Data on the course of mental disorders during imprisonment are scarce. Longitudinal studies from high-income Western countries point to improvements of symptoms over time. The aim of the present study was to assess mental disorders and symptoms three years after baseline evaluation at imprisonment and to determine predictors of change in a South American prison context.Consecutively admitted prisoners in Santiago de Chile were assessed at intake and reassessed after three years using the Mini International Neuropsychiatric Interview and the Symptom-Check-List 90 Revised (SCL-90-R). The global severity index (GSI) was calculated with standard deviations (SD) and compared using paired t-tests. The prevalence of mental disorders at baseline and at follow-up were compared using McNemar tests. Analyses of variance were conducted to evaluate whether prespecified socio-demographic variables and disorders at baseline predicted symptom change at follow-up.47 (64%) at intake vs. 23 (32%) at follow-up had major depression (p<0.001); 22 (30%) at intake vs. 10 (14%) at follow-up had psychosis (p = 0.008). The mean GSI improved from 1.97 (SD 0.65) at intake to 1.16 (SD 0.82) at follow-up (p<0.001). Depression at baseline  and working or studying during imprisonment  were associated with strong improvement of the GSI at follow-up, whereas psychosis at intake was associated with relatively small symptom improvement .73 (94%) out of 78 prisoners participated. The prevalence of major mental illnesses was lower at follow-up: In a resource poor prison context in South America, mental health symptoms and disorders improve considerably over three years during imprisonment. This applies especially to people with depression at intake. Offers to work or study during imprisonment may improve mental health outcomes. The number of imprisoned people has increased worldwide over the past two decades and this is especially pronounced in South American countries . The incFifteen longitudinal studies on changes in mental health symptoms within the prison environment were included in a recent review . All of The aim of the present study was to assess the course of mental disorders and symptoms in a South American prison context over a three-year follow-up period and to identify factors that predict improvements.We conducted a longitudinal observational follow-up study on consecutively admitted individuals to three prisons in Chile. Prisoners were assessed at baseline and three years later.The inclusion criteria for follow-up assessments were: having participated in the baseline study in 2013 and remaining imprisoned or being consecutively imprisoned at follow-up (which was conducted between November 2016 and January 2017); living in the metropolitan region of Santiago de Chile; and having capacity to provide informed consent.At baseline in 2013, 427 randomly selected prisoners were assessed within their first weeks of imprisonment in three central remand prison facilities of the metropolitan region of Santiago de Chile . After tAge, marital status, employment status, educational level, social network, legal status, previous imprisonments, psychological and psychiatric treatment were assessed using structured questions. Marital status was categorized in the exclusive categories: single, married, co-residing, separated, divorced and widowed. Educational level was categorized according to the International Standard Classification of Education (ISCED), comprising levels 4, 5 and 6  to one level . Legal sThe Spanish version of the Mini-International Neuropsychiatric Interview (MINI) was used to establish diagnoses in accordance with the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). The MINI is a fully structured interview developed by Sheehan et al. 1998). Since it was first used to assess the mental health status of a prison population in 2004, it has been applied in several countries –18. The 98. Sincenot at all’ to ‘extremely’. The instrument covers symptom dimensions including Somatization, Obsessions–Compulsions, Interpersonal Sensitivity, Depression, Anxiety, Hostility, Phobic Anxiety, Paranoid Ideation and Psychoticism. The SCL-90-R was found to be a reliable and valid instrument used for the screening of imprisoned people for mental disorders and has previously been used in prison populations [The Spanish revised version of the Symptom Check list with 90 items (SCL-90-R) was used to assess the severity of psychological symptoms. Study participants select from a 5-point Likert-type scale that ranges from ‘ulations , 20, 21.The procedure for the baseline assessments has been described in detail elsewhere . PotentiWritten and oral informed consent was obtained from every participant prior to inclusion in the follow-up assessment. The study information contained a statement that study participation was voluntary and independent from all legal issues or other benefits. After resolving all questions, it was emphasized that the consent to participate could be withdrawn at any later point of time without further explanations and without any consequences. Capacity to provide informed consent was deducted from the capacity to sufficiently concentrate on the oral and written study information and to reproduce parts of it in order to show that contents and procedures were understood. No treatments were offered to participants of the study.The study was approved by the institutional ethics review board of the University Hospital of the University of Chile , by the Ministry of Justice  and by the national prison administration, Gendarmería de Chile .P-values <0.05 were considered statistically significant. All statistical data analyses were conducted using SPSS version 24.Socio-demographic characteristics and prevalence rates of mental disorders were calculated as per cent values at baseline and at follow-up. The age and the scores on the SCL-90-R were calculated as means with standard deviations. McNemar tests were conducted to test whether, and how, the prevalence of mental disorders differed between baseline and follow-up. A paired sample t-test was used to assess the difference between the mean GSI and subscale scores on the SCL-90-R symptom score at baseline and follow-up. A paired sample t-test was also used to test whether mean GSI scores differed for groups of diagnostic entities at baseline. Analysis of variance with parameter estimates was used to assess the association of prespecified socio-demographic factors and groups of diagnostic entities at baseline with change of the GSI. We included gender, educational level, which was dichotomized for this purpose as low (ISCED 0–1) and other (ISCED 2–6), any mental health treatment, working (including working for remuneration or studying), legal status (remand vs. sentenced) and consecutive vs. intermittent imprisonments during follow-up  outside prison during follow-up). Psychiatric morbidities at baseline were included. 37 (51%) had been released from prison at least once since the baseline assessment. All participants in the study completed the MINI, with 72 participants completing the SCL-90-R (data missing for one participant).At three-year follow-up 78 individuals were eligible for participation in the follow-up study. Three did not respond on the third call, one did not give consent and one was ineligible due to acute psychotic symptoms incompatible with the interview. The non-response rate was therefore 3.8% and the refusal rate was 2.5%, adding up to 6.4%. Seventy-three prisoners were included in the follow-up study, of which Socio-demographic characteristics of the sample are reported in 47 (64%) individuals with major depression at baseline, 17 (23%) still met the diagnostic criteria at follow-up, and 26 (36%) had been remitted at follow-up and there were 6 new cases. The prevalence decreased from 64% to 32% (p<0.001). The prevalence of anxiety disorders was 32 (44%) at baseline and 27 (37%) at follow-up. The prevalence of current psychotic disorders decreased from 20 (27%) at baseline to 8 (11%) at follow-up (p = 0.008). Personality disorders  were present in 52 (71%) at baseline and in 51 individuals (70%) at follow-up. Forty-seven (64%) had substance use disorder at baseline and 36 (50%) at follow-up. There were 10 new cases of illicit drug use disorders among the 26 prisoners who did not have this disorder at baseline.DSM-IV diagnoses at admission and at follow-up as well as the outcomes of the McNemar tests are reported in 10 to 5, high suicide risk from 21 to 10) while prevalence of low suicide risk increased from 14 (19%) to 20 (27%). Eleven participants (15%) attempted suicide during the three-year imprisoned period, 9 during the current imprisonment, 7 of them had shown high suicide risk at baseline.Suicide risk was present in 45 (62%) participants at baseline and in 35 (48%) at follow-up. Prevalence rates of high and moderate suicide risk dropped to half (moderate suicide risk from 35 (49%) deteriorated or did not reach the level of reliable clinical change.The mean values of the GSI and the nine subscale scores at baseline and follow-up are reported in The mean GSI at baseline and follow-up is shown for different diagnostic groups at baseline in β = -0.71; p = 0.002). Depression at baseline  and intermittent imprisonment  predicted symptom improvements. Current psychosis at baseline predicted high symptom levels at follow-up .The association between socio-demographic variables, prison related variables, psychiatric morbidities at baseline and change of the GSI are reported in The prevalence of major mental illnesses including depression and psychotic disorders was significantly lower at the 3-year follow-up than at intake into prison. Psychological symptom levels improved between baseline and follow-up in all domains. Working for remuneration or studying during imprisonment showed the strongest association with symptom improvement at follow-up. People with depression at baseline were likely to show marked improvements of psychological symptoms, whereas people with psychosis at baseline had the smallest symptom improvements at follow-up.To our knowledge, this is the first study of its kind in South America and has several methodological strengths. It follows the course of psychiatric disorders in a random admission sample. The sample is representative of people consecutively admitted to the penal justice system who are continuously or intermittently imprisoned after three years. The response rate at follow-up was very high (94%). The study used standardized and validated diagnostic instruments applied by trained researchers.The major limitation of this study is the relatively small sample size, which limits the power of the statistical tests. Also, comorbidity was not taken into account, and diagnostic groups may be overlapping, potentially complicating the prediction of long-term courses. The sample was not representative for the total prison population. Corresponding to the longitudinal long-term follow-up design of the study, we only recruited people continuously or intermittently involved with the penal justice system over a relatively long time period. The study design over-represents prisoners with long sentences and high turnover rates compared to the total prison population.The prevalence of major depression decreased mostly without specific therapeutic interventions. These findings are in line with other studies from prison samples in high-income countries. Longitudinal studies in such samples indicated that levels of depression decrease during imprisonment , 7. ThisThe prevalence of psychosis was lower at follow-up, but symptom levels remained high in this group. People with psychosis at intake should be prioritized with respect to screening and treatment development since the course of their disorders may be relatively unfavorable in the prison environment.Substance use disorders constitute an important health problem among prisoners –26. TheyAnxiety disorders remain high during imprisonment, as well as personality disorders which we expected to be relatively stable.Risk for suicide in prison is high  and has Global distress and all nine dimensions of psychopathology covered by the SCL-90-R improved significantly during the three years of follow-up, but rates remained above those of the general public (as established in a study in Chile ). LongitShort-term prisoners had lower levels of distress than long-term prisoners, which has also been observed in another sample of imprisoned individuals . The int


PINOID (PID), a gene involved in the regulation gynoecium apical development (style development). Here, we mutated two ETT-bound AuxREs within the PID promoter and observed increased style length in gynoecia of plants carrying mutated promoter variants. Furthermore, mutating the AuxREs led to ectopic repression of PID in one developmental context while leading to ectopically upregulated PID expression in another stage. Our data also show that IND associates with the PID promoter in an auxin-sensitive manner. In summary, we demonstrate that targeted mutations of cis-regulatory elements can be used to dissect the importance of single cis-regulatory elements within complex regulatory regions supporting the importance of the ETT-IND interaction for PID regulation. At the same time, our work also highlights the challenges of such studies, as gene regulation is highly robust, and mutations within gene regulatory regions may only display subtle phenotypes.The plant hormone auxin controls almost all aspects of plant development through the gene regulatory properties of auxin response factors (ARFs) which bind so-called auxin responsive elements (AuxREs) in regulatory regions of their target genes. It has been proposed that ARFs interact and cooperate with other transcription factors (TFs) to bind to complex DNA-binding sites harboring cis-elements for several TFs. Complex DNA-binding sites have not been studied systematically for ARF target genes. ETTIN  is a key regulator of gynoecium development. Cooperatively with its interacting partner INDEHISCENT (IND), ETT regulates  Over the last decades, great progress has been made in understanding how eukaryotic transcription factors (TFs) can specifically recognise the genes that they regulate ,2,3. Eukarf6/8 and ettin (ett/arf3) mutants) or even to plant death as is the case in monoperteros (mp/arf5) mutants, which cannot form a root .,21.PID, pid-8 mutant phenotype shows a dramatic reduction in fruit size and a reduction of the valves [pid-8 phenotype regarding the defects in valve development and silique length (Col-0). In five independent lines for each construct, we measured ten styles per line, and the results indeed revealed a significant difference in style length (wt) were sufficient to fully rescue the pid-8 phenotype regarding both silique length and style length, mutating either the first (pPID1M) or the second (pPID2M) AuxRE moderately, yet significantly, increased the style length when compared to wild-type and pPIDwt lines. However, style lengths of the pPID1M and pPID2M lines did not differ significantly when compared to each other. In contrast, the double-mutant pPID1+2M lines had significantly longer styles than the Col-0, pPIDwt, pPID1M, and pPID2M lines. This indicates that both AuxREs in the examined region affected style length in an additive manner. The data also suggest that the two AuxRE had an equal contribution to style length. Finally, the results imply that the two AuxRE were indeed biologically important for the correct regulation of PID gene expression during style development.The e valves . Interese length B–D, and e length . Our mace length E,F. SpecPID gene expression, we decided to quantify the PID promoter activity in the promoter mutant lines. We generated promoter-reporter lines, that contain the same 5-kb PID promoter variants as the rescue lines, but this time controlled the expression of a nuclear GFP. Additionally, these constructs carried a nuclear mCherry controlled by a constitutive ACTIN2 (ACT2) promoter for normalisation of the GFP signals and, thus, allowed quantitative studies of gene expression. When transformed into Col-0 plants, the ratio of GFP to mCherry corrected total cell fluorescence (CTCF) can be used as a measure of promoter activity and gene expression [To assess whether the mutation in the AuxRE sites affected the pression . The proGFP/CTCFmCherry) in lines carrying the wild-type promoter variant, while fluorescence in lines with the promoter mutated in the first AuxRE were moderately, but not significantly, stronger. GFP fluorescence in lines mutated in the second AuxRE was significantly increased compared to the wild-type but not compared to the single mutant in the first AuxRE. The highest relative fluorescence was measured in the doubly mutated promoter lines. For these lines, the expression was significantly higher compared to pPIDwt and pPID1M lines but not pPID2M. The results showed significant differences between lines of different promoter variants E, with wPID promoter activity. Even though activity of pPID1M lines did not differ significantly from wild-type promoter or pPID2M promoter activity and appeared as intermediate between the two, combining mutations in the first and the second AuxRE had an additive effect on PID promoter activity. This suggests that both AuxREs are regulatory elements important for the repression of the PID gene. Comparing the PID promoter activity with the phenotypic style-length data, it becomes evident that high promoter activity at stage 12 correlated positively with longer styles  were identified, which intriguingly overlapped with the AuxREs , which rescued the defects of the strongly indehiscent ind-2 mutant. The ChIP experiment showed that interaction of the IND:YFP protein with the examined regulatory patch around 0.4 kb upstream of the PID coding region was significantly reduced after auxin treatment . This leads to auxin accumulation at the gynoecium apex, triggering a bilateral-to-radial symmetry switch to establish the radial style [PID is expressed [Here, we attempted to uncover the importance of two ETT-binding AuxRE sites within the promoter of the ongation . During al style . At latexpressed .PID promoter play a role in the regulation of PID gene expression during style elongation. Phenotypic analysis showed that the PID gene under control of any of the four examined promoter variants was able to rescue the pid-8 ovary defects . This suggests that the examined AuxREs do not play a major role in ovary formation. Besides the two AuxREs studied here, the PID promoter contains several other cis-regulatory elements, including several AuxREs [PID at developmental stage 12. The presented data show that both AuxREs identified in the l AuxREs ,24,26. APID expression during gynoecium development [spt mutants as well as in ett ind double mutants, the PID gene is ectopically expressed at the apex of developing gynoecia during early stages, indicating that these factors act as repressors of PID expression [PID promoter in this region, and that the effect of changing auxin levels may depend on whether ETT or SPT is bound.It is well established that, besides ETT, two bHLH transcription factors, SPT and IND, are essential regulators of elopment . In spt pression ,25. Sequpression . Moreovepression . These oPID promoter in planta, presumably via the E-box element that IND has been shown to bind in yeast one-hybrid studies [PID promoter in the presence of auxin [PID promoter to repress gene expression in low auxin levels. High auxin concentrations can disrupt ETT–IND interactions and IND-DNA interactions, releasing IND from the PID promoter and leading to an up-regulation of PID. In contrast, data for the mutated PID promoter lines presented here suggest that DNA-bound ETT maintains some residual repressor activity that fine-tunes PID expression during style elongation.We show that IND can bind the  studies ,26. Introf auxin . The mecETT and IND are expressed at the gynoecium apex and style from early stages throughout development [SPT is expressed until stage 11 but absent from stage 12 and onwards [ETT and SPT contributes to the developmentally specific regulation of PID expression. Alternatively, it is possible that competitive protein–DNA interactions and/or complex protein–protein interactions are important. These possibilities are not mutually exclusive and will be addressed in future studies.elopment ,24,26. I onwards . It willPID) in the developmental context of gynoecium development. This work shows that targeted mutations of potential cis-elements can be used to dissect the importance of cis-regulation within complex regulatory regions in planta. However, it also shows the challenges involved in assessing the contributions of these elements, as gene regulation is highly robust, and mutations within gene regulatory regions may display subtle phenotypes. To conclude, this study provides a starting point for a more in-depth study understanding cis-regulation of auxin-responsive genes, as the data still do not permit full elucidation of the mechanism by which ETT regulates PID expression. For example, it remains an open question how ETT is recruited to its cis-binding sites and whether ETT binds as a monomer, homo-, or heterodimer. In line with this, it is yet to be addressed whether IND acts as a pioneering factor and if ETT and SPT compete to bind their overlapping DNA binding sites. Nonetheless, this work indicates that cis-elements affect the complex formation at target loci, and their regulation reveals the advantage of studying cis-regulation in planta through focusing on a specific developmental process.Here, we present an approach to test the contribution of two ETT-binding AuxREs in the promoter of an auxin-responsive gene (


Recent theoretical works have proposed atomic clocks based on narrow optical transitions in highly charged ions. The most interesting candidates for searches of physics beyond the Standard Model are those which occur at rare orbital crossings where the shell structure of the periodic table is reordered. There are only three such crossings expected to be accessible in highly charged ions, and hitherto none have been observed as both experiment and theory have proven difficult. In this work we observe an orbital crossing in a system chosen to be tractable from both sides: Pr Atomic clocks are based on the frequency of optical transitions and offer high precision. Here the authors demonstrate a configuration crossing in the highly charged ion praseodymium (Pr These experiments could be improved by exploiting clock transitions with a much reduced sensitivity to frequency shifts caused by external perturbations. Transitions in highly charged ions (HCI) naturally meet this requirement due to their spatially compact wave functions7. Unfortunately, in most cases this raises the transition frequencies beyond the range of current precision lasers. While some forbidden fine-structure transitions remain in the optical range, these are generally insensitive to physics beyond the Standard Model. More interestingly, at configuration crossings due to re-orderings of electronic orbital binding energies along an isoelectronic sequence, many optical transitions between the nearly degenerate configurations can exist8. For the 10, recently reviewed in ref. 11. It is highly sensitive to potential variation of the fine-structure constant, Current single ion clocks reach fractional frequency uncertainties mentclass2pt{minim14. Nonetheless, predictions do not reach the accuracy needed for finding the clock transition in a precision laser spectroscopy experiment.With two electrons above closed shells, PrIn the following, we present measurements of all the optical magnetic-dipole (M1) transitions with rates of at least order 100 s15. In this setup, a magnetically focused electron beam traverses a tenuous beam of C16. Exploratory searches with a broad entrance slit detected weak lines at reduced resolution. By monitoring the line intensities while scanning the electron beam energy we determined their respective charge state, finding 22 Pr17 calculations were found to reproduce the spectra with average difference  were accurate to 19.The Heidelberg electron beam ion trap (HD-EBIT) was employed to produce and trap Prmentclass2pt{minim16, to include HFS in the Paschen-Back regime because 20, yielding those necessary to address the 21. The non-diagonal Zeeman matrix element between the near-degenerate fine-structure states, characterizing the magnitude of interference, was extracted by fitting the experimental line shapes, and was found to be in good agreement with AMBiT  predictions. The magnetic field strength acts in this setting as a control parameter of quantum interference. In future laser-based high-precision measurements, a much weaker magnetic field will be used. This will minimize interference and enable a better determination of field-free transition energies, and consequently of the clock lines.For confirmation and determination of level energies at the part-per-million level, high-resolution measurements were carried out. This revealed their characteristic Zeeman splittings in the entclass1pt{minimaentclass1pt{minimaentclass1pt{minima4 and become accessible in HCI using well-established quantum-logic spectroscopy techniques24. The 25.After discovering this orbital crossing and the interesting clock transition, in the following we discuss its properties. Without HFS, the 4. However, the static dipole polarisability 8. Our calculations of the static polarisability for Pr5. An atomic clock based on PrBlackbody-radiation (BBR) shift is a dominant source of systematic uncertainty in some atomic clocks such as Yb7. Sensitivity to 26), but with opposite sign. The sign change can be understood in the single-particle model: the YbBeyond their favourable metrological properties, HCI have been suggested for probing variation of fundamental constants due to their high sensitivity to thismentclass2pt{minim27. While Michelson-Morley experiments verify the isotropy of the speed of light, recent atomic experiments have placed strong limits on LLI-breaking parameters in the electron-photon sector29. The sensitivity of transitions for such studies is given by the reduced matrix element of 30.We also investigate the sensitivity of the clock transitions to invariance under local Lorentz transformations. LLI is a fundamental feature of the Standard Model and has been tested in all sectors of physics32. Populations calculated using FAC show that a Pr33, further enhanced by employing non-classical states of motion34. We estimate an achievable displacement rate of tens of kHz exciting coherent states of motion for realistic parameters of laser radiation at 408 nm detuned by 1 MHz from the 24. State selectivity can be provided by the global detuning of the ODF and the unique 24.Future precision spectroscopy of the clock transitions will require that the internal Pr23. Using realistic laser parameters similar to above, tuned near the electronic resonance, we estimate that a scan with 10 MHz steps using 10 ms probe pulses can be performed without missing the transition. Assuming that each scan point requires 100 repetitions we can scan the 22 on the clock transition can commence. Since the linewidth of the transition is significantly narrower compared to the currently best available lasers35, we expect laser-induced ac Stark shifts that need mitigation using hyper-Ramsey spectroscopy or a variant thereof45.Despite the high resolution of the measured lines, the We have measured optical inter-configuration lines of PrIn the hyperfine Paschen-Back regime, the energy shift of a fine-structure state’s magnetic sublevel in an external magnetic field is given byEquation  was fittentclass1pt{minima46. In atomic units  calculations of the transition energies were performed within the framework of the projected Dirac-Coulomb-Breit Hamiltonian48 was employed to facilitate convergence.The calculations started from the closed-shell reference [Kr]449 was used, composed of even-tempered Gaussian type orbitals, with exponents given byThe uncontracted universal basis sets, 31 p, 26 d, 21 f, 16 g, 11 h, and 6 i functions; the convergence of the obtained transition energies with respect to the size of the basis set was verified. All the electrons were correlated.The basis set consisted of 37 The energy calculations were performed using the Tel-Aviv Relativistic Atomic Fock-Space coupled-cluster code (TRAFS-3C), written by E. Eliav, U. Kaldor and Y. Ishikawa. The final FSCC transition energies were also corrected for the QED contribution, calculated using the AMBiT program.51. We used the DIRAC17 program package52, as the Tel-Aviv program does not allow for addition of external fields. The v3z basis set of Dyall was used53; 20 electrons were correlated and the model space consisted of 5The polarizabilities were also calculated using the Fock-space coupled-cluster method within the finite-field approach18. This code implements the particle-hole CI+MBPT formalism54, which builds on the combination of configuration interaction and many-body perturbation theory described in ref. 55 . This method also seeks to solve Eqs.  corrections60.Correlations with the frozen core orbitals (including 61 for relevant formulas). By contrast Diagonalisation of the CI matrix gives energies and many-body wave functions for the low-lying levels in Prentclass1pt{minimaDirect decay of the 62, and were found to be in reasonable agreement with the experiment on the level of the CI+MBPT results. As a first step, an MCDF calculation was performed, with the active space of one- and two-electron exchanges ranging from the 63 and mixing coefficients for sublevels of equal magnetic quantum numbers were also evaluated.Transition energies, hyperfine structure coefficients, and


A non-invasive, computationally-efficient method for the identification of fracture risk scenarios under the representation of neuro-musculoskeletal dynamics does not exist. We introduce a computational workflow that integrates modally-reduced, quantitative CT-based finite-element models into neuro-musculoskeletal flexible multibody simulation (NfMBS) for early bone fracture risk assessment. Our workflow quantifies the bone strength via the osteogenic stresses and strains that arise due to the physiological-like loading of the bone under the representation of patient-specific neuro-musculoskeletal dynamics. This allows for non-invasive, computationally-efficient dynamic analysis over the enormous parameter space of fracture risk scenarios, while requiring only sparse clinical data. Experimental validation on a fresh human femur specimen together with femur strength computations that were consistent with literature findings provide confidence in the workflow: The simulation of an entire squat took only 38 s CPU-time. Owing to the loss  of bone mineral density (BMD), the strain measure that is associated with bone fracture increased by 31.4%; and yielded an elevated risk of a femoral hip fracture. Our novel workflow could offer clinicians with decision-making guidance by enabling the first combined  Additionally, dynamic stress analyses are essential to evaluate the mechanical properties of endoprosthetic implants in-situ during dynamic activities to improve implant design, implant durability and in turn, patient outcome8.It is of major importance to reliably and rapidly obtain information on the dynamic 9. Of the 1.7 million fragility fractures in 2011 in the US10 and 3.5 million fragility fractures in the E27 countries11, the osteoporosis-related femoral hip fracture in particular has become a major socioeconomic problem: The femoral hip fracture has a relative incidence of approximately 23%, making it the most common fragility fracture and has caused an annual treatment cost of $19 billion USD in 2004 in the US and €37 billion in 2010 in the E27. Because of the association of BMD loss with age, these numbers are expected to increase by roughly 25% until 2025 as the elderly population (>65 yrs.) continues to increase.In this regard, bone diseases demonstrate a massive public health problem, especially bone mineral density (BMD) loss that eventually leads to fragility fractures which are associated with serious consequences in terms of morbidity, mortality, and socioeconomic burden15. In this respect, finite-element analysis (FEA) has been used extensively to address musculoskeletal research questions by means of non-invasive computational analysis; e.g., to study the mechanical behavior of human bones18, bone remodeling21, bone adaption23 and/or to estimate the progression of osteoarthritis in normal and overweight subjects26. Thereby, it has become a state-of-the-art method to assign the Hounsfield units (HU) of computed tomography (CT) imaging data to the finite-element mesh to capture the patient-specific bone density distribution17. This so-called quantitative CT (QCT) FEA28 has become a key tool in the assessment of the bone status, e.g., via predicting its mechanical bone strength30. For example, in assessing the risk of BMD loss-related bone fractures, it has been shown that a subject-specific FEA that utilizes QCT for material property identification, is beneficial over the current clinical standard that utilizes dual-energy X-ray absorptiometry-based (DXA) BMD measurements for diagnosis and medication effect assessment in osteoporotic patients30.Targeting the early identification of adverse bone metabolism, direct measurements of stresses and strains in or on living individuals’ bones are impossible, from an ethical point of view, due to their invasiveness. Therefore, they are restricted to a limited number of superficial bone sites within cadaver studies using strain gauges32. NMBS models are regularly employed to enable rapid and reliable dynamic analysis over an enormous parameter space, to gain insight into human locomotion37 or to evaluate surgical treatment options38 by providing methods that quantify forces in muscles, ligaments, and joints while avoiding invasive interventions. Another application of these NMBS is the extraction of boundary conditions for FEA23 or the co-simulation of FEA and NMBS that can be used to investigate, for e.g., the effects of gait modifications40.In contrast to FEA, patient-specific neuro-musculoskeletal multibody simulation (NMBS) seeks to optimize clinical decision-making by reliably predicting numerous patient-specific quantities in terms of musculoskeletal health from only scarce, non-invasive medical imaging and gait lab data5 to ultimately allow for the functional analysis of the bone. Moreover, FEA is usually limited to static or quasi-static loading cases and involves an immense computational cost that renders it computationally impractical for dynamic analysis of the entire neuro-musculoskeletal (NMS) system23. On the other hand, NMBS assumes bones as rigid bodies which makes the estimation of the field parameters stresses and strains impossible. In an attempt to resolve these issues, model reduction techniques have been employed within biomechanical FEA41. In the context of clinically relevant load cases that involve only small linear-elastic deformations, modally reduced flexible superelements models42 (SEMs) were derived from finite-element models (FEMs) of bone segments and were implemented into NMS multibody models to allow for strain computation: Hughes et al.43 observed lower tibial strains in individuals undergoing repetitive physical activity, which might suggest a lower risk of stress fractures in those individuals, due to positive bone remodeling as a result of increased physical activity. Gervais et al.7 reproduced the fracture site of an osteosynthetic plate at the lateral, distal femur in accordance with a case study and reported that only the dynamic computation of stresses yielded realistic results.However, established clinical diagnosing standards including QCT-based FEA lack the capability to estimate stresses and strains that arise due to the dynamic multiaxial loading of the bone under varying loading conditions as usually present in daily living activities and specific to every individualHowever, the implementation from SEMs into NMBS is still in its infancy, and several limitations need to be overcome to arrive at a NMBS with clinical significance. In fact, till date, an experimentally validated study investigating the translation of QCT-based FEA into the workflow of a subject-specific NMBS does not exist: It is unclear how subject-specific QCT-based FEA translates into a subject-specific NMBS in terms of the prediction performance of osteogenic field parameters and computational efficiency.in-silico approaches into clinical practice. Therefore, the question of if and to what extent state-of-the-art NMBS can predict those biophysical stimuli for assessing the healthy and the osteoporotic femur under physiological-like conditions remains open.Despite these challenges, it would be desirable to enable the prediction of physiological, i.e. dynamic, bone stresses and strains during physiological tasks to monitor the bone health and provide a numerical indication for early tendencies towards abnormalities that may yield the risk of fracture. Moreover, the high prevalence of femoral hip fractures stresses the importance of monitoring dynamic stresses and strains especially in the living femur that due to the surrounding soft tissue is difficult if not impossible to analyze; thus, further complicates the validation and translation of such In addressing these limitations, the objective of the present study is to augment the clinicians’ diagnosis and monitoring repertoire by enabling the reliable and rapid prediction of patient-specific stresses and strains, solely based on gait lab and medical imaging data. Hence, our work introduces a clinically motivated workflow, enabling neuro-musculoskeletal flexible multibody simulation (NfMBS) that features dynamic stress and strain computation Fig.  by incorin-silico prediction of BMD loss-related fracture risk in bones under the consideration of structural and functional patient specificity, i.e., of material and structural properties as well as of musculoskeletal architecture and motion dynamics of the individual NMS system.Our study investigates the Craig-Bampton method42. Both the domain-specific simulation models of the femur, i.e. the FEM and SEM, were validated by conducting static and dynamic biomechanical tests on the fresh human femur specimen after computer model reconstruction. Finally, two simulation studies were conducted: The first simulation study resembled the bone strength experiments done by Orwoll and coworkers4, in which QCT-based FEMs were deployed for the risk assessment of femoral hip fractures, due to BMD loss, within a cohort study. Then, native and BMD loss-affected SEMs were implemented into our previously presented NMBS with a computed-muscle controller44 featuring a full-body NMS computer model that is based on the 4thGrand Knee Challenge to Predict In Vivo Knee Loads45.We generated a specimen-specific FEM of a fresh human femur specimen from a male donor (age = 58 yrs) from QCT scans with an included BMD calibration phantom. Next, we derived a modally reduced flexible SEM from the very same FEM by deploying the bone strength characterizing experiments, as conducted by Orwoll et al.4, we compared the experimentally measured displacement of the force application point and the (tensile/compressive) strains on the strain gauge (SG) locations SG-1 to SG-6 in response to static compressions, to the predictions of the FEA . Note that due to technical problems with the wiring of the SG during the experiment, one out of five trials had to be discarded.Due to the use of linear strain gauges, the vertical strain components in red Fig. . The expThe FEM reproduced the experimental SG measurements well with an average root-mean-square-error (RMSE) of 145.25 µstrain (range 22.25 µstrain to 301.77 µstrain) between all the strain gauges and a RMSE of 0.018 mm for the vertical femoral head displacement. The computation of the FEM resembling the static experimental trial took 19.56 min CPU-time.von Mises stress distribution as predicted over the whole bone surface by the SEM is in great agreement with the validated FEM. The deviation in the von Mises stresses computed by the FEM and the SEM were negligibly small with an average RMSE of 0.0478 MPa (range 0.0223 MPa–0.0790 MPa) over the complete simulation time  as well as the stress and strain recovery (t = 14.01 min) add up to the SEM generation, the SE analysis outperformed the dynamic FEA by the factor of 11.91 in terms of CPU time. Moreover, the SEM generation is required only once; after which the SEM can be incorporated into a variety of loading cases.Owing to the modal reduction in the degrees of freedom (DoF) from the FEM (DoF = 370’362) to the SEM (DoF = 32), the CPU-time for the dynamic experimental trial over 5 s in real time, decreased considerably from 328.68 min for the dynamic FEA to 0.15 min for the SEM. Although the modal reduction  as the applied load from the resulting load-deformation curve at 4% deformation (=4000 µstrain) of the femoral head with respect to the greater trochanter  and an excellent correlation between femoral bone strength and osteoporosis-related hip fractures.To obtain a measure of the hip fracture risk, computational ter Fig. . This te46, which provided insight into the change of osteogenic parameters during dynamic squat motion for the fracture risk assessment after BMD-loss leading to osteoporotic conditions in the previously analyzed femur specimen. The osteoporotic bone model was parametrically derived from the above described FEM by reducing the Young’s moduli of the cortical and trabecular bone elements to 84% and 67% (referred to as the osteopenic C84 T67) or to 68% and 34% (referred to as the osteoporotic C68 T34) in the cortical and trabecular bone compared to the originally QCT-based Young’s moduli assignment, respectively. To verify the osteoporotic bone models, we conducted numerical bone strength analyses according to the protocol by Orwoll et al.4. The load-displacement curves were then generalized to stress-strain curves to allow for fracture risk assessment under more complex and varying boundary conditions  as well as the parametrically modeled BMD loss-affected bone models C84 T67  and C68 T34  agree with the classification criterions, according to Orwoll et al.4, which reported the bone strength to be an average of µ = 5939 N ± 1919 N for the non-fracture cases and µ = 3782 N ± 1563 N for the fracture cases. As expected, the weakened bone exhibits lower bone strength, which results in higher strains at lower stresses.The results of the numerical bone strength experiments exhibit a very good agreement in the load-displacement curves as predicted by the FEA and SEM up to the bone failure criterion of εSupplementary Information on the validation of the musculoskeletal multibody model  and osteopenic (C84 T67) SEMs into our NfMBS and compared the in stress-strain curves defined in Fig. For hip fracture risk assessment, we implemented the baseline  that features dynamic stress and strain computation Fig.  by incorvon Mises stresses and bone strength. In this context, our experimentally validated in-silico analysis of the human femur under loading conditions normally seen in daily living activities is the first study of its kind and provides great insight into highly prevalent femoral hip fractures, which are practically impossible to analyze in-vivo. Although the bone quality was varied only parametrically from healthy (C100 T100) to osteopenic (C84 T67) to osteoporotic bones (C68 T34), the results seem representative of osteoporosis-related fractures, since the predicted femoral bone strengths were in very good agreement with the literature data48. Our results provide confidence that NfMBS could predict the individual bone strength  as a major diagnostic parameter for the assessment of risks and medication effects under physiological-like conditions in an accurate and efficient manner. Notably, is has been shown that there can be more complex criteria derived from the predicted mechanical stresses and strains for quantifying the resistance of the femoral bone against failure51.The major contributions of our work are the integration of a subject-specific, QCT-based FEA of the human femur into the workflow of patient-specific NMBS together with its validation. The inclusion of structural patient specificity, i.e. morphological and material properties of the bone, and functional patient specificity, i.e. musculoskeletal architecture and motion dynamics of the NMS system, is necessary to enable clinically relevant NfMBS to identify early tendencies towards femoral hip fractures as it is a major risk scenario. We could show that our QCT-based FEM translated very well to the flexible SEM for its implementation into NfMBS, while maintaining the capability to reproduce osteoporosis-related bone weakening under dynamic NMS boundary conditions. The comparison of FEM and SEM exhibited negligible deviations between the target parameters at the femoral neck in terms of Our most important limitation was that our study has a rather methodological character with its emphasis on the validity of the proposed workflow. A limitation of the presented work is that only one healthy femur specimen was analyzed. From the clinical point of view, it would be, therefore, desirable to apply the workflow to a larger, statistically relevant number of osteoporotic bone specimens and eventually to patient cohorts.bone strength and bone fracture localization over DXA-based BMD measurements47. As mentioned above, BMD alone is not sufficient to describe the in-vivo intricacies that involve bone morphology and material-structural bone properties47. Thus, the logic extension to QCT-based FEA is the integration of patient-specific NMS dynamics. Clearly, the risk of bone fractures could be more accurately diagnosed with the complementation of NfMBS-predicted bone strength data under physiological-like representation with skeletal dynamics and soft tissue interaction8. NfMBS provides much deeper insight into relevant risk factors, as NMS dynamics—such as soft tissue damage or motor control dysfunctions—can be included into the set of boundary conditions to ultimately better resemble the patient-specific in-vivo situs. Consequently, NfMBS could enhance key aspects of QCT-FEA to ultimately arrive at a predictive tool that enables a combined in-silico analysis protocol of BMD measurement and dynamic NMS computer simulation for an improved diagnosis, e.g., of osteoporosis.However, an extensive body of studies has shown that QCT-based FEA is a powerful diagnosis tool that possesses superior accuracy and reliability in the assessment of 32. Contrarily, very complex load cases, like the forward dynamic NMS squat simulation, have not been achieved up till date, by the use of FEA.In fact, the direct comparison of our experimentally validated QCT-based FEM against the flexible SEM, in terms of the prediction accuracy and efficiency of clinically relevant bone parameters, revealed that NfMBS can handle the trade-off between these aspects extremely well, i.e., the SEM preserved very high accuracy while outperforming the dynamic QCT-based FEA in terms of magnitude in CPU-time. It should be noted that, currently, only NfMBS possesses the capability to sample the enormous parameters space for clinically relevant solutions by running numerous non-invasive parameter analyses on the patient’s NMS system under dynamic boundary conditionsbone strength assessment according to Orwoll et al.4 is applicable: the stress-strain curve of the femoral bone is roughly linear until the ultimate load is reached53, which should never occur during daily living activities. Generally, the consideration of microstructural processes along a timely trajectory, e.g. the architectural change of the trabecular bone, cannot be easily predicted using NfMBS. After capturing the patients current NMS condition, the clinically-relevant predictive capacity of NfMBS lies more in the incorporation of structure-mechanical and NMS boundary conditions for rapid and extensive osteogenic parameter analysis than in the inclusion of overly complex FEMs, as simple macroscopic QCT-based FEAs have been proven efficient53. Moreover, it was shown that there is only a marginal difference in the mechanical response when using anisotropic material models54.Regarding the QCT-based FEA, our FEM resembled the structure-mechanical properties of the tested bone specimen by, first, reconstructing the bone specimen’s morphology using high-resolution QCT and then, discretizing the 3D solid into quadratic tetrahedral finite elements that were assigned bone-specific BMD-dependent Young’s moduli for inhomogeneous and HU-value dependent, but isotropic and linear-elastic, material properties. The structural behavior of the bone in the plastic strain range beyond the yield point, especially the bone’s failure mechanism itself, has not been investigated within this study and is not sufficiently described using a linear-elastic material model. However, the 48. In this context, NfMBS resolves the trade-off between the predictive capability of fracture risk/fracture site and computational efficiency.However, our results show that decreases in BMD, e.g. due to osteoporosis or lytic bone changes, lead to abnormalities in the stresses and strains, which indicates a higher risk of fractures especially around the femoral neck. This agrees with numerous studies on the fracture risk of osteoporotic bone and its clinical prevalence, which report femoral hip fractures as the most prevalent osteoporosis-related fracturebone strength, i.e., as an early diagnosis tool of fracture risk before the possibility of a fracture arises. In this respect, Anitha et al.47 has shown that even low-quality CT imaging does not affect the prediction capability of QCT-based FEA. Hence, more frequent follow-up CT scans in combination with NfMBS would allow more regular monitoring and earlier treatment of BMD loss-related bone conditions.As such, our approach might be particularly valuable in the regular assessment of patient-specific 32. We took great care of the representation of the musculoskeletal geometry, i.e. bone morphology, kinematic topology, and muscle attachment sites, throughout the entire modeling process, since musculoskeletal architecture is known to have considerable impact on muscle-driven motion patterns and joint loading56, and most likely on bone loading as well. For validation purposes, the entire workflow was specifically based on experimental datasets55, and the musculoskeletal architecture, in particular, was refined in close collaboration with an orthopaedic surgeon. Additionally, we validated the boundary conditions due to musculoskeletal dynamics in terms of the quadriceps force58 and the resultant hip reaction force59  and the complementation of these data by our own experiments allowed for efficient validation of our workflow. This, however, stresses the importance of research on methods that help to identify an individuals’ musculoskeletal system on the way toward clinically-relevant NfMBS40. Despite limited technical or methodological challenges, a considerable effort must be directed toward the clinical integration of QCT-based FE modeling and, ultimately, of NfMBS.The use of publicly available datasets , in which the NMS simulation model with a flexible femur SEM was implemented, and the client Matlab/Simulink® , in which the computed muscle control was implemented. All simulations were run on an off-the-shelf desktop PC (Intel® Core™ i7-4790 CPU @3.60 GHz 8.00 GB RAM).15  to reconstruct the 3D bone surface model using triangulated surfaces. The resulting surface model was smoothed and converted into a surface of analytical non-uniform rational B-splines using Geomagic Studio , and finally exported to the FE pre-processor via the IGES interface.The reconstruction of the CT scans to the 3D FEM followed the protocol described inIn this pre-processing step, the optimized 3D surface model was converted into a 3D solid model and meshed with quadratic, 10-node, tetrahedral finite elements (C3D10) using Abaqus/CAE® .Ei to each node i of the FEM that is in dependence on the HU values obtained from the QCT scans of the very same femur at the respective node location. To do so, the calibration phantom with a known BMD served as a reference for the linear regression relating the HU value of the phantom to the known BMD’s equivalent As we were considering clinically relevant load cases with rather small deformations, we chose a linear-elastic HU-dependent material model. More specifically, our in-house mapping algorithm assigns a Youngs’ modulus et al.62:Ei is the Young’s modulus in GPa and 3 for the respective FE-node 46. Note that values below 1 MPa were set to 1 MPa, to avoid negative or zero elasticities63.The bone’s Young’s modulus could then be assigned nodewise, according to its respective ash density, following another relation presented in Cong The mesh quality was optimized within a convergence analysis: the element size was incrementally decreased from 7.4 mm to 2.0 mm until the change in the computed strains and deformations fell below 5%. The final mesh for our baseline model consisted of 123,454 nodes and of 83,845 elements with an element size of 3.8 mm.The numerical boundary conditions and locations of the strain gauges were extracted from the 3D scan to ensure that they resembled the experimental setup. To go into further detail: The FE nodes of the distal part of the femoral cortex below the casting resin surface were entirely constrained to zero DoF, and a compression load similar to the experimental loading was applied to a reference point that kinematically distributed the resulting displacement to the FE nodes on the upper hemisphere of the femoral head.64. The dynamic loading regimen was implemented as sinusoidal function equivalent to the experimental loading regimen as described in Supplementary Information on the experimental protocol of the in-vitro analysis. The resulting force was applied at the femoral head to a reference point that was directly coupled to the FE nodes of the femoral head via kinematic coupling representing the experimental stamp.Based on the described static FE model, the femur specimen was also analyzed within a dynamic FEA with an implicit solver over 10 s simulation time. A dynamic loading regimen was defined and a constant mass density of 1940 kg/m³ was assumedCraig-Bampton modal reduction method42 in the floating frame of reference formulation was employed for the SEM generation from the specimen-specific FEM.Since clinically relevant load cases only cause small linear-elastic deformations in the bone that otherwise undergo large rigid body motion, the Craig-Bampton modes, The unreduced FEM,Craig-Bampton mode shape analysis using Abaqus/CAE®.The mode shapes flexible body input interface into the multibody dynamics software environment SIMPACK® for subsequent, flexible multibody dynamic analysis. The numerical boundary conditions were defined similarly to the FEM  vector of stresses - partial derivative operator matrix D and As it concerns the stress and strain computation, the SEM’s stresses are recovered by deploying a linear-elastic material law. According tohttps://simtk.org/home/kneeloads) as made available to the public within the 4thGrand Challenge Competition to Predict In Vivo Knee Loads45. To put it briefly, the SimTK dataset is a comprehensive and consistent collection of subject-specific models and measurements from one male subject  that enables the validation of NMBS estimates in the lower extremity. The database included the geometry of the lower-right extremity  from CT scans (pre- and post-op) and marker trajectories from motion capture experiments. To implement the femur specimen SEM into the NMBS, bone geometries and marker trajectories of the SimTK dataset were globally scaled to the size of the femur specimen (111.53%) using Geomagic Studio.The NfMBS model Fig.  was base66 was linked via a one DoF revolute joint to the pelvis’ sacrum endplate center. In addition, spring-damper force elements (referred to as symmetry condition) restricted the motion of the sagittal plane by exerting forces and torques to the pelvis with respect to the ground, thus, eliminating abnormal bending torques around the sagittal plane during a symmetric squat motion. In this manner, the lower-left extremity was represented by its reaction forces and torques, acting upon the pelvis.The reconstructed bone segments were mutually linked by ideal joints to an open kinematic chain Fig. . Startin68, which allowed for the description of joint dynamics and the identification of the attachment sites of relevant muscle structures of the lower extremity as documented in the Twente Lower Extremity Model 2.0 dataset55. The origins and insertions of the muscles, in particular, were verified by an experienced orthopaedic surgeon. Since a single bone segment was defined as the sum of its corresponding soft tissue and bone structures, soft tissue masses could be estimated, based on the subject’s mass using regression techniques69.The preservation of the bone geometry and anatomical landmarks allowed for the definition of mass properties, for the identification of joint rotation axes, by fitting spheres or cylinders into the articulating surfaces of adjacent segments, and moreover, for the establishment of standardized reference systems55. Deflection phenomena from muscles around the bone were considered by deploying segment-fixed via-points and wrapping70. A complete list of muscle structures with their Hill-type model parameters is summarized in the Supplementary Table 60.Relevant muscles were implemented in the form of unidimensional Hill-type force elements acting along their anatomical attachment sites. To account for the exertion of physiological forces, the functional units of muscles were subdivided into several force elements to account for wide attachment areaset al.55 and not the area of each subunit itself.Joint markers and muscle attachment sites—including muscle via-points—adjacent to the flexible femur SEM, required the definition of interface nodes in the FE modeling step as they potentially deform the femoral bone and thus, must be considered during modal reduction. As it concerns the joint markers, the subsets of FE-nodes were defined according to the contacting cartilage surfaces of the femoral head and condyles. As it relates to the muscle attachment sites, the FE-nodes located within a radius of approx. 0.5 cm around the respective attachment site were defined as the interface node’s subset of respective coupling nodes. The choice of the radius of 0.5 cm results from FE model’s element size of 3.8 mm and the fact that the attachment site area is accounted for by the subdivision of the whole muscle into functional subunits as defined by Carbone SimTK dataset45 comprises the trajectories of reflective skin markers that were applied to the male subject’s body at prominent anatomical landmarks to track its motion. The subject performed three squat cycles with a self-selected speed. Utilizing the kinematic topology of the NMS model as defined above, the marker motions and the resulting overall motion of the rigid skeletal multibody system were converted into trajectories of the minimal coordinates in joint space The two-leg squat motion scenario as available from the 71 to track the experimentally obtained joint trajectories In our NfMBS featuring dynamic stress and strain computation, we deployed a computed muscle control (CMC) algorithmThe NMS system dynamics is then superposed with a generic feedback control,72,i-th muscle by means of the translational Jacobian matrix j-th joint. We deployed Hill-type muscles of the form,The resulting net torques to generate muscle forces. Therein, 72. The muscle force element is then defined as an actuator whose force generating capacity depends on its theoretical maximum force For the sake of simplicity, the force-length-velocity factor was set to NfMBS_2legsquat_Geier-et-al


Substantial efforts are currently focused on investigating and developing new multidrug-resistant tuberculosis (MDR-TB) drugs and diagnostic methods. In Yemen, however, the evaluation of health-related quality of life (HRQoL) and the effect of current MDR-TB treatment on the QoL are commonly ignored. This study evaluated the HRQoL during and after treatment and identified the risk factors that are predictive of HRQoL score differences.A prospective cohort study was conducted in four of the five main MDR-TB centres in Yemen. The patients confirmed with MDR-TB completed the SF-36 V2 survey at the beginning of treatment, end of treatment (continous phase) and at the 1 year follow-up after completing treatment. A total normal base score (NBS) of < 47 reflects impairment of functions, whereas a mental component summary (MCS) score of < 43 indicates a risk of depression.At the beginning of treatment, the mean scores for all health domains were < 47 NBS points . At the completion of treatment, all eight health domains increase compare to beginning of treatment , but a follow-up duration of 1 year after completing treatment showed decreased NBS points in all domains . Age, history of streptomycin use, baseline lung cavity, marital status and length of sickness before MDR-TB diagnosis were predictive of in PCS score differences, whereas, age, smoking, baseline lung cavity, stigma, residence, marital status and length of sickness before MDR-TB diagnosis were predictive of MCS scores differences.The length of sickness before DR-TB diagnosis was found to be predictive of the trends in both PCS and MCS scores. Despite the positive outcome of MDR-TB treatment, the low HRQoL scores obtained for all heath domains and especially for mental health reflect a high depression status of patients even after 1 year of completing therapy. Moreover, the poor HRQoL, particularly regarding mental health, of study participants at the end of treatment demands the need for urgent attention from national tuberculosis control programme managers. Therefore, the Yemen Ministry of Health and the National Tuberculosis Control Programme should implement an intervention programme to enhance HRQoL at the end of treatment to avoid any further negative consequences of MDRTB in patients after treatment. Moreover, The HRQoL data of patients with MDR-TB must be collected at the different stages of MDR-TB treatment to provide an additional parameter for assessing the effectiveness of the treatment programme.SNOYEM 1452. Registered 01 February 2013. Tuberculosis (TB) is consider as one of the most transmittable disease, causing approximately 2 million deaths annually . TB is mMycobacterium tuberculosis (MTB) that is resistant to both isoniazid and rifampicin. MDR-TB is a chronic, devastating disease that requires protracted chemotherapy (≥ 20 months) with a severe regimen of potentially toxic and less efficacious second-line anti-TB drugs [Health-related quality of life (HRQoL) is defined as “the extent to which patient’s subjective perception of physical, mental and social wellbeing are affected on a day to day basis by a disease and its treatment(s)” , 7. PatiTB drugs , 12. MDRTB drugs .Despite the considerable attention given to traditional microbiological and clinical indicators, the effect of MDR-TB on the HRQoL of patients has largely been neglected . Few stuThis work is a prospective cohort study conducted in four among 5 main MDR TB centres in Yemen. These centers consider as the largest in Yemen. In addition all major diagnosis test such as culture is performed only in these centers. All eligible candidates  were patients with MDR-TB enrolled for treatment at the study site and follow-up after 1 year of completing treatment. Those excluded comprised patients with a history of MDR-TB treatment and physical and/or cognitive limitations that prevent them from being able to answer questions. The treatment protocol of MDR-TB patients enrolled in this study has been previously reported [The eligible MDR-TB patients completed the SF-36 V2 survey at the beginning and end of treatment and after 1 year of follow up after completing the treatment. The short form SF-36 V2 health survey has been utilized by numerous TB studies and has shown acceptable reliability and validity , 20–22. A pilot testing of SF-36v2 (Arabic translation) was performed on 38 eligible patients with MDR-TB, excluding those involved in the final study. All eight health domain scales displayed good internal consistency. The reliability coefficients ranged from 0.73–0.92, which were well within the acceptable limits . PCS exhibited strong correlation with PF, RP and BP (r ≥ 0.5) and moderate correlation with GH (r = 0.49). Similarly, MCS was strongly correlated with MH, RE and SF (r ≥ 0.5) and moderately correlated with VT (r = 0.47).During the study period, all eligible patients with MDR-TB who consented to participate in the study were requested to self-complete SF-36v2 at three time points: i) at beginning of treatment, ii) end of treatment and iii) 1 year follow-up after completing treatment. The registered subjects who did not participate at the second follow-up were not requested to complete the questionnaire on the third follow up. During the study recruitment period, 135 patients with MDR-TB were registered for the treatment at the study site. Fifty-five patients (41%) were ineligible (illiterates and < 18 years old) and were thus excluded. Eighty patients were eligible and completed the questionnaire at the baseline visit. Afterward, 71 and 52 patients completed the questionnaire on the second and final follow-ups, respectively  of the eight health domains and summary components were calculated based on the standard scoring algorithms (US weights) recommended by the developers of the instrument  and by sp-value of < 0.05 was considered statistically significant. Cohen recommended frequently applied guidelines to rank the effect of size  [Data were analyzed using SPSS 24. General linear model (GLM) repeated measures ANOVA was used to determine a possible significant interaction effect and variation in the pattern of subjects over time, as well as which independent variables were predictive of changes in summary scores. Following the detection of statistically significant interaction, Bonferroni post hoc test was applied to refine the interpretation. A  = 0.14) .The baseline clinical and socio-demographic characteristics of the patients participating in the study are provided in Table Table During the treatment, MID was observed for both PCS and MCS, although both scores remained < 47 NBS points on all settings. An increment in the PCS and MCS scores was observed the longer a patient remains under treatment. PCS was greater than MCS in both the beginning of treatment and after 1 year of completing treatment. However, MCS and PCS decreased after completing treatment. For both PCS and MCS scores, one-way repeated measure ANOVA revealed significant interaction effect for time  of the eight health domain scales showed improved scores at the end of treatment. A low score, particularly on mental health, reflects the severely deteriorated condition of the patients. Similar poor HRQoL in patients with drug-susceptible and MDR-TB has been previously reported , 22, 32.The second evaluation at the end of treatment showed significant improvements in all health domain scales and both component summary measures. A plausible reason for the improvements between the two time points may be the positive effect of treatment. This finding is consistent with several studies on patients with drug-susceptible TB that reported MID at the end of treatment , 32, 33.Notwithstanding clinically significant improvements, the HRQoL scores of the study participants at the end of TB treatment were less than the general population norms (47–53 NBS points), except for PF and GH. This finding is logical, as one may anticipate high prevalence of residual impairment in the HRQoL of these patients, given the lingering and destructive nature of MDR-TB and lengthy therapy with toxic drugs for 2 years. Similar residual impairments of HRQoL among patients with drug-susceptible TB have been reported in detailed reviews and specific studies , 20, 34.Furthermore, this study identified a high prevalence of depression risk among the study participants. Preliminary assessment showed that a majority of the study participants are at risk of depression (MCS < 43 NBS points), though this proportion declined upon MDR-TB treatment. Nonetheless, a considerable proportion of the patients remain at risk of depression after 1 year of treatment. The high proportion of patients at risk of depression can be attributed to prior multiple treatment failures, knowledge of suffering from a debilitating form of TB and psychiatric side-effects related to the use of cycloserine, ethionamide and fluoroquinolones . A high In this study, we determined the length of sickness before MDR-TB diagnosis interacted with time to predict trends in the PCS and MCS scores within the subject. Similarly, the general linear repeated model measure of ANOVA test showed that age, smoking, and rural residency and marital status interacted with time to predict the mental scores within the subject.Based on the predictive of difference in MCS scores, mental health or well-being was significantly associated with smoking, age of > 45 years, baseline lungs cavity, stigma, residence, marital status and length of sickness. The non-smokers, patients aged ≤45 years, those with no baseline lung cavity, rural dwellers and non-stigmatised patients displayed higher MCS scores at every time point compared to their counterparts. These findings are consistent with some studies carried out in Canada and India , 26. HowThe old age of > 45 years among patients was predictive of differences in overall MCS scores. Women are twice more likely than men to develop depression because of biological responses, self-concepts and coping mechanisms , 39, eveMarital status interacted with time to be predictive of change in mean scores of component summary measures (PCS and MCS). The substantial increase in the mean MCS score of married patients during the first 12 months of treatment may be a result of the improved care and emotional support provided by the spouses and children of married patients . MarriagThe length of sickness before DR-TB was the only independent variable that interacted with time to predict trends in PCS scores. The length of sickness also showed statistically significant interaction with time to predict trends in MCS scores and was predictive of difference in PCS and MCS scores. The relatively lengthy period of futility, social stigma, insufficient social support, sense of irrelevance, fear of disease and expected demise may have contributed to the relatively worse physical and mental health of the patients. The length of sickness and depression are positively associated among patients with TB .The direct relationship between physical deterioration and low mental health  and the The provision of rapid drug susceptibility testing (Xpert MTB/RIF assay) will greatly decrease the delay in MDR-TB diagnosis, which in turn will prevent further reduction in patients’ HRQoL. Another reason for the prolonged duration of sickness with TB prior to the diagnosis of MDR-TB may be the delay in unreasonably searching for treatment centres by chest symptomatics, eventually reaching the chest clinic and being diagnosed with TB . Ways thThe length of sickness before DR-TB diagnosis interacted with time was found to be predictive of the trends in both PCS and MCS scores. However, age, smoking, residence, marital status and length of sickness before DR-TB diagnosis showed statistically significant interaction with time to predict trends in MCS scores. Despite the positive outcome of MDR-TB treatment, the poor HRQoL of study participants, particularly their mental health, at the end TB treatment demands the need for the urgent attention of NTP managers. Many of the patients face the risk of depression during MDR-TB treatment. The HRQoL data of patients with MDR-TB must be collected at the different stages of MDR-TB treatment to provide an additional parameter for assessing the effectiveness of the treatment programme. Patients with MDR-TB with known risk factors for poor HRQoL must be given special attention in the form of regular psychological counselling and material support . The psychological support can be provided to patients with MDR-TB through peer-to-peer and support groups, which may enable patients to meet and socialize with other patients and provide psychological support to each other. Inviting cured patients to support groups may provide emotional support for the patients on treatment.The study was conducted in four main TB centres among all centres in Yemen. Thus, the findings must be interpreted with the major limitation of a small number of participating patients. Given that this study comprised patients from an extensive geographical area, the findings may reflect the effect of MDR-TB treatment on patients’ HRQoL across Yemen. Nonetheless, a multi-centre study with a large sample size and drug susceptible TB controls is needed to corroborate the findings. Given that the self-administered version of SF-36v2 health survey was used and the majority of the patients enrolled at the study site for treatment were illiterate, some were unable to fully participate in the study.


To report the prevalence and severity of metamorphopsia, estimate its impact on vision-related quality of life (VRQoL) and evaluate predictors of VRQoL in patients with vitreomacular traction (VMT).A prospective, cross-sectional multi-centre study in the United Kingdom of 185 patients with VMT, with or without a full thickness macular hole (FTMH). Self-reported metamorphopsia was determined using the metamorphopsia questionnaire. VRQoL was assessed using the Visual Function Questionnaire (VFQ-25). Physicians recorded clinical and ocular characteristics in both eyes including a physician assessment of metamorphopsia. ANOVA and predicted least-squares means were used to estimate the impact of metamorphopsia on VRQoL. Predictors of VRQoL were assessed using ordinary-least-squares regression adjusting for clinically important variables.The prevalence of self-reported metamorphopsia was 69.7% (95% CI 62.6–76.3%) and was higher in eyes with a concomitant FTMH vs. without FTMH (85.4% vs. 64.2%). Physician assessment of metamorphopsia was 53.0% (95% CI: 45.5–60.3%). Comparing eyes with metamorphopsia vs. without metamorphopsia, the VFQ-25 composite score was lower (82.3 vs. 91.4), and mean VA (LogMAR) was worse (0.44 vs. 0.33). The largest difference in VFQ-25 scores was observed for near activities . The adjusted model showed that metamorphopsia severity and age were significantly associated with lower VFQ-25 scores.Metamorphopsia was highly prevalent in patients with VMT and associated with significantly lower VRQoL. Physician assessment of symptoms underestimated the self-reported presence of metamorphopsia. Metamorphopsia severity acts as a predictor of impaired VRQoL, over and above decrements due to reduced vision. Vitreomacular adhesion (VMA) is characterised by persistent macular attachment of the posterior vitreous within 3 mm of the fovea without an altered foveal contour and results from incomplete posterior vitreous detachment (PVD) . VMA maySome studies have investigated metamorphopsia and its association with vision-related quality of life (VRQoL) in retinal disorders, however none of these relate to metamorphopsia in VMT –13. It cThe aim of the present Metamorphopsia (MeMo) study was to determine the self-reported prevalence and severity of VMT-related metamorphopsia in patients presenting to eye clinics in the United Kingdom (UK), to report the impact of metamorphopsia on VRQoL, and to explore possible clinically relevant predictors of VRQoL.The MeMo study was a prospective, observational, cross-sectional, multi-centre study conducted at NHS hospital eye clinics across the United Kingdom (UK). Ethical approval was granted by the West of Scotland Research Ethics Service (REC reference number: 14/WS/0092) and institutional R&D approval was obtained for the protocol and study-related documents. The study adhered to Good Clinical Practice and to the tenets of the Declaration of Helsinki. Informed consent was obtained from every participant prior to enrolment.Sites were chosen to provide a representative sample of VMT patients, specifically, sites from large and small cities and a wide geographical spread across the UK. Ophthalmology clinics operating treatment protocols that included observation (watchful waiting) and/or pharmacological (ocriplasmin) or surgical (vitrectomy) vitreolysis were enroled. Participating physicians had experience with the diagnosis and treatment of VMT and were characterised by a mixed referral basis. Treating physicians continued their usual practice and patient management, no protocol-driven treatment or test was administered to preserve the observational design. Recruitment extended from July 1, 2014 until July 1, 2015.Inclusion criteria included a confirmed diagnosis of VMT, with or without a concomitant FTMH, within prior 6 months and ability to provide written informed consent. Consecutive patients were enroled as they presented for a routine clinic visit to address potential sources of bias. Exclusion criteria, assessed in the affected eye, included: VMT associated with an underlying macular disease ; FTMH or epiretinal membrane (ERM) without a tractional component; traumatic MH; FTMH > 400 μm; high myopia (>8 dioptres); advanced glaucoma; prior vitrectomy or intravitreal intervention; and intraocular surgery other than vitrectomy within prior 3 months.Physicians collected baseline data at the single visit for each participant using a standardised data form consisting of inclusion/exclusion criteria, patient characteristics, current medical and ocular conditions, ocular interventions, date of first symptoms, and ocular examinations. The investigator noted ocular dominance through asking the patient, using one of the recommended tests  or alternatively the test applied in their clinical practice. In addition, the physician’s assessment of symptoms , ocular diagnosis and date of diagnosis were recorded. All ocular assessments were performed for the affected and fellow eye. Patients completed the metamorphopsia questionnaire and the National Eye Institute Visual Function Questionnaire, hence these were all self-reported outcomes.The primary outcome measure of the MeMo study was the prevalence of metamorphopsia in patients with VMT. The presence (and severity) of metamorphopsia was based on the patient’s self-reported perception of abnormal vision quality as evaluated using the MeMoQ. The metamorphopsia questionnaire, developed by Arimura et al. consists of ten items focusing on symptoms of subjective metamorphopsia in a patient’s daily life . ArimuraPatients completed the self-assessed, self-administered version of the VFQ-25 to assess VR-QoL. Each of the 25 VFQ questions is assigned to one of the 12 subscales: general health, general vision, ocular pain, near activities, distance activities, social functioning, mental health, role difficulties, dependency, driving, colour vision, and peripheral vision. Subscales scores range from 0 to 100, where 100 indicates the highest possible function or minimal subjective impairment . The NEIIn addition to the primary determination of metamorphopsia prevalence (self-reported from the MeMoQ), the physician’s assessment of metamorphopsia was positive if the patient reported distorted vision and/or curvy objects in either eye.MeMo was a descriptive study with the primary aim of estimating the prevalence of metamorphopsia in VMT. Based on a 95% two-sided confidence interval (CI) and an assumed prevalence between 60 and 90%, a sample size of approximately 200 allows a precision of the prevalence estimate within an 8.4–13.6% range.P values assessing differences between metamorphopsia subgroups were derived from the Student’s t-test. Due to the exploratory nature of this study, no formal hypothesis testing was conducted. Thus, any P-value generated should be regarded as a descriptive, rather than inferential, statistic.The prevalence of metamorphopsia assessed by the MeMoQ was computed for the overall population and for subgroups according to the presence of a FTMH. Clopper-Pearson method was performed to obtain 95% CI around prevalence estimates. Physician assessment of the presence of symptoms of metamorphopsia was summarised for the overall population and by self-reported presence of metamorphopsia. The agreement between physician and patient evaluation of metamorphopsia was calculated using the Kappa statistic . DescripThe effect of the presence of metamorphopsia on VFQ-25 was explored through a univariate (ANOVA) model. In the ANOVA model, the VFQ-25 score was the dependent variable and an indicator variable denoting presence of metamorphopsia was the independent variable. The least-square mean VFQ-25 scores were reported for patients with metamorphopsia and patients without metamorphopsia. The estimated difference between both groups were reported including 95% CI.A multivariate ordinary least squares (OLS) regression was fit to identify the predictors of VFQ-25 scores, including metamorphopsia severity score, whether the affected eye was the best seeing eye, whether the affected eye was the dominant eye, patient age, visual acuity of best seeing eye (in LogMAR), visual acuity of the dominant eye (in LogMAR). The selection of these variables was based on clinical reasoning. Analyses were performed on patients who had non-missing data. In the scoring of questionnaire data, the rules surrounding missing items was applied for each specific questionnaire.This study included a total of 185 patients enroled at 19 hospital eye clinics  and higher among patients with a concomitant FTMH  vs. patients with no FTMH  was primarily based on self-reported perception of subjective symptoms of metamorphopsia. Furthermore, physicians assessed the presence of metamorphopsia symptoms, denoted as distorted vision and/or curvy objects in any eye, which was lower (53.0%). The agreement between self-reported (MeMoQ) and physician assessment (symptom-based) of the presence/absence of metamorphopsia was concordant in 112 patients (60.5%). (In 77 patients the self-reported assessment on the presence of metamorphopsia agreed with the physician’s and in 35 patients the self-reported assessment on the absence of metamorphopsia agreed with the physician’s assessment). The assessment of metamorphopsia status was discordant in 73 (52 + 21) patients (39.5%). The Kappa statistic measuring the difference between observed and expected agreement  was 0.192 (95% CI 0.058–0.326) indicating a slight agreement (Table P < .05), except for the driving subscale and general health item VFQ-25 . VRQoL, as measured by the VFQ-25 composite score was 85.1 points in the overall population and was markedly lower in patients with metamorphopsia (82.3) vs. patients without metamorphopsia .Based on the univariate model that examined the impact of the presence of metamorphopsia on VFQ-25, the mere presence of metamorphopsia was associated with a significantly lower VFQ-25 score. The mean VFQ-25 composite score for patients with metamorphopsia was 82.3  vs. 91.4  for patients without metamorphopsia. Therefore, the disutility associated with the presence of metamorphopsia was −9.1  compared to patients without metamorphopsia . This difference of 8.09 points was significant (P = 0.0015). Similar findings were observed in patients with a concomitant FTMH or ERM: quality of life in patients with metamorphopsia was 81.54 (n = 53) compared with 93.12 (n = 11) in patients without metamorphopsia. This difference of 11.58 points was significant (P = 0.046). A similar analysis using any-eye level data confirmed that the presence of metamorphopsia significantly impacts vision-related QoL regardless of the ocular diagnosis  in the affected eye, while 64 patients had a concomitant FTMH or ERM. Results indicate that quality of life (as measured by the VFQ-25 composite score) was lower in VMT patients when metamorphopsia was present  and patient age (P < 0.05). Each unit increase in metamorphopsia severity score was associated with a 14.5-point reduction in the VFQ-25 composite score. Each additional 10 years in patient’s age was associated with 3-point reduction in VFQ-25. VA of the best seeing eye was marginally predictive of VFQ-25 (P = 0.086).The OLS regression model estimated the effect of the different covariates on VFQ-25 composite score Table . The varIn patients with VMT, metamorphopsia is considered one of the cardinal symptoms which impairs a patient in the ability to perform activities such as reading, face recognition, cooking, watching television and driving. This study shows that 69.7% of patients with VMT attending NHS hospital eye clinics in the UK reported the presence of metamorphopsia. The prevalence was notably higher among VMT patients with a concomitant FTMH (85.4%) compared to patients with no FTMH (64.2%). Patients who self-reported metamorphopsia had a noticeably lower VRQoL compared to patients with no metamorphopsia (a 9.1-point decrease on the VFQ-25 composite score). Moreover, the independent effect of the severity of metamorphopsia, over and above VRQoL decrements due to reduced VA, is an important finding indicating that despite controlling for vision, metamorphopsia impacts the quality of vision.The present literature reveals a paucity of data on the prevalence and severity of metamorphopsia self-reported by patients with VMT. Indeed, there are no prospective reports from multi-centre settings relating to metamorphopsia in VMT in clinical practice. However, the recent interest in pharmacotherapy for the treatment of VMT generated data relating to symptoms and VRQoL in VMT from clinical trials. The OASIS study  was a muOne major finding in the MeMo study is the discordance in self-reported presence of metamorphopsia using the MeMoQ versus patient-reported symptoms on questioning by the ophthalmologist. When metamorphopsia was diagnosed based on the ophthalmologist’s assessment of symptoms of distorted vision and/or curvy objects in any eye, rather than patient self-assessment, the prevalence was lower (53.0%). Both the presence of metamorphopsia and VRQoL were self-reported and reflect a patient-level (not eye-specific) assessment. Similarly, physicians assessed symptoms in affected and fellow eye. The analysis of agreement between physician and self-reported assessments used data for any eye, hence, the discordance cannot be attributed to a mono vs. binocular assessment. Several factors may underlie this disparity including misinterpretation of the questions posed by the ophthalmologist, differences between physicians’ questions and the MeMoQ, or patients feeling unsure whether to disclose the full extent of symptoms. Disparities between patients and physicians in reporting or describing symptoms have been reported previously, including retinal disorders , 23.Our results show impaired VRQoL using the VFQ-25 in patients with recently diagnosed VMT. The MIVI-TRUST clinical programme reported a mean baseline VFQ-25 composite score of 82 points for placebo-treated and 77.1 for ocriplasmin-treated patients . This VMAfter adjusting for baseline VA, age, and other clinically important variables, the severity of metamorphopsia was the most predictive of impaired VRQoL. These results may under-estimate the full impact of metamorphopsia since the multivariate analysis controls for VA and other variables that may in themselves be affected by metamorphopsia. Nevertheless, the results underscore the importance of metamorphopsia as a predictor for VRQoL in patients with VMT. Surprisingly, the involvement of the dominant eye did not appear to affect VRQoL. This could be because the measurement of dominance is influenced by the pathology  or due to the crude method of assessment of eye dominance used in clinical practice.A number of previous studies have assessed the severity of metamorphopsia in other retinal disorders, using Amsler grid, M-CHARTS and/or PHP, and found that changes in the severity of metamorphopsia was an important factor of changes in VRQoL –8, 10–12In the MeMo study, a diagnosis of VMT was reported in 17% of fellow eyes , and physicians assessed the presence of symptoms of metamorphopsia in 11% of fellow eyes. Impairment in VRQoL could partially be attributed to VMT or macular pathology in the fellow eye, however, based on the results of the multivariate regression analysis adjusting for covariates such as fellow eye involvement did not significantly affect the impact of metamorphopsia on VFQ-25 composite scores. In addition, subgroup analyses confirmed that the presence of metamorphopsia significantly impacted vision-related quality of life both in patients with isolated VMT as well as in patients with a concomitant FTMH or ERM.The MeMo study is the first prospective study using the questionnaire developed by Arimura et al. to assess metamorphopsia based on self-reported perception of abnormal vision quality.This study has several strengths, including the use of a prospective, multi-centre study design with large sample size and the collection of rich phenotypic data including information from SD-OCT imaging as well as patient-centred reporting of metamorphopsia and VRQoL. The limitations include the lack of use of a wider range of methods to quantify the severity of metamorphopsia due to the time limitations on patients and clinicians in real-world clinical settings . Indeed, at a feasibility study at the time of the MeMo study design confirmed unanimously that diagnostic tools to detect metamorphopsia in the UK NHS eye clinics, such as Amsler grid, were not used in clinical practice because of their inability to quantify the degree of metamorphopsia. In addition, no validated tool was available or adopted in UK clinical practice, meaning the introduction of such objective measurement instrument would have altered real life  practice. Additional research to detect and assess metamorphopsia with validated tools is warranted to investigate the correlation between the patient’s perception of the severity of metamorphopsia and an objective quantification. Although reading vision is a key component in the assessment of metamorphopsia, an important limitation of our study was the absence of this assessment. Indeed, near vision function was affected in close to half of the patients. Further research to include an assessment of full visual function performance such as reading acuity or contrast sensitivity is warranted. Finally, the MeMo study population was restricted to patients with a FTMH diameter smaller than or equal to 400 µm, to be consistent with the population studied in the ocriplasmin clinical trials. Although this may restrict generalisability of the results, it allows better comparability with the existing evidence on VFQ-25 outcomes in VMT patients eligible for pharmacological treatment.In summary, the MeMo Study is a large prospective patient-centred study reporting the prevalence and severity of self-reported metamorphopsia and its independent effect on VRQoL in patients recently diagnosed with VMT attending hospital eye clinics in the UK. The results show that metamorphopsia is a highly prevalent symptom, particularly in those with a concomitant FTMH, and impairs VRQoL independent of the presence of a FTMH and reduced VA. Given the importance of metamorphopsia as a symptom in patients with VMT, it is important to consider the impact of new and existing treatments on this disabling symptom. Further research supporting a full psychometric evaluation of the questionnaire in populations with retinal disorders, including VMT is warranted.A small number of studies have reported the prevalence of metamorphopsia (distorted vision) and its association with impaired vision-related quality of life (VRQoL) in retinal disorders.None of these relate to metamorphopsia in patients with vitreomacular traction (VMT).Metamorphopsia is a common symptom of abnormal vision in patients recently diagnosed with VMT, and is a predictor of impaired quality of life, over and above quality of life decrements due to reduced visual acuity. Increasing severity of metamorphopsia and age were associated with a poorer vision related quality of life, independently of visual acuity.Metamorphopsia was reported more frequently when using a metamorphopsia-specific patient questionnaire as compared to symptom-based assessment by the ophthalmologist.Given the importance of metamorphopsia as a symptom in patients with VMT, the use of a patient-reported questionnaire to detect symptoms of metamorphopsia may be considered in clinical practice.MeMo supplementary figures and tables