR. MATERIALS AND METHODS: We performed purposive sampling of 10 open operations. For each case, six providers (anesthesiology attending, in-room anesthetist, circulator, scrub, surgery attending, and surgery resident) were queried about the number of mutually shared cases. We identified communication events and created dyad-specific communication rates. RESULTS: Analysis of 48 h of audio-video content identified 2570 communication events. Operations averaged 58.0 communication events per hour (range, 29.4-76.1). Familiarity was not associated with communication rate (P = 0.69) or communication ineffectiveness (P = 0.21). Cross-disciplinary dyads had lower communication rates than intradisciplinary dyads (P < 0.001). Anesthesiology-nursing, anesthesiology-surgery, and nursing-surgery dyad communication rates were 20.1%, 42.7%, and 57.3% the rate predicted from intradisciplinary dyads, respectively. In addition, cross-disciplinary dyad status was a significant predictor of having at least one ineffective communication event (P = 0.02). CONCLUSIONS: Team members do not compensate for unfamiliarity by increasing their verbal communication, and dyad familiarity is not protective against ineffective communication. Cross-disciplinary communication remains vulnerable in the OR suggesting poor crosstalk across disciplines in the operative setting. Further investigation is needed to explore these relationships and identify effective interventions, ensuring that all team members have the necessary information to optimize their performance.

Modeling Surgical Technical Skill Using Expert Assessment for Automated Computer Rating.

OBJECTIVE: Computer vision was used to predict expert performance ratings from surgeon hand motions for tying and suturing tasks. SUMMARY BACKGROUND DATA: Existing methods, including the objective structured assessment of technical skills (OSATS), have proven reliable, but do not readily discriminate at the task level. Computer vision may be used for evaluating distinct task performance throughout an operation. METHODS: Open surgeries was videoed and surgeon hands were tracked without using sensors or markers. An expert panel of 3 attending surgeons rated tying and suturing video clips on continuous scales from 0 to 10 along 3 task measures adapted from the broader OSATS: motion economy, fluidity of motion, and tissue handling. Empirical models were developed to predict the expert consensus ratings based on the hand kinematic data records. RESULTS: The predicted versus panel ratings for suturing had slopes from 0.73 to 1, and intercepts from 0.36 to 1.54 (Average R2 = 0.81). Predicted versus panel ratings for tying had slopes from 0.39 to 0.88, and intercepts from 0.79 to 4.36 (Average R2 = 0.57). The mean square error among predicted and expert ratings was consistently less than the mean squared difference among individual expert ratings and the eventual consensus ratings. CONCLUSIONS: The computer algorithm consistently predicted the panel ratings of individual tasks, and were more objective and reliable than individual assessment by surgical experts.

Cftr Modulates Wnt/ß-Catenin Signaling and Stem Cell Proliferation in Murine Intestine.

BACKGROUND & AIMS: Cystic fibrosis (CF) patients and CF mouse models have increased risk for gastrointestinal tumors. CF mice show augmented intestinal proliferation of unknown etiology and an altered intestinal environment. We examined the role of the cystic fibrosis transmembrane conductance regulator (Cftr) in Wnt/ß-catenin signaling, stem cell proliferation, and its functional expression in the active intestinal stem cell (ISC) population. Dysregulation of intracellular pH (pHi) in CF ISCs was investigated for facilitation of Wnt/ß-catenin signaling. METHODS: Crypt epithelia from wild-type (WT) and CF mice were compared ex vivo and in intestinal organoids (enteroids) for proliferation and Wnt/ß-catenin signaling by standard assays. Cftr in ISCs was assessed by immunoblot of sorted Sox9 enhanced green fluorescent protein(EGFP) intestinal epithelia and pHi regulation by confocal microfluorimetry of leucine-rich G-protein-coupled receptor 5 ISCs. Plasma membrane association of the Wnt transducer Dishevelled 2 (Dvl2) was assessed by fluorescence imaging of live enteroids from WT and CF mice crossed with Dvl2-EGFP/ACTB-tdTomato,-EGFP)Luo/J (RosamT/mG) mice. RESULTS: Relative to WT, CF intestinal crypts showed an ∼30% increase in epithelial and Lgr5+ ISC proliferation and increased Wnt/ß-catenin signaling. Cftr was expressed in Sox9EGFPLo ISCs and loss of Cftr induced an alkaline pHi in ISCs. CF crypt-base columnar cells showed a generalized increase in plasma membrane Dvl2-EGFP association as compared with WT. Dvl2-EGFP membrane association was charge- and pH-dependent and increased in WT crypt-base columnar cells by Cftr inhibition. CONCLUSIONS: CF intestine shows increased ISC proliferation and Wnt/ß-catenin signaling. Loss of Cftr increases pHi in ISCs, which stabilizes the plasma membrane association of the Wnt transducer Dvl, likely facilitating Wnt/ß-catenin signaling. Absence of Cftr-dependent suppression of ISC proliferation in the CF intestine may contribute to increased risk for intestinal tumors.

A Statewide Surgical Coaching Program Provides Opportunity for Continuous Professional Development.

OBJECTIVE: We sought to develop and evaluate a video-based coaching program for board-eligible/certified surgeons. SUMMARY BACKGROUND DATA: Multiple disciplines utilize coaching for continuous professional development; however, coaching is not routinely employed for practicing surgeons. METHODS: Peer-nominated surgeons were trained as coaches then paired with participant surgeons. After setting goals, each coaching pair reviewed video-recorded operations performed by the participating surgeon. Coaching sessions were audio-recorded, transcribed, and coded to identify topics discussed. The effectiveness with which our coaches were able to utilize the core principles and activities of coaching was evaluated using 3 different approaches: self-evaluation; evaluation by the participants; and assessment by the study team. Surveys of participating surgeons and coach-targeted interviews provided general feedback on the program. All measures utilized a 5-point Likert scale format ranging from 1 (low) to 5 (high). RESULTS: Coach-participant surgeon pairs targeted technical, cognitive, and interpersonal aspects of performance. Other topics included managing intraoperative stress. Mean objective ratings of coach effectiveness was 3.1 ±â€Š0.7, ranging from 2.0 to 5.0 on specific activities of coaching. Subjective ratings by coaches and participants were consistently higher. Coaches reported that the training provided effectively prepared them to facilitate coaching sessions. Participants were similarly positive about interactions with their coaches. Identified barriers were related to audio-video technology and scheduling of sessions. Overall, participants were satisfied with their experience (mean 4.4 ±â€Š0.7) and found the coaching program valuable (mean 4.7 ±â€Š0.7). CONCLUSIONS: This is the first report of cross-institutional surgical coaching for the continuous professional development of practicing surgeons, demonstrating perceived value among participants, as well as logistical challenges for implementing this evidence-based program. Future research is necessary to evaluate the impact of coaching on practice change and patient outcomes.

Examining the influence of personal goal interference and attainability on psychological distress in non-metastatic breast cancer patients.

The present study investigated the relationship between two goal-related appraisals - perceived cancer-related interference and perceived attainability of important personal goals - and psychological distress among non-metastatic breast cancer patients across the short-term treatment and recovery period. Forty-five women completed self-report questionnaires at approximately 1 and 6 months following surgery. A mixed idiographic-nomothetic goal methodology assessed perceived cancer-related interference and attainability of self-generated important personal goals. Psychological distress symptoms were assessed with the Depression Anxiety Stress Scales short form. Correlation analyses and general linear modelling were used to evaluate the hypothesised relationships over time. Average cancer-related interference and attainability of important personal goals were significantly associated with concurrent depression, anxiety and stress symptoms at 6 months following surgery. Perceived attainability of highly important goals at 6 months post-surgery uniquely predicted change in psychological distress symptoms over time. The findings suggest that low perceived attainability of important personal goals may be an important predictor of elevated distress symptoms across the short-term following surgery. Further insight into the relationship between these negative goal appraisals and psychological functioning among different groups of cancer patients could inform the provision of targeted psychosocial support across the cancer continuum.

Within- and Between-Family Associations of Marital Functioning and Child Well-being.

This study clarifies within-family and between-family links between marital functioning and child wellbeing. Expanding on existing prospective research, this study tests whether changes in parents' marital functioning are associated with corresponding changes in their children's wellbeing, independent from associations that exist when comparing different families. Participants (N = 1033) were members of married, opposite-sex couples with children who participated in five waves of a larger study of marriage in the U.S. Army. Spouses' constructive communication, verbal conflict, and marital satisfaction each showed between-family associations with parent-reported child internalizing and externalizing problems. In contrast, within-family associations were significant only for parents' communication behaviors. That is, parents who reported lower levels of marital satisfaction also reported lower child wellbeing, whereas change in parents' communication was associated with change in child wellbeing over time. Isolating within-family effects is important for understanding marital and child functioning and for identifying potential targets for effective intervention.

Changes in premiums of cancelled nongroup plans under the Affordable Care Act.

OBJECTIVES: To examine the effect of the Affordable Care Act (ACA) on changes in premiums for subscribers of nongrandfathered, nongroup insurance plans that were "cancelled." STUDY DESIGN: Retrospective multivariate analyses. METHODS: Changes in annual premiums post ACA were evaluated across subgroups of subscriber and health plan characteristics. Data was derived from databases containing information on premiums, plan benefit, and demographics for subscribers aged 18 to 64 years within Kaiser Permanente of the Mid-Atlantic States. A linear regression model was used to examine the independent association between subscriber and health plan characteristics on the relative change in premiums. RESULTS: In 2013, 4169 nongroup subscribers were enrolled in plans that were cancelled as a result of the ACA. The median pre-ACA premium was $3240 (range = $780-$39,492), which increased by a median of 21.3% (range = -77.4% to 193.6%), or $685 (range = -$27,464 to $8676), post ACA in 2014. Premiums increased more for high-deductible plans (median = 63.7%) than standard-deductible plans (median = 8.4%). Due to shifts in the age curve, premiums decreased for more than half of women aged 18 to 44 years, but increased by 35.2% for women aged 55 to 64 years. Premiums fell by 15.5% for subscribers who did not pass standard medical underwriting due to preexisting conditions. CONCLUSIONS: Changes in premiums in the nongroup market post ACA, varied substantially across subgroups, primarily due to differences in the amount of coverage, changes in rating criteria, shifts in the age curve, and anticipated differences in risk selection and composition of the risk pool. Given the extent of this variation, it would be incorrect to conclude the ACA as being uniformly beneficial or detrimental to subscribers of these cancelled plans.