To conduct brainstem MRI shape analysis across neurodegenerative parkinsonisms and control subjects (CS), along with its association with clinical and cerebrospinal fluid (CSF) correlates.We collected demographic and clinical variables, performed planimetric and shape MRI analyses, and determined CSF neurofilament-light chain (NfL) levels in 84 participants: 11 CS, 12 with Parkinson’s disease (PD), 26 with multiple system atrophy (MSA), 21 with progressive supranuclear palsy (PSP), and 14 with corticobasal degeneration (CBD).MSA featured the most extensive and significant brainstem shape narrowing , mostly in the pons. CBD presented local atrophy in several small areas in the pons and midbrain compared to PD and CS. PSP presented local atrophy in small areas in the posterior and upper midbrain as well as the rostral pons compared to MSA. Our findings of planimetric MRI measurements and CSF NfL levels replicated those from previous literature. Brainstem shape atrophy correlated with worse motor state in all parkinsonisms and with higher NfL levels in MSA, PSP, and PD.Atypical parkinsonisms present different brainstem shape patterns which correlate with clinical severity and neuronal degeneration. In MSA, shape analysis could be further explored as a potential diagnostic biomarker. By contrast, shape analysis appears to have a rather limited discriminant value in PSP.Atypical parkinsonisms present different brainstem shape patterns.• Shape patterns correlate with clinical severity and neuronal degeneration.• In MSA, shape analysis could be further explored as a potential diagnostic biomarker.• The online version contains supplementary material available at 10.1007/s00330-023-09435-0. Structural MRI has been widely studied in the differential diagnosis of neurodegenerative parkinsonisms: Parkinson’s disease (PD), multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). Many studies have focused on the brainstem due to its frequent involvement in atypical parkinsonisms . Atrophy of the midbrain in PSP –3 or theAn alternative approach is shape analysis, which detects local narrowing in specific regions of complex structures, as opposed to conventional volumetric analysis only reporting changes in the overall volume . This teWith the hypothesis that brainstem MRI shape analysis might differentiate neurodegenerative parkinsonisms, we aimed at characterizing and comparing brainstem shape changes across these conditions, as well as analyzing the clinical and biological correlates of shape changes. As secondary goals, we intended to replicate prior findings of cerebrospinal fluid (CSF) levels of neurofilament-light chain (NfL) and automatic measures of the pons to midbrain ratio (PM) ratio.This is a cross-sectional study of patients recruited between 2015 and 2020 at the Parkinson’s Disease & Movement Disorders Unit of the Hospital Clinic in Barcelona as part of different research projects implying the availability of both high-field MRI and CSF samples for almost each participant.There was not a formal sample size calculation, but rather a post hoc analysis of the aforementioned projects considering that sample size was in the range of prior published studies on this topic, along with the uniqueness of our cohort due to having available both MRI and CSF data in almost all patients  –21. HencMovement disorders specialized neurologists  collected the following demographic and clinical variables of all participants: age at disease onset, sex and age and disease duration at the time of the study procedures. Cognition was assessed by means of the MoCa  , 23 subjects were acquired with TE = 2.98 ms, TR = 2.98 s, and voxel size 1 × 1 × 1 mm3. The T1-weighted MRI acquisition parameters for the other 10 subjects ranged from TE = 2.17 to 6.30 ms, TR = 14.40 ms to 2.4 s, and voxel sizes between 0.94 × 0.94 × 0.94 and 1.2 × 1.05 × 1.05 mm3. Details on the number of acquisitions with each protocol per group can be found in Supplementary MRI was performed within 2 months of lumbar puncture. MRI was acquired with a 3-T Prisma Siemens scanner, including sagittal T1-weighted volumes acquired with 3-dimensional magnetization prepared rapid gradient echo (3D-MPRAGE) sequences with TR = 2.4 s, TE = 2.22 ms, FlipAngle = 8; and isometric voxel size of 0.8 × 0.8 × 0.8mmMA) and midsagittal pontine area (PA), the number of voxels segmented as midbrain and pons in the midsagittal slice were counted and multiplied by voxel size and PM was calculated. To validate the results of the automated measurements, the MA and PA measurements were replicated manually  [Pons and midbrain regions obtained from the FreeSurfer Brainstem Bayesian parcellation module were merged and modelled using Spherical Harmonics Point Distribution Models (SPHARM-PDM) obtained from the SlicerSALT software (er.org/) , 39. Forer.org/) , includier.org/) . MultiplU-test, as appropriate. CSF and morphometric quantitative MRI biomarkers were compared between diagnostic groups using non-parametric analysis of covariance with age as covariate. To study the influence of CSF and MRI biomarkers (independent variables) on clinical variables (dependent variables) in parkinsonian disorders, we first transformed into ranges the independent variables and then applied multiple linear regression limiting covariables to age to minimize the risk of overfitting. For statistical purposes, HY was converted to a binary variable as HYbin: I-II vs. III-V.Sample size was defined on a pragmatic basis considering previous studies and the rarity of atypical parkinsonisms. Qualitative variables are presented as frequencies and were compared by means of Fisher’s exact test. Quantitative data are presented as median/interquartile range (IQR) and were compared using Kruskal–Wallis test or Mann Whitney’s To verify intra-rater and automatic-to-manual agreement, intraclass correlation coefficients (ICC) of agreement and consistency were calculated. These were considered as poor (ICC < 0.40), fair (0.40–0.59), good (0.60–0.74), and excellent (0.75–1.00) .Statistical tests were two-tailed, with significance set at ≤ 0.05, corrected for multiple comparisons by false-discovery rate (FDR)  (except We included 21 patients with PSP (14 PSP-Richardson’s syndrome (PSP-RS), 6 PSP parkinsonism (PSP-P), and 1 PSP-progressive gait freezing (PSP-PGF)), 14 CBD, 26 MSA (18 MSA-parkinsonian (MSA-P) and 8 MSA-cerebellar (MSA-C)), 11 PD, and 12 control subjects. The clinical diagnosis was neuropathologically confirmed in three participants . Demographic and clinical data are shown in Table These are summarized in Supplementary table 2. CSF NfL levels were significantly higher in atypical parkinsonisms vs. PD and CS.MA was significantly reduced, except when comparing with CBD, and the PM ratio was significantly increased when comparing with all the other groups. CBD patients presented significantly lower MA compared to PD and CS, and the PM ratio was significantly lower when compared to PSP and higher when compared to MSA and PD. Finally, MSA patients presented significantly lower PA than PSP, PD, and CS, and lower PM ratio than PSP and CBD. Significant associations of CSF and automatic MRI measures with clinical variables are summarized in Supplementary Automatic and manual measures are summarized in Supplementary Areas with statistically significant shape differences are shown in Fig. We found significant positive correlations between higher motor scales’ scores  and greater brainstem shape atrophy across the different parkinsonisms Fig. . SpecifiWe also found significant predominantly negative correlations between SEADL scores and brainstem shape alterations  in CBD, PSP, and PD. Specifically, negative correlations predominated in the midbrain in CBD and PSP, and were scattered through the midbrain and the pons in PD. In MSA, there was a more mixed pattern of both negative and positive correlations  with the negative correlation surfacing in the middle posterior pons.A positive correlation between CSF NfL levels and shape  in PSP, MSA, and PD was seen in several small midbrain and pons areas. In CBD, significant negative correlations (enlargement of these areas related to increased NfL) were seen Fig. .Fig. 3CoWe herein report for the first time: (1) different brainstem atrophy patterns across neurodegenerative parkinsonisms with remarkable differences in MSA; (2) local atrophy association with clinical and CSF variables across the spectrum of degenerative parkinsonisms. In addition, we have replicated previous findings of PM ratio , 45 and The novelty from our study comes from brainstem shape analysis. Shape analysis has become of increasing interest in neurodegenerative diseases, as Alzheimer and Parkinson’s disease. Significant shape differences have been found between PD and control subjects in different subcortical structures, including the subthalamic nucleus , the gloTo interpret narrowing as atrophy and enlargement as inflammation or regional elastic compensation, first we compared diseased vs. control groups, then compared diseased groups, shifting from an atrophy vs. non-atrophy paradigm to an atrophy-differences one. In this vein, our results show a gradation ranging from a more extensive affectation in MSA, followed by CBD to a more limited one in PSP Fig. . Shape aThe similar atrophy gradation of MSA and CBD vs. CS (more marked) and vs. PD (more limited) is clinically and radiologically plausible since PD is the diseased group with lesser brainstem affection , hence lGreater atrophy in PSP in the superior colliculus (upper midbrain) indicates greater dento-rubro-thalamic tract and red nucleus involvement Fig.  in keepiGreater brainstem shape atrophy was associated with worse motor state in all parkinsonisms and worse daily living function scores in CBD, PSP, and PD, while in MSA patients the correlations with SEADL were mixed: the negative correlation  arose in the posterior middle pons, where tegmental pontine nucleus involvement has been correlated with severe MSA-related orthostatic hypotension, one of the most disabling MSA symptoms . The posThe association of greater atrophy with higher NfL levels in PSP, MSA, and PD is in keeping with the notion that CSF NfL levels indicate neuroaxonal damage. The finding of higher NfL associated with lesser atrophy in CBD is difficult to interpret. A stochastic association is unlikely due to stringent FWE correction and multivariate analyses. An alternative explanation is that it could reflect ongoing neuronal injury in areas still undergoing inflammation before atrophy . In CBD,APs presented higher CSF NfL levels compared to PD and CS, but no significant differences among themselves, with increasing NfL levels significantly associated with disease severity, in agreement with previous literature , 57.Shape analysis provides novel and complementary information with respect to other traditional atrophy metrics and can contribute to a better understanding of the pathological processes. First, compared to traditional indices based on planimetric measurements, shape analysis provides 3D sensitivity, that is, it is able to detect changes in all the structure, not only in the MR slice of interest. In this sense, clear differences between MSA and PSP were found by shape analysis out of the midsagittal plane. With regard to other methods quantifying atrophy as a decrease in the total volume of the anatomical region, since they provide one only measure for the whole region, they might not be sensitive to scenarios where the difference is not only the global decrease or volume but rather the specific location of the volume decrease (as shown in the comparison between MSA and PSP).Our study is not without limitations. The different subgroups size is relatively small, yet in the range of previous published studies on MRI shape in parkinsonisms , 20, 21 In conclusion, we have found different patterns of local brainstem atrophy across atypical parkinsonisms by means of MRI shape analyses in association with clinical and CSF indicators of disease severity. More specifically, shape analysis might be further explored as a potential MSA diagnostic biomarker. In contrast, and despite its significant clinical and CSF correlations, in PSP shape analysis appears to be of rather limited discriminant value. Our results remain preliminary and additional prospective studies of larger cohorts will help confirm or not our findings and should further assess the combination of MRI shape analysis and CSF biomarkers.Supplementary file1 (DOCX 1862 KB)Below is the link to the electronic supplementary material.


Background: European guidelines recommend the use of pulse oximetry (PO) during newborn resuscitation, especially when there is a need for positive pressure ventilation or supplemental oxygen. The objective was to evaluate (i) to what extent PO was used, (ii) the time and resources spent on the application of PO, and (iii) the proportion of time with a useful PO signal during newborn resuscitation. Methods: A prospective observational study was conducted at Stavanger University Hospital, Norway, between 6 June 2019 and 16 November 2021. Newborn resuscitations were video recorded, and the use of PO during the first ten minutes of resuscitation was recorded and analysed. Results: Of 7466 enrolled newborns, 289 (3.9%) received ventilation at birth. The resuscitation was captured on video in 230 cases, and these newborns were included in the analysis. PO was applied in 222 of 230 (97%) newborns, median (quartiles) 60  seconds after placement on the resuscitation table. The proportion of time used on application and adjustments of PO during ongoing ventilation and during the first ten minutes on the resuscitation table was 30% and 17%, respectively. Median two healthcare providers were involved in the PO application. Video of the PO monitor signal was available in 118 (53%) of the 222 newborns. The proportion of time with a useful PO signal during ventilation and during the first ten minutes on the resuscitation table was 5% and 35%, respectively. Conclusion: In total, 97% of resuscitated newborns had PO applied, in line with resuscitation guidelines. However, the application of PO was time-consuming, and a PO signal was only obtained 5% of the time during positive pressure ventilation. Approximately 5% of newborns require resuscitation with positive pressure ventilations (PPV) at birth ,2,3,4. AECG does not replace the need for PO for evaluation of oxygenation and subsequent titration of oxygen to avoid hyper- and hypoxia ,11. InteThe objectives were to evaluate (i) to what extent PO was used during newborn resuscitations; (ii) the number of healthcare providers (HCPs) involved, the number of single-use sensors required for the application of PO, time spent on application or adjustments of PO; and (iii) the proportion of time with a PO signal during provision of positive pressure ventilation at birth.A prospective observational study was conducted at Stavanger University Hospital, Norway from 6 June 2019 to 16 November 2021. The hospital is well suited for population-based studies, being the only hospital in the region with obstetric and neonatal services and 4200 annual deliveries. Vaginal births take place in the labour ward and the midwife-run low-risk ward, and the caesarean sections in the operating theatre. PPV is provided to 3.6% of newborns, mainly by flow-driven t-piece resuscitator , alternatively a self-inflating silicone resuscitator  [Video recordings of resuscitations were obtained passively using motion-triggered cameras placed above the resuscitation tables, capturing the newborn and the hands of the HCPs. Dry-electrode ECG  was placed on the chest or upper abdomen of the newborn by the midwife assistants as soon as possible after birth. NeoBeat displays and stores HR within seconds of birth and provide continuous HR measurements. If a newborn required PPV, the cord was clamped and cut, and the newborn was carried to the resuscitation table. HCPs were instructed to apply 3-lead gel-electrode ECG  on the newborns’ chest and PO  on the newborns’ right hand or wrist. The order of ECG and PO placement was left to the discretion of the HCPs. However, in anticipated events, one HCP was assigned the task of applying the PO sensor. The monitor used was Carescape Patient monitor B450 or B650 . Video recordings were used to evaluate the time from birth to the start of ventilation, duration of PPV, application of PO and ECG, and to detect HR and PO signals displayed on the monitor. Extraction of patient characteristics were automated from electronic medical records.Parents were informed and consented to participation during routine follow up in pregnancy. Newborns born at gestational age (GA) ≥ 28 weeks who required resuscitation with PPV at birth with the resuscitation captured on video, were enrolled.All videos were manually reviewed by independent researchers (V.K. and S.R. or H.P.). Timelines were started when the newborn was placed on the resuscitation table, and for a duration of ten minutes. Videos were annotated using the ELAN 5.8 tool . The start of PPV was defined as when the first inflation was provided. The duration of PPV was defined as the time difference between the first and last inflation. The number of HCPs involved in applying the PO equipment and the number of single-use PO sensors used were recorded. The time spent applying the PO was defined from when one started drying the skin or picking up the sensor, whichever came first, until the PO was attached, regardless of whether a useful signal was obtained. The PO adjustment time included repositioning or reapplying the sensor, reattaching the PO cord to the monitor and/or changing the sensor. The PO signal was annotated based on reviewing a recording of the monitor screen. The time to reliable PO signal was defined as the time when a continuous pulse wave, HR, and/or saturation values were displayed for at least 3 s ,12,14.Data and annotations were extracted and analysed using Matlab R2022b . Continuous variables are expressed as median (quartiles) or count (%).This study was a part of the Safer Births Stavanger research project on newborn resuscitation, with ethical approval from the Norwegian regional ethical committee 27 April 2018 (ref.2018/338).In total, 10,539 newborns were born during the study period, of which 10,503 with gestational age ≥28 weeks. Of these, 7466 (71%) parents agreed to participation, of which 289 (3.9%) received PPV at birth. The resuscitation was captured on video in 230/289 cases, and these newborns were included in the analysis. A flow diagram of over participants and patient characteristics is shown in Among 230 resuscitated newborns, 222 (97%) had PO applied during the first 10 min on the resuscitation table. PO was applied median (quartiles) 60  seconds after placement on the resuscitation table.Auscultation with the stethoscope was performed in 211 (92%) median 39  seconds after placement on the table.n = 204).ECG was applied in 220 (96%) newborns. Standard 3-lead gel-electrode ECG was placed in 192 newborns at a median of 60  seconds. Dry-electrode ECG was in most instances placed in the delivery room, and the time of placement of NeoBeat was therefore median 0  seconds from placement on the resuscitation table  seconds after the newborn was placed on the resuscitation table. Time spent on applying and adjusting PO in the first 10 min of resuscitation was median 99  seconds. The time spent placing the PO is illustrated in blue lines in Video of the PO monitor signal was available in 118 (53%) of the 222 newborns. In 110 of 118 newborns a PO signal was obtained within the first ten minutes on the resuscitation table. The time when a PO signal was first displayed and the proportion of time with a PO signal in relation to PPV is shown in In this population-based video study of 230 newborns receiving PPV at birth, we found that PO was applied in 97% of resuscitations, in line with guideline recommendations . HoweverAn accurate HR assessment is considered important to evaluate the newborn condition, to guide management, and to evaluate the effect of resuscitative interventions. PO has several limitations with regard to monitoring HR in the delivery room. Our group has recently shown that PO displayed HR values later and for a shorter proportion of newborn resuscitation, when compared to the dry-electrode ECG device NeoBeat or standard three-lead ECG . PO may In the current study, the median time to obtain a PO signal was 237 s after placement on the resuscitation table. Similar findings have been reported previously, with a success rate in obtaining saturation measurements varying between 20–100% at one minute after birth . SeveralThe results challenge the role of PO in the assessment of HR during newborn resuscitations. PO does, however, have an important role in the titration of oxygen provision during resuscitation in order to avoid hypoxia and hyperoxia with oxidative stress . AlthougConsiderable resources went into the placement of PO. HCPs spent 30% of the time during active resuscitation applying PO, without obtaining PO signal in the majority of cases. Where resources are limited, prioritizing the placement of PO during ventilation may be impractical.This study was limited by the loss of PO signal data in 104 newborns due to technical errors, including frame freezing of the monitor video and loss of resuscitation videos due to a server failure without a backup. In this study, we analysed the availability of PO signal during resuscitation, but have not evaluated the HR signal accuracy compared to the gold standard ECG. The population was limited to newborns with gestational age ≥28 weeks, since extremely premature newborns were resuscitated and stabilized in incubators not equipped with video cameras. The strengths of the study are the population-based design and a high number of included newborns. The setting is representative of high-resource contexts.During delivery room resuscitation, 97% of newborns had PO applied in line with European Resuscitation Council Guideline recommendations. However, the application of PO was time-consuming, and PO signal were only displayed for 5% of the time of active resuscitation with PPV.


Therefore, our proposed dynamic MVC obtained sEMG amplitudes closer to its physiological maximum value and is thus more capable of normalizing the sEMG amplitude for low back muscles.Surface electromyography (sEMG) is generally used to measure muscles’ activity. The sEMG signal can be affected using several factors and vary among individuals and even measurement trials. Thus, to consistently evaluate data among individuals and trials, the maximum voluntary contraction (MVC) value is usually calculated and used to normalize sEMG signals. However, the sEMG amplitude collected from low back muscles can be frequently larger than that found when conventional MVC measurement procedures are used. To address this limitation, in this study, we proposed a new dynamic MVC measurement procedure for low back muscles. Inspired by weightlifting, we designed a detailed dynamic MVC procedure, and then collected data from 10 able-bodied participants and compared their performances using several conventional MVC procedures by normalizing the sEMG amplitude for the same test. The sEMG amplitude normalized by our dynamic MVC procedure showed a much lower value than those obtained using other procedures (Wilcoxon signed-rank test, with  Surface electromyography (sEMG) is an important technique in ergonomic risk assessments and the diagnosis of musculoskeletal disorder (MSD) . sEMG daFor different muscles, different MVC exercises are used to record the sEMG amplitude when only a target muscle is activated under a proper external force to reach its maximum contraction. This procedure is straightforward for major muscles of the upper and lower limbs. Yet, due to the complex musculature of the low back and the presence of several layers of muscles under the skin, several muscles contribute to trunk bending and resistance against an external force. Therefore, it is hardly possible to: (i) isolate the contraction of a muscle while maximizing its contraction to resist an external force, and (ii) ensure that the same group of muscles are involved in the MVC task and the movement during the actual test . As a reIn general, the sEMG amplitude recorded for low back muscles, namely the left/right latissimus dorsi and left/right thoracolumbar fascia, which are commonly used during physical tasks ,13, may Usually, static exercises are used for MVC collection for low back muscles; some common examples are seen in Thus, we expanded upon the MVC procedures to include dynamic tasks to explore the highest sEMG amplitude recorded from the involved low back muscles. During the dynamic MVC procedure, participants were instructed to lift a 45 lbs. weight only using their low back muscles, which meant that they needed to keep their elbows and knees straight during the movement . AdditioTo investigate the efficiency of the dynamic MVC measurement procedure, a set of experimental procedures was designed. Data were collected from 10 able-bodied participants without any history of musculoskeletal disorders . Four EMG sensors  were placed on both the right and left latissimus dorsi and thoracolumbar fascia, the muscles mainly involved in weightlifting tasks . The locFinally, the participants were instructed to perform a manual lifting task three times at their preferred pace. The task consisted of lifting a 45 lbs. weight from the floor to the participant’s chest, and then lowering it to the floor again. sEMG data collected during the performance of four conventional MVC exercises and via the proposed dynamic MVC procedure were normalized. Then, the normalized sEMG results for each muscle were compared together.Remove the baseline error using the medium value during a quiet, lying down period.Band-pass filter the EMG signal using a 4th-order Butterworth filter, with cut-off frequencies of 10 Hz and 500 Hz.Perform full wave rectification.Smooth the results using a moving average filter with 500 sample points.Calculate the root mean square (RMS) of the sEMG amplitude during the working period.Normalize the results of five different MVC procedures.The raw sEMG signal’s amplitude can have a range of ±5000 µV, with its energy being concentrated mostly between 20 Hz and 150 Hz. The sEMG recording is usually rectified and band-pass filtered before further data interpretation ,17,18. IWe hypothesized that the best MVC collection procedure would obtain the highest sEMG amplitude, and thus, the lowest normalized sEMG amplitudes in the same actual lifting test. To investigate if those undergoing the dynamic MVC procedure outperformed those in undergoing the other conventional MVC measurement procedures, we used the paired Wilcoxon signed-rank test . We compared the results normalized according to the dynamic MVC measurement procedure to those normalized according to each of the conventional MVC procedures. The significance level  was set to 0.05 ,20.p values being less than 0.05, according to The sEMG amplitudes during the lifting task, which were normalized according to all four conventional MVC procedures, were frequently larger than 100% . Only thAccording to The normalization of sEMG amplitude translates raw voltage data into muscle activity relative to MVC and can provide meaningful information about muscle fatigue and MSDs ,22. Due p values for Wilcoxon signed-rank test were smaller than 0.05, except for trunk bending and standing MVC procedure for right latissimus dorsi). Additionally, we observed that the sEMG amplitudes normalized according to the dynamic MVC procedure were from 18% to 46% lower than those normalized according to conventional MVC procedures. We observed that in the dynamic MVC procedure, we obtained higher sEMG amplitudes than we did during each of the four conventional MVC procedures, and the sEMG amplitudes normalized according to the dynamic MVC procedure were, in general, lower than those normalized according to conventional MVC procedures for the four studied low back muscles  different tasks involving the low back muscles, and (ii) other body parts with complex musculature. Additionally, the feasibility of the proposed MVC approach should be further investigated in a larger and more diverse participant population.This study introduced a novel, dynamic MVC measurement procedure for low back muscles. The dynamic MVC measurement procedure showed a better performance compared to that of the conventional static MVC tests for low back muscles, which is evident from us having obtained higher sEMG amplitudes during the dynamic MVC procedure compared to those obtained using the conventional MVC procedures. The proposed dynamics MVC procedure was also the only MVC procedure that obtained normalized sEMG amplitudes, which were always less than 100%, unlike the conventional MCV procedures. The efficiency of our proposed dynamic MVC should be further investigated for other skeletal muscles.


Elevated protein levels in cerebrospinal fluid (CSF) can occur in various pathologies and are sometimes difficult to interpret. We report a 62-year-old male patient with subacute neurological deterioration, progressive tetraparesis, and cytoalbumin dissociation in the lumbar CSF. The patient had a pre-existing cervical spinal stenosis with mild tetraparesis. Based on the initial cytoalbumin dissociation , Guillain–Barré syndrome was initially considered. For further diagnosis, a CSF sample was taken from a pre-existing ventriculoperitoneal shunt, which showed a normal protein and cell count considering the patient’s age . In conclusion, we suggest that intermediate aggravation of tetraparesis was due to pneumonia with septic constellation, and the cytoalbumin dissociation was interpreted as Froin’s syndrome (FS) due to spinal stenosis. In this unique case, we were able to prove the -often suspected- case of FS by parallel analysis of ventriculoperitoneal shunt and lumbar CSF. The triad of xanthochromia, high protein levels, and marked coagulation was first described by Georges Froin and occurs in various processes leading to severe spinal stenosis. The altered composition of lumbar CSF might be due to impaired CSF circulation; however, the exact mechanisms of this phenomenon require further investigation. Cerebrospinal fluid (CSF) analysis is an important diagnostic tool in the workup of neurological diseases. An elevation of CSF protein level may indicate intrathecal protein synthesis or may occur in the context of a disrupted blood–brain barrier (BBB) during infections, leptomeningeal metastasis, or subarachnoid hemorrhage. As an alternative cause for increased CSF protein levels, disturbances in CSF circulation between the upper and lower spinal cord can falsify the CSF results from lumbar punctures. Highly elevated CSF protein levels in lumbar puncture should lead to the differential diagnosis of Froin’s syndrome (FS) during routine clinical practice . AlthougWe here report on a 62-year-old male patient who presented with increasing subacute neurological deterioration of a known tetra-paresis and impoverishment of speech production within one week. A cervical spinal canal stenosis  and supportive OAfter pulmonary stabilization, the patient was transferred to the neurological immediate care (IMC) for further diagnostics and treatment of the progressive tetra-paresis and vigilance mitigation.On admission, the clinical–neurological examination revealed a somnolent patient in reduced general condition, oriented to person only, without meningism. Cranial nerves were unremarkable, and no sensory disturbances were notable. A pronounced tetra-paresis with an emphasis on the left side and especially lower extremities, as well as generalized areflexia, were detectable. Disturbances of bladder and bowel function were not evident.Cranial imaging with computer tomography and magnetic resonance imaging (MRI) showed no evidence of acute ischaemia, hemorrhage, or elevated intracranial pressure. Shunt dysfunction was excluded by careful assessment of ventricular size, shunt location, and puncture by the neuroradiologists and neurosurgeons. We also compared CSF parameters of the ventriculoperitoneal shunt before the actual clinical deterioration from a previous clinical stay and did not observe significantly different parameters compared to the current analysis, also indicating stable shunt function and location. The pre-existing right frontal parenchymal defect and pituitary adenoma were unchanged from previous imaging.An additional MRI of the spinal cord showed myelopathy in the T2-weighted images at the level of cervical vertebra 3 and a narrowed spinal canal (Kang grade 3) constant to the previous findings 5 years ago see A–D and sIn the context of clinically worsened tetraparesis and cytoalbumin dissociation in the CSF, the diagnosis of Guillain–Barré syndrome was first considered, and intravenous immunoglobulins started. Additional neurographies showed conspicuous F-waves and mild amplitude reductions, which had already been described in a previous neurological work-up 4 years ago. The supplementary nerve sonography showed some caliber irregularities, but there was a regular presentation of the roots C5 on both sides and C6 left side, so additional diagnostics were not clearly supportive for GBS.For further clarification of the cytoalbumin dissociation, cerebrospinal fluid was taken from the ventriculoperitoneal shunt 3 days after the lumbar puncture. The findings were unremarkable , neuroimmunological diseases such as GBS, malignancies, intracranial hemorrhage, endocrinological diseases like hypothyroidism , degenerFS was first described by Georges Froin 1874–1932) in 1903 as a triad of high protein content, xanthochromia, and marked coagulation 874–1932  and assoIn conclusion, CSF protein elevations are a frequent finding, which can be attributed to various causes and are sometimes difficult to interpret in the clinical setting. Our case clearly demonstrates marked differences in the analysis of ventricular versus lumbar-derived CSF and highlights the complex mechanisms of CSF circulation. Further studies on the exact dynamics of both ventricular and lumbar-derived CSF, including pressure measurements, could contribute to a better pathophysiological understanding of CSF circulation.


It is unclear whether unipolar (UHA) or bipolar (BHA) hemiarthroplasty should be the preferred treatment of femoral neck fracture (FNF).We investigated the reoperation rate at 13 years post-fracture after BHA and UHA as treatment of FNF, including a subgroup analysis of individuals who survived 5 years or more, and described the reasons for reoperation after BHA and UHA respectively.In an observational cohort study on prospectively collected national register data, 16,216 BHA and 22,186 UHA were available for matching. A propensity score for treatment with bipolar HA was estimated using logistic regression. Matching was done using the 1:1 nearest neighbor matching without replacement. Of the 16,216 BHA patients, 12,280 were matched to a UHA control. A subgroup analysis based on the matched sample excluded individuals who died within 5 years and comprised 3,637 individuals with BHA and 3,537 with UHA. Kaplan-Meier survival analysis was used.In the Kaplan-Meier analysis, 92% of the BHA group was free from reoperation at 13 years (95% CI 0.91–0.93), compared to 92% in the UHA group (CI 0.89–0.94). BHA was associated with more reoperations until 3 years. Reoperation due to infection was most common after BHA, n = 212 (1.7%) compared to n = 141 (1.1%) after UHA. Dislocation led to reoperation in 192 of the BHA cases (1.6%) and in 157 of the UHA cases (1.3%). Acetabular erosion/pain occurred in 0.1% and 0.4%. Amongst those surviving ≥ 5 years, 93% of the BHA group was free from reoperation (CI 0.92–0.94) at 13 years, 92% after UHA (CI 0.90–0.94). BHA had more reoperations during the 1st year only. The causes for reoperations showed similar rates except for acetabular erosion/pain. Here the BHA group had 2 cases (0.1%), the UHA had 39 (1.1%).With a modular hemiarthroplasty relatively few patients need a reoperation. During the first years, there is a higher reoperation rate after BHA compared to UHA. Thereafter, no differences are seen. In patients who survive ≥ 5 years after the fracture there are more reoperations due to acetabular erosion after UHA, but crude numbers are extremely low, and the total reoperation rate is not affected. In the case of a displaced femoral neck fracture in an elderly individual, hip hemiarthroplasty (HA) is the most common treatment option . In unipHowever, this has been difficult to show in clinical studies, and clinical equipoise still exist as whether the articulation in a hemiarthroplasty should be unipolar or bipolar. Metanalyses have shown similar results for BHA and UHA, with the exception of slightly less acetabular erosion with BHA , 3, A hiThe proposed benefit of the dual articulation of the BHA to decrease acetabular wear has to be weighed against potential disadvantages . Is therOur primary aim was to investigate any difference in the reoperation rate between BHA and UHA after treatment of femoral neck fractures, including a subgroup analysis of healthier individuals who had a survival of 5 years or more.Our secondary aim was to describe the reasons for reoperation after BHA and UHA respectively.This is an observational cohort study on prospectively collected data. 57,800 primary operations due to hip fracture were identified between 2005 and 2015 in the Swedish Arthroplasty Register (SAR). SAR has registered HA since 2005 and has for this procedure a 97% completeness [2,664 patients were treated with bilateral arthroplasties due to subsequent, bilateral fractures within the study period. If the patient had a bilateral surgery during the study period only the first surgery was included. Exclusion criteria were missing information on type of head (BHA/UHA), type of approach, cement less design and surgery in private hospitals. Surgeries reported in 2015 were excluded to allow a minimum 1-year follow-up. This led to 16,216 BHA and 22,186 UHA that were available for matching . The ability of the PS matching to balance the baseline covariates was assessed using absolute standardized mean differences (SMD). A SMD < 10% was considered non-significant.Of the 16,216 patients treated with bipolar HA, 12,280 patients were matched to a unipolar HA control within the specified caliper distance. 3,936 patients (24%) were excluded.To depict the outcome in less frail individuals with a theoretical higher activity level at the time of fracture, a subgroup analysis was conducted including only those patients who had at least 5 years of follow-up time, i.e. individuals who died within 5 years from the index surgery are excluded. The analysis was based on the matched sample and comprised of 3,637 individuals with BHA and 3,537 with UHA .Kaplan-Meier survival analysis was used for the different subgroup analysis, and any reoperation was set as an event. R version 3.6.1 was used for all statistical analyses.The study was approved by the Regional Ethical Review Board in Gothenburg, Sweden (ref. 882 − 17) and the the Swedish National Ethical Review Board (ref. 2019–05024). Patients are informed about registration in the SAR at the time of their arthroplasty procedure and have the possibility to decline participation. As the patient information also mentions that register data can be used in research, no further informed consent is necessary. The study adhered to the Helsinki Declaration and is reported based on the STROBE guidelines.This work was supported by grants from the Southern Health Care Region, Sweden. It was also funded by an ALF grant . The funding bodies had no involvement in the conduction of the study or the preparation of the article. No competing interests were declared.Before matching, the mean age and the ASA class of the BHA group was lower, whilst surgery during the early study period, posterior approach and women were overrepresented Table . After mIn the matched cohort with 12,280 in each group, 603 (4.9%) were re-operated after BHA and 476 (3.9%) after UHA the end of the follow-up period , compared to 92% in the UHA group (95% CI 0.89–0.94). Numbers at risk were 102 and 111, respectively.Groups were similar in most aspects Table . The reoAt 13 years, 93% of the BHA group was free from reoperation (95% CI 0.92–0.94), compared to 92% in the UHA group (95% CI 0.90–0.94).In the entire matched cohort, BHA and UHA had the same major causes for reoperation. Infection was most common after BHA, n = 212 (1.7%) compared to n = 141 (1.1%) after UHA. Dislocation led to reoperation in 192 of the BHA cases (1.6%) and in 157 of the UHA cases (1.3%). Periprosthetic fracture occurred in 1.3% and 0.9%, acetabular erosion/pain in 0.1% and 0.4%.  the UHA had 39 (1.1%) (Table A Kaplan-Meier survival analysis showed 1-, 5- and 10-years mortality rates of 26%, 68% and 91% after BHA. The results in the UHA group were 27%, 69% and 91% Fig. .In a matched cohort with a long-term follow-up, we found more early reoperations after bipolar hemiarthroplasty compared to unipolar. This difference was not measurable past 2 years and up to 13 years post-fracture, UHA and BHA had the same rate of reoperation.To identify a subgroup of patients that would theoretically benefit from receiving a BHA, we selected the patients who survived 5 years or more after their fracture and performed a subgroup analysis. Neither in this assumingly healthier and more active group were there benefits for BHA in terms of fewer reoperations.Regardless of implant type, patients in general were reoperated for three major reasons – infection, dislocation, and periprosthetic fracture. In those with a long survival the pattern was slightly different; for the patients operated with UHA reoperation due to acetabular erosion was just as common as these three aforementioned causes. Dislocation is known to occur within the first few months, regardless of whether BHA or UHA is used –13.We confirm the earlier findings from Sweden that the UHA is associated with a lower early reoperation / revision rate compared to the BHA . Our lonOur results are well aligned with data from a recent register study from Australia, showing few differences between UHA and BHA : UHA hadAs this study is register-based, conclusions regarding causality cannot be drawn. We are limited by the variables in the register, meaning that information on certain possible confounders, such as comorbidities, frailty and activity level is lacking. Neither do we have data on non-surgically treated complications, radiological outcome, or patient-reported outcome. We acknowledge that the absence of a reoperation does not equal a successful post-fracture recovery. Despite the good completeness of primary procedures and revisions to the SAR, we are aware of some underreporting of reoperations to the register. Still, we expect this possible underreporting to apply to both implant types equally. The somewhat higher risk of periprosthetic fractures in association with BHA is more of a stem problem, where certain common combinations of anatomically shaped stems and UHA might have biased our results. Our study is one of the largest to analyze differences in the long-term reoperation rate between UHA and BHA. The completeness and national coverage of the SAR are high. In Sweden the use of either UHA or BHA are decided on a departmental level. This, and the matched design of the study, renders comparable study groups, which also is underpinned by the similar mortality rates. We consider the external validity to be good, as all patients, regardless of cognitive function, and all surgeons and hospitals are included. Reoperation of any kind was chosen as the primary outcome, and not revision surgery, as secondary surgery in the frail often is limited to minor procedures.With a modern modular hemiarthroplasty after femoral neck fracture relatively few patients need a reoperation. During the first years, there is a higher reoperation rate after BHA compared to UHA, but thereafter, no differences are seen. In patients who survive more than 5 years after the fracture there are more reoperations due to acetabular erosion after UHA, but crude numbers are extremely low, and the total reoperation rate is not affected.


Pneumonia contributes to about 15% of child deaths globally, with 20% of the overall deaths occurring in India. Although WHO recommends the use of pulse oximeters (PO) in first-level facilities for early detection of child pneumonia in low- and middle-income countries (LMICs), this has not yet been implemented in India. We aimed to assess the feasibility and acceptability of introducing PO in integrated management of neonatal and childhood illnesses (IMNCI) services at primary health centres (PHC) in the rural Pune district.We identified medical officers (MO) and auxiliary nurse midwives (ANM) from six PHCs as study participants due to their involvement in the treatment of children. We developed in-depth interview (IDI) guides for both groups to explore their IMNCI knowledge and attitude towards the program through a qualitative study. We conducted interviews with MOs (n = 6) and ANMs (n = 6) from each PHC. The PO module was added to explore perceptions about its usefulness in diagnosing pneumonia. After baseline assessment, we conducted training sessions on adapted IMNCI services (including PO use) for MOs and ANMs. PO devices were provided at the study PHCs.At baseline, no PO devices were being used at study PHCs; PHC staff demonstrated satisfactory knowledge about paediatric pneumonia management and demanded refresher IMNCI training. They also felt the need to reiterate the PO use for early diagnosis of pneumonia in children and highlighted the challenges encountered in managing pneumonia at PHCs, such as health system-related challenges and parents’ attitudes towards care seeking. There was positive acceptance of training and PO started to be used immediately in PHCs. There was increased confidence in using PO at endline. PO use in examining symptomatic children increased from 26 to 85%.Paediatric PO implementation could be integrated successfully at PHC levels; we found pre-implementation training and provision of PO to PHCs to be helpful in achieving this goal. This intervention demonstrated that an algorithm to diagnose pneumonia in children that included PO could improve case management. Pneumonia is a major cause of under-five mortality worldwide, especially in India -3, wherePrevious studies have shown that clinical symptoms alone are insufficient for an accurate diagnosis of paediatric pneumonia and the estimation of hypoxia . Manual The implementation of paediatric PO in LMICs has been limited, particularly in India, with few studies conducted in primary healthcare settings ,12,17,26This is a primarily qualitative study, supplemented by secondary quantitative data.The study was conducted in the rural administrative blocks of Ambegaon and Junnar in Pune district, located 75-80 km from Pune city, with a combined population of around 625 700. The most common employment among the semi-urban, rural, and tribal inhabitants in this area are agriculture and industrial labour. A primary health centre (PHC) is the first point of contact for health care for the village population; each serves 20 000-30 000 individuals and is staffed by medical officers (MOs), paramedics, and others. We selected six PHCs for the study from a list of all PHCs in the Pune district using purposive sampling; in collaboration with the district health officials from the Ambegaon and Junnar blocks, PHC staff helped the King Edward Memorial Hospital Research Centre (KEMHRC) team with implementing the study. These six PHCs together catered to a population of about 135 000 individuals with approximately 14 000 children under five years of age . Four ofWe used an in-depth interview (IDI) schedule for data collection, developing IDI guides for MOs and ANMs separately to explore their knowledge about and attitudes towards IMNCI. The interview guide was created by the KEMHRC Vadu team and consisted of questions designed to assess participants' knowledge about IMNCI and their perceptions, experiences, and challenges they faced regarding the introduction of paediatric PO in the healthcare system. We piloted the interview tool to validate its effectiveness, clarity, and cultural sensitivity with a small sample. Then, researchers identified and refined issues, assessed interview flow and timing, and trained the two interviewers in the qualitative data collection process. This was done to ensure the validity and reliability of the tool.We used IDI guides, process mapping guides, and clinical case record forms for data collection. A module on pulse-oximetry was added to understand perceptions about the expected usefulness, acceptability, and effectiveness in diagnosing and classifying pneumonia, alongside questions on operational challenges and facilitators. We further developed process mapping tools and workflow tracking sheets for documenting processes at paediatric outpatient departments of primary health centres. A study team comprising project coordinators (PC) (n = 2) and field research assistants (FRAs) (n = 4-6) were trained in data collection. PCs were specifically trained in qualitative data collection methods; they interviewed the MOs and ANMs in the local Marathi language, as they were adept in its use. We conducted interviews with MOs (n = 6) and ANMs (n = 6) from each PHC. Pre-scheduled appointments of the MOs and ANMs were taken for the interviews. We stopped data collection when saturation was reached.We conducted a baseline assessment of the six selected PHCs to observe the functioning of the system, IMNCI implementation, documentation practices, and overall workload at the outpatient department (OPD) services for treating under-five children. We also conducted IDI with six MOs and six ANMs.After the baseline assessment, MOs and ANMs were trained on adapted IMNCI services, including PO implementation. The training sessions covered study overview, IMNCI algorithm understanding through visuals, hands-on PO device usage, reading values, IMNCI chart referencing, and proper documentation. Frequent staff transfers led to arranging training for new personnel and offering refresher courses to existing staff, ensuring proficiency in delivering IMNCI services.2 in under-five sick children presenting with respiratory symptoms were provided at each of the six PHCs. The study team provided technical support to the PHC staff through regular visits, addressing documentation difficulties, encouraging usage of PO for assessment of under five children with respiratory symptoms, and monitoring adherence to the IMNCI algorithm; this was done without interference with the routine activities in the healthcare system.Paediatric PO devices  for measuring SpOThe study team conducted endline assessment of the six selected PHCs to observe the functioning of the system, IMNCI implementation, documentation practices followed, and overall workload at the OPD services for treating under-five children. Furthermore, IDIs were conducted with six MOs and six ANMs.2 saturation. The PO devices were distributed in the last week of May 2021. Data collection continued from June through November 2021 to assess the change in the proportion of usage of PO after procurement of the device. Retrospectively, we obtained the number of under-five children attending OPDs of these six PHCs prior to the start of the study; however, information related to respiratory illness and usage of PO was not available.We collected baseline information on under-five children seeking healthcare services in the six selected PHCs from March to May 2021 using IMNCI forms. Based on this information, we were able to calculate the number of children with respiratory symptoms and the proportion of cases for which the available adult PO device was used by healthcare staff to determine SpOWe transcribed the interviews from the local language (Marathi), translated them into English, and entered into the MAXQDA software for analysis. We analysed the data using an inductive approach with a thematic framework. Thematic qualitative analysis systematically identifies recurring patterns, themes, and concepts in collected data, providing a deeper understanding of participants' experiences and perspectives. The process involves data familiarisation, coding meaningful units, and organising them into broader themes, yielding a comprehensive narrative and valuable insights. This approach offers flexibility and rigour, enabling rich interpretations from qualitative data. For the quantitative data, we calculated the number of under-five children seeking health care services and proportion of PO devices used in the pre- and post-intervention period was calculated.The KEM Hospital Research Centre institutional ethics committee (Ref No. KEMHRC/RVM/EC/1312), the Academic and Clinical Central Office for Research and Development (ACCORD), and the Edinburgh Medical School Research Ethics Committee (Ref No. 20-EMREC-014) approved this study. We implemented the study following the National Ethical Guidelines for Biomedical and Health Research involving Human Participants issued by the Indian Council of Medical Research in 2017 and the recent National Guidelines for Ethics Committees Reviewing Biomedical & Health Research During COVID-19 Pandemic issued in 2020. All participants who signed the consent form were included in the study. We also obtained a support letter from the Additional Director of Health Services, Pune district (Ref No. SFWB/KEMHRC research study/2019/82227-28 dated 24/12/2019).At the baseline assessment, we observed the OPD services and process followed by the PHC staff for under-five children across all six PHCs. Generally, only one MO and one ANM were responsible for handling all the OPD patients, including adult and paediatric populations, resulting in substantial backlogs. The ANM was taking the weight and temperature of all children. The MO was performing a general and systemic physical examination. All under-five children with symptoms of cough and cold were classified as having either an upper respiratory tract infection (URTI) or a lower respiratory tract infection (LRTI). No PO device were being used during the physical examination. The MO documented his/her findings and prescribed treatment on the OPD case paper. There was no separate documentation to suggest that the IMNCI protocol was being followed. The IMNCI charts were not displayed in the OPD room.The MOs were in the age range of 38-59 years with basic educational qualification of Bachelor of Ayurvedic Medicine and Surgery (BAMS) barring one who was Bachelor of Medicine and Surgery (MBBS)  course. The group represented an equal proportion of respondents from tribal and rural areas respectively. The period of service completed to date was in the range of 5-34 years.The following baseline themes emerged in the analysis of IDIs both from MOs and ANMs with respect to the feasibility of the introduction of the paediatric PO in the system  workers in their villages, teaching them how to use the paediatric PO for screening children and making referrals to the PHCs. The ANMs have provided positive feedback about the ASHA workers' involvement, as they showed great motivation in carrying out their outreach duties. This has significantly strengthened the implementation of IMNCI. However, the actual number of patients referred is not reported due to gaps in documentation and record-keeping practices.2 with the PO has significantly boosted the self-confidence of the MOs and ANMs. Due to increased awareness about children's health post-pandemic, parents now expect SpO2 checking in every respiratory clinical examination.MOs found paediatric PO to be highly useful in the early identification of high-risk children at risk of pneumonia infection. Additionally, parents' appreciation for checking SpOANMs gained confidence in using the paediatric PO after receiving training. They were able to obtain accurate readings as the children's fingertips fit the sensors perfectly. However, one MO had a differing opinion, which is evident from the verbatim mentioned below.– A MO from rural PHC.I disagree. The pediatric PO is not necessary for diagnosing pneumonia in children. Observing physical signs can serve the purpose. A child might have pneumonia even if the oximeter readings are normal. If the child experiences hypoxemia, even the mother can identify the signs without the need for a PO. PO (adult device) was used among 26% of paediatric patients with respiratory tract symptoms from March to May 2021, increasing to 8% from June to November 2021 after paediatric PO devices were provided  and among those classified as pneumonia/severe-pneumonia than as no-pneumonia  [The WHO modified its recommendations on the management of pneumonia in healthcare facilities and recommended the use of pulse oximetry, depending on availability . Previousettings , the Bansettings . The stu < 0.01) . The fin < 0.01) .Research studies have shown that using the paediatric PO has made it easier to diagnose severe pneumonia in healthcare centres as well ,15. In aA qualitative study in Bangladesh and Malawi explored the experiences of the use of paediatric PO, and found that health care professionals gained confidence through the use of the PO, gained caregivers’ trust, experienced challenges while implementing it on smaller children and reported battery issues which were similar to the present study .The observation of an overall drop in the paediatric OPD attendance at the six PHCs could be the result of COVID-19-associated restrictions. Some other reasons could be seasonal change, parents' ignorance, and reluctance to bring children to PHCs due to fear of the pandemic ,32. AccoOur findings about ANM and MO recalling having previously received IMNCI training, but requesting refresher training suggests that a one-time impartment of training is not beneficial unless periodically reiterated. The pre-implementation training helped the healthcare professionals; depending on their training and experience, they may have used their clinical judgment while referring the patients. Additionally, there is a requirement for periodic training, as a few health professionals have not attended the training. The IMCI global survey report reveals that many countries are using an abridged version of the training due to costs incurred and the long absence of healthcare professionals from services. In India, it has been often highlighted that the training targets cannot be fulfilled. Regular technical assistance to the healthcare staff kept them motivated, and routine training and supervision is key for the positive incorporation of PO within primary health care. Timely action should be taken to avoid delays in the treatment and referral of children ,18,29,30The study has several limitations. During the study, the second wave of the COVID-19 pandemic reached its peak, and most public health personnel were assigned to COVID-19 management. Identification and procurement of the appropriate paediatric PO device was a challenge, necessitating significant time and effort from the KEMHRC team. Additionally, the identification of a good, calibrated PO device that is cost-effective, readily available, and sturdy to handle may pose a challenge in scaling up this implementation.While there was established periodic monitoring during the implementation process, there was no system to scientifically assess whether the providers were accurately diagnosing the conditions. Future research should include a rigorous evaluation. As interviewers were from the national health programmes, they could have expressed opinions favourable to the interviewers.Our findings show that paediatric PO could be integrated at the primary healthcare level successfully. The pre-implementation training and the provision of the device to PHCs were found to be helpful. The fact that paediatric PO is being used more frequently demonstrates that there is a need for the device, and that it is possible to introduce and use it in the healthcare system in a way that could assist in identifying pneumonia in children under five years. The intervention demonstrated that an algorithm including PO to diagnose pneumonia in children could improve case management. The Sustainable Development Goal (SDG) target of reducing under-five mortality will be more achieavable by enhancing case management of pneumonia at the primary care level by expanding ARI diagnostic aids, improving coverage of IMNCI, strengthening referral pathways, and improving the quality of treatment in referral facilities.


The lateral calcaneal displacement (dS-dN) tended to be greater when CCLD limbs were compared to limbs with intact CCL. A magnitude of calcaneal displacement of 3.45 mm differentiated limbs with RLS from intact limbs with 87.5% sensitivity and 68.7% specificity. The calcaneus was displaced further laterally by about 3 mm on neutral radiographs (dN) when limbs with experimental TT were compared to those without TT (p < 0.05). A calcaneus located at least 3.25 mm from the sulcus differentiated limbs with TT from intact limbs with 87.5% sensitivity and 87.5% specificity. The technique reported here allowed detection of RLS, especially within limbs. A calcaneus located at least 3.25 mm on neutral radiographs of large dogs should prompt a presumptive diagnosis of TT.Cranial cruciate ligament deficiency (CCLD) results in internal rotational instability of the stifle (RLS). By contrast, tibial torsion (TT) is an anatomical feature of the tibia along its longitudinal axis. The objective of this study was to validate a dynamic radiographic technique to measure internal rotational laxity of the stifle and differentiate it from TT. Models included transection of the CCL for RLS and an osteotomy for TT. One limb within eight pairs of canine cadaveric hind limbs was randomly assigned to CCLD. The contralateral limb underwent TT, followed by CCLD. Neutral and stress radiographs were taken with the limb in a custom rotating 3-D printed positioning device before and after each modification. The position of the calcaneus on neutral views and the magnitude of its displacement under standardized torque were compared within limbs and between groups. Transection of the CCL increased the magnitude of displacement of the calcaneus by 1.6 mm (0.3–3.1 mm,  Cranial cruciate ligament deficiency (CCLD) is the most common cause of lameness and degenerative joint disease in the stifle of dogs with a prevalence that has doubled over the last 30 years . The CCLJoint laxity is generally defined as increased mobility of the joints to an externally applied force. Laxity tests evaluate the passive envelope of motion of a joint in an unloaded limb without considering muscles and loading activity. On the other hand, joint instability is a kinematic abnormality, occurring with dynamic loading  during daily physiological activities . These tex-vivo study of normal bones  is an anatomical feature, quantifying the twisting of the tibia in relation to its longitudinal axis. The lateral displacement of the calcaneus relative to the sulcus of the talus has been proposed as a radiographic indicator of TT in dogs . The preal bones . In thisal bones  took caual bones . InsteadThe objective of this project is to develop and validate a radiographic technique to quantify RLS and differentiate RLS from TT. We hypothesized that the radiographic position of the calcaneus would be located further laterally relative to the sulcus of the talus when the tibia is maintained in a neutral position (dN) in limbs with tibial torsion compared to intact and CCLD limbs of large dogs. We also hypothesized that the calcaneal displacement would be greater in limbs with RLS than in intact limbs or those with induced tibial torsion when standardized torque is applied to the tibia (dS–dN).The device was 3D printed with a combination of Formlabs Tough Resin and Color Resin and 12 mm diameter plastic bearings purchased online . The device includes medial and lateral adjustable rails and clips, a graduated ring over the stifle and a carbon rod connected to a digital torque meter  . This raAll procedures were approved by the Institutional Animal Care and Use Committee (IACUC) of Western University of Health Sciences. Sixteen normal pelvic limbs were obtained from eight large mixed-breed dogs who died of reasons unrelated to the study . Pelvic limbs were included if their femurs measured at least 18 cm in length and if no abnormality of the stifle was identified on physical examination and radiographs . Medio-lWithin each dog, one limb was assigned to CCLD, while the other underwent osteotomy prior to CCLD . Limbs wn = 8 limbs), as a model of internal rotational instability which was induced by transecting the CCL . The joint capsule, subcutaneous tissue, and skin were closed subsequently in a routine fashion prior to imaging. The contralateral limb was assigned to TT (n = 8) via transverse osteotomy of the mid tibial diaphysis of the same dog. The distal fragment was rotated internally by approximately 15° relative to the proximal segment prior to plate fixation. This degree of torsion was chosen for its clinical relevance and is consistent with a previous study  with the following exposure settings: 60 kVp, 5.0 mAs, and a focal distance of 100 cm. marker was placed at the level of the limb on each radiograph to calibrate the images. Neutral and stress radiographs were obtained on intact limbs and after each modification , 3, withMeasurements were made on digital radiographs with an imaging software  by two veterinarians with previous training in radiographic evaluation of canine limb conformation . The distance between the medial aspect of the calcaneus and the base of the sulcus of the talus was measured on calibrated neutral (dN) and stress (dS) caudocranial views of the tibia before and after each modification  15, 20), 2015, 2The tibia was disarticulated and soft tissues dissected from each limb at the end of the study. Two K-wires were glued to the tibia, proximally and distally along the caudal condylar axis (CdC) of the proximal portion of the tibia and the cranial tibial axis (CnT) of the distal portion of the tibia, respectively. The tibia was positioned on a clear support and digital images were taken in a proximo-distal direction , with the camera aligned with the tibial axis . Plates All statistical tests were conducted using the SAS software for Windows version 9.4 . Descriptive statistics were presented as median, first and third quartiles and range for each parameter per group. Three radiographic parameters  were compared within dogs and between groups. A Friedman test was conducted to compare left and right intact limbs within dogs. The influence of each modification within limbs was tested by calculating the difference for each radiographic measurement between TT or CCLD limbs and the values in the corresponding intact limb. This difference was compared with median = 0 using signed rank test. The same calculation and comparison were used to compare CCLD + TT values with TT values within each dog.Three comparisons between groups were selected, taking into consideration the clinical relevance of the study and its objectives. First, the ability of our radiographic technique to detect the presence of TT was tested by comparing all limbs with TT (combination of limbs with TT and TT + CCLD) to all limbs without TT (combination of intact and CCLD limbs). Second, the ability to detect internal rotational laxity of the stifle was tested by comparing all limbs with CCLD (combination of limbs with CCLD and TT + CCLD) to limbs without CCLD (combining intact and TT limbs). Third, the ability to distinguish the presence of TT in CCLD was tested by comparing CCLD limbs with limbs with CCLD and TT. These three comparisons were made with the Wilcoxon rank sum test. Cut-off values for the clinical use were calculated for sensitivity and specificity. Several values were produced to differentiate RLS or TT from intact limbs or to differentiate TT from RLS or to identify the presence of tibial torsion in the limbs with CCLD.P < 0.05.The Pearson correlation coefficient was calculated to test the correlations angles of rotation calculated on the neutral radiographs and the measured images of anatomic specimens in intact and osteotomized (TT) tibiae. All statistical tests were two-sided, and statistical significance was set at n = 7 limbs in 5 dogs) with or without osteoarthrosis and positive cranial drawer sign. One pair of limbs was excluded because it was tested on the initial prototype of the positioning device, which was subsequently modified. Dogs included in the study consisted of four male and four female large mixed breed dogs. Their femoral lengths ranged from 18.5 to 26.9 cm . Tibiae measured 18.2 to 28.2 cm in length  and 1.31 to 2.20 cm in width .A total of 14 canine cadavers were examined and six were excluded due to abnormalities, including joint effusion . Transection of the CCL induced an overall lateral translation of the calcaneus on neutral radiographs (dN) by a median of 0.93 mm (p < 0.05), although this change was not consistent  (p > 0.05). Transection of the CCL increased the magnitude of displacement of the calcaneus (dS-dN) by a median of 1.6 mm , corresponding to 3.1° of rotation (p < 0.05). By contrast, no difference was observed in the magnitude of displacement of the calcaneus when TT specimens were compared to intact limbs or to TT + CCLD limbs  . TransecLD limbs .p <0.05), but the magnitude of displacement of the calcaneus (dS-dN) when internal torque was applied did not differ (p < 0.05).The calcaneus was displaced further laterally by about 3 mm on neutral radiographs (dN) when limbs with experimental TT were compared to those without TT  of 3.25 mm differentiated limbs with tibial torsion from intact limbs with 87.5% sensitivity and 87.5% specificity, and from those with RLS with 87.5% sensitivity and 75.0% specificity. A magnitude of calcaneal displacement (dS–dN) of 3.45 mm differentiated limbs with RLS from intact limbs with 87.5% sensitivity and 68.7% specificity. Lastly, a calcaneal displacement (dN) of 3.8 mm in limbs with CCLD differentiated the presence of tibial torsion from limbs with CCLD only with 75% sensitivity and 100% specificity.The median tibial torsion measured in intact tibiae was 7.75 (ranging from−4 to 15). Tibial torsion angles calculated on radiographs correlated moderately with those measured on images of bone specimens (correlation coefficient = 0.525). A medial torsion of 15.9° (11 to 31°) was measured on bone specimens assigned to TT, before plate removal. These angles correlated strongly with those calculated on the radiographs of the TT limbs (correlation coefficient = 0.722).ex-vivo canine model. The main finding of the study was that the calcaneus was positioned further laterally on neutral radiographs  of limbs with induced tibial torsion, including those with CCLD. This finding prompts us to accept our first hypothesis. The position of the calcaneus of the limbs with internal rotational laxity of the stifle (RLS) on neutral views did not differ from the limbs with intact CCL. Our results also provided evidence to support our second hypothesis as the magnitude of lateral displacement of the calcaneus on stress views  was increased within limbs after transection of the CCL and tended to be greater when limbs with rotational laxity  were compared to limbs without rotational laxity. However, the radiographic technique described here did not reliably detect rotational laxity in limbs with tibial torsion. This result could be attributed to inter-individual variations, affecting our ability to detect differences between groups. The presence of other supporting structures such as the joint capsule and lateral collateral ligament could also limit the impact of CCL transection on rotational laxity the lack of physiological loading, mobilizing active restraints, could also have contributed to our findings.In this study, we validated the use of a stress radiographic technique to detect rotational laxity of the stifle and differentiate it from tibial torsion in an Positioning limbs for caudocranial radiographs of the tibia aims for symmetrical superposition of the fabellae and for the medial edge of the calcaneus to be aligned over the sulcus of the talus. The position of the calcaneus on neutral radiographs of intact limbs in our study varied within ~3 mm on either side of the sulcus of the talus, which is consistent with previous studies . TransecA calcaneal displacement (dN) of 3.25 mm on neutral radiographs differentiated limbs with tibial torsion from those with RLS with 87.5% sensitivity and 75.0% specificity in our study. Our findings differ from those reported by Apelt et al.  who concThe trigonometric method used to calculate the angle of rotation of the calcaneus was selected to take into consideration the size of each dog. Indeed, the lateral displacement of the calcaneus of the caudocranial radiograph provides an absolute value preventing extrapolation of our findings to smaller dogs. By contrast, the calculated angle of rotation approximates the radius of the arc of rotation to the craniocaudal length of the calcaneus on mediolateral projections of the tibia. These angles correlated moderately with those measured on bone specimens, providing some evidence to support the application of this approach. However, this method did not allow us to detect the presence of TT or RLS in this experimental model, compared to the absolute measurements of displacement. We attribute this result to the lack of sensitivity of radiographic measurements, amplified in the formula. Indeed, this method requires three measurements obtained on three radiographs, combined into a ratio. By contrast, the displacement of the calcaneus requires only two measurements on radiographs obtained with the limb in the same positioning device.ex-vivo nature and the origin of cadavers. The absence of historical information of these cadavers did not allow us to use gait data as a criterion for inclusion. However, the presence of a chronic gait abnormality is unlikely as normal orthopedic and radiographic examinations were required for inclusion. In addition, although we created a model of rotational instability of the stifle (RIS), we were only able to assess the rotational laxity of the stifle (RLS) because RIS cannot be assessed with cadaveric limbs. Texting laxity allows to examine only the passive envelope of motion of a joint without considering muscles and physiological loading. Thus, a future prospective study, taking into consideration the influence of active physiological loading is warranted. Finally, the positioning device was designed for large breed dogs. Further developments are needed to improve its versatility and facilitate its application in live dogs. The proximal limb may need to be held manually or with the help of positioning aids as well as sedation for live patients.The budget available for this study precluded inclusion of computed tomographic examination of the limbs, which may be considered a limitation since this modality has become standard of care to evaluate tibial torsion in dogs. Instead, limbs were dissected at the end of the study to determine their anatomical axis, using a method recently described to validate three-dimensional computed tomographic determination of TT in canine cadavers . AnotherIn conclusion, experimental TT induced a lateral displacement of the calcaneus on neutral radiographs and transection of the CCL amplified the magnitude of this displacement when internal torque was applied to the tibia. A lateral displacement of the calcaneus exceeding 3.8 mm on neutral caudocranial radiographs of the tibia should prompt a presumptive diagnosis of tibial torsion in large breed dogs, regardless of the degree of RLS. The use of a 3D-printed rotating device for stress radiography may be considered to monitor rotational laxity of the stifle (RLS) in individual limbs, but did not reliably detect RLS, especially in limbs with induced TT.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The animal study was reviewed and approved by Institutional Animal Use and Care Committee of Western University of Health Sciences.DG designed this study, secured funding from Western University of Health Sciences, did all the surgeries, and provided in-line scientific editing of the manuscript. GW and DG designed the prototype of the 3D print rotating device subsequently adjusted with input from DG, GW, and JY. JY wrote the first draft of the manuscript and obtained all radiographic studies, read by AM and JY. FD analyzed the data for statistical significance. AM, DG, FD, and GW participated in the interpretation of data and reviewed the manuscript. All authors reviewed and endorsed the final version.


Recommendations for the performance of prophylactic central neck dissection (pCND) in patients with clinically node-uninvolved (cN0) papillary thyroid carcinoma (PTC) are not the same. This meta-analysis set out to compare the effectiveness of pCND with total thyroidectomy (TT) in different countries and regions, mainly between western countries and China.The electronic databases PubMed, EMBASE, and Cochrane Library were searched for studies published until August 2022. The incidence rate of cervical lymph node metastases (LNMs), locoregional recurrences (LRRs), and postoperative complications were pooled by a random-effects model. Subgroup analyses based on different countries and regions were performed.Eighteen studies involving 5,346 patients were analyzed. In the subgroup of western countries, patients undergoing pCND with TT had a significantly lower LRR rate  and a higher rate of temporary hypoparathyroidism (HPT)  than that of the TT alone group, while no statistically significant difference was found in the rate of permanent HPT and temporary and permanent recurrent laryngeal nerve (RLN) injury. In the Chinese subgroup, the pCND with TT group had a significantly higher incidence rate of both temporary HPT  and permanent HPT  than that of the TT alone group, while no significant difference was detected in the rate of LRR and temporary and permanent RLN injury.Compared with the TT alone for cN0 PTC patients, pCND with TT had a significantly lower LRR rate while having a higher temporary HPT rate in Europe, America, and Australia; however, it showed no significant difference in decreasing LRR rate while having a significantly raised rate of temporary and permanent HPT in China. More population-based results are required to advocate precision medicine in PTC.https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022358546. Thyroid carcinoma (TC), the most common endocrine malignancy, has been diagnosed worldwide with increasing frequency in the last decades, especially among women –3. Most There is no controversy about the operation of therapeutic central neck dissection (CND) when clinical LNMs exist in the central neck compartment , while pWe suspect if there exists any biological difference of PTC among different ethnic groups in different countries and regions, manifesting as dissimilarities in terms of LNM, recurrences, postoperative complications, and survival rate, further influencing the formulation and revisal of guidelines. Therefore, this current meta-analysis was performed to compare the efficacy of pCND with TT for cN0 PTC in different countries and regions, mainly between western countries and China. We also compare the incidence rate of LRR, recurrent laryngeal nerve (RLN) injury, and hypoparathyroidism (HPT) between the pCND with TT group and the TT alone group in two different regions.This systematic review and meta-analysis followed the outline suggested by Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) . The regThe PubMed, EMBASE, and Cochrane Library electronic databases were searched for relevant literature from inception to August 2022. The Medical Subject Headings terms were as follows: 1) Thyroid Cancer, Papillary OR Papillary Thyroid Carcinoma, 2) Neck Dissection OR prophylactic central neck dissection. Two terms were combined by “and.” The references of previous studies and identified trials were manually backtracked to broaden the search for related literature.The inclusion criteria were as follows: 1) study population should be PTC patients without LNM according to preoperative imaging and intraoperative inspection; 2) studies contained pCND with TT and TT alone groups; and 3) the incidence of central LNM, LRR, or complications could be available or calculated. Studies were restricted to those published in English.Studies were excluded because of at least one of the following: 1) patients with clinically involved lymph nodes; 2) patients undergoing thyroidectomy previously; 3) patients undergoing other thyroid surgery besides pCND and TT; 4) publication region was not in China, Europe, America, or Australia; or 5) the full text was not available online.For retrospective and prospective studies, the Newcastle-Ottawa Scale (NOS)  was adopDetailed characteristics of enrolled articles were extracted as follows: the first author, publication year, publication country, study design, study period, and follow-up duration. Baseline and clinicopathological data were acquired as follows: number of patients who underwent pCND with TT or TT alone, the lost to follow-up, age, sex, tumor size, extrathyroidal extension, multifocality, number of T3/4 patients, incidence of central LNM, and number of patients performing postoperative RAI treatment. The number of patients having LRR or postoperative complications  was obtained as the outcome data.2 statistics and Cochran’s Q-statistic test with a p value. I2 > 50% and p < 0.1 would be deemed as significantly heterogeneous. Publication bias was assessed by Begg’s and Egger’s tests, and p < 0.1 was defined as a statistically significant publication bias.Heterogeneity was assessed by IOdds ratio (OR) and its associated 95% confidence intervals (CIs) were adopted to appraise dichotomous outcomes, and p < 0.05 was regarded as statistically significant. Combined with the result of heterogeneity analysis and study type, the Mantel–Haenszel random-effects model was exerted in this meta-analysis. Additionally, subgroup analyses were performed to estimate if there were differences in LRR and complications caused by the difference of ethnic groups and regions.STATA software, version 14.0  was exploited to statistical analyses.A total of 2,909 studies were identified from three databases, among which 1,023 were from PubMed, 1,816 were from EMBASE, and 72 were from Cochrane Library databases. Eighteen studies were ultimately included, of which 14 were from western countries and four were from China Figure 1All of the 18 included studies were published between 2010 and 2020, and there were 15 retrospective cohort studies , 22–34, A total of 5,346 patients with cN0 PTC underwent TT, of whom 2,341 were in the pCND with TT group and 3,005 in the TT alone group. Three studies , 23, 37 Women accounted for most of the included patients. The mean tumor size ranged from 5.0 to 27.0 mm. The mean age at diagnosis was between 40.0 and 57.0 years old. The proportion of T3/4 PTC was not more than half. The proportion of PTC with multifocality and extrathyroidal invasion varied slightly because of the diverse inclusion criteria across studies Table 1.Almost all of the studies provided good follow-up on patients, while two , 36 of tThe quality of the 16 retrospective and prospective studies was proven to be high with a score of 7 or 8. Two RCTs received scores of 4, which demonstrated a relatively high quality Table 1.2 < 50% and p > 0.1 . While the pooled central LNM rate of the pCND with TT group in four Chinese studies was 52% (95% CI 40%–63%). These subgroup analyses had no significant heterogeneity, with an I p > 0.1 Figure 2The LRRs were reported in 13 western-country studies and three Chinese studies. Acceptable criteria for recording recurrences by doctors were defined as positive blood test results with raised thyroglobulin (Tg), antithyroglobulin antibody (TgAb), or thyroid-stimulating hormone (TSH) concentration , 33–37; According to the subgroup of western countries, the pooled prevalence of LRR was significantly lower in the pCND with TT group than that in the TT alone group . In the subgroup analysis of Chinese studies, the pooled prevalence of LRR was obviously lower in the pCND with TT group ; however, the difference was not statistically significant . There was no significant heterogeneity in the two subgroup analyses, and the publication bias confirmed by the Begg’s and Egger’s tests was not significant  Figure 3Eight western-country studies and three Chinese studies assessed temporary RLN injury. The pCND with TT group did not show a significantly higher risk of temporary RLN injury than the TT alone group both in the subgroup of western-country research  and in the subgroup of Chinese research . No statistically significant heterogeneity was observed in subgroup analyses. The Egger’s and Begg’s publication bias tests showed that the bias statistic was not significant  Figure 4Permanent RLN injury was investigated in 11 western-country articles and four Chinese articles. Like the results of temporary RLN injury, no significant difference was observed in the pooled incidence rate of permanent RLN injury between the pCND with TT and TT alone groups, according to the subgroup of western countries  and the Chinese subgroup . There was no evidence of heterogeneity in these analyses. No publication bias was detected by the Begg’s and Egger’s tests  Figure 52 = 47.3% and p = 0.048; however, we found no significant heterogeneity in subgroup analyses of Chinese studies and no indication of publication bias among this body of articles   but also in the Chinese subgroup . We encountered mild heterogeneity in the studies of western countries, with an I= 0.927) Figure 62 = 47.7% and p = 0.033. However, the difference was counted to be statistically significant in the Chinese subgroup  with no statistically significant heterogeneity. Overall, no evidence of publication bias was found by the Begg’s (p = 0.687) and Egger’s tests (p = 0.412) . The difference between two groups failed to be statistically significant in the western country subgroup , which had a slight heterogeneity, with I= 0.412) Figure 7To our knowledge, this meta-analysis to date firstly evaluated the efficiency of pCND with TT for patients with cN0 PTC in different countries and regions. The outcome of pCND reducing the risk of lymph node recurrence for cN0 PTC varies in different studies and still remains controversial. Both Zhao et al.  and ChenAs we can see, there were just three Chinese articles reporting the difference of LRR rates between pCND with TT and TT , 27, 32 In terms of postoperative complications, we found some similarities. In both western-country and Chinese subgroups, the difference of temporary and permanent RLN injury did not reach statistical significance between the pCND with TT and TT alone groups, while the pCND with TT group had a significantly higher rate of temporary HPT than that of the TT alone group. This finding was consistent with that of Henry et al.  who repoAccording to the American and European guidelines, the attitude toward pCND for cN0 PTC patients in western countries is relatively conservative. According to our subgroup analyses of western-country literature, pCND has the characteristics of reducing recurrence and leading to relatively few severe complications, so why do not western guidelines consistently recommend it? After pCND with TT, LNMs were confirmed in 41% of PTCs, which indicated a moderate level of finding positive lymph nodes, as Rotstein  reckonedThe consensus among Chinese experts and professors on pCND has been relatively radical from the past to now. As reported in our subgroup analyses of Chinese studies, the cervical LNM rate was 52%, which was higher than that in the western country subgroup Figure 2In view of the excellent survival rates of patients with PTC , very feCertain limitations were also contained in this meta-analysis. First, retrospective studies accounted for the majority of the included research, and bias is inevitable. Second, the number of accessible Chinese articles in English databases is insufficient. Third, the different standards for pCND or RAI treatment probably introduced selection bias. Moreover, the surgical experience and skills of surgeons, even if in the same district, are rarely on the same level. Finally, as the included studies were from different countries and regions, the economic level (high-income countries were proven to have the highest incidence of thyroid cancer) , medicalCompared with the TT alone for cN0 PTC patients, pCND with TT had significantly lower LRR rate while higher temporary HPT rate in Europe, America, and Australia. Alternatively, it showed no significant difference in decreasing LRR rate while significantly increased the incidence rate of temporary and permanent HPT in China. Further research is needed to estimate the value of pCND among different ethnic groups in different countries and regions. More population-based results are required to advocate precision medicine in thyroid carcinoma.The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.Conception and design: JY; Administrative support: GY; Provision of study materials: YH and CC; Collection and assembly of data: JC and JL; Data analysis and interpretation: JY and KX; Article writing: All authors; All authors contributed to the article and approved the submitted version.