A KLHL40 3' UTR splice-altering variant causes milder NEM8, an under-appreciated disease mechanism.

Nemaline myopathy 8 (NEM8) is typically a severe autosomal recessive disorder associated with variants in the kelch-like family member 40 gene (KLHL40). Common features include fetal akinesia, fractures, contractures, dysphagia, respiratory failure and neonatal death. Here, we describe a 26-year-old man with relatively mild NEM8. He presented with hypotonia and bilateral femur fractures at birth, later developing bilateral Achilles' contractures, scoliosis, and elbow and knee contractures. He had walking difficulties throughout childhood and became wheelchair bound from age 13 after prolonged immobilization. Muscle magnetic resonance imaging at age 13 indicated prominent fat replacement in his pelvic girdle, posterior compartments of thighs and vastus intermedius. Muscle biopsy revealed nemaline bodies and intranuclear rods. RNA sequencing and western blotting of patient skeletal muscle indicated significant reduction in KLHL40 mRNA and protein, respectively. Using gene panel screening, exome sequencing and RNA sequencing, we identified compound heterozygous variants in KLHL40; a truncating 10.9 kb deletion in trans with a likely pathogenic variant (c.*152G > T) in the 3' untranslated region (UTR). Computational tools SpliceAI and Introme predicted the c.*152G > T variant created a cryptic donor splice site. RNA-seq and in vitro analyses indicated that the c.*152G > T variant induces multiple de novo splicing events that likely provoke nonsense mediated decay of KLHL40 mRNA explaining the loss of mRNA expression and protein abundance in the patient. Analysis of 3' UTR variants in ClinVar suggests variants that introduce aberrant 3' UTR splicing may be underrecognized in Mendelian disease. We encourage consideration of this mechanism during variant curation.

Stereotype Threat and Gender Bias in Internal Medicine Residency: It is Still Hard to be in Charge.

BACKGROUND: Despite similar numbers of women and men in internal medicine (IM) residency, women face unique challenges. Stereotype threat is hypothesized to contribute to underrepresentation of women in academic leadership, and exploring how it manifests in residency may provide insight into forces that perpetuate gender disparities. OBJECTIVE: To quantify the prevalence of stereotype threat in IM residency and explore experiences contributing to that stereotype threat. DESIGN: We used a mixed methods study design. First, we surveyed IM residents using the Stereotype Vulnerability Scale (SVS) to screen for stereotype threat. Second, we conducted focus groups with women who scored high on the SVS to understand experiences that led to stereotype threat. PARTICIPANTS: The survey was sent to all IM residents at University of California, San Francisco (UCSF), in September-November 2019. Focus groups were conducted at UCSF in Spring 2020. APPROACH: The survey included an adapted version of the SVS. For focus groups, we developed a focus group guide informed by literature on stereotype threat. We used a thematic approach to data analysis. The mixed methods design enabled us to draw metainferences by integrating the two data sources. KEY RESULTS: Survey response rate was 61% (110/181). Women were significantly more likely than men to have a score indicating stereotype threat vulnerability (77% vs 0%, p < 0.001). Four themes from focus groups characterized women's experiences of gender bias and stereotype threat: gender norm tension, microaggressions and sexual harassment, authority questioned, and support and allyship. CONCLUSIONS: Gender-based stereotype threat is highly prevalent among women IM residents. This phenomenon poses a threat to confidence and ability to execute patient care responsibilities, detracting from well-being and professional development. These findings indicate that, despite robust representation of women in IM training, further attention is needed to address gendered experiences and contributors to women's vulnerability to stereotype threat.

Who should proof my paper?

This column is intended to address the kinds of knotty problems and dilemmas with which many scholars grapple in studying health professions education. In this article, the authors address the challenges in proofreading a manuscript. Emerging researchers might think that someone in the production team will catch any errors. This may not always be the case. We emphasize the importance of guiding mentees to take the process of preparing a manuscript for submission seriously.

I'd like to use a questionnaire (sub-text: this will be an easy way to get data. Right?).

This column is intended to address the kinds of knotty problems and dilemmas with which many scholars grapple in studying health professions education. In this article, the authors address the question of using questionnaires in education research, considering the why, when, and how, as well as its potential pitfalls. The goal is to guide supervisors and students who are considering whether to develop and use a questionnaire for research purposes.

Assessing supervisor versus trainee viewpoints of entrustment through cognitive and affective lenses: an artificial intelligence investigation of bias in feedback.

The entrustment framework redirects assessment from considering only trainees' competence to decision-making about their readiness to perform clinical tasks independently. Since trainees and supervisors both contribute to entrustment decisions, we examined the cognitive and affective factors that underly their negotiation of trust, and whether trainee demographic characteristics may bias them. Using a document analysis approach, we adapted large language models (LLMs) to examine feedback dialogs (N = 24,187, each with an associated entrustment rating) between medical student trainees and their clinical supervisors. We compared how trainees and supervisors differentially documented feedback dialogs about similar tasks by identifying qualitative themes and quantitatively assessing their correlation with entrustment ratings. Supervisors' themes predominantly reflected skills related to patient presentations, while trainees' themes were broader-including clinical performance and personal qualities. To examine affect, we trained an LLM to measure feedback sentiment. On average, trainees used more negative language (5.3% lower probability of positive sentiment, p < 0.05) compared to supervisors, while documenting higher entrustment ratings (+ 0.08 on a 1-4 scale, p < 0.05). We also found biases tied to demographic characteristics: trainees' documentation reflected more positive sentiment in the case of male trainees (+ 1.3%, p < 0.05) and of trainees underrepresented in medicine (UIM) (+ 1.3%, p < 0.05). Entrustment ratings did not appear to reflect these biases, neither when documented by trainee nor supervisor. As such, bias appeared to influence the emotive language trainees used to document entrustment more than the degree of entrustment they experienced. Mitigating these biases is nonetheless important because they may affect trainees' assimilation into their roles and formation of trusting relationships.

Should I do a synthesis (i.e. literature review)?

This column is intended to address the kinds of knotty problems and dilemmas with which many scholars grapple in studying health professions education. In this article, the authors address the question of whether one should conduct a literature review or knowledge synthesis, considering the why, when, and how, as well as its potential pitfalls. The goal is to guide supervisors and students who are considering whether to embark on a literature review in education research.

Multidisciplinary surgical considerations for en bloc resection of sacral chordoma: review of recent advances and a contemporary single-center series.

OBJECTIVE: Contemporary management of sacral chordomas requires maximizing the potential for recurrence-free and overall survival while minimizing treatment morbidity. En bloc resection can be performed at various levels of the sacrum, with tumor location and volume ultimately dictating the necessary extent of resection and subsequent tissue reconstruction. Because tumor resection involving the upper sacrum may be quite destabilizing, other pertinent considerations relate to instrumentation and subsequent tissue reconstruction. The primary aim of this study was to survey the surgical approaches used for managing primary sacral chordoma according to location of lumbosacral spine involvement, including a narrative review of the literature and examination of the authors' institutional case series. METHODS: The authors performed a narrative review of pertinent literature regarding reconstruction and complication avoidance techniques following en bloc resection of primary sacral tumors, supplemented by a contemporary series of 11 cases from their cohort. Relevant surgical anatomy, advances in instrumentation and reconstruction techniques, intraoperative imaging and navigation, soft-tissue reconstruction, and wound complication avoidance are also discussed. RESULTS: The review of the literature identified several surgical approaches used for management of primary sacral chordoma localized to low sacral levels (mid-S2 and below), high sacral levels (involving upper S2 and above), and high sacral levels with lumbar involvement. In the contemporary case series, the majority of cases (8/11) presented as low sacral tumors that did not require instrumentation. A minority required more extensive instrumentation and reconstruction, with 2 tumors involving upper S2 and/or S1 levels and 1 tumor extending into the lower lumbar spine. En bloc resection was successfully achieved in 10 of 11 cases, with a colostomy required in 2 cases due to rectal involvement. All 11 cases underwent musculocutaneous flap wound closure by plastic surgery, with none experiencing wound complications requiring revision. CONCLUSIONS: The modern management of sacral chordoma involves a multidisciplinary team of surgeons and intraoperative technologies to minimize surgical morbidity while optimizing oncological outcomes through en bloc resection. Most cases present with lower sacral tumors not requiring instrumentation, but stabilizing instrumentation and lumbosacral reconstruction are often required in upper sacral and lumbosacral cases. Among efforts to minimize wound-related complications, musculocutaneous flap closure stands out as an evidence-based measure that may mitigate risk.

Recovery Rates of Diagnostic Cardiac Procedural Volume in Oceania 1 Year Into COVID-19: The IAEA Non-Invasive Cardiology Protocol Survey on COVID-19 (INCAPS COVID 2).

AIM: The aim of this study was to assess the recovery rates of diagnostic cardiac procedure volumes in the Oceania Region, midway through the coronavirus disease 2019 (COVID-19) pandemic. METHODS: A survey was performed comparing procedure volumes between March 2019 (pre-pandemic), April 2020 (during first wave of COVID-19 pandemic), and April 2021 (1 year into the COVID-19 pandemic). A total of 31 health care facilities within Oceania that perform cardiac diagnostic procedures were surveyed, including a mixture of metropolitan and regional, hospital and outpatient, public and private sites, as well as teaching and non-teaching hospitals. A comparison was made with 549 centres in 96 countries in the rest of the world (RoW) outside of Oceania. The total number and median percentage change in procedure volume were measured between the three timepoints, compared by test type and by facility. RESULTS: A total of 11,902 cardiac diagnostic procedures were performed in Oceania in April 2021 as compared with 11,835 pre-pandemic in March 2019 and 5,986 in April 2020; whereas, in the RoW, 499,079 procedures were performed in April 2021 compared with 497,615 pre-pandemic in March 2019 and 179,014 in April 2020. There was no significant difference in the median recovery rates for total procedure volumes between Oceania (-6%) and the RoW (-3%) (p=0.81). While there was no statistically significant difference in percentage recovery been functional ischaemia testing and anatomical coronary testing in Oceania as compared with the RoW, there was, however, a suggestion of poorer recovery in anatomical coronary testing in Oceania as compared with the RoW (CT coronary angiography -16% in Oceania vs -1% in RoW, and invasive coronary angiography -20% in Oceania vs -9% in RoW). There was no statistically significant difference in recovery rates in procedure volume between metropolitan vs regional (p=0.44), public vs private (p=0.92), hospital vs outpatient (p=0.79), or teaching vs non-teaching centres (p=0.73). CONCLUSIONS: Total cardiology procedure volumes in Oceania normalised 1 year post-pandemic compared to pre-pandemic levels, with no significant difference compared with the RoW and between the different types of health care facilities.

Enhancing robotic efficiency through the eyes of robotic surgeons: sub-analysis of the expertise in perception during robotic surgery (ExPeRtS) study.

BACKGROUND: Robotic technology affords surgeons many novel and useful features, but two stereotypes continue to prevail: robotic surgery is expensive and inefficient. To identify educational opportunities and improve operative efficiency, we analyzed expert commentary on videos of robotic surgery. METHODS: Expert robotic surgeons, identified through high case volumes and contributions to the surgical literature, reviewed eight anonymous video clips portraying key portions of two robotic general surgery procedures. While watching, surgeons commented on what they saw on the screen. All interactions with participants were in person, recorded, transcribed, and subsequently analyzed. Using content analysis, researchers double-coded each transcript applying a consensus developed codebook. RESULTS: Seventeen surgeons participated. The average participant was male (82.4%), 47 (SD = 6.6) years old, had 13.2 (SD = 8.23) years of teaching experience, worked in urban academic hospitals (64.7%) and had performed 643 (SD = 467) robotic operations at the time of interviews. Emphasis on efficiency (or lack thereof) surfaced across three main themes: overall case progression, robotic capabilities, and instrumentation. Experts verbally rewarded purposeful and "ergonomically sound" movements while language reflecting impatience with repetitive and indecisive movements was attributed to presumed inexperience. Efficient robotic capabilities included enhanced visualization, additional robotic arms to improve exposure, and wristed instruments. Finally, experts discussed instrument selection with regards to energy modality, safety features, cost, and versatility. CONCLUSION: This study highlights three areas for improved efficiency: case progression, robotic capabilities, and instrumentation. Development of education materials within these themes could help surgical educators overcome one of robotic technology's persistent challenges.

Who should be an author on this paper?

This column is intended to address the kinds of knotty problems and dilemmas with which many scholars grapple in studying health professions education. In this article, the authors address the question of who should be listed as an author on a given publication and provide advice as to how to navigate potential tensions in the authorship decision-making process.

My paper has been rejected without review. What do I do now?

This column is intended to address the kinds of knotty problems and dilemmas with which many scholars grapple in studying health professions education. In this article, the authors address the question of why papers may be desk rejected (rejected without going out for formal peer review) and describe simple steps for authors to optimize their work so it gets past the desk reject stage.

How should I determine author order for this paper?

This column is intended to address the kinds of knotty problems and dilemmas with which many scholars grapple in studying health professions education. In this article, the authors conclude their short series of articles on academic authorship by addressing the question of how to determine author order, including taking into account power dynamics that may be at play.

Pediatric all-terrain vehicle (ATV) related head injury rates and patterns: A 10-year nationwide analysis.

INTRODUCTION: The use of all-terrain vehicles (ATVs) carries significant risk of permanent injury and death, disproportionately affecting children. These injuries commonly affect the head and are especially severe among children as they are often unhelmeted and more likely than adults to experience rollover injuries. Many studies examining patients with ATV-related injuries are single-center cohort studies, with few focusing specifically on head injuries. In the present study, we aimed to characterize the annual incidence of ATV-related head injuries between 2012 and 2021, classify and compare head injury types, and identify descriptive characteristics of ATV-related head injury victims. METHODS: Using the US Consumer Product Safety Commission's National Electronic Injury Surveillance System (NEISS) database, we queried all head injuries associated with operating or riding an ATV in children under 18 years-old from over 100 emergency departments (EDs). Patient information regarding age, race, sex, location of incident, diagnoses, and sequelae were analyzed. We also collected the estimated number of ATV-related head injuries from all US EDs using the NEISS algorithm provided by the database. RESULTS: Using the NEISS algorithm we identified 67,957 (95% CI: 43,608 - 92,305) total pediatric ATV-related head injuries between 2012 and 2021. The annual incidence of ATV-related head injury was similar throughout this study period except for a 20% increase during the COVID-19 pandemic period of 2019-2021 (2019: 6382 injuries, 2020: 6757 injuries, 2021: 7600 injuries). A subset of 1890 cases from approximately 100 EDs were then analyzed. Unspecified closed head injuries were the prevailing type of injury (38%, 900/1890), followed by concussions (27%, 510/1890). More severe injuries included intracranial hemorrhages in 91 children (3.8%, 91/1890). Injuries of all types were predominantly seen in 14-17 year-old's (780/1890, 41%) and in males (64.1%, 1211/1890). In addition, ATV-associated injuries were significantly more common in those coded as white (58.0%, 1096/1890) than any other racial group. ATV-associated accidents among children younger than 9 more commonly occurred at the home compared to accidents involving children older than 9 (57% vs. 32%, p < 0.0001). CONCLUSION: ATV-related head injuries cause a significant annual burden among children, with growing incidence in recent years. Further research may wish to explore potential benefits of helmet use and supervision of younger children in possible prevention of these accidents and their associated economic and non-economic costs.

The epidemiology of crib-related head injuries: A ten-year nationwide analysis.

INTRODUCTION: Falls from cribs resulting in head injury are understudied and poorly characterized. The purpose of this study was to advance current understanding of the prevalence, descriptive characteristics of injury victims, and the types of crib fall-related head injuries (CFHI) using queried patient cases from the National Electronic Injury Surveillance System (NEISS) database. METHODS: Using the US Consumer Product Safety Commission's System NEISS database, we queried all CFHIs among children from over 100 emergency departments (EDs). Patient information regarding age, race, sex, location of the incident, diagnoses, ED disposition, and sequelae were analyzed. The number of CFHI from all US EDs during each year was also collected from the database. RESULTS: There were an estimated 54,799 (95% CI: 30,228-79,369) total visits to EDs for CFHIs between 2012 and 2021, with a decrease in incidence of approximately 20% during the onset of the COVID-19 pandemic (2019: 5616 cases, 2020: 4459 cases). The annual incidence of injuries showed no significant trend over the 10-year study period. An available subset of 1782 cases of head injuries from approximately 100 EDs was analyzed, and 1442 cases were included in final analysis. Injuries were sorted into three primary categories: unspecified closed head injury (e.g., closed head injury, blunt head trauma, or traumatic brain injury), concussion, or open head injury and skull fracture. Unspecified closed head injuries were the most common of all head injuries (95.4%, 1376/1442). Open head injuries (14/1442, 0.97%) and concussions 3.6% (52/1442, 3.6%) were rare. Most injuries involved children under the age of 1 (42.6%) compared to children who were 1, 2, 3, or 4-years old. About a fourth of patients had other diagnoses in addition to their primary injury including scalp/forehead hematomas, emesis, and contusions. Female patients were more likely to present with other diagnoses in addition to their primary head injury (Difference: 12.3%, 95% CI: 9.87%-15.4%, p < .0001). CONCLUSION: Despite minimum rail height requirements set by the Consumer Safety Product Commission (CPSC), head injuries associated with crib falls are prevalent in the United States. However, most injuries were minor with a vast majority of patients being released following examination and treatment.

Investigating feedback orientation in medical learners.

BACKGROUND/PURPOSE: Feedback processes in health professions education (HPE) are not always successful. While recommendations to improve feedback provision dominate the literature, studying specific learner attributes that impact feedback uptake may also improve feedback processes. Feedback orientation is a concept from management science involving four dimensions of learner attributes and attitudes that impact their feedback uptake: utility, accountability, social awareness, and feedback self-efficacy. Feedback orientation may represent a valuable concept in HPE. We aimed to understand medical learners' feedback orientation at different stages in their development. METHODS: We used the Feedback Orientation Scale, a 20-item survey instrument, for a cross-sectional analysis of feedback orientation in medical students and Internal Medicine residents at one large academic center. We performed descriptive statistics and analysis of variance for data analysis. RESULTS: We found the same factors (dimensions) to feedback orientation in our population as in management science. Overall feedback orientation scores were high and were largely consistent across trainee levels. Utility was the domain that was highest across learners, whereas feedback self-efficacy was lowest. CONCLUSIONS: Feedback orientation represents a useful concept to explore medical learners' attitudes toward feedback's role in their development. The four domains can help guide further nuanced feedback research and application.[Box: see text].

Developing a programmatic approach to faculty development and scholarship using the ASPIRE criteria: AMEE Guide No. 165.

Faculty Development (FD) has become essential in shaping design, delivery and quality assurance of health professions education. The growth of FD worldwide has led to a heightened expectation for quality and organizational integrity in the delivery of FD programmes. To address this, AMEE, An International Association for Health Professions Education, developed quality standards for FD through the development of the AMEE ASPIRE to Excellence criteria. This guide uses the ASPIRE criteria as a framework for health professions educators who wish to establish or expand approaches to FD delivery and scholarship within their institutions.

The process of harmonizing competency-based curricula for medicine and nursing degree programmes: A Multi-institutional and multi-professional experience from Tanzania.

In many low- and middle-income countries, there seems to be a mismatch between graduate skills and healthcare industry requirements due to variability in curricula. With the current increased global demand for competent health profession graduates, harmonizing competency-based curricula (CBC) is necessary to address this mismatch. This paper describes how three health professions training universities in Tanzania and their two long-standing United States partners embarked on developing harmonized CBC for undergraduate medicine and nursing degrees. The main goal of the activity was to develop templates to harmonize curricula that would support graduates to acquire mandatory national Graduate Minimum Essential Competencies (GMEC) irrespective of the institution of their training. The paper describes the processes of engaging multiple institutions, the professions of medicine and nursing and various stakeholders to develop mandatory curricula generic competencies, creating milestones for assessing competencies, training faculty at each of the three partnering institutions in curriculum delivery and assessments, resulting in the adoption of the curricula by the University leadership at each institution. Ultimately the Tanzania Commission for Universities (TCU) a regulatory body required all schools of medicine and nursing in the country to adopt the curricula, thus creating a harmonized national standard for teaching medicine and nursing beginning October 2022.

Professionalism of Admitting and Consulting Services and Trauma Patient Outcomes.

OBJECTIVE: To determine whether trauma patients managed by an admitting or consulting service with a high proportion of physicians exhibiting patterns of unprofessional behaviors are at greater risk of complications or death. SUMMARY BACKGROUND DATA: Trauma care requires high-functioning interdisciplinary teams where professionalism, particularly modeling respect and communicating effectively, is essential. METHODS: This retrospective cohort study used data from 9 level I trauma centers that participated in a national trauma registry linked with data from a national database of unsolicited patient complaints. The cohort included trauma patients admitted January 1, 2012 through December 31, 2017. The exposure of interest was care by 1 or more high-risk services, defined as teams with a greater proportion of physicians with high numbers of patient complaints. The study outcome was death or complications within 30 days. RESULTS: Among the 71,046 patients in the cohort, 9553 (13.4%) experienced the primary outcome of complications or death, including 1875 of 16,107 patients (11.6%) with 0 high-risk services, 3788 of 28,085 patients (13.5%) with 1 high-risk service, and 3890 of 26,854 patients (14.5%) with 2+ highrisk services (P < 0.001). In logistic regression models adjusting for relevant patient, injury, and site characteristics, patients who received care from 1 or more high-risk services were at 24.1% (95% confidence interval 17.2% to 31.3%; P < 0.001) greater risk of experiencing the primary study outcome. CONCLUSIONS: Trauma patients who received care from at least 1 service with a high proportion of physicians modeling unprofessional behavior were at an increased risk of death or complications.

Understanding Contributors to Racial/Ethnic Disparities in Emergency Department Throughput Times: a Sequential Mixed Methods Analysis.

BACKGROUND: Ensuring equitable care remains a critical issue for healthcare systems. Nationwide evidence highlights the persistence of healthcare disparities and the need for research-informed approaches for reducing them at the local level. OBJECTIVE: To characterize key contributors in racial/ethnic disparities in emergency department (ED) throughput times. DESIGN: We conducted a sequential mixed methods analysis to understand variations in ED care throughput times for patients eventually admitted to an emergency department at a single academic medical center from November 2017 to May 2018 (n=3152). We detailed patient progression from ED arrival to decision to admit and compared racial/ethnic differences in time intervals from electronic medical record time-stamp data. We then estimated the relationships between race/ethnicity and ED throughput times, adjusting for several patient-level variables and ED-level covariates. These quantitative analyses informed our qualitative study design, which included observations and semi-structured interviews with patients and physicians. KEY RESULTS: Non-Hispanic Black as compared to non-Hispanic White patients waited significantly longer during the time interval from arrival to the physician's decision to admit, even after adjustment for several ED-level and patient demographic, clinical, and socioeconomic variables (Beta (average minutes) (SE): 16.35 (5.8); p value=.005). Qualitative findings suggest that the manner in which providers communicate, advocate, and prioritize patients may contribute to such disparities. When the race/ethnicity of provider and patient differed, providers were more likely to interrupt patients, ignore their requests, and make less eye contact. Conversely, if the race/ethnicity of provider and patient were similar, providers exhibited a greater level of advocacy, such as tracking down patient labs or consultants. Physicians with no significant ED throughput disparities articulated objective criteria such as triage scores for prioritizing patients. CONCLUSIONS: Our findings suggest the importance of (1) understanding how our communication style and care may differ by race/ethnicity; and (2) taking advantage of structured processes designed to equalize care.

Decompensation of cardiorespiratory function and emergence of anemia during pregnancy in a case of mitochondrial myopathy, lactic acidosis, and sideroblastic anemia 2 with compound heterozygous YARS2 pathogenic variants.

Myopathy, lactic acidosis, and sideroblastic anemia 2 (MLASA2) is an autosomal recessive mitochondrial disorder caused by pathogenic variants in YARS2. YARS2 variants confer heterogeneous phenotypes ranging from the full MLASA syndrome to a clinically unaffected state. Symptom onset is most common in the first decade of life but can occur in adulthood and has been reported following intercurrent illness. Early death can result from respiratory muscle weakness and cardiomyopathy. We report a case of MLASA2 with compound heterozygous YARS2 pathogenic variants; a known pathogenic nonsense variant [NM_001040436.3:c.98C>A (p.Ser33Ter)] and a likely pathogenic missense variant not previously associated with disease [NM_001040436.3:c.948G>T (p.Arg316Ser)]. The proband initially presented with a relatively mild phenotype of myopathy and lactic acidosis. During pregnancy, anemia emerged as an additional feature and in the postpartum period she experienced severe decompensation of cardiorespiratory function. This is the first reported case of pregnancy-related complications in a patient with YARS2-related mitochondrial disease. This case highlights the need for caution and careful counseling when considering pregnancy in mitochondrial disease, due to the risk of disease exacerbation and pregnancy complications.