In this retrospective study, we longitudinally analyzed axial impairment and falls in people with Parkinson’s disease (PD) and subthalamic nucleus deep brain stimulation (STN-DBS). Axial scores and falling frequency were examined at baseline, and 1, 10, and 15 years after surgery. Preoperative demographic and clinical data, including PD duration and severity, phenotype, motor and cognitive scales, medications, and vascular changes on neuroimaging were examined as possible risk factors through Kaplan–Meier and Cox regression analyses. Of 302 individuals examined before and at 1 year after surgery, 102 and 57 were available also at 10 and 15 years of follow-up, respectively. Axial scores were similar at baseline and at 1 year but worsened at 10 and 15 years. The prevalence rate of frequent fallers progressively increased from baseline to 15 years. Preoperative axial scores, frontal dysfunction and age at PD onset were risk factors for axial impairment progression after surgery. Axial scores, akinetic/rigid phenotype, age at disease onset and disease duration at surgery predicted frequent falls. Overall, axial signs progressively worsened over the long-term period following STN-DBS, likely related to the progression of PD, especially in a subgroup of subjects with specific risk factors. The positive effects of STN-DBS in PD are maintained over time despite the disease progression, thus confirming a favorable risk-benefit ratio also in the long-term period9. However, the sustained clinical benefits from STN-DBS in PD are undermined by the occurrence of disabling symptoms that are resistant to medical and surgical treatments, including axial impairment and falls10. By leading to physical restrictions and injuries, axial impairment  and falls give rise to a high burden for patients and caregivers and are among the most challenging clinical issues in advanced PD11. Indeed, the severity of the axial disability is linked to individual risk of death after DBS surgery12, whereas falls are associated with reduced survival and high economic repercussions in PD11.Since the early FDA approval of subthalamic nucleus deep brain stimulation (STN-DBS), several randomized clinical trials have documented the efficacy of this treatment for the relief of advanced Parkinson’s disease (PD) symptoms23. Moreover, when considering the long-term period, while a few authors agreed on the progressive decline of axial functions up to 10 years after surgery25, no studies have examined the impact of STN-DBS on the occurrence of falls in PD. Hence, a definite consensus concerning the evolution of axial impairment and falls in people with PD after STN-DBS surgery is still absent. A further relevant issue concerns the current lack of preoperative factors predicting axial impairment progression and fall occurrence in the very long-term period after STN-DBS in PD. Indeed, although some authors suggested the preoperative severity of axial impairment and axial sensitivity to L-Dopa as predictors of post-surgical axial disability27, these findings have not been consistently replicated in large cohorts of patients. Also, the only study investigating predictors of falls after STN-DBS surgery in PD failed to find significant risk factors21. Small sample sizes, short follow-up periods and non-focused experimental designs may have precluded the achievement of firm conclusions on the evolution and predictors of axial impairment and falls after STN-DBS surgery in PD. Accordingly, prolonged longitudinal observations of large samples of individuals with PD after STN-DBS surgery would be necessary to address these issues. The knowledge of the long-term evolution and preoperative risk factors of axial impairment and falls after STN-DBS surgery would help select patients for surgery. Also, it could implement preventive therapeutic strategies to improve axial disability and avoid injuries in PD.Previous studies have reported inconsistent results concerning the progression of axial signs and the occurrence of falls in the short-term after STN-DBSIn this retrospective study, we analyzed a large dataset of people with PD and STN-DBS, followed longitudinally up to 15 years after surgery, with the main objectives of evaluating axial signs, including gait, posture and balance disorders, and falls progression and associated risk factors. To fill the gap in the literature, we focused on the very long-term evolution of axial signs and falls in people with PD by evaluating patients 10 and 15 years after STN-DBS surgery under the chronic treatment conditions . Moreover, in addition to the long-term evaluation, our time-dependent analysis also included a short-term time point  to examine early changes in axial function and fall occurrence after surgery, supporting the identification of risk factors for these disorders.A total of 417 people with PD and bilateral STN-DBS operated between 1993 and 2010 was retrieved from the Movement Disorders Centre database of the Grenoble University Hospital, France. From the analyses, 115 subjects were excluded because of incomplete medical records, surgical complications responsible for persistent neurological sequelae, other brain surgical procedures, or electrode misplacement. Accordingly, based on exclusion criteria and data availability in medical records, 302 people were included with 1-year follow-up . There were 102 patients available at 10 years  and 57 patients at 15 years .Table X2(3) = 107.728, p < 0.001]. The Wilcoxon signed-rank test demonstrated similar axial scores at baseline and at 1-year follow-up , but progressively higher axial scores at 10- and 15-year follow-ups   Table .Fig. 1Evχ2 test demonstrated a progressive increase in the number of people with PD presenting frequent falls from baseline through the 15-year follow-up (baseline vs. 1-year follow-up: χ2(1) = 3.98, p = 0.046; baseline vs. 10-year follow-up: χ2(1) = 62.41, p < 0.001; baseline vs. 15-year follow-up: χ2(1) = 49.89, p < 0.001; 1-year vs. 10-year follow-up: χ2(1) = 37.655, p < 0.001; 1-year vs. 15-year follow-up: χ2(1) = 84.99, p < 0.001; 10-year vs. 15-year follow-up: χ2(1) = 9.59, p < 0.01) (Table The 1) Table .Preoperative independent variables selected through the univariate analysis and entering the stepwise selection process are reported in Table The multivariable Cox regression analysis showed that higher axial scores in the ON medication condition (adjusted hazard ratio (HR) 1.468), lower frontal scores HR 0.952), and higher age at PD onset (HR 1.095) acted as risk factors for axial impairment progression after STN-DBS , akinetic/rigid phenotype (HR 1.869), higher age at PD onset (HR 1.051), and longer disease duration at surgery (HR 1.117) acted as risk factors for frequent falls after STN-DBS , at 1-year , at 10-year , and at 15-year follow-ups . Frequency parameter of STN-DBS was not associated with axial scores at any time points as well as with the “frequent faller” condition at baseline, at 1- and at 10-year follow-ups (p > 0.05). Conversely, frequency parameter of stimulation was inversely correlated with the “frequent faller” condition at 15 years .The Spearman’s rank correlation test showed that axial scores and the “frequent faller” condition  correlated at baseline  part III only directly referred to static and dynamic postural control, thus excluding other axial signs, like voice and facial expression disorders, possibly representing confounding factors in the interpretation of data.When assessing axial impairment in the short-term period, axial scores at 1 year after STN-DBS were comparable with preoperative evaluation in the ON medication condition. This finding is fully in line with previous studies showing unchanged axial functions in the short-term follow-up after STN-DBS in PD32. These data confirm the progressive decline of axial functions in PD in the long-term period, likely resulting from the natural history of the disease, as reported in non-operated patients34. Although not conclusive, the lack of correlations between the frequency parameter of stimulation and the axial scores is in line with this hypothesis. Overall, the evidence of progressive axial impairment over the long-term period despite STN-DBS supports the current consensus criteria for DBS in PD that recommend to not consider for surgery individuals suffering from L-Dopa unresponsive axial symptoms35. Also, these findings further emphasize the need for predictive factors of axial impairment progression to properly select patients undergoing STN-DBS and promptly perform preventive strategies.Concerning the very long-term period, the worsening of axial functions in our patients confirms findings from previous studies with shorter follow-ups 21. Conversely, the lack of significant changes in the short-term rate of falls after STN-DBS reported in some previous studies could be attributed to the limited number of patients enrolled 23. The present study also investigated fall occurrence at 10 and 15 years after STN-DBS, showing a progressive increase in the number of subjects suffering from frequent falls. Several possible mechanisms may contribute to this progressive worsening of fall frequency after STN-DBS. Given the unchanged axial scores at baseline and at 1-year follow-up, it is unlikely that postural and gait disorders are responsible for the increased prevalence rate of frequent fallers in the short term. Accordingly, people with PD might fall more frequently in the short-term period after STN-DBS owing to improved motor performances and increased activity levels providing new opportunities for falling2. Conversely, the progressive decline of axial functions would play a relevant role in fall severity in the long-term period. Indeed, in line with this hypothesis, the correlation between axial scores and fall occurrence was stronger at 10 and 15 years than at baseline and at 1-year follow-up. Also, the “frequent faller” condition inversely correlated with the frequency parameter of STN-DBS at 15 years, possibly reflecting clinical efforts to improve axial signs through lower stimulation frequencies37. Lastly, the percentage of subjects presenting frequent falls at 15 years  was slightly but significantly higher than at 10 years after surgery , in accordance with the “inverted u-shaped curve” model of falls in PD38. This model predicts that the number of falls in people with PD progressively increases as motor conditions deteriorate, up to the occurrence of severe physical restrictions confining subjects to wheelchairs or beds and, thus, limiting the falling frequency38.The prevalence rate of frequent fallers in our cohort increased progressively over time after surgery. Our findings are in line with those from a recent study that found increased fall frequency 1 year after STN-DBS in a large sample of people with PD26. Although axial responsiveness to L-Dopa did not reach a statistical significance in our predictive model, the association of axial impairment progression with axial scores in ON medication, but not in OFF medication, supports the hypothesis that the lower improvement of axial signs under dopaminergic stimulation involves a higher risk for axial disability progression, in agreement with previous observations29. Accordingly, in PD, the increasing impairment of static and dynamic postural functions likely reflects the progressive involvement of extranigral pathways which remain unaffected by L-Dopa and STN-DBS39.People with PD presenting at baseline with a more severe axial disability, frontal cognitive dysfunction, and older age at the disease onset showed a mildly increased risk for axial impairment progression after STN-DBS surgery. Accordingly, we here confirm the relevant role of preoperative axial disability in predicting the progression of axial signs after STN-DBS40. Indeed, people with PD typically show worsened balance and gait during dual-task paradigms as a result of reduced cognitive reserve and increased attentional demand for motor performances40. Further supporting the strict relationship between axial impairment and cognitive dysfunction in PD40, our results highlight the need for strict selection criteria when considering STN-DBS in people with PD by including those with preserved executive abilities to maximize the opportunity for long-term benefits after surgery.The present study suggests that higher frontal abilities may act as a protective factor for axial impairment progression in people with PD and STN-DBS. This finding confirms the well-known impact of cognitive functions, primarily concerning frontal executive abilities, on balance and gait27. Moreover, it expands previous observations of a better general motor outcome in younger patients undergoing STN-DBS by confirming similar conclusions concerning axial functions41. In addition to disease-specific issues, several age-related factors  could contribute to deteriorating cognitive and motor performances in PD, resulting in increased severity of axial signs in older individuals with STN-DBS.Lastly, our analysis suggests that higher age at PD onset would contribute as an additional risk factor to axial impairment progression in people with PD and STN-DBS. This result is in line with a previous study showing early deterioration of axial signs in individuals with advanced age at surgery43. Indeed, axial impairment and akinetic/rigid phenotype are strictly linked in PD and are both associated with increased cognitive decline and malignant course of the disease compared to patients with preserved axial abilities and tremor-dominant appearance44. This study replicates the same conclusions in patients undergoing surgery, thus suggesting that these pathophysiological mechanisms underlying falls are unrelated to STN-DBS in PD.In our cohort of people with PD and STN-DBS, preoperative severity of axial disability , akinetic/rigid phenotype, age at disease onset and PD duration at surgery were associated with a mildly increased risk for frequent falls after surgery. Previous studies similarly reported abnormal axial functions and akinetic/rigid phenotype as predictors of falls in people with PD under medical treatment44. Indeed, in a community-living healthy population, more than one-third of subjects older than 65 falls each year, further pointing to the harmful synergy between disease-related issues and ageing in PD. Hence, although no specific age cut-off has been defined for STN-DBS, particular care should be taken when considering surgery for older individuals and prudently analyze the benefits-to-risks ratio35.Besides the prediction of axial impairment, higher age at PD onset was also associated with frequent falls after STN-DBS. This finding is in line with previous observations that older people with PD are usually those with earlier onset of falls and faster disease progression compared to younger subjects45, it is also associated with more severe clinical symptoms likely explaining an increased occurrence of falls. Therefore, STN-DBS may have greater beneficial effects for patients with less advanced PD by limiting the incidence of falls and allowing sustained maintenance of individual autonomy5.A final comment concerns our observation of a longer PD duration at surgery as a possible risk factor for frequent falls after STN-DBS. Although longer disease duration has been previously found as a predictor of a positive outcome for STN-DBS24, the lack of a control group precluded the direct comparison of the evolution of axial signs and fall occurrence in subjects with and without STN-DBS. Accordingly, some of the conclusions of this study were based on the indirect comparison with the natural history of the disease previously reported in cohorts of non-operated subjects34. Owing to the very long-term longitudinal observation of people with PD and STN-DBS, this study was unavoidably burdened by a high percentage of subjects lost to follow-up, possibly underestimating the incidence of axial impairment and falls after STN-DBS surgery. Lastly, the clinical evaluation of patients at 10- and 15-year follow-ups was performed under the chronic treatment conditions , thus precluding the assessment of the isolated effects of the STN-DBS on acute axial impairment and acute fall occurrence. Nevertheless, according to the prominent postoperative LEDD reduction compared to the preoperative period as well as dopamine receptor desensitization following continuous STN stimulation47, it is likely that differences between the ON and OFF medication conditions under DBS stimulation would be minimal. This dopamine desensitization is, indeed, particularly evident in people with long-term STN-DBS, in whom the sudden lack of stimulation can be fatal and clinical improvement not achieved even by very high doses of L-Dopa 48. Finally, it should be considered that axial dysfunction becomes progressively refractory to L-Dopa49, further suggesting that also STN-DBS would lose its beneficial effects on these signs over time. Overall, the assessment of axial impairment and falls in the chronic treatment conditions would reflect real-life patients’ status, and thus provide ecologic information on these signs in our cohort of people with PD.When considering the present study, some limitations should be taken into account. Although using a standardized item of the UPDRS part II , the evaluation of falls can be affected by “recall bias” that would underestimate the frequency of this issue in people with PD and STN-DBS. Also, medical records did not allow to classify falls according to severity and associated injuries, possibly limiting the interpretation of findings. Similarly, incomplete medical records concerning white matter hyperintensities (WMH) on brain magnetic resonance imaging (MRI) in a high percentage of people with PD  may have overlooked the prognostic role of this variable on the evolution of axial impairment and falls after STN-DBS surgery. Moreover, like in previous longitudinal studies involving patients undergone surgeryIn conclusion, although axial function in PD remains stable in the short term after STN-DBS surgery, it progressively worsens in the long-term period, likely as a result of the natural history of the disease. Conversely, STN-DBS may be indirectly involved in the increased occurrence of falls since the first year after surgery by improving motor performance and leading to increased activity levels. Specific motor, cognitive and demographic features at baseline, including axial disability, frontal dysfunction and age at PD onset, can act as possible risk factors for axial impairment progression after STN-DBS. Similarly, axial disability, akinetic/rigid phenotype, age at disease onset and disease duration at surgery would contribute to the occurrence of frequent falls in people with PD and STN-DBS. Therefore, in the selection procedures for STN-DBS, it would be relevant to consider these factors to provide patients and their caregivers with reasonable prognostic information and maximize the long-term outcomes of candidates for surgery. Our study focused on the preoperative features predicting axial impairment progression and falls in PD people with STN-DBS. Future studies will clarify the potential impact of postoperative variables on these disorders in PD, including factors related to active lead contact and stimulation parameters.50.This study was conducted in accordance with the “Strengthening the Reporting of Observational studies in Epidemiology” guidelines  were excluded from this study. All subjects provided written informed consent for data collection and use for research purposes. The institutional research centre authority of the Grenoble Alpes University Hospital approved the study protocol.Consecutive subjects with PD who underwent bilateral STN-DBS at the Grenoble Alpes University Hospital, France, between 1993 and 2010 were retrospectively included in this cohort study. DBS surgery was performed according to accepted indications and procedures, as well as standard stereotactic techniques52, were collected at baseline. The preoperative assessment was performed in the OFF and ON medication conditions and included the following clinical scales: UPDRS53, Hoehn and Yahr scale (H&Y)54, Mattis Dementia Rating Scale (MDRS)55, frontal score 56 and Beck Depression Inventory-II57. The postoperative assessment included the UPDRS (up to 2011) or Movement Disorder Society-sponsored revision of the UPDRS (from 2012)58 in the ON stimulation/OFF and ON medication conditions at 1 year, and in the chronic ON stimulation/ON medication condition at 10- and 15-year follow-ups. Axial impairment was assessed through the axial score, ranging from 0 to 16, intended as the sum of the items 27 or 3.9 , 28 or 3.13 , 29 or 3.10  and 30 or 3.12  of the UPDRS or MDS-UPDRS, respectively18. Concerning the assessment of falls, item 13  of the UPDRS part II, with scores ranging from 0 to 4 based on the falling frequency  was used. Finally, the L-Dopa equivalent daily doses (LEDDs) were calculated in people with PD before and after STN-DBS according to standardized procedures59.Data were collected from clinical evaluations at baseline and 1, 10, and 15 years after STN-DBS surgery. Demographic and clinical data, including age, sex, age at disease onset, disease duration at surgery, phenotype, and presence of WMH of vascular origin on brain MRI based on a semi-quantitative visual assessment through the Fazekas’ scaleχ2 test was used to compare the prevalence rate of frequent fallers by considering the number of people reporting frequent falls based on item 13 of the UPDRS part II ≥ 2  when in ON medication at baseline and ON stimulation/ON medication at follow-ups.The primary outcome consisted of changes in the axial score and prevalence rate of frequent fallers at baseline, 1-, 10- and 15-year follow-ups after STN-DBS surgery. The Friedman and Wilcoxon signed-rank tests were used for comparing axial scores at baseline and follow-ups in the best treatment conditions . The p < 0.20 in the univariate analysis entered the stepwise selection process for the final building of multivariable Cox regression models, in line with previously reported procedures62. To rule out collinearity and lack of independence among variables, pairwise correlations were checked among key covariates and those presenting strong reciprocal associations were excluded from the analysis. A threshold of 0.7 was considered to exclude strong associations among the independent variables, as previously suggested64. Kaplan–Meier product-limit method was utilized to display the “axial worsening-free survival”  and the “frequent falls-free survival”  in the total sample and subgroups of patients based on identified risk factors. To distinguish subgroups of patients, we divided subjects based on the presence of categorical risk factors . Alternatively, in the case of risk factors consisting of continuous variables , the median baseline scores in the most impaired subjects  were considered cut-off values for discriminating subgroups . The log-rank test was also performed for each significant variable entered the final Cox models. Concerning candidate risk factors, the following independent variables were assessed: age at disease onset, disease duration at surgery, phenotype , presence of WMH on brain MRI, UPDRS part III (OFF and ON conditions), H&Y (OFF and ON conditions), axial score (OFF and ON conditions), L-Dopa responsiveness of axial signs, MDRS, frontal score, and LEDDs. Survival analysis statistics were calculated from baseline to outcome achievement or censored data at the last available follow-up. HR with a 95% confidence interval was also measured. The pairwise deletion method was adopted to handle missing data.The secondary outcome was the evaluation of risk factors for axial impairment progression and frequent falls after surgery. Multivariable Cox regression analysis was used to simultaneously assess the effect of preoperative independent variables. Concerning axial impairment progression, for statistical purposes, an event was defined as the achievement of the median value of the axial score in the most impaired patients , reflecting a clinically meaningful worsening of axial signs . Univariate analysis was first used to examine the association of preoperative independent variables with the outcome variables and determine factors providing the best fit for prediction models. Preoperative independent variables showing significance with Finally, Spearman’s rank correlation test was utilized to investigate the relationship between axial scores and the “frequent faller” condition at baseline and follow-ups. Spearman’s rank correlation test was also used to examine the possible association of axial scores and the “frequent faller” condition with the frequency parameter of STN-DBS. For all statistical tests, the significant level was set at 0.05 (two-tailed).Statistical analysis was performed with the SPSS package .Supplementary Information


Our results show that coupled spindles and uncoupled spindles recruit distinct parts of the brain. Specifically, we found that hippocampal activation during sleep is not uniquely related to spindles. Rather, this process is primarily driven by SWs and SW-spindle coupling. In addition, we show that SW-spindle coupling is critical in the activation of the putamen. Importantly, SW-spindle coupling specifically recruited frontal areas in comparison to uncoupled spindles, which may be critical for the hippocampal-neocortical dialogue that preferentially occurs during sleep.Spindles are often temporally coupled to slow waves (SW). These SW-spindle complexes have been implicated in memory consolidation that involves transfer of information from the hippocampus to the neocortex. However, spindles and SW, which are characteristic of NREM sleep, can occur as part of this complex, or in isolation. It is not clear whether dissociable parts of the brain are recruited when coupled to SW vs. when spindles or SW occur in isolation. Here, we tested differences in cerebral activation time-locked to uncoupled spindles, uncoupled SW and coupled SW-spindle complexes using simultaneous EEG-fMRI. Consistent with the “ This dialogue is required for the consolidation of new memories  spindles are dissociable from one another in terms of their functional neuroanatomical substrates. Here, we expected to observe dissociable patterns of recruited brain activity in areas time-locked to SW-SP coupled events, as compared to uncoupled spindle events, or compared to uncoupled slow wave events. We hypothesize that brain activations time-locked to coupled SW-spindles would preferentially occur in brain areas known to be critical for the hippocampal-neocortical dialogue and the striatum, required for the consolidation of new memories.All participants were 20–35 years of age. Participants were initially screened for irregular sleep schedules , left-handedness, shift work, and the use of medications known to affect sleep. Participants were also excluded from the study if they considered themselves a smoker, consumed >1–2 caffeinated beverages/day, consumed >7 alcoholic beverages/week, or had a history of chronic pain, seizures or head injury. Participants were required to refrain from recreational drug use and limit caffeine (to no more than 1 beverage in the A.M.) and alcohol intake at least 3 days prior to, and throughout participation in the study. Actigraphy and sleep logs were used to confirm the participants’ sleep and activity cycles throughout the study. To rule out participants with signs of depression or anxiety and ensure normal sleep-wake patterns, participants also completed the Beck Depression  and AnxiN = 21 participants  were included in the final data analyses.A total of 35 participants met study inclusion criteria. A minimum of 30 coupled and 30 uncoupled spindle events were necessary for analysis purposes. An additional fourteen participants did not meet this criterion. In total, All study procedures and methods adhered to the Declaration of Helsinki and were approved by the Western University Health Science research ethics board. All participants were given a letter with details of the study, provided informed consent, and were financially compensated for their participation.All participants who met the study inclusion criteria underwent an orientation session where they were given the study instructions, a sleep diary and an activity monitor to verify their sleep–wake cycle . A minimvia two MR-compatible 32-channel amplifiers . EEG recordings were referenced to FCz and digitized at 5,000 samples per second with a 500-nV resolution. The single ECG lead included in the EEG cap offers limited visualization of the r-peak of the QRS complex, needed for accurate ballistocardiograph (BCG) correction. Thus, three additional bipolar ECG recordings were taken using a MR-compatible 15-channel amplifier . To reduce BCG artifact by up to 40% (Polysomnographic (PSG) recordings were obtained using a 64-channel magnetic resonance (MR)-compatible EEG cap, which included one electrocardiogram (ECG) lead  and 64-channels of EEG recorded p to 40% , particivia fiber-optic cable and hardware synchronized to the scanner clock using the Brain Products “Sync Box” (Brain Products GmbH). As recommended in the literature  escribed , adaptedescribed , and wri3 written for MATLAB R2019b (The MathWorks Inc.). Detailed processing steps, procedures, and method validation are reported elsewhere  using an established  and valilsewhere . Brieflylsewhere  used a clsewhere . The metlsewhere . From tht-test were used for the comparison of the SW-SP complexes, measured in time bins of 200 ms along the 4 s window.Using the slow wave negative peak latencies and the spindle peak latencies from Fz, Cz, and Pz, we performed coupling detection procedures using the approach originally developed and validated by Additionally, the phase of the bandpass-filtered slow-wave signal in radians at the spindle peak latency was computed. The mean direction of the phase angles for all coupled spindle events were determined using the CircStat toolbox . HilbertA 3.0 Tesla Magnetom Prisma MRI system (Siemens) with a 64-channel head coil were used to obtain brain images. Structural T1-weighted MRI images were acquired using a 3-D MPRAGE sequence . During the sleep session, multislice T2*-weighted fMRI images were acquired using an EPI sequence using axial slice orientation . Up to 2 h of sleep EEG-fMRI data was acquired among all participants during fMRI acquisition.4 implemented in MATLAB R2015a (The Mathworks Inc.). fMRI images were corrected for slice acquisition time differences and realigned to correct head motion using rigid body transformation. A mean realigned image was then created from the resulting images. The structural T1 image was coregistered to this mean functional image using a rigid body transformation optimized to maximize the normalized mutual information between the two images. Coregistration parameters were then applied to the realigned BOLD time series. The co-registered structural images were segmented into gray matter, white matter, and cerebrospinal fluid. An average participant-based template was created using DARTEL in SPM12. All functional and anatomical images were spatially normalized using the resulting template, which was generated from the structural scans. Finally, spatial smoothing was applied to all functional images .Functional images were preprocessed and analyzed using SPM12 (Welcome Department of Imaging Neuroscience)informed basis set,” generating three contrast t-maps, one for the canonical HRF, one for the temporal derivative, and one for the dispersion derivative, for each participant. The resulting contrast images  are then entered in a second-level , random effects analysis  corrected, at p < 0.05, at the cluster-level.The first-level contrasts maps of coupled SW-SP and uncoupled spindles, and uncoupled SW events comprised of the informed basis set  were entered together into a second-level ANOVA. In this way, we could examine the HRF response for each group comparison without the assumption that the temporal and dispersion functions were constant . It is nAll participants had more than a total of 14 min of sleep during the recording session in the MRI scanner, and on average, 46.10 min (SD = 23.42 min). The average sleep latency was 8.21 min (SD = 10.64 min), and the average time when participants fell asleep in the scanner was at 22:20 h (SD = 28 min). NREM data from 21 participants were included in the analyses . The avet(20) = 2.65, p = 0.01). There were no differences between coupled SW-SP and uncoupled spindles in terms of the number (t(20) = 1.56, p = 0.13) duration (t(20) = −1.97, p = 0.06) or density (t(20) = 1.39, p = 0.18), hence suggesting they were evenly distributed.Coupling status was determined using a previously reported and validated procedure developed by t(20) = −5.45, p < 0.001). The percentage of coupled spindles during the upstate , was also higher than the succeeding 1 to 2 sec interval (t(20) = 5.89, p < 0.001). Finally, the percentage of coupled spindles during the upstate was significantly higher than during the downstate (t(20) = −3.19, p = 0.005).Inspection of the temporal distribution of spindles co-occurring within the 4 sec window around the negative peak of the slow wave  revealedp < 0.001, V-test]. Further individual-level analyses revealed a non-uniform distribution  of the preferred phases of SW-SP in 10 out of 21 participants, suggesting that spindles were coupled to slow waves preferentially adjacent to or immediately following the positive slow wave peak.Next, to investigate the phase relationship between spindles and slow waves, the slow wave phase at the spindle peak for each SW-SP event was extracted and mean phase angle per individual was computed . The couActivations time-locked to uncoupled spindles were observed in the bilateral thalamus, middle cingulate cortex (MCC), right posterior cingulate cortex (PCC), superior medial frontal cortex (sPFC), and bilateral occipital lobe .Uncoupled slow waves showed a very similar pattern of activation  as compaActivations time-locked to SW-SP were observed in the occipital lobe, bilateral postcentral gyrus, bilateral STG, bilateral middle frontal gyrus (MFG), bilateral inferior frontal gyrus (IFG), bilateral thalamus, bilateral putamen, and hippocampus .A conjunction analysis showed that both SW-coupled and uncoupled spindles presented robust activation of the bilateral thalamus and bilateral occipital lobe . FurtherConjunction analysis revealed the common areas in both coupled SW-SP and uncoupled slow waves, including the occipital lobe, bilateral postcentral gyrus, bilateral superior temporal gyrus (STG), bilateral IFG, bilateral thalamus and bilateral hippocampus . Only thIn the present study, we investigated functional dissociations in cerebral activation that are specifically related to the occurrence of SW-SP coupling. Previously, converging evidence from multiple studies has implicated SW-SP coupling as an important mechanism supporting the consolidation of new information into long term memory . Howeverreactivation of brain areas) during sleep is not unique to spindles, but primarily driven by slow waves, and that the co-occurrence of spindles allows the recruitment of frontal areas, creating a unique functional activation pattern, which may be critical for the hippocampal-neocortical dialogue that preferentially occurs during sleep, and is known to support memory consolidation processes  and fast spindles (13–16 Hz), nor was it possible to subdivide spindles from NREM2 and SWS due to the limited sleep duration and number of events recorded while participants were sleeping in the MRI scanner. In addition, we did not directly investigate any relationship between spindles, slow waves and SW-coupled spindles following new learning or associated with cognitive abilities. This remains to be directly investigated in future studies specifically designed to assess the reactivation of memory traces and the related behavioral outcomes. However, this study does represent a necessary first step in this line of investigation.via reactivation. Furthermore, and surprisingly, the present study revealed that this pattern of activation may be driven more so by slow waves than spindles. We propose that it is possible that hippocampal reactivation during sleep is not uniquely related to spindles. Rather, this pattern of activation may be primarily driven by slow waves. Our results also suggest that SW-spindle coupling may be critical for functional recruitment of the putamen. Importantly, the co-occurrence of spindles and slow waves may allow the recruitment of frontal areas, which may be critical for the hippocampal-neocortical dialogue that preferentially occurs during sleep. Future studies linking coupling-driven activation with memory performance are needed to further elucidate the dissociable contribution of isolated spindles, isolated slow waves and SW-SP complexes to memory consolidation and other functions.In summary, we investigated differences in cerebral activation linked to SW-coupled spindles and both their differences and similarities with uncoupled spindles and uncoupled SWs. The results demonstrate a clear differentiation in brain areas recruited time-locked to SW-coupled spindles and uncoupled spindles supporting that both events are functionally dissociable. By contrast, these results show largely similar activation patterns between SW-coupled spindles and uncoupled slow waves. For the first time, we provide direct evidence of hippocampal activation linked specifically to coupled SW-SP complexes in comparison to isolated spindles. This finding is consistent with other studies that show coordinated activity of these precisely timed complexes is specifically involved in memory consolidation Sleep is known to aid in memory consolidation. This involves transfer of information from the hippocampus to the neocortex and is facilitated by slow wave – spindle – hippocampal ripples complexes during sleep. However, no study to date has specifically examined if the patterns of functional brain activations of isolated spindles differ from slow wave coupled spindles. Here, we found a clear differentiation in brain areas recruited for each event. Coupled spindles recruited frontal areas and parahippocampus in comparison to uncoupled spindles. This suggests that coupled spindles may be critical for the hippocampal-neocortical dialogue that occurs during sleep. Our results lay the groundwork for future studies to differentiate between spindles according to coupling status.sfogel@uottawa.ca.The datasets presented in this article are available by request to the corresponding author, following required ethical approval and inter-institutional data sharing agreements. Requests to access the datasets should be directed to SF, The studies involving human participants were reviewed and approved by Western University Health Science Research Ethics Board. The patients/participants provided their written informed consent to participate in this study.SF and AO designed the study and supervised the research. SF, ZF, DB, and LR carried out the research and collected the data and contributed to the data analyses. DB, SF, and LR prepared the figures and wrote the manuscript. AG, DS, JD, and SF revised the manuscript. All authors discussed the results and commented on the manuscript.


While a growing body of research has documented severe psychosocial consequences of the new Coronavirus disease (COVID-19) for the affected people, research mainly focused either on health care workers or the general population. There is a dearth of scientific research on the mental health status of recovered patients, especially in low- and middle-income countries. The purpose of the current study was to determine the mental health symptomatology and its associated factors among Iraqis who recovered from COVID-19. Participants were Iraqi Kurdish individuals who had previously been diagnosed with COVID-19 during the first wave of COVID-19, and they were recruited based on lists of recovered patients provided by from public health institutions. Using standardized demographic and mental health questionnaires, structured telephone interviews with 57 recovered patients were contacted. It was found that 31.6% of the participating recovered patients with COVID-19 met the diagnostic criteria for post-traumatic stress disorder (PTSD), and 21.05% were classified with probable depression. Hospitalized survivors had higher PTSD and depression symptoms than those not hospitalized. We also found that higher levels of PTSD and depression symptoms were predicted by younger age, hospitalization due to COVID-19, and having a family member who died from COVID-19. In the context of the global COVID-19 pandemic, psychological and psychiatric treatment may be particularly relevant for younger adult patients and those with more severe COVID-19 symptoms who experienced hospitalized care. A new coronavirus disease COVID-19) in 2019 resulted in one of the largest-scale worldwide outbreaks of infections in modern history. Evidence from previous health pandemics and epidemics, such as Severe Acute Respiratory Syndrome (SARS), Middle East Respiratory Syndrome (MERS), and Ebola virus disease, has suggested that the outbreak’s negative impacts are not limited to affecting one’s physical health or economic, social, and political disruption, but there has also been a mental health toll, as well 9 in 2019.Consistent with findings from previous epidemics, several studies have investigated the potential mental health impacts of COVID-19, reporting various mental health issues including mood, anxiety, insomnia, and post-traumatic stress disorder (PTSD), and they identified various risk factors for negative mental health outcomes in affected populations –11.While these studies provide significant pathways in understanding and treating mental health conditions among affected people, considerable limitations exist in researching health sequelae of COVID-19. First, the research in this area focuses mainly either on health care workers or the general population –15. LittIt's well known that social factors on both individual  and societal levels  greatly influence individuals' mental health –19. SuchThe present study attempts to fill the above-mentioned gaps, and it’s aimed to understand the mental health symptomatology and its associated factors of Iraqis who survived COVID-19 infection in the early phase of the pandemic. In particular, we aimed to estimate prevalence rates of PTSD and depressive disorders using valid and reliable screening tools among Iraqi patients who had recovered from COVID-19. For this purpose, we drew a small sample based on recovered patients lists from public health institutions who are managing COVID-19 patients in northern Iraq.The participants in this study were Iraqi Kurdish individuals who had previously been diagnosed with COVID-19 during the first wave of COVID-19. They were identified based on data (list of COVID-19 recovered patients between August and October 2020) available through the General Health Directorate of Raparin in the northern Iraq.Inclusion criteria were as follows; (1) age 18 or older; (2) previously diagnosed with COVID-19 based on a polymerase chain reaction (PCR) test; (3) with no reported and registered psychiatric history; (4) fully recovered from COVID-19 for at least one month and confirmed by a negative lab-based PCR test. In total, sixty-two individuals meet the above criteria. Five of the 62 persons contacted declined participation, so the response rate was 91.94%. Due to COVID-19 movement restrictions and for safety protection of participants and researchers, telephone semi-structured rather than face to face interviews were conducted in the Kurdish-Sorani language.During the interview, participants were asked about their socio-demographic information , health issues  and experiences regarding COVID-19  as well as depression and PTSD symptoms, which were assessed using valid and reliable Kurdish Sorani versions of the Depression Scale of the Hopkins Symptom Checklist-25 (DHSCL-25) and the PTSD Checklist for DSM-5 (PCL-5) , 23. PCLSD = 11.55; range 18–80). The vast majority of participants (84.2%) were married, and they had completed between 0 and 19 years of formal education . At the time of interview, nine of the 57 participants (15.8%) reported experiencing chronic diseases.All 57 study participants were Iraqi Kurdish patients who had recovered from COVID-19. Nearly three quarters of participants were male (73.7%). The mean age was 38.39 years , and 17.6% of the total participants had at least one close family member who died as a result of COVID-19 . One fifth (21.1%) of participants experienced hospitalization due to COVID-19. Hospitalized participants had stayed between 1 to 13 days in hospitals , and they were aged 18 to 70 years . While half of the hospitalized participants had been admitted to intensive care units (ICU) for 1 to 4 days , only 33.33% of them had been on a ventilator.Almost two-thirds of participants (63.2%) had at least one family member who was also affected by COVID-19 .Descriptive (means and standard deviations) and frequency statistics were used to describe and summarize the characteristics of participants. The significant difference between demographic groups was calculated using independent samples t-tests. Pearson correlation coefficient was used to estimate the relationship between variables. Multivariate linear regression was utilized to predict potential factors associated with PTSD and depression symptoms. The data were analyzed using IBM SPSS Statistics (Version 28).SD = 13.96) on the PCL-5 and 21.43 (SD = 6.10) on the DHSCL-25. There were no significant gender differences in levels of depression and PTSD symptoms (P > 0.05). Using the contextually valid cutoff score of 23 for the PCL-5 and the internationally accepted cutoff score of 1.75 for the DHSCL-25, 31.6% of participants had probable PTSD diagnosis, and 21.1% were classified with probable depression.The mean sum scores of mental health symptomatology levels were 17.43 . Among hospitalized patients, comparisons between ICU and non-ICU patients led to no statistically significant difference in either depression or PTSD symptoms (p > 0.05). Also, no associations were found between length of stay in ICU and symptoms of PTSD and depression .Participants who had been hospitalized due to a COVID-19 infection reported significantly higher levels of PTSD and depression symptoms compared with those not hospitalized , multivariate linear regression was performed. The sum scores of PTSD and depression were identified as outcome variables, and participants' gender, age, marital status, been hospitalized due to COVID-19, and death of family members due to COVID 19 were introduced as independent variables. As demonstrated in Table The present study was designed to determine the mental health symptomatology and associated factors among patients who recovered from COVID-19 in Iraq. For this purpose, a group of Iraqi patients were recruited in this study, and the recruitment was based on recovered lists from public health institutions. The analyses identified high levels of mental ill-health symptomatology with several clinical, social, and demographic predictors. The study thus adds important scientific knowledge on the potential impact of the COVID-19 pandemic in the LMICs.In line with present systematic reviews and meta-analyses on the psychiatric consequences of coronavirus infections , 26, we Regarding predictors of mental health symptomatology, consistent with previous findings, we found that hospitalization due to COVID-19 is associated with poor mental health outcomes . Due to In addition, we found that the loss of a family member due to COVID-19 increased the risks of developing PTSD and depressive symptoms. Taking the nature of grief in Kurdish culture, which is a family-oriented and collectivist culture, into account, this result is not surprising. Previous research has shown that across all cultural values, the death of a loved one is associated with various mental ill-health symptoms, including but not limited to anxiety, depression, and PTSD , 32. TheThe present results confirmed previous findings and contributed additional evidence suggesting that older adults have higher resilience to the mental health effects of COVID-19 –38. HoweOverall, our findings are consistent with previous studies in other populations, which observed considerable rates of mental health symptoms among patients with COVID-19 even after their recovery. Stress-related symptomatology can be an important impairment for general health recovery after illness . In the The high levels of mental ill-health symptomatology found in this study, shed light on the importance of providing mental health care for Iraqi COVID-19 survivors. Iraqi society has been traumatized by large scale political repression and organized violence, and adequate mental health services in Iraq are lacking , 41. So The key strength of this study is the sample of full recovery Iraqi COVID-19 patients who had no recorded psychiatric history. Moreover, contextually valid and reliable measurements for assessing mental health symptoms were used and were administered in semi-structured telephone interviews. Nevertheless, caution must be applied with respect to the small sample size, and the findings might not be transferable to other contexts. Moreover, since the prevalence rates of mental health conditions presented in the current study are based on screening tools rather than clinical interviews, the present investigation has not been able to estimate representative prevalence rates of PTSD and depression among COVID-19 patients in Iraq.While we controlled for the impact of some individual characteristics of the participants, other potential risk factors for mental health problems amidst a pandemic, such as living situation, financial and job insecurity, social isolation, and lack of support were not assessed . AlthougThis study examined mental health symptomatology and its associated factors among Iraqi adults who fully recovered from COVID-19. Findings suggest high prevalence rates of COVID-19-related PTSD and depression. Moreover, findings also showed that younger and hospitalized patients, as well as those who lost family members due to COVID-19, are more vulnerable to experiencing more PTSD and depression symptoms.


Occult infections in spinal pseudarthrosis revisions have been reported in the literature, but the relevance of such an infection on patient outcomes is unknown. We aimed to elucidate clinical outcomes and re-revision risks between patients with and without occult infections in spinal revision surgery for pseudarthrosis.In this matched case-control study, we identified 128 patients who underwent thoracolumbar revision surgery from 2014–2019 for pseudarthrosis of the spine. Among them, 13 (10.2%) revealed an occult infection (defined by at least two positive intraoperative tissue samples with the same pathogen), and nine of these 13 were available for follow-up. We selected 18 of the 115 controls using a 2:1 fuzzy matching based on fusion length and length of follow-up. The patients were followed up to assess subsequent re-revision surgeries and the following postoperative patient-reported outcome measures (PROMs): overall satisfaction, Oswestry Disability Index, 5-level EQ-5D, and Short Form 36.Patient characteristics, surgical data, and length of follow-up were equal between both study groups. The rate of re-revision free survival after the initial pseudarthrosis revision surgery was higher in the occult infection group (77.8%) than the non-infectious controls (44.4%), although not significantly (0.22). The total number of re-revision surgeries, including re-re-revisions, was thirteen (in ten patients) in the control and two (in two patients) in the occult infection group (p = 0.08) after a median follow-up of 24 months (range 13-75). Four cases in the control group underwent re-revision for pseudarthrosis compared to none in the infected group. Satisfactory scores were recorded in all PROMs, with similar scores between the two groups.The presence of an occult infection accompanying spinal pseudarthrosis revision was not inferior to non-infected pseudarthrosis revisions in a matched, small sample size cohort study. This may be explained due to the possibility of targeted treatment of the identified cause of pseudarthrosis. Pseudarthrosis, or failure of adequate bony fusion, is one of the most important and challenging reasons for revision surgery after attempted spinal fusion Clinicians frequently detect the presence of an occult low-grade infection during spinal revision surgery, with incidences varying between 9-56%, depending on the indication for revision and the method of tissue sampling In general, long-term antibiotic treatment is recommended if an occult infection is detected, with the treatment-regimen being defined by interdisciplinary infectiology boards The aim of this study was to compare overall clinical outcomes and re-revision risks of patients undergoing pseudarthrosis revision surgery with and without occult infections.This study was approved by the state authorities (BASEC 2019-02077). Symptomatic spinal pseudarthrosis was defined as mechanical back pain related to failure of bony fusion or screw loosening on conventional radiographs and computed tomography (CT) at least > 6 months after the index surgery.We identified 152 adult patients who underwent pseudarthrosis revision surgery via a posterior-only approach since the introduction of routine sampling n pseudarthrosis cases in our institution in September 2014 until end of 2019 . After eWhereas almost half of the initial surgeries were performed outside, all revision surgeries were performed at our tertiary university spine department. We detected an occult infection in 13 (10.2%) patients, whilst 115 (89.8%) revealed negative samples. Four of these 13 infections were further excluded for the following reasons: two deaths (unrelated to surgery or infection) and two refusals to participate; leaving overall nine infected patients for follow-up assessments. None of the four excluded patients in the occult infection group underwent any further re-revision surgery after pseudarthrosis revision during their time of follow-up in our outpatient clinic .As length of follow-up correlates with the risk of undergoing a revision operation and the length of fusion construct further impacts patient-reported outcome measures (PROMs), we matched the cohort using a 2:1 fuzzy matching based on these two factors. The fuzzy matching technique enabled the study population to forego any further sample size decrease in the group of nine occultly infected cases and roughly balance them  to the much larger pool of the non-infected controls (n=115). Thereby, we selected 18 out of the 115 uninfected patients as controls . BesidesWe defined an occult infection as the presence of ≥ 2 intraoperative tissue samples that were incubated for 14 days for aerobic and anaerobic cultures. In general, two samples were gathered from the posterolateral pseudarthrosis and one from the lamina or pedicle, but additional samples were obtained from adjacent levels in some cases. Additionally, sonication of the removed hardware was routinely performed ,20. A psAfter a follow-up time ranging 13-75 months after revision surgery for pseudarthrosis of the spine, patients were asked about their general satisfaction regarding the clinical outcome . Details on any subsequent re-revision surgeries performed outside the index institution were recorded. The following PROMs were assessed: the Oswestry Disability Index (ODI), the 5-level version of the EuroQol five-dimensional self-administered questionnaire (EQ-5D-5L) and the Short Form 36 (SF-36). The summary index (SI) of the EQ-5D-5L was calculated based on the value set of the German population. Further, the EQ-5D visual analogue scale (VAS) was recorded, which measures health status on a vertical scale between 0 and 100  on the day of assessment. The eight scales of the SF-36 were also calculated based on the German population norm. Preoperative PROMs were not available for most patients and could not be included for analysis. All infected patients cured after recommended long-lasting antibiotic therapy. to decrease the influence of confounding factors for patient outcomes. Fuzzy matching was performed on length of follow-up (+/- 6 months) and length of fusion (+/- 1 level). The 18 control patients were thereby matched to the nine occult infection cases. Intergroup analyses were performed using SPSS . As calculated per the Shapiro-Wilk test, data were non-normally distributed and data were reported using medians and ranges and ordinal variables were represented by frequencies (%). We used Mann-Whitney U-tests for continuous variables and the Fisher's exact tests for categorical variables. Due to the low number of infections, we renounced on multivariate analyses. The level of statistical significance was set at p < 0.05 for two-tailed analyses.A fuzzy matching algorithm was performed using MATLAB p=0.06). In contrast, the number of prior lumbar surgeries was significantly lower in the controls . None of the study patients smoked. The median follow-up time was 25 months  in the controls and 23 months  in the infection group, p=0.791.The demographics of the two study groups were similar , other tCutibacterium acnes was cultivated in five patients, Staphylococcus epidermidis in three patients, and Enterococcus faecium in one patient. There were no polymicrobial infections. No pathogens were isolated from any single probe in the control group, although at least 5 samples were taken per definition in any included pseudarthrosis revision.The diagnosis of symptomatic pseudarthrosis and screw loosening was made based on the CT findings in conjunction with excruciating pain and point tenderness over the pseudarthrosis segment in all 27 patients (9 infected and 18 controls). None of the subjects had an infectious etiology suspected by the clinician or radiologist pre-or intraoperatively. All patients were initially instrumented and revised from posterior only with pedicle-screw instrumentation, with or without transforaminal/posterior interbody fusion. C. acnes infections were treated with oral clindamycin. The antibiotic treatment of the staphylococci and of the E. faecium depended on the microbiologic profile, susceptibility testing, and patient's tolerance. None of the patients with an occult infection had any major complications related to the surgery or antibiotic treatment.Immediate targeted antibiotic treatment was initiated for three months for all infected patients according to the Infectious Diseases consultations at that time. During the time of follow-up, the rate of re-revision free survival after the initial pseudarthrosis revision surgery was higher in the occult infection group (77.8%) than the non-infectious controls (44.4%), although not significantly (0.22). The odds ratio for undergoing a re-revision surgery after pseudarthrosis revision was 0.4  in the occult infection group versus the controls. The total number of re-revision surgeries, including possible re-re-revisions after the index pseudarthrosis revision, was thirteen (in ten patients) in the control and two (in two patients) in the occult infection group (p = 0.08) after a median follow-up of 24 months (range 13-75). Three patients in the control group each underwent two re-operations after the index pseudarthrosis revision during the time of follow-up. Four cases (22.2%) in the control group underwent re-revision surgery because of additional re-pseudarthrosis, whereas no pseudarthrosis re-revision was observed in the occult infection group.The microbiological samples of the pseudarthrosis re-revisions  remained negative despite 14 days of incubation. Furthermore, three patients (16.7%) in the control group underwent more than one re-revision surgery following the initial pseudarthrosis revision. As for the infected group, only two patients underwent a further re-revision (one for screw-loosening and one for adjacent segment disease) and none of the two was further re-re-revised .Table 2.Overall, we recorded satisfactory-to-poor scores in all PROMs, similarly distributed between the two study groups. Median patient satisfaction was 3 (satisfactory) in both groups (p=0.501). The ODI Score was 62 points (controls) versus 64 points (infected) (p=0.699). The EQ-5D-5L index was 0.31 in both groups (p=0.797), EQ-5D VAS was 58 (controls) versus 50 (infected) (p=0.365), and SF-36 scores were all similar in all the eight physical and mental scales. Further details are illustrated in According to our single-center case-control study among adults who are surgically revised for spinal pseudarthrosis, the detection of an occult infection (even if relatively frequent) did not impair the patient's final outcome, provided that such infected pseudarthroses were surgically and antibiotically treated.Because several patient and surgical history-related factors have been associated with less favorable outcomes after spinal fusion, we aimed to create two comparable groups and minimize confounding factors. However, despite the 2:1 fuzzy matching procedure, the two study groups still revealed some differences, most prominently the number of prior lumbar surgical procedures, which was significantly higher in the occult infection group. Also, a trend toward older age and a higher number of comorbidities was observed in the control group. Indeed, an increasing age and number of comorbidities are known to negatively impact clinical and/or radiographic outcomes after spinal fusion ,23, but All the investigated postoperative PROMs were at best satisfactory in both groups of this study. Although excruciating pain and point tenderness over the non-fused segment was reported preoperatively, it remains an unspecific and unreliable finding that only complements the clinical picture of a symptomatic pseudarthrosis and was not investigated postoperatively Our re-revision risks tended to be lower (22% versus 56%) in favor of the occult infection group, even though the difference was not statistically significant. In general, surgical site infections not only require enduring long-term antibiotic treatment, but are also associated with poorer clinical outcome scores and higher risk for revision surgery ,36. TherC. acnes, coagulase-negative staphylococci and E. faecalis. This reflects the most common spectrum of pathogens detected after spinal hardware removal for low-grade infection C. acnes, a slow-growing, microaerophilic Gram-positive rod, is usually considered as a contaminant by many authors C. acnes counts as the only and true pathogen causative of many spinal surgical site infections, spondylodiscitis, and vertebral osteomyelitis cases [In our occultly infected group, patients were infected with is cases ,42,43. ISome surgeons may argue that routine sampling in unsuspicious pseudarthrosis revisions will lead to too many false positives and unnecessary antibiotic treatments or that occult infections may be self-limiting after implant removal or replacement, and antibiotic treatment is redundant. From our personal standpoint, the risk of missing an infectious etiology, which is by evidence around 10% Besides the low sample size given by the rarity of the pathology and the obvious retrospective, observational design, our study has further limitations. Little is known about the performance of antibiotic treatment in low-grade infections. To our knowledge, no study has compared the outcomes of infected pseudarthrosis with revision surgery alone versus revision and antibiotic treatment. Finally, it is impossible to definitively distinguish between colonization and low-grade infection based on microbiological findings alone, even with the standardized workup protocol used in our institution. Two positive samples do not entirely rule out contamination of a pseudarthrosis which has been concomitantly caused by other reasons, but we define them as a true infection in concordance to previous studies ,19. WherBased on our data, an a-priori sample size estimation using g*power (version 3.1.9.7) showed that a sample size of 39 in the occult infection group and 78 in the control group would be necessary to reach statistical significance  in a 2:1 matched study design. In an unmatched study assuming an occult infection rate of 10%, 30 infected spinal pseudarthrosis cases and 300 non-infected controls would be necessary to investigate whether re-revision rates truly differ in patients with occult infections. However, the rarity of the here investigated cohort, namely occult infected pseudarthrosis patients justifies reporting of this findings even if statistical underpowering might limit their evidence. Further, by plausibility, increase of sample size would tend to support the here reported non-inferiority of occult infection not impairing patient's final outcome, provided that such infected pseudarthroses are surgically and antibiotically treated.The presence of an occult infection accompanying spinal pseudarthrosis revision seem not to lead to inferior outcomes if compared to non-infected pseudarthrosis revisions in a matched, small sample size cohort study. This may be explained due to the possibility of targeted treatment of the identified cause of pseudarthrosis.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.


Experiences of end-of-life care and early bereavement during the COVID-19 pandemic are poorly understood.To identify clinical and demographic risk factors for sub-optimal end-of-life care and pandemic-related challenges prior to death and in early bereavement, to inform clinical practice, policy and bereavement support.Online national survey of adults bereaved in the UK (deaths between 16 March 2020 and 2 January 2021), recruited via media, social media, national associations and organisations.711 participants, mean age 49.5 . 628 (88.6%) were female. Mean age of the deceased was 72.2 . 311 (43.8%) deaths were from confirmed/suspected COVID-19.p < 0.001). COVID-19 was also associated with worse experiences before and after death; for example, feeling unsupported by healthcare professionals (p < 0.001), social isolation/loneliness , and limited contact with relatives/friends . Expected deaths were associated with a higher likelihood of positive end-of-life care experiences. The deceased being a partner or child also increased the likelihood of positive experiences, however being a bereaved partner strongly increased odds of social isolation/loneliness, for example, OR = 0.092 (95% CI: 0.028–0.297) partner versus distant family member.Deaths in hospital/care home increased the likelihood of poorer experiences at the end of life; for example, being unable to visit or say goodbye as wanted (Four clear risk factors were found for poorer end-of-life care and pandemic-related challenges in bereavement: place, cause and expectedness of death, and relationship to the deceased. What is already known about the topic?Since the start of the pandemic, it is estimated that over 50 million family members and friends have been bereaved due to COVID-19, with millions more bereaved due to other causes.Bereavement of any cause during the COVID-19 pandemic is associated with specific challenges, including limited access to people before their death, pressure on health and social care providers, quarantining due to infection or exposure, lockdowns and social distancing.No previous studies have identified factors associated with sub-optimal end-of-life care or challenging experiences in bereavement, and this evidence is needed to inform clinical practice, bereavement support and policy.What this paper adds?Our study highlights four risk factors for poorer end-of-life care and increased risk of pandemic-related challenges in early bereavement: place, cause and expectedness of death and relationship to the deceased.COVID-19 deaths, hospital and care home deaths and unexpected deaths were generally associated with poorer outcomes, while being a partner of the person who died (regardless of cause) and bereavement due to COVID-19 increased the odds of experiencing social isolation and loneliness in bereavement.Implications for practice, theory or policyPartners bereaved due to an unexpected COVID-19 death in hospital may be at particular risk of poor outcomes and need additional follow-up and support.Deaths in hospitals and care homes can be improved by prioritising communication with and involvement of relatives, facilitating contact between loved ones prior to death as much as possible and improving sign-posting to bereavement support.Clear and consistent national guidance on hospital, hospice and care home visiting and prioritising personal protective equipment for end-of-life care providers is essential in a pandemic to ensure equity, support staff and improve experiences among bereaved people. With each death associated with approximately nine close bereavements, an estimated 50.4 million family members and friends have been bereaved due to COVID-19 since the start of the pandemic. Deaths during the pandemic are associated with risk factors for poor bereavement outcomes identified pre-pandemic, including traumatic end-of-life and death experiences, being unable to say goodbye, loss of community networks and social support, and social and economic disruption.39 Many of these challenges are relevant to non-COVID-19 deaths as well as bereavements due to COVID-19.The COVID-19 pandemic has resulted in widespread, mass bereavement on an unprecedented global scale, with 5.6 million deaths from COVID-19 recorded so far. and qualitatively investigated bereavement experiences and support needs. However, there remains little evidence to inform optimal clinical practice, bereavement support and the policy response to COVID-19 as a mass bereavement event. This study aimed to identify clinical and demographic risk factors associated with experiencing sub-optimal end-of-life care or pandemic-related challenges prior to death and in early bereavement, using baseline data from a mixed-methods longitudinal study of bereavement during the pandemic in the UK.13In the UK, infection control advice was first issued by the government on 16 March 2020. End-of-life care and infection control restrictions such as social distancing policies have varied since the start of the pandemic, with inconsistencies across geographical areas and care settings. Recent research has described the challenges of providing end-of-life-care during the pandemicSupplemental material 1), disseminated to a convenience sample of people bereaved during the pandemic in the UK.An open web survey  and ‘social isolation’ . All items were answered yes/no. For each participant, the number of problems experienced in each subscale and the total number of problems overall were calculated by summing item scores . Cronbach’s α was 0.57, 0.57 and 0.64 for the ‘contact prior to death’ subscale, ‘social isolation’ subscale and total respectively. These values for Cronbach’s α indicate adequate levels of reliability/internal consistency.18 or have been identified as indirectly associated with experiences of end-of-life care .20 We used postcode data to identify geographical region of residence and (for England) socio-economic deprivation.We assessed whether demographic and clinical factors independently predicted end-of-life care experiences and pandemic-related challenges. Factors included in the analysis are recognised risk factors for poor bereavement outcomes  and was open from 28th August 2020 to 5th January 2021. It was disseminated to a convenience sample on social and mainstream media and via voluntary sector associations and bereavement support organisations, including those serving ethnic minority communities. These organisations helped disseminate the survey by sharing on social media and other forums and via direct invitations to potential participants . For ease of access, the survey was posted onto a bespoke study-specific website with a memorable URL. Two participants chose to complete the survey in paper format. Summaries of survey results (including interim results released November 2020) were posted on the study website and provided to interested participants.The voluntary survey was administered via Jisc softwareSupplemental material 1).Inclusion criteria: aged 18+; family or close friend bereaved since social-distancing requirements were introduced in the UK (16/03/2020); death occurred in the UK; ability to consent. Anyone not meeting these criteria was excluded from participating. The initial section of the survey requested informed consent and details of data protection  and refined iteratively by all members of the research team. The main research questions explored in this paper were: how common were pandemic-related end of life and social issues such as lack of contact, disrupted mourning rituals and isolation, and what were the most important factors that affected them?h effect size effect was used to measure the differences between two proportions. For any comparisons, the maximum value of h is presented to provide an estimate of (maximum) effect size . Chi-squared tests and Fisher’s exact test were used for categorical outcome data. GLM was used to examine pandemic-specific challenges as a function of factors identified as having a strong and/or significant effect on outcomes, as derived from Cohen’s h effect sizes and univariate calculations. Region of the UK was included as a random effect, whereas all other variables were coded as fixed effects. Results of the mixed-effects GLM analysis are presented as odds ratios in supplemental tables. To provide a comparison to the results from the mixed-effects GLM, odds ratios were also found via simple logistic regression. All calculations were carried out using SPSS V26.Frequency tables were used to explore the data. A Directed Acyclic Graph was also used to visualise the relationships between variables and generate hypotheses for statistical testing in both univariate calculations and mixed-effects logistic regression via a mixed-effects generalised linear model (GLM). Cohen’s The study protocol and supporting documentation was approved by Cardiff University School of Medicine Research Ethics Committee (SMREC 20/59). The study was conducted in accordance with the Declaration of Helsinki and all respondents provided informed consent.711 bereaved people participated . 12 survn = 152, 21.4%). 72 people (10.1%) had experienced more than one bereavement since 16th March 2020. 33 people (4.7%) self-identified as from a minority ethnic background.Participants represented diverse geographical areas, deprivation indexes and levels of education. 628 (88.6%) participants were female; the mean age was 49.5 years . 395 (55.6%) participants had experienced the death of a parent, followed by partner/spouse . Questionnaires were completed a median of 152 days (5 months) after the death (range 1–279 days).The mean age of the deceased person was 72.2 years  . 311 . The three most prevalent items were restricted funeral arrangements (93.4%), limited contact with other close relatives/friends (80.7%) and social isolation and loneliness (66.7%).Participants reported a mean of 4.17 (median = 4) pandemic-related problems (out of a maximum of 6) . People h were used to determine those factors and covariates that had the strongest influence on the outcome measures and we describe the effects of these factors on the outcomes in detail below. Effect sizes measured via Cohen’s Tables S1–S7). If the death occurred in a hospice or at home the bereaved were more likely to be involved in decisions about the care for their friend or relative (p < 0.001) and feel well supported by healthcare professionals immediately after the death (p = 0.003) than if the death occurred in a hospital or care home (Tables S1 and S4). If the person had died in hospital the bereaved was less likely to know the contact details for the professional responsible for their friend or relative’s care (p = 0.001) compared with other settings. Where the death had occurred in a hospice the bereaved person was most likely to have been provided with information about bereavement support services both at the time of death and during a follow-up call, while this was least likely for care home deaths (p < 0.001).Place of death had a moderate to strong influence on end-of-life care outcomes (p < 0.001) compared with other places of death (Tables S8–S10). Differences did not reach statistical significance for restricted funeral arrangements, social isolation and loneliness, and limited contact with other close relatives/friends (Tables S11–S13).The effect size for place of death was high across all pandemic-related challenges. When a person had died in hospital or in a care home participants were most likely to report problems for all items in the ‘contact with loved one prior to death’ subscale (of death . Mixed-eTables S1–S7), with deaths due to COVID-19 associated with worse outcomes (p < 0.001) (Table S1) and less likely to be well supported by healthcare professionals immediately after the death (p < 0.001) (Table S4).Cause of death (COVID vs non-COVID) had a moderate to weak effect on end-of-life care outcomes (outcomes . In partp < 0.001) ; social isolation and loneliness ; and limited contact with other close relatives/friends .COVID-19 deaths were also associated with worse pandemic-related challenges, with weak to large effects sizes . The tot< 0.001) , and theTables S1–S4), namely: an expected death led to the bereaved being more likely to be involved in care decisions, know the contact details for the professional responsible, receive information about the approaching death, and be well supported by healthcare professionals immediately after the death .Whether the death was expected or not had a moderate to strong effect on four end-of-life care outcomes (p < 0.001) (Tables S8–S13).The bereaved person expecting their loved one to die was also significantly associated with fewer experiences of some pandemic-related challenges (often < 0.001) . Resultsp = 0.001) and be provided with information about bereavement support services at the time of death (p < 0.001). Relationship to the deceased had a medium to large effect on these variables (Tables S1–S7).Closer relationships  compared with more distant relationships (distant family/colleague or friend) led to the bereaved person being more likely to know the contact details for the professional responsible for their loved one’s care (p < 0.001) (p < 0.001).Relationship to the deceased was also significantly associated with some pandemic-specific challenges. The inability to visit prior to death was highest if the deceased was a grandparent (77.8%) and lowest if the deceased was their child (33.3%) or partner (41.4%) compared with other groups (< 0.001) . Social Table S8). Similar patterns occurred for limited contact in last days of life and being unable to say goodbye (Tables S9 and S10). Parents whose child had died had a decreased risk of limited contact with them in last days of their life compared with partners  (Table S10). Odds of restricted funeral arrangements were reduced for all groups compared with the reference group of partner, although this was significant only for colleague or friend versus partner  (Table S11). The odds of social isolation and loneliness were strongly and significantly reduced for all groups compared to the reference group of partner, for example, OR = 0.092 (95% CI: 0.028–0.297) for other family member (Table S12).These results were confirmed in logistic regression and mixed-effects GLM. Relationships other than ‘partner’ had strongly increased odds of being unable to visit their friend or relative before death, for example, participants whose grandparent had died were nine times more likely not to have been able to visit them before death compared with bereaved partners  (p = 0.028) and contacted by the hospital or care provider following the death (p = 0.011) (Tables S1–S8).Participants with higher levels of qualification were significantly more likely to report being well supported by healthcare professionals immediately after the death (Tables S1–S8). However, there were no significant differences (p > 0.05) and no obvious and consistent pattern across outcomes (region of the UK was therefore included in the mixed-effects GLM as a random-effect).Decile of deprivation (England) and region of the UK occasionally had a strong or moderate effect on end-of-life care outcomes (Tables S1–S7). Odds of social isolation and loneliness and separately limited contact with other close relatives/friends were higher for women compared with men, although this was only significant for limited contact with other close relatives/friends. The odds of restricted funeral arrangements were higher for women compared with men, although this was significant only for logistic regression .The effects of gender identity were generally weak , fear and anxiety around catching/spreading the virus, and the social challenges and alienation associated with COVID-19 bereavement.When a death was unexpected the bereaved was less likely to be involved in care, feel supported by healthcare professionals or be contacted afterwards, and the odds of social isolation and loneliness were higher. Partners and parents of the deceased were more likely to report supportive end-of-life care compared with distant family members/friends, however social isolation and loneliness was highest among partners.People with higher levels of qualification reported better support from healthcare professionals and more contact following the death, possibly because people with higher levels of education are more able to elicit professionals’ support. Compared to men, women seemed more likely to report limited contact with other close relatives or friends. Both of these findings warrant further investigation.2629 Modelling of routine data from the first 10 weeks of the pandemic in the UK (7 March–15 May 2020), found deaths in care homes increased by 220%, and home and hospital deaths by 77% and 90% respectively, while hospice deaths fell by 20%. The increase in home deaths was sustained and hospices shifted their resources to the community. Our findings suggest that despite the rise in home deaths during the pandemic, they were associated with better experiences of end-of-life care than deaths in other settings, indicating that primary and community care services were comparatively successful in supporting home deaths, despite the additional pressures on services.Bereaved people reported worse experiences of hospital and care home deaths than deaths at home or hospice, as in pre-pandemic studies.3436 For example, among the COVID-19 bereaved, poorer bereavement outcomes might be explained by the higher likelihood of poor end-of-life care experiences as well as the increased likelihood of pandemic-related challenges due to infection control restrictions. The study’s longitudinal and qualitative data will throw further light on such outcomes and experiences in this sample.Our findings could help explain why the pandemic may increase levels of prolonged grief disorder and other longer-term poor bereavement outcomes satisfaction with social support did not differ between people bereaved by COVID-19 versus other types of deaths – however, given the small number of COVID-19 deaths (n = 49) these findings should be treated with caution. A US survey of people bereaved by COVID-19 (n = 307) found a close relationship with the deceased was associated with reduced functional impairment due to the loss. In China (n = 422), the death of a close relation due to COVID-19 was associated with more severe grief symptoms. The higher levels of loneliness and social isolation we observed amongst bereaved partners may help explain these associations.We found increased levels of social isolation and loneliness among people bereaved due to COVID-19, with partners at particular risk. In contrast, in a survey in the NetherlandsThe study sample was large, with good spread across geographical areas, education and deprivation, but was biased towards female and white respondents, despite targeted advertising to men and people from ethnic minority communities. By recruiting mostly online, we were less likely to reach the very old or other digitally marginalised groups, hence the high levels of social isolation we identified might under-estimate levels in the general bereaved population. Convenience sampling might have resulted in more people with negative experiences completing the survey. Despite these limitations, group sizes were sufficient to enable comparisons  and, while not providing population-level prevalence data, the sample does enable identification of risk factors to inform future practice and policy.Another strength of this study is the use of an explicit and structured statistical analysis plan. A Directed Acyclic Graph was used to visualise the relationships between variables and appropriate hypotheses were thereby generated . These hypotheses were tested for statistically by using both univariate calculations and mixed-effects logistic regression (i.e. the GLM). Patients admitted to hospital with COVID-19 often experience an unpredictable clinical course with high risk of sudden death. Discussions with next of kin should happen early, with this risk explained clearly and compassionately. Partners bereaved due to an unexpected COVID-19 death in hospital may be at particular risk of poor outcomes and need additional follow-up and support, particularly when they live alone or have a previous history of mental disorders. However, many challenges were experienced by people bereaved by non-COVID-19 deaths, and difficulties across the bereaved population should not be minimised. In particular, after sudden deaths of any cause bereaved people require attention and follow-up, given perceptions of poor support after death. Clear, consistent national guidance on hospital, hospice and care home visiting is essential to ensure equity and support staff. We found only a third of bereaved people had been given information about bereavement support services. Signposting at the time of death and in follow-up must be improved to ensure people know how and where to seek professional support and help alleviate access barriers.The evidence of sub-optimal end-of-life care demonstrates the difficulty of adequately supporting families during the pandemic, but also highlights areas for improvement. Communication with relatives must be prioritised and contact between loved ones at the end of life facilitated and optimised, even in the context of a pandemic. It is therefore crucial that end-of-life care providers are prioritised when supplies of personal protective equipment are overstretched, so that they are able to offer in-person visits, however there is evidence that this did not occur in 2020.4143 The experiences of bereaved men and people from Black and minority ethnic communities during the pandemic require further investigation.Further research is needed to examine the impact of end-of-life care experiences and pandemic-related social challenges on bereavement outcomes, and to determine the prevalence of poor bereavement outcomes including prolonged grief disorder among people bereaved during the pandemic, with comparisons to non-pandemic times. This is crucial given discrepancies in emerging evidence.Place, cause and expectedness of deaths and relationship to the deceased were risk factors for sub-optimal end-of-life care and challenging experiences in early bereavement during the pandemic. People bereaved by COVID-19 and partners bereaved by all causes of death were at particular risk of social isolation and loneliness. To learn from COVID-19 as a mass bereavement event, these findings should inform optimal clinical practice, bereavement support and the policy response.Click here for additional data file.Supplemental material, sj-pdf-1-pmj-10.1177_02692163221074876 for Risk factors associated with poorer experiences of end-of-life care and challenges in early bereavement: Results of a national online survey of people bereaved during the COVID-19 pandemic by Lucy Ellen Selman, DJJ Farnell, M Longo, S Goss, K Seddon, A Torrens-Burton, CR Mayland, D Wakefield, B Johnston, A Byrne and E Harrop in Palliative MedicineClick here for additional data file.Supplemental material, sj-pdf-2-pmj-10.1177_02692163221074876 for Risk factors associated with poorer experiences of end-of-life care and challenges in early bereavement: Results of a national online survey of people bereaved during the COVID-19 pandemic by Lucy Ellen Selman, DJJ Farnell, M Longo, S Goss, K Seddon, A Torrens-Burton, CR Mayland, D Wakefield, B Johnston, A Byrne and E Harrop in Palliative MedicineClick here for additional data file.Supplemental material, sj-pdf-3-pmj-10.1177_02692163221074876 for Risk factors associated with poorer experiences of end-of-life care and challenges in early bereavement: Results of a national online survey of people bereaved during the COVID-19 pandemic by Lucy Ellen Selman, DJJ Farnell, M Longo, S Goss, K Seddon, A Torrens-Burton, CR Mayland, D Wakefield, B Johnston, A Byrne and E Harrop in Palliative Medicine