The COVID-19 pandemic resulted in disruptions to medical school training and the transition to residency for new post-graduate year 1 resident-physicians (PGY1s). Therefore, the aim of this study was to understand the perspectives of United States PGY1s regarding the impact of the pandemic on these experiences. Our secondary aims were to understand how desire to practice medicine was impacted by the pandemic and whether PGY1s felt that they were able to meaningfully contribute to the COVID-19 response as students.We conducted a national, cross-sectional study of PGY1s who had recently graduated from medical school in 2020. A survey was distributed to PGY1s from across specialties, in programs distributed throughout the United States. It included questions about medical school training during the pandemic, impact on graduation timing and transition to internship, concerns about caring for patients with COVID-19, desire to practice medicine, and ability to meaningfully contribute to the pandemic. Findings are presented using descriptive statistics and univariate logistic regression models.p < 0.0001), the health or medical conditions of others in the home , and PGY1s with children  were more likely to report a decreased desire.1980 PGY1s consented to participate, 1463 completed the survey (74%), and 713 met criteria for this analysis. 77% of PGY1s reported that the pandemic adversely affected their connection with their medical school communities, and 58% reported that the pandemic impeded their preparation for intern year. 4% of PGY1s reported graduating medical school and practicing as an intern earlier than their expected graduation date. While the majority of PGY1s did not have a change in desire to practice medicine, PGY1s with concerns regarding personal health or medical conditions (OR 4.92 [95% CI 3.20–7.55] The COVID pandemic disrupted the social connectedness and educational experiences of a majority of PGY1 residents in a sample of trainees in United States training programs. Those with health concerns and children had particularly challenging experiences. As the current and subsequent classes of PGY1s affected by COVID-19 proceed in their training, ongoing attention should be focused on their training needs, competencies, and well-being.The online version contains supplementary material available at 10.1186/s12909-021-02777-7. The Coronavirus disease 2019 (COVID-19) pandemic has caused unprecedented disruptions to healthcare systems and exerted a profound effect on medical education and training . AlthougAfter medical school, in the United States, new doctors enter residency to further their training in their chosen specialty . The first year of residency is often termed internship. Trainees are categorized by their postgraduate year and new doctors in their first year of residency are referred to as post-graduate year 1 resident-physicians (PGY1s). Graduating medical students transitioning to residency and assuming new roles as PGY1s faced unique challenges. Some lost scheduled medical school opportunities designed to better prepare them for their internships, such as critical clinical rotations  or interDespite these disruptions, to our knowledge, there have been no studies to understand the unique experiences of these new doctors. Therefore, the goal of this study was to understand the perspectives of new United States PGY1s regarding the impact of the COVID-19 pandemic on their medical school training and transition to residency. Our secondary aims were to understand how desire to practice medicine was impacted by the pandemic and whether PGY1s felt that they were able to meaningfully contribute to the COVID-19 response as students.We conducted a national, cross-sectional survey of PGY1s at United States residency training programs who graduated from medical school in 2020.To assess the experiences of PGY1s who had recently graduated and transitioned to internship amidst the COVID-19 pandemic, we designed a voluntary and anonymous survey that was embedded within the ninth year of a longitudinal nationwide study of resident-physician schedules, safety, health and well-being . The stuWe followed a multi-pronged recruitment approach with the intent of reaching all graduating medical students who matched to a United States residency program. We contacted medical school deans, program directors, designated institutional officials, and affinity medical groups and requested they forward our email advertisements to their constituents. Potential participants who visited the website were able to read about the study and provide electronic consent. Participants received a $25 gift card for completion of the baseline survey and the four monthly surveys that were part of the parent study. They were also entered into a random drawing for a larger cash prize. On June 28, 2020 individual password-coded links to the baseline survey  were emailed to all PGY-1 s who consented to participate. The survey administration methodology has been extensively field tested and refined through its administration in prior years –18.The study population was defined as respondents who graduated medical school in 2020 in order to limit the analysis to those whose training experience was potentially altered by the COVID-19 pandemic. We excluded respondents who had not completed the survey by August 1, 2020 and those who did not answer the question querying the impact of the pandemic on components of their medical training. Descriptive statistics were used to characterize responses from the study sample. The distribution of continuous variables was assessed to determine the most appropriate descriptive presentation. Impact of the COVID-19 pandemic on components of medical school training, change in desire to practice medicine, and satisfaction with ability to respond to the pandemic were collected using 5-point Likert-type scales , April 13/713 residents (1.8%), May 11/713 residents (1.5%), June 8/713 residents (1.1%)). The breakdown of what was included in scheduled clinical experiences is displayed in Fig. Only 5.5% (39/713) of respondents reported caring for patients with diagnosed or suspected COVID-19 as a medical student. Of those, 50% reported doing so as part of their medical school curriculum and 50% as part of a voluntary experience.21% (151/711) of PGY1s reported graduating medical school earlier than their expected graduation date. However, of those, only 21% (31/151), which reflects 4% of the entire study population, reported receiving a license and practicing as an intern before their expected residency start date. Of the 31 respondents that reported graduating early and practicing as an intern before their expected residency start date, 77% practiced only at a site affiliated with their medical school, 7% practiced only at a site affiliated with their future residency program, and an additional 7% practiced both at a site affiliated with their medical school as well as a site affiliated with their future residency program.The majority of respondents reported a combination of virtual and in-person activities during their PGY1 orientation . Despite the logistical challenges, 86% (613/712) reported being able to be certified in all required life support training . 77% of respondents reported receiving formal training/education in Personal Protective Equipment (PPE). Despite the training, at the time of survey completion (during the first month of residency), only 37% (264/713) reported feeling very or extremely competent in its use.Concerns about taking care of patients with COVID-19 secondary to either a personal health or medical condition  or that of someone living in their home  were fairly common. These respondents reported a variety of schedule modifications listed in Table p < 0.0001) or the health or medical conditions of others in the home (OR 4.41 ) were more likely to report a decreased desire to practice medicine. This was also true for residents with children . Resident-physicians specializing in internal medicine did not have a decreased desire to practice medicine as compared to other specialties . No other demographic factors listed in Table The majority of respondents did not have a change in desire to practice medicine as a result of the pandemic  with a relatively equal number of residents reporting an increased desire  and a decreased desire . Residents with concerns regarding personal health or medical conditions (OR 4.92 [95% CI 3.20–7.55] n = 39) as part of their medical school experience were no more likely to report satisfaction with their ability to contribute . However, respondents who graduated and practiced as an intern early (n = 31) were more likely to report satisfaction with their contribution .More than half of all respondents reported being not at all or only somewhat satisfied  with their ability to meaningfully contribute to the COVID-19 pandemic. Respondents who cared for COVID-19 patients (The transition from medical school to internship is a critical milestone for physicians. We found that most activities surrounding this transition were altered by the COVID-19 pandemic, including disruptions to clinical activities, graduation, and onboarding. Additionally, we found that PGY1s perceived the COVID-19 pandemic to have an unfavorable impact on most aspects of medical school training and that many were not fully satisfied with their ability to meaningfully contribute to the pandemic. Governing bodies  and mediSelf-determination theory postulates that the three basic needs of autonomy, competence and relatedness are necessary to stimulate and sustain intrinsic motivation . Our stuIn order to ensure the safety of health care professionals and residents during the pandemic, it is critical they are trained and competent in the use of PPE . Our stuAlthough it is reassuring that the majority of PGY1s did not have a change in their desire to practice medicine, certain populations were differentially affected. Amidst school and daycare closures, parents across the country have been forced to negotiate between their roles at work and at home. This is a particular challenge for resident-physicians who often work irregular schedules and up to 80 h per week, with limited flexibility to work from home . Thus, iGiven that our study cohort included only a fraction of all PGY1s in the United States, a potential limitation is nonresponse bias. However, we are reassured that the demographic characteristics of our participants are comparable to national demographic characteristics. It is also possible that respondents to this survey were not representative of PGY1s nationally in ways that we did not assess. The advertised topic of the study was schedules, safety, and well-being. Because this secondary topic of COVID-19 medical school experience and transition to residency was not mentioned on the study website, it likely did not attract those with heightened interest in this topic, further mitigating the risk of nonresponse bias. Additionally, for some questions, PGY1s were asked to recall events from several months earlier, potentially resulting in recall bias. However, we attempted to minimize this bias by excluding participants that completed the survey after August 1st. Lastly, the experiences of PGY1s in the United States may be different than the experience of PGY1s in other countries worldwide which may impact generalizability. Nevertheless, the geographically diverse sample and the themes represented in this analysis have important implications for medical school training and transition to residency as we continue to face uncertainty about the future amidst the COVID-19 pandemic and in anticipation of future pandemics.Future studies should focus on continuing to understand the experiences of medical students and new residents as the pandemic and the response to the pandemic continues to evolve. Additional studies should focus on whether objective competence of graduating medical students has been impacted by the pandemic.This study identifies the multiple ways in which the transition to internship among PGY1s was impacted by the COVID-19 pandemic. As the pandemic continues, it is prudent to monitor the experience of resident-physicians and to continue to identify opportunities to improve the experience for future medical students and new resident-physicians. These lessons could also inform responses to future pandemics.Additional file 1:. Supplemental content: survey questions


Sensory modulation difficulties are common in children with conditions such as Autism Spectrum Disorder (ASD) and could contribute to other social and non-social symptoms. Positing a causal role for sensory processing differences requires observing atypical sensory reactivity prior to the emergence of other symptoms, which can be achieved through prospective studies.In this longitudinal study, we examined auditory repetition suppression and change detection at 5 and 10 months in infants with and without Neurofibromatosis Type 1 (NF1), a condition associated with higher likelihood of developing ASD.In typically developing infants, suppression to vowel repetition and enhanced responses to vowel/pitch change decreased with age over posterior regions, becoming more frontally specific; age-related change was diminished in the NF1 group. Whilst both groups detected changes in vowel and pitch, the NF1 group were largely slower to show a differentiated neural response. Auditory responses did not relate to later language, but were related to later ASD traits.These findings represent the first demonstration of atypical brain responses to sounds in infants with NF1 and suggest they may relate to the likelihood of later ASD.The online version contains supplementary material available at 10.1186/s11689-021-09364-3. Autism Spectrum Disorder (ASD) is characterised by difficulties in social communication and restrictive and repetitive behaviours . A ranIdentifying causal pathways to symptom emergence requires prospective longitudinal studies of infants with an elevated likelihood of developing ASD. One common approach has been to study infants with an older sibling with ASD , 84, 91.A complementary approach to familial designs is thus to study infants who have an elevated likelihood of developing ASD due to the presence of a monogenic disorder that can be identified in infancy. A strong candidate monogenic condition associated with ASD is Neurofibromatosis Type 1 (NF1), an autosomal dominant neurocutaneous disorder with a birth incidence of 1:2700 . Fifty pNF1 is a suitable monogenic condition for studying early developmental pathways to ASD for several key reasons. First, the phenotypic profile of ASD in NF1 is broadly similar to idiopathic ASD , with a One promising domain of investigation in infants with NF1 is low-level auditory processing. Important to pathways to translational research, auditory paradigms can be meaningfully reproduced across the lifespan and in animal models , 99 whern = 75) scored lower on a phoneme deletion task, indicating impaired phonological processing. However, there has been no work on early auditory development in infants with NF1, and no efforts to examine the relationship between auditory processing and the presence of ASD within the sample.Previous work has indeed identified alterations in auditory responses in children with NF1. A study of 22 children and adults with NF1 found that while peripheral acoustic hearing was within the normal range, differences emerged in temporal auditory processing during standardised tests, including phonological processing and temporal resolution . DifficuOne common method that has been used to measure responses to auditory repetition and change in the developing brain is electroencephalography, or EEG. EEG is suitable for infants and children of all ages because it is relatively non-invasive and does not require verbal or behavioural responses. The high temporal resolution of EEG also allows it to accurately capture the time-course of neural correlates of auditory processing. EEG studies have shown that neural responses to auditory stimuli decrease with repetition and that the magnitude of this effect increases with age . A relatAnother fundamental feature of low-level auditory processing is the ability to detect when changes occur in a sequence of repeated tones. The mismatch negativity is a frontocentral negative deflection in an event-related waveform, elicited by subtracting responses to an infrequent “deviant” from a repeatedly presented “standard” tone , 63, 96.In the current study, we examined age-related changes in auditory repetition suppression and change detection responses in infants with typical development (TD) and those diagnosed with NF1. We assessed infants at 5 and 10 months, which is a sensitive period for auditory development, as well as the comprehension and production of speech , 111. FuIn the typically developing population, we expected a clear reduction in response between repetition of the first and second standard vowel sound at 5 and 10 months of age. We additionally expected a stronger change detection response (increased ERP negativity) towards pitch change at 5 months, and towards Vowel category change at 10 months, to reflect increasing specialisation to language processing . FurtherWe recruited 25 infants with NF1 and 52 typically developing (TD) infants into a longitudinal study running from 2013 to 2019. Some NF1 infants missed the 5-month entry point and entered at 10 months due to delays with families receiving the diagnosis (expert consultations take longer to be scheduled and attended). Infants were enrolled in the study if they either had Neurofibromatosis Type 1 or were typically developing. EEG was collected at 5 and 10 months, and a range of phenotypic measures were collected at a 14-month follow-up visit. We defined typical development (TD) as infants who had no first-degree relatives with a diagnosis of ASD or ADHD, with parents reporting no developmental concerns. These TD infants were recruited from a volunteer database at the Centre for Brain and Cognitive Development, Birkbeck, University of London. Inclusion criteria included full-term birth . At the time of enrolment, none of the infants in this cohort had a known medical or developmental condition. Participants in our NF1 cohort were recruited through local medical and genetic centres. All participants had their diagnosis confirmed via molecular testing of cord blood samples or clinical diagnosis based on NIH consensus criteria  and had Informed written consent was provided by the parent(s) prior to the commencement of the study. The testing only took place if the infants were in a content and alert state. Ethical approval was granted by the National Research Ethics Service and the Research Ethics Committee of the Department of Psychological Sciences, Birkbeck, University of London. Participant families were reimbursed expenses for travel, subsistence and overnight stay if required. Infants were given a certificate and t-shirt after each visit.n = 15 and 3 at the 5- and 10-month time points respectively), noisy data (n = 4 and 4 at the 5- and 10-month time points respectively) or technical difficulties with the EEG protocol (n = 2 and 1 at the 5- and 10-month time points respectively) , as this does not affect the strength of the responses observed , were greater over the left area ; and varied over the waveform , with pairwise comparisons indicating greater change in amplitude between 5  and 10 months of age  in the TD group  than in the NF1 group ; Bonferroni corrected to p = .013.Responses decreased with Age , and varied across the waveform with the most pronounced difference between conditions around 200ms  = 10.71, p < .001, ηp2 = .03]) and were greatest over right areas .Amplitudes slightly decreased with Age at trend level  and changed over the waveform with the most pronounced difference between conditions around 200ms . Age effects varied by Group , with decreasing effects of repetition on the neural response in the TD group between 5  and 10 months  ; responses in NF1 group did not change  ; Bonferroni corrected to p = .013.Amplitudes were greater over central areas . Responses did not vary by Group .Amplitudes slightly decreased with Age at trend level , were greater over central than lateral regions ; and varied over the waveform such that differentiation between conditions was greater around 200ms   and 10 months  in the TD group ; responses in the NF1 group were largely stable ; Bonferroni corrected to p = .013.Amplitudes slightly decreased with Age at the trend level ; and varied over the waveform such that the difference between conditions was most pronounced around 300ms ; Fig. p = .44, ηp2 = .01].Responses were greater over the left areas ; and varied over the waveform such that the difference between conditions was most pronounced around 200-300ms ; Fig. p = .61, ηp2 = .003].Responses were greatest over central areas ; Fig. p = .001, ηp2 = .005].Responses varied over the waveform such that the difference between conditions was most pronounced around 150ms and 300ms ; and varied over the waveform such that the difference was most pronounced around 100ms ; Fig. p = .01, ηp2 = .003; with number of trials retained covaried F = 12.07, p = .001, ηp2 = .005], with pairwise comparisons demonstrating the response to pitch becoming more positive than to vowel between 5  and 10 months  in the TD group ; responses in the NF1 group changed in the opposite direction ; Bonferroni corrected to p = .013.Responses were greatest over central areas , no effect of Group  and no interaction of Group by Age .To consolidate our predictor variables, we examined relations between factor scores  and later development. Of note, we also conducted LMMs on our factor scores  with the following fixed factors: Age  and Group . The repeated covariance type was set as ‘compound symmetry’ and the maximum likelihood estimate was used for the model. We found no significant effect of Age  or Language Production composite scores . Interestingly, when examining the language subscales individually, we found that increased Initial Response/Change to the Standards at 10 months was associated with better Receptive Language scores on the MSEL at 14 months; however, this should be treated with caution given the multiple comparisons  as well as more ASD traits as measured on the AOSI   = .49, p = .12]. When controlling for AOSI Raw Score, the relationship between Initial/Change Response to Standards at 10 months and IBQ-R Activity Level became non-significant with a much reduced effect size, though it is important to note the small sample size . As such, the Initial Response/Change to Standards factor at 10 months seems to be more closely related to early ASD traits. Further analyses split by brain region and condition indicated that the associations with the AOSI were broadly present for both the initial response to the standards and repetition suppression to the second standard across both frontal and posterior areas of the brain (SM5).In order to scrutinise whether the neural response was more related to ASD or ADHD traits, we conducted two partial correlations. When controlling for IBQ-R Activity Level, the relationship between the Initial Response/Change to the Standards at 10 months and AOSI Raw Scores dropped to a trend level though still with a strong effect size [This is the first study to examine the neural correlates of auditory processing in infants with NF1. Results showed that infants with NF1 are able to discriminate between different auditory stimuli (e.g. they are able to detect auditory repetition and detect auditory stimulus change). However, response profiles differed between the groups. Whilst effects over posterior regions decreased in magnitude between 5 and 10 months of age in typically developing infants , this developmental change was less pronounced in the NF1 group. Further, typically developing infants largely differentiated stimulus repetition or change earlier in the waveform than the NF1 group over frontal (but not posterior regions), suggestive of processing delays in infants with NF1. Individual differences in these neural responses did not relate to Language Comprehension or Expressive Language, but did relate to early ASD and ADHD-related behaviours.Both our NF1 and TD cohorts showed suppression of the neural response to Standard 2 relative to Standard 1. Given our paradigm, the effects of repetition likely reflect both sensory gating and fast-decay forms of habituation. Sensory gating refers to the suppression of a neural response to a rapidly repeated stimulus and has been observed as early as 50ms after auditory stimulus onset in infants aged between 1 and 4 months , 52, 57.The topography and timing of the effects of repetition were however different between infants with and without NF1. Specifically, over frontal regions, repetition suppression emerged later in the waveform for the NF1 than TD group at both ages. However, the pattern was different over posterior regions. Whilst at 5 months the TD group were again faster to detect repetition than the NF1 group over posterior regions, at 10 months, the NF1 group were faster. Further, the linear mixed models showed developmental decreases in the repetition effect over posterior regions between 5 and 10 months in the TD group but not the NF1 group. We believe these patterns of neural response to be demonstrative of less mature  repetition detection. Specifically, we posit that there is a shift in the topography of the neural response in typical development from a more global to a more localised fronto-central mature profile. This is evidenced by both the diminishing effect of suppression with age in the linear mixed model analyses over posterior regions in the TD group; and the suppression effect happening faster at 10 months than 5 months over frontal areas in the TD group, whilst the suppression effect doesn’t change in timing over posterior regions. This profile is altered in the NF1 group. This group does not show changes over posterior regions in the magnitude of the suppression effect and show a faster suppression effect across both frontal and posterior regions at 10 than 5 months. The pattern of these changes suggests that activity was becoming more frontally focused in the TD but not the NF1 group, reflecting a more mature topographic profile. Of note, this pattern of repetition suppression was specific to the change between the first and second standards; there were no group differences in responses to Standard 2 versus Standard 3 (SM1). This could indicate specificity of these differences to more rapid forms of suppression; however, it is important to note the limitation that the Standard 2/Standard 3 comparison may be affected by preparatory responses during the third standard .The magnitude of the response to the first stimulus and the degree of suppression to the second stimulus were associated with later behavioural traits of ASD (measured with the AOSI). Although significant associations were initially seen with a PCA-formed composite of EEG repetition measures that did not itself vary by age or group, we also saw associations with responses to the first standard and the Standard 1-Standard 2 change over frontal and posterior scalp regions analysed separately. The AOSI predicts later ASD relatively well , 38, butOne note of caution is however that our results are not necessarily specific to later ASD symptoms. In the present dataset, we also observed an association between responses to the first and second stimuli and later ADHD-related traits . Both changes produced characteristic fronto-central negative deflections, as well as positive-going deflections over posterior regions. For the change in pitch, the TD group showed a stable differentiation over fronto-central regions but a diminishing differentiation over the posterior cortex between 5 and 10 months. Further, the differentiation occurred earlier in the waveform over frontal regions at 10 than 5 months, but did not change over posterior regions. Again, this is potentially reflective of the emergence of the mature fronto-centrally focused MMN component in the TD infants. Previous research with adults has shown that the auditory MMN response is predominantly observed over the auditory cortex with some recruitment of the frontal and parietal regions  are processed in terms of probability rather than surface features. Interestingly, this was only seen in our TD group, which suggests alterations in the way the NF1 group detect changes in deviant categories. Consistent with this hypothesis, in the LMM, analyses examining the posterior region indicated that whilst the response to pitch was greater than to vowel by 10 months in the TD group, progression moved in the opposite direction for the NF1 group. Again, this may be consistent with a reduction in sensitivity to vowel change over posterior cortex with age in typical infants, with a movement to the more neurotypical fronto-central distribution,A further avenue of research would be to investigate auditory processing in younger infants. Our present results are consistent with the NF1 group showing less mature auditory processing. As such, future research could study auditory processing in the first 2 years of life to map the protracted developmental trajectory of repetition and change detection. Additionally, the paradigm is easily adaptable to be used with other sensory modalities (e.g. the tactile domain) in order to determine if atypicalities in sensory processing are domain general or are specific to within a sensory system. Indeed, this may be a particularly pertinent area of investigation given the sensory sensitivities related to touch within the ASD literature , 33.When examining the relationship between auditory processing and later development, we did not find a correlation between the neural response and either composite scores for Language Production or Language Comprehension. A possible explanation for this lack of relationship could be due to the age at which we were measuring language skills. It may be that 14 months of age is perhaps too young to get an accurate representation of language development, especially in terms of expressive language, and it may be more fruitful to examine this relationship later in development (e.g. toddlerhood). Other studies have found associations between neural responses to vowel or pitch change and language development , 101. AlFurther research in this area could be translational in nature. Auditory paradigms, in general, lend themselves to being used translationally with a wide range of species (both asleep and awake) due to the passive nature of the task. Non-human animal models have been particularly informative in NF1 research , 43, 103Further to the use of the current paradigm with animal participants, if replicated the task could also potentially be used in a battery of screening measures for infants at elevated likelihood of developing neurodevelopmental disorders such as ASD or ADHD. With the relative ease and accessibility of EEG as a methodology, and the particular ease of the task with infant populations, it would be feasible to use the measure with infants even in the neonatal period. Additionally, the nature of the task also means that it is possible to administer with older populations, which would allow for more frequent evaluations and detailed longitudinal comparisons. Whilst the current task used very short, simple phonemes that infants may not have recognised as language components, it would be possible to incorporate more complex language stimuli to tease apart low level auditory processing and language processing. Finally, to further test the hypothesised shift from posteriorly to frontally focused neural activity, future avenues of research may be inclined to co-register fMRI and EEG for source analyses. This may allow greater mechanistic insights into the neural systems that underpin the scalp-level changes apparent in the present study.We present the first evidence of atypical neural correlates of auditory processing in infants with Neurofibromatosis Type 1. We found that infants with NF1 showed slower neural detection of repetition or change, and diminished developmental change in the scalp profile of neural responses. Whilst auditory responses were not related to later language development, an increased neural response to an initial auditory stimulus was related to more ASD-relevant behaviours at 14 months. Taken together, this auditory neural response may indicate alterations in early sensory processing and specialisation that could provide valuable options for developmental screening within groups of infants with NF1.Additional file 1.


Background and objective: There is a general clinical concern on the negative impact of obesity on surgical complications and functional outcomes. We hypothesized that the patients with morbid obesity are exceptionally prone to a significantly increased risk for surgical and short-term complications after primary total hip arthroplasty (THA). We aimed to identify the range of Body Mass Index (BMI) values of patients with a significant risk for lower functional improvement after THA. Materials and methods: In Stage 1 of the study, we conducted a retrospective comparative analysis of the rate of complications and functional outcomes in patients treated by primary THA, with normal weight  vs. Class 1 , Class 2 , and Class 3  obese patients. After the statistical similarity rates of complications and 6- and 12-month functional outcomes (by Harris Hip and SF-36 scores) were revealed in Class 1 patients and patients with normal BMI, we conducted the Stage 2 prospective study, by the same comparison protocol, on the cohorts of Class 2 (N = 29) and Class 3 (N = 16) patients compared to the Class 1 patients (N = 37) as controls. Results: Stage 1: There was no difference in surgical complications and function on 6- and 12-month postoperative follow-up  between Class 1 and patients with normal BMI (p > 0.05). Surgical complications were significantly higher in Class 2 (p < 0.05) and Class 3 (p < 0.001) patients. Functional activity on the 12-month follow-up increased significantly in all study groups, but in the Class 3 patients, the functional parameters were significantly lower (0.001). The mental health status on the follow-up was similar in all study groups. Stage 2 study revealed similar to the retrospective study comparison of parameters, except for the significantly lower mental health scores in Class 2 and Class 3 patients (p < 0.05) and functional scores in Class 3 patients (p < 0.05). Conclusion: Although the functional ability increased in all patients, it was significantly lower in Class 3 patients (with morbid obesity). Therefore, the patients with Class 1 and Class 2 obesity should be conceptionally distinguished from Class 3 patients in the decision-making process for a primary THA because of the less favorable functional and mental health improvement in those with morbid obesity (Class 3). Primary total hip arthroplasty (THA) in patients with morbid obesity is a technically demanding surgical procedure, with substantial risks for early and late postoperative complications ,2.There is published evidence that following THA in obese patients, there is an increased risk for postoperative complications , but thiStudies on long-term prosthesis survivorship and the risk for revision surgery after THA in obese patients have shown that over five years postoperatively, obese patients required revision surgery about 60% more often than patients with an normal weight .Naturally, the uncertainty about the significance of obesity as a risk factor for THA failure should be resolved because this factor can affect the preoperative decision-making process when a bodyweight factor potentially contradicts the clinical necessity for THA. The recommendation has to be based on reliable clinical data, especially in light of the foreseen improvement in postoperative ambulation that might partly resolve the overweight in a sedentary person due to a painful hip.According to these considerations and our previous clinical observations, we hypothesized that only patients with morbid obesity are expected to suffer from considerable peri- and postoperative complications after primary THA. Therefore, the purpose of this study was to identify the impact of morbid obesity on THA outcome by detecting the range of BMI values of patients with a risk for lower functional improvement after THA.2; Class 2—35.00–39.99 kg/m2; Class 3 (morbid obesity) ≥ 40 kg/m2 [Two experienced senior orthopedic surgeons did all the surgeries. To narrow the margins of the significant effect of obesity on the surgical outcome, we subdivided the study group patients according to World Health Organization classification of obesity severity, i.e., according to the BMI values: Class 1—30.00–34.99 kg/m40 kg/m2 .We executed this study in two stages. Initially (Stage 1), we aimed to consolidate our clinical impression on the effect of obesity on THA outcome by reviewing the retrospective data on the already treated patients. Then (Stage 2), we have investigated the same parameters by a prospective controlled study. The study was approved by the Institutional Ethical Committee , all the patients signed the informed consent form. ®, Warsaw, IN, USA, or DePuy®, Paramount Drive, MA, USA). These prostheses have similar designs for cementless implantation. The prostheses implantations were performed via the standard anterolateral surgical approach to the hip joint. The perioperative management of patients, surgical technique and type implant, and postoperative and rehabilitation protocols were similar. All the evaluated patients were surgically treated for hip joint osteoarthritis , characThe lengths of the surgeries, perioperative blood loss (expressed by the hemoglobin levels and rate of blood transfusions), early postoperative wound infections , periprosthetic fractures and joint dislocations, neural surgical damage, and early aseptic loosening  of the iThe functional activity in all patients was recorded preoperatively and at 6- and 12-month follow-ups by the Harris Hip Scale (HHS) . The hipIn the study period (2010–2015), 2750 patients were treated by the primary THA. In the five years of the postoperative period, 31 patients died (for the unrelate to this surgery reasons), and additional 834 patients were unavailable for the follow-up. Therefore, in the retrospective analysis, we studied the records of 1885 consecutive patients  after primary THA (operated between 2010–2015). The study group included 1205 patients with average body mass index (BMI) and 680 patients with various degrees of obesity . These p2) patients  requires at least 65 patients ,13. The The results are presented as average values with indication of standard error of mean (SEM).t-tests compared the normally distributed continuous variables for unpaired variables, a paired t-test for paired (matched) variables, and a one-way ANOVA for more than two variables. We compared nonparametric data using the Mann–Whitney test. For all statistical tests, we set the level of statistical significance at p < 0.05.The Chi-square test and Fisher′s exact test (when over 25% of cells had less than five cases) were used in comparing categorical data. Independent We used the SPSS Statistics 22.0 statistical software . p = 0.68). Surgery time in patients with Class 2 and 3 obesity was significantly longer in comparison to the patients with normal BMI .The surgery time was similar for patients with Class 1 obesity and patients with a normal BMI . Twenty-four hours postoperatively, we found a significantly higher drop in hemoglobin content in Class 2 and Class 3 patients in comparison to the patients with normal BMI , without significant difference among Class 1 patients in comparison to the non-obese patients. Similarly, the rate of the requirement for allogenic erythrocyte transfusions was significantly higher in Class 2, and Class 3 patients in contrast to patients with normal BMI , and there was the same blood transfusion rate in Class 1 and non-obese patients.There was no difference in the preoperative blood hemoglobin levels . There was no significant difference in scores′ profiles of Class 1 and 2 patients compared to the patients with normal BMI . The normal BMI patients′ group exhibited significantly better dynamics of improvement in the physical constituent of health a year after surgery in comparison to Class 3 patients  and Class 1 obesity (0.25%), with considerably higher and rising rates from the Class 2 up to the Class 3 patients . The rates of postsurgical infections , prosthesis dislocations, thromboembolic and neurological complications were 2–3 times higher in patients with Class 2 and Class 3 obesity in comparison to patients with Class 1 obesity and normal BMI  but was not different in comparison to patients of the Class 2 group (p = 0.06). The length of the surgery in the Class 3 patients was significantly longer (in 26%) than in patients of the Class 1 group (p = 0.558). Twenty-four hours postoperatively, we found a significantly higher drop in hemoglobin content in Class 3 and Class 2 patients than the Class 1 patients ). There was no significant difference in the required rate for allogeneic erythrocyte transfusions in Class 1, Class 2, and Class 3 patients . There was no difference in the preoperative blood hemoglobin levels in all patients  and at the shorter six-month follow—up .Preoperatively there was no significant difference in HHS scores among all the groups of patients , but these scores were significantly lower in comparison to Class 1  compared to considerably higher and rising rates from the Class 2 to the Class 3 patients  range in relation to the highest probability of increased surgical and postsurgical complications. Recent large scale systematic review  intendedThe results of the present study substantiate this important but previously unresolved concern. In the Stage I retrospective large-scale study, we clearly show that the Class 1 patients are identical in the prediction of perioperative and short-term complications with patients with normal BMI . AccordiAs hypothesized, the Class 3 morbidly obese patients have a significantly higher rate of perioperative complications and decreased functional abilities . However, since these patients improved in their function to some extent following the surgery and their mental health scoring  reflected similar to the not obese  patients improvement at 12-month follow-up .Thus, we clearly showed the difference in perioperative complications rate and short term postoperative function ability between Class 2 and Class 3 patients that indicates the necessity for the different preoperative decision-making processes, with a clear indication that mildly obese Class 1 patients (below BMI of 35) should be treated as patients with normal BMI.The Stage 2 study was designed to consolidate these results by evaluating the observed perioperative and short-time follow-up difference in Class 2 and Class 3 patients′ surgical outcomes by implementing similar to the Stage 1 study protocol, prospectively.The main finding of this study, according to the prospective study results that substantially support the indication from the retrospective study, is a significant difference in the rate of surgical complications and functional ability, at the 12-month follow-up, with more favorable outcomes in Class 2 patients vs. Class 3 patients. Interestingly, as opposed to the Stage 1 study, the mental health scores were similarly reduced in both groups, and there was no increase in blood transfusion rates in both groups. However, in both, there was significantly higher blood loss. The later facts might be attributed to the recent more conservative approach for blood transfusion indications  and higher expectations for functional improvement in the later period of the prospective study.Therefore, because there is an apparent difference in complications and outcomes between Class 2 and Class 3 patients and the preoperative weight reduction in obese patients is a highly complicated process, the necessity of preoperative attempts for weight loss should be directed primarily to the Class 3 patients with morbid obesity. The Class 2 patients, although they should be encouraged to lose weight, should not be rejected for the primary THA only based on the obese weight, because the significantly improved ambulation ability that is expected after the surgery might facilitate the weight loss and subsequentially reduce the risk of prosthetic wear due to high body weight. Unfortunately, this argument is less implacable to patients with morbid obesity (Class 3); therefore, these two groups of obese patients should be distinguished at the preoperative decision making. The main limitation of this retrospective (Stage 1) study is the 31% rate of patients available for the follow-up, but this relative disadvantage is “compensated” by the results of the prospective (Stage 2) study that shows substantially similar results. Additional important limitation is the inherent bias of the scoring recordings at the follow up.From these studies, substantial conclusions can be raised. Patients with a BMI up to 35 should be considered to have the lowest rate of perioperative complications and are expected to have favorable short-term functional and mental outcomes. Patients with BMI above 35 have an increased risk for perioperative complications, but this risk is much higher and distinguishable in Class 3 morbid patients (BMI above 40). Although an increase was observed in all patients, the functional outcome improvement after THA is significantly lower in Class 3 patients.


The genetic makeup of Indigenous populations inhabiting Mexico has been strongly influenced by geography and demographic history. Here, we perform a genome-wide analysis of 716 newly genotyped individuals from 60 of the 68 recognized ethnic groups in Mexico. We show that the genetic structure of these populations is strongly influenced by geography, and our demographic reconstructions suggest a decline in the population size of all tested populations in the last 15–30 generations. We find evidence that Aridoamerican and Mesoamerican populations diverged roughly 4–9.9 ka, around the time when sedentary farming started in Mesoamerica. Comparisons with ancient genomes indicate that the Upward Sun River 1 (USR1) individual is an outgroup to Mexican/South American Indigenous populations, whereas Anzick-1 was more closely related to Mesoamerican/South American populations than to those from Aridoamerica, showing an even more complex history of divergence than recognized so far. Indigenous populations, including in those in Mexico are underrepresented in genetic studies. Here, the authors perform a population genetics study of indigenous peoples in Mexico to explore demographic histories of the region in the context of geography and cultural influences. There has been great interest in understanding the genetic structure of Native American populations, partly because studying these populations has been helpful in elucidating aspects of the global dispersal of modern humans6. Today, the 68 recognized ethnic groups in Mexico are clustered into 11 linguistic families7, with unique customs and cultures. These populations can be divided into two main geographic/cultural areas: Mesoamerica and Aridoamerica. Mesoamerica comprised central and southern Mexico, and during the pre-Hispanic era was inhabited by sedentary agricultural societies favored by the great biodiversity of this region. Aridoamerica encompassed a semiarid area in northern Mexico that preserved nomadic forms of subsistence throughout the pre-Hispanic era.Mexico has long acted as a natural bridge for human migration from North America to Central and South America and vice versa. Together with historical events, these movements have been crucial in shaping the genetic makeup and structure of populations in the Americas8. Therefore, key questions about the genetics of Mexican Indigenous populations remain unsolved.Despite being one of the largest and most diverse groups in America, the Mexican Indigenous populations are still underrepresented in terms of the number of genotyped individuals and geographic regions sampled. To the best of our knowledge, few Mexican ethnic groups have been examined at the genome-wide level, yet a complex genetic structure has been observed in such groups11, which were merged with previously published data sets, yielding a total of 1086 Native Americans from Mexico, representing all linguistic families except Kickapoo (Algonquian language family)  cohort12, including Mexican Native American populations previously reported by Reich et al.8, Moreno-Estrada et al.2, and Silva-Zolezzi et al.12. The merged data set comprised 3490 individuals from 218 populations and 61,393 autosomal SNVs. Principal component analysis (PCA)13 indicated that Mexican Indigenous populations clustered with other Native American groups from North and South America  with 146 previously published populations worldwide15 in each data set, except for Reich et al.8 data set as detailed in the “Methods” section. Non-Native ancestry tracks were masked in the individuals from Indigenous populations, and the masking accuracy was assessed by running the admixture analyses again assuming K = 4 clusters  and Lacandon (Southeast)2, had the highest levels of genetic differentiation when compared with the other populations based on this statistic  tree based on the pairwise-ion Fig. . The NJ ion Fig. .14 using K = 2–16 clusters . On the other hand, two of the clusters were mainly observed in several ethnic groups inhabiting the Center and South (here referred to as multi-ethnics), principally in populations from the Oto-mangue linguistic family, and the other cluster in populations from the Southeast that are part of the Mayan linguistic family. We observed that the multi-ethnic and Mayan components had opposite gradients, where the Mayan component was the most prevalent in the Southeast and the multi-ethnic components were more prevalent in the Center and South of Mexico  across time based on two different methods. We included 48 ethnic groups from the masked data set, all of them with sample sizes of at least 10 individuals  tracks implemented in the IBDNe software19. We observed a decline in the Ne between 15 and 30 generations ago in all tested populations that overlaps with the beginning of the European colonization of the Americas, followed by an expansion , which is similar to previous findings21. However, here we documented a variation in the long-term Ne between ethnic groups . Other ethnic groups had a long-term Ne between 1825 and 3331 individuals . As expected, the Seri and Lacandon groups had the highest proportion of the genome in ROH compared to the other populations tested, suggesting that the high genetic differentiation observed in these populations is due to genetic drift as previously reported2  assuming a clean split between them. To scale T in years, we assumed 28 years per generation25. Seri and Lacandon populations have the highest T values compared to other populations   or large (>10 cM) shared IBD blocks revealed possible spatiotemporal interaction dynamic patterns among indigenous groups. Intermediate IBD block sizes are suggested to be dated to 500–1500 years ago (oldest), while large tracks are thought to be originated 0–500 years ago (youngest)Analysis of intermediate block sizes revealed that the Central East, South, and Southeast regions have older connections among them than do the northern regions 29 individuals with our data from the most representative sample of Indigenous peoples in the Mesoamerican and Aridoamerican regions of Mexico to date. First, we compared the ancient genomes with 59 worldwide populations and 325 individuals from our data set with at least 99% Native American ancestry . This analysis showed a high affinity of both ancient genomes with present-day Mexican Indigenous samples  using the Ancient Southern Ontario population Canada_Lucier31 and Athabaskan32 ancient genomes as representatives of NNA/ANC-B ancestry. We found these results to be consistent with D ~ 0, suggesting that the NNA/ANC-B populations are an outgroup for those from Aridoamerica and Mesoamerica from Mexico . We found that Mesoamerican populations share more alleles with Aridoamerica than Anzick-1 shares with Aridoamerica , where the ancient samples were either USR1 or Anzick-1, and the South American samples were either Karitiana or Aymara. We also included the Tzotzil population as an internal control. When USR1 was used to represent the ancient population, we did not observe any significant deviation from zero in any of the tests  when Karitiana and Tzotzil were used in the comparison, we observed a similar trend when Aymara was used in the test 29, and that a split ~15 ka years ago in the far North led to the northern (NNA/ANC-B) and southern (SNA/ANC-A) population branches in the Americas29. The SNA/ANC-A branch includes the ancestors of the Clovis child (Anzick-1) and all Indigenous peoples from Mexico to South America28. Nevertheless, the complex genetic structure observed in Mexican Native populations in this study, as well as the intricate series of migrations into South America identified in two other recent studies58, suggest that the history and ancestry of Indigenous populations in Mexico may be more complex than reported.On the other hand, studying ancient genomes has been helpful to elucidate ancient population relationships and migration patterns. In the last few decades, an increasing body of evidence has suggested that the peopling of the Americas brought at least four distinct streams of migration from Asia, beginning as early as ~23 ka ago29, and that the Mexican Indigenous populations experienced one of the following scenarios: (1) a split between Aridoamerica and Mesoamerica occurred prior to the split between Mesoamerica and Anzick-1 with posterior gene flow between the Aridoamerican and Mesoamerican populations, or (2) a split between Aridoamerica and Mesoamerica occurred after they split from the Anzick-1, with Aridoamerican populations carrying gene flow from a population that split above the population represented by Anzick-1 and below the NNA/ANC-B branch . From this cohort, a total of 716 unrelated individuals belonging to 71 Indigenous communities representing 60 ethnic groups from 10 linguistic families were selected for genome-wide genotyping based on the availability of samples  in Mexico City (protocol number 31/2011/I) with the support of the National Commission for the Development of Indigenous Communities  and with the agreement of the Indigenous leaders from each community. All participants provided written informed consent, and authorities or community leaders participated as translators when necessary.61. Each data set was processed individually, including per marker and per sample examinations. We removed SNVs with genotyping rates <98% and those with a minor allele frequency of 1%, and then removed mitochondrial and sex chromosome SNVs. Finally, we excluded individuals with missing rates >3% and with discordant gender information.To perform our estimations, we generated several data sets merging our genotype data with those previously published for several worldwide populations and modern and ancient Native American individuals as follows. For data generated using only an SNV array, we performed the data handling and quality control procedures in Plink v1.98, Moreno-Estrada et al.2, and Silva-Zolezzi et al.12. After QC in each data set, all data were merged using the mergeit function of the Eigensoft v5.0. Software13. After merging, SNVs with highly discordant allele frequencies (p < 0.001) between the same populations in different data sets or strand bias were excluded. A total of 3490 individuals from 219 populations and 61,393 autosomal SNVs were included. We used this data set to identify the proportion of admixture with other worldwide populations in the Indigenous samples from Mexico. We ran PCA13 analyses using default parameters and admixture analyses assuming K = 4 clusters, including cross-validation error estimation, a block relaxation algorithm as the optimization method, and 100 replicates. Finally, the run with the highest likelihood was selected.First, we merged our 716 Mexican Indigenous samples with worldwide populations reported by Reich et al.n = 716) and those previously reported by Reich et al.8 (n = 57), Moreno-Estrada et al.2 (n = 350), and Silva-Zolezzi et al.12 (n = 86), yielded a total of 1209 samples from 60 different Mexican ethnic groups  between the same populations in different data sets or strand bias were excluded. Finally, samples were merged and the same QC was repeated for the whole data set, including the removal of first- and second-degree relatives, yielding an intersect of 1086 individuals and 61,393 autosomal SNVs  identified in the admixture 2, both genotyped using the Affymetrix Genome-Wide Human SNP Array 6.0, yielding a total of 996 individuals from 60 populations and 504,581 autosomal SNVs 66. PCR duplicates were removed using picard-tools MarkDuplicates67, and local realignment was carried out following the GATK best practices guide69. Diploid genotypes were called using HaplotypeCaller from GATK v4.069.Fastq files from publicly available ancient genomes from the Americas and present-day South Americans were downloaded from their respective repositories69, and then converted to eigenstrat format using the converf program from Eigensoft v5.013. Finally, these data were merged with the array data from the 325 individuals from the MAIS cohort with a Native American ancestry >99  in R package APE v5.1. The consensus tree was generated under DendroPy v4.0.070 using the whole data NJ tree to maintain the topology, and each replicate was used to obtain the bootstrap values.The FST statistics and geographic distances between populations in R package adegenet v2.1.171.To test whether isolation by distance explained part of the genetic diversity observed in Native populations from Mexico, we performed a Mantel test for a matrix of pairwise-Ne across time from the LD analysis based on the method reported by McEvoy et al.16 in R package NeON17 with default parameters. To estimate more recent demographic history, we estimated Ne by identifying IBD tracks based on the pipeline reported by Browning et al.21. Briefly, the data sets were phased together using Beagle 5.172. IBD segments in the data from each selected population were detected by IBDseq19. We then used IBDNe18 for non-parametric estimation of the recent demographic history from IBD segments with the default parameters and a minimum IBD segment length of 2 centiMorgan (cM) to estimate the Ne across generations.The effective population sizes of Indigenous Mexican populations were estimated in a set of 48 selected populations from the second masked data set (Supplementary Table T) in generations in the 48 selected populations mentioned in the previous section .ROH were calculated by Plink v1.9 software26 was used to detect IBD segments between individuals with >99% Native American ancestry  with an individual selected at random from population B. Therefore, we divided the total number of individual pairs connected by more than 7 cM of IBD by the total number of possible individual pairs, for each pair of indigenous groups analyzed. Following the definition of the five geographical regions identified in the NJ tree and previously described in Contreras-Cubas et al9. IBD networks were generated in R with function ggnetworkmap from the GGally v2.1.2 library. Vertices are located on geographical sampling coordinates from each population. Connections between groups have a width proportional to the probability of any individual from population A sharing at least one IBD segment with any individual from population B. Five IBD networks were generated, where each figure focuses on the connections from populations within a given geographical region: North, Northwest, Central-east, South, and Southeast  or large (>10 cM) size, which have been reported to originate at different time points in the past. This analysis was made incorporating the populations at the regional level to display with a more detailed resolution, the difference in connectivity between different regions (Supplementary Fig. f-statistic framework to explore the relationship between USR1 and Anzick-1 ancient genomes and modern Mexican Native populations. The outgroup f3-statistic and D-statistic tests were computed in Admixtools v4.1 using the estimators described in Patterson et al.75, and standard errors were obtained using a block jackknife procedure over 5 Mb blocks in the genome.We used the 76 based on the Ancient and Modern Native American data sets. The tree was rooted using the Yoruba population as an outgroup, and standard errors were estimated using blocks of 50 SNVs.A maximum-likelihood tree was constructed using TreeMix v1.13Alternatively, we tested the presence of gene flow between Mexican Indigenous populations assuming 1–20 migration edges with TreeMix using the previously generated maximum-likelihood tree to maintain the topology of each tree and USR1 genome as an outgroup.Further information on research design is available in the Supplementary InformationPeer Review FileDescription of Additional Supplementary FilesSupplementary Data 1-8Reporting Summary