The incidence of head and neck cancers (HNC) is rising worldwide especially with HPV-related oropharynx squamous cell carcinoma. The standard of care for the majority of patients with locally advanced pharyngeal disease is curative-intent radiotherapy (RT) with or without concurrent chemotherapy. RT-related toxicities remain a concern due to the close proximity of critical structures to the tumour, with xerostomia inflicting the most quality-of-life burden. Thus, there is a paradigm shift towards research exploring the use of imaging biomarkers in predicting treatment outcomes. Diffusion-weighted imaging (DWI) is a functional MRI feature of interest, as it quantifies cellular changes through computation of apparent diffusion coefficient (ADC) values. DWI has been used in differentiating HNC lesions from benign tissues, and ADC analyses can be done to evaluate tumour responses to RT. It is also useful in healthy tissues to identify the heterogeneity and physiological changes of salivary glands to better understand the inter-individual differences in xerostomia severity. Additionally, DWI is utilised in irradiated salivary glands to produce ADC changes that correlate to clinical xerostomia. The implementation of DWI into multi-modal imaging can help form prognostic models that identify patients at risk of severe xerostomia, and thus guide timely interventions to mitigate these toxicities. Head and neck cancer (HNC) of the mucosa is increasing worldwide, currently accounting for up to 4% of all malignancies . More thFor this review, a comprehensive search was conducted on PubMed during April to May 2021, using Medical Subject Headings (MeSH) of head and neck cancer, radiotherapy, magnetic resonance, and diffusion magnetic resonance imaging. Studies were screened using specific selection criteria, and were included in this review if they reported use of DWI/MR imaging for evaluation of salivary glands and/or treatment assessment of HNCs. Literature were excluded if they studied oligometastatic disease, previously resected tumours or explored novel adjuvant therapies. Only results in the English language were included.Traditionally, conventional RT such as computed tomography (CT)-based three-dimensional conformal radiotherapy (3DCRT) have had limitations on protecting normal tissues, resulting in considerable toxicity rates and modest disease locoregional control (LRC) , 11. ThiRadiation-related xerostomia is dry mouth resulting from radiation-induced damage to the salivary glands. It is a subjective assessment that is difficult to quantify due to discrepancies between clinician and patient perceptions . The parAdditionally, the development of xerostomia is not just determined by mean total dose. Buettner et al. demonstrated that the spatial distribution of doses between the superficial and deep lobes of the parotid glands also impact toxicity . This imAdaptive radiotherapy (ART) is an approach that aims to address the complexities of intra-treatment glandular changes. It incorporates imaging during the treatment course, so that RT plans can be re-adapted according to anatomical movements and the shrinking tumour volume , 4. A doThe advantages of MRI’s have also been deployed in other aspects of HNC management. Bruijnen et al. utilised cine MR imaging to quantify respiratory- and swallowing-induced intra-fractional tumour motion for nasopharyngeal, oropharyngeal and laryngeal cancers, such that adequate PTV margins  can be applied for each HNC subtype . It is pFurthermore, MRI’s excellent imaging quality has made it easier for artificial intelligence (AI) and deep-learning machines to be integrated into treatment planning. Doshi et al. developed an MRI-based software that automatically contours tumour volumes with reproducibility . Such toAs the implementation of MRI with ART is still in its early stages, some caveats have emerged that poses additional challenges. Namely, this technology requires the use of the MRI magnet outside radiology departments, where such technologies would normally be subject to strict protocols. There will be an initial learning curve in establishing protocols that meet safety requirements. Concomitantly, adaptive techniques can be a resource-intensive practice as it requires increased time investment by multidisciplinary teams to review and re-adapt plans between each fraction.2/s) [Diffusion-Weighted Imaging (DWI) is a function of MRI being explored in HNC management. It is a non-invasive technique that measures the random motion of water molecules within different tissue compartments , 33, 34.2/s) , 33, 35.2/s) . This ph2/s) . Larger Studies have begun utilising DWI as part of HNC treatment planning. Felice et al. proposes that DWI should be incorporated during tumour contouring as it can possibly delineate the target volume with more accuracy . During A key strength of DWI is its signals not being influenced by post-treatment effects such as inflammation. This is not the case for Fluorodeoxyglucose (FDG)-Positron Emission Tomography (PET)—another popular functional imaging modality – as it has the propensity to give false-positive signals due to FDG’s avidity towards inflammatory activity . Hence, The assessment of normal physiology is crucial in understanding the pathological processes of radiation-induced tissue damage. Previously, there has been two practical methods in objectively measuring salivary gland function: salivary gland scintigraphy (SGS) with technetium Tc99m pertechnetate, and manual measurement of salivary flow. DWI has been added as a non-invasive and convenient method in visualising gland function, as ADC changes occur during gustatory stimulation of salivary glands. Thoeny et al. demonstrated significant decreases in ADC values of the salivary glands within minutes of ascorbic acid stimulation . HoweverAdditionally, the adjustment of b values of DWI can present various information from salivary glands. A prospective study by Thoeny et al. investigated the influence of varying b values on the ADC’s of healthy parotid glands, and demonstrated that the selection of lower b values led to higher ADCs . This isDWI has recently been used for evaluating post-RT salivary gland function and xerostomia severity. A study by Loimu et al. conducted post-treatment ADC analyses of the parotid glands of HNC patients treated with IMRT, to assess if the signal changes can be correlated with SGS. Results showed that irradiated glands exhibit significantly higher maximum ADC values during stimulation compared to pre-irradiation p < 0.001). A dose–response relationship was also found where glands that absorbed more doses showed higher pre- to post-treatment ADC changes and equated to less salivary flow rates on SGS . Additio. A dose–Furthermore, the production of ADC histograms provides additional information not revealed within basic descriptive statistics. The ADC histogram provides sets of parameters that can be compared with each other, which reflect the distribution of ADC values and thus representing tissue heterogeneity within the glands . A prospAnother factor that influences the prediction of xerostomia is the onset of salivary gland ADC changes in response to RT. A study by Zhang et al. assessed early ADC changes in salivary glands with late xerostomia and found that the mean ADCs of parotid and submandibular glands were significantly higher than pre-RT values as soon as 2 weeks after RT commencement . Additiof), diffusion coefficient of tissue molecular diffusion (D), and perfusion-related diffusion coefficient (D*) [Additionally, more sophisticated DWI techniques have been developed to improve on the features of conventional DWI. One example is the Intravoxel Incoherent Motion (IVIM) model, where the function separately quantifies tissue perfusion and diffusion . This poent (D*) . A prospent (D*) . The IVIent (D*) . Meanwhient (D*) . These tAnother advanced technique is Diffusion Kurtosis Imaging (DKI), where the model accounts for diffusion restriction that occurs within the complicated microstructures of tissues. This may be more accurate than conventional DWI as the latter assumes that water diffusion obeys standard distribution in vivo . DKI parDespite DWI’s unique strengths and potential to supplement HNC management, there are some drawbacks. Firstly, it is challenging to acquire high-quality diffusion-weighted sequences for the region. Head and neck anatomy is complexed, which is challenging for observers to contour. The region also has several air-tissue interfaces, and since most HNCs are of squamous cell origin, they tend to line the epithelial surface close to the air cavities . Areas wSecondly, there are inconsistencies in reported ADC values within this field of research. While multiple studies reported in Driessen et al.’s systematic review were able to differentiate malignant tumours from benign lesions using ADC analyses, there is no established consensus on what the ADC threshold for discrimination is . SeveralIt is also important to recognise that DWI lacks features that are provided by other functional imaging modes. Rasmussen et al. compared the volumes of interest (VOI) defined by DWI versus FDG-PET images on an integrated PET/MR scanner. The study found that the VOIs from the two only had partial overlap, as the high cellularity provided by DWI showed weak correlation with the glucose uptake represented by FDG-PET . This suFinally, while prediction of late xerostomia may be possible with multi-modal imaging, such toxicities cannot be prevented even with early detection because the effects of RT would have already been applied. Therefore, the best clinical measures can only mitigate the severity of xerostomia. Currently, intra-treatment interventions include image-guided adaptive RT , 4, acupThis review has its strengths and limitations. Firstly, included studies only involved patients from a population of interest, i.e. locally advanced head and neck cancers. Another strength is that most included studies provide a stratified breakdown of patient characteristics , which identified possible confounding factors. However, there are some limitations with the included evidence. We admit that excluding studies of patients with oligometastatic status does leave out a large proportion of the HNC cohort, and as a result may only focus on those with long-term survival for late toxicities, whilst assuming that those with distant metastasis may not survive long enough to have late toxicities of significance. Additionally, each study was conducted using different methods, based on protocols and treatment guidelines of their respective era/region. And while many of these studies suggest similar trends, there has been considerable inconsistencies in the quantitative values reported. Such differences make it challenging to establish standards that can be applied universally. Furthermore, several studies were done with small sample sizes (< 30) and inadequate follow-up times, affecting the significance of those results. We acknowledge that these studies may have been restricted by patient ineligibilities or resource constraints.In HNC chemoradiotherapy, it is unfeasible to avoid xerostomia as the salivary glands are highly radio-sensitive and often mandatorily included in RT treatment volumes. These side effects remain difficult to assess clinically. Thus, recent research has shifted towards optimising imaging techniques for better treatment assessment and prediction of toxicities to allow for early intervention. The DWI function of MR imaging is of interest due to its high-quality tissue contrast and visualisation of cellular structures, as molecular diffusion can be quantified by ADC values. Existing studies suggest that ADC analyses provide crucial information on tumour differentiation, inter-individual tissue heterogeneity and intra-treatment tissue changes for a comprehensive patient assessment. Future research should validate the use of DWI in conjunction with other functional imaging modalities and correlate imaging data with clinical information, such that prognostic models can be developed to accurately predict patients at risk of severe toxicities.


There is a revived interest to explore spinal cord epidural stimulation (SCES) to improve physical function after spinal cord injury (SCI). This case report highlights the potential of eliciting multiple functional improvements with a single SCES configuration, a strategy which could improve clinical translation.To determine whether SCES intended to facilitate walking also acutely yields benefits in cardiovascular autonomic regulation and spasticity.Case report from data collected at two timepoints 15 weeks apart from March to June 2022 as part of a larger clinical trial.Research lab at Hunter Holmes McGuire VA Medical Center.27-year-old male, 7 years post a C8 motor complete spinal cord injury.A SCES configuration intended to enhance exoskeleton-assisted walking training applied for autonomic and spasticity management.via isokinetic dynamometry with and without SCES.The primary outcome was cardiovascular autonomic response to a 45-degree head-up-tilt test. Systolic blood pressure (SBP), heart rate (HR), and absolute power of the low-frequency (LF) and high-frequency (HF) components of a heart-rate variability analysis were collected in supine and tilt with and without the presence of SCES. Right knee flexor and knee extensor spasticity was assessed At both assessments with SCES off, transitioning from supine to tilt decreased SBP . At assessment one, SCES on in supine (3 mA) increased SBP (average 117 mmHg); in tilt, 5 mA stabilized SBP near baseline values (average 111.5 mmHg). At assessment two, SCES on in supine (3 mA) increased SBP (average 140 mmHg in minute one); decreasing amplitude to 2 mA decreased SBP (average 119 mmHg in minute five). In tilt, 3 mA stabilized SBP near baseline values (average 93.2 mmHg). Torque-time integrals at the right knee were reduced at all angular velocities for knee flexors (range: −1.9 to −7.8%) and knee extensors (range: −1 to −11.4%).These results demonstrate that SCES intended to facilitate walking may also enhance cardiovascular autonomic control and attenuate spasticity. Using one configuration to enhance multiple functions after SCI may accelerate clinical translation.https://clinicaltrials.gov/ct2/show/, identifier NCT04782947. The potential of individual SCES configurations to improve multiple functions warrants further exploration.Spinal cord injury (SCI) can result in complications such as low blood pressure and muscle spasticity. An emerging strategy to improve function after SCI is spinal cord epidural stimulation (SCES). SCES has emerged as an experimental therapy that can facilitate restoration of motor control in persons with SCI. The potential of SCES to reduce spasticity has been known for over 40 years . SCES waRecently, SCES has shown potential to improve multiple functions, including overground ambulation  and reguTo date, reports show that individual SCES configurations – i.e., electrode arrangement and stimulation parameters – are needed to enable individual functions . In factThe participant received an implanted a pulse generator with two eight-electrode percutaneous SCES leads  between the T11-L1 vertebrae to cover the lumbosacral enlargement  as part ® (chlorhexidine) soap skin cleanser and Bactroban® (mupirocin) 2% ointment were provided for 7 days to reduce bacterial colonization of the participant’s skin. An anesthesia preoperative evaluation was performed, and consent obtained prior to entrance into the operating room. After local anesthetic injection with lidocaine, 14-gauge epidural sterile needles were used using x-ray guidance and loss of resistance technique to access the epidural space at the L2/L3 intervertebral space. The leads were then threaded in the epidural space and the configuration  were set to evoke motor potentials as indicated by visible motor contractions of the paralyzed muscles. The leads were then taped and glued to the skin after being connected to the external stimulator and remained for 5 days before explantation of the temporary leads.This is a 2-step process where temporary implantation precedes permanent implantation. The SCES system  was used to electrically stimulate the lumbosacral enlargement. During temporary implantation, two 8-electrode lead arrays were implanted utilizing fluoroscopic guidance to extend between T11-L1 vertebral bodies. Prior to both temporary and permanent procedures HibiclensFour weeks later, the participant underwent permanent implantation with monitored anesthesia care sedation in the operating room. After accessing the epidural space with 2 separate 14-gauge epidural needles, the leads were then navigated in the epidural space to the right and left sided final positions. The pulse generator was then placed after creating a pocket between the muscles and skin in the participant’s lower back between the iliac crest and the 12th rib, ipsilateral to the incision site . FollowiThe process was split into temporary and permanent implantation to ensure appropriate placement of the leads to accurately elicit motor function. Additionally, the temporary implantation may reveal possible unanticipated emerging medical events and may lead to withdrawal from the study. Furthermore, the participant may deny participation because of feeling of discomfort or pain following temporary implantation and may decide to withdraw before undergoing permanent implantation.The SCES mapping was approximately conducted after 6 months from permanent implantation. The detailed process of establishing rhythmic, locomotor-like activity was previously described by our laboratory . We atteA SCES configuration that yielded rhythmic, locomotor-like activity in supine was subsequently used to enhance gait during exoskeleton-assisted walking (EAW) training – detailed results are presented elsewhere  was set at variable assistance mode that allowed the participant to integrate his volitional effort with EAW . The minwith EAW .During this period, participant was also engaged in 60 min task specific training for 3× per week that focused on sit-to-stand activity, Romanian deadlift for trunk control either through using a standard walker or standing frame. The goal of this training period is to enhance his ability to allow him to enable trunk control and secure independent standing with SCES on. Two or more research assistants were commonly involved during the training to provide necessary physical support when needed.After 4 weeks of EAW training with the rhythmic, locomotor -like activity configuration, the participant self-reported reduced symptoms of low blood pressure when using this configuration outside of training in his daily life. Thus, an interim assessment of the acute effects of this configuration (hereon referred to as “EAW enhancement SCES”) on systolic blood pressure (SBP), heart rate (HR), and low-frequency (LF) and high-frequency (HF) components of a heart rate variability analysis to a 45-degree head-up-tilt test was conducted. Beat-to-beat SBP and HR, and a five-lead echocardiogram  were recorded non-invasively . Following this, the participant also self-reported that use of EAW enhancement SCES attenuated his spasticity. 15 weeks after the first interim assessment when regularly scheduled study assessments took place, the acute effects of EAW enhancement SCES on spasticity were tested by measuring passive torques on an isokinetic dynamometer  Biodex .Detailed results of head-up-tilt testing are presented in At assessment two, the participant’s SBP averaged 98.9 mmHg in supine with SCES off. Activating EAW enhancement SCES in supine increased SBP almost twice as much as assessment one (average 140 mmHg in minute one), leading the study team to decrease SCES amplitude to 2 mA. Upon tilt at 2 mA, SBP decreased over 4 min. Increasing SCES amplitude to 3 mA stabilized SBP (average 93.2 mmHg) at values close to that of SCES off supine. 5 mA was not re-tested to avoid further risk of an unwanted increase in SBP. During SCES off, both LF and HF appeared to be attenuated during tilt. However, the HF remarkably dropped during tilt at an amplitude of 3 mA with a modest change in LF.Thus, at assessment one, EAW enhancement SCES at 3 mA moderately increased SBP in supine (+ 20 mmHg), but did not prevent a drop in SBP upon tilt; whereas at assessment 2, EAW enhancement SCES delivered at 3 mA produced a larger increase in supine SBP (+41 mmHg), yet stabilized SBP during tilt. At both assessments, tonic, non-rhythmic and non-patterned lower extremity muscle activity was induced when SCES was delivered at 3 mA or greater . The amoThese results show that EAW enhancement SCES produced favorable changes in cardiovascular regulation during an orthostatic challenge, and attenuated resistive torque evoked by passive movement. Thus, the participant’s self-report that this configuration reduced symptoms of low blood pressure and helped with spasticity has merit. When first tested, one amplitude (3 mA) increased SBP in supine but did not prevent a drop in SBP upon tilt. However, after 15 weeks of use during both EAW training and in the participant’s daily life, the same stimulation amplitude caused twice the increase in SBP in supine, yet when tilted stabilized SBP at a value similar to his supine SBP without SCES. Thus, over time, a lower stimulation amplitude was necessary to prevent a drop in SBP upon orthostatic challenge.The novelty of this case report needs to be highlighted. We have utilized percutaneous SCES implantation and not paddle implantation as has been demonstrated with several other groups . The poiUnlike other reports who specifically stated that performing specific detailed mapping procedures to control for autonomic nervous system . We simpThe LF and HF bands of a heart rate variability analysis indicate baroreceptor activity and parasympathetic drive, respectively . TiltingExoskeleton-assisted walking enhancement SCES reduced passive torques at the knee by an average of 5.2%. There appeared to be differential effects of SCES for knee extensors vs. flexors at some angular velocities – while the functional implications of this remain unclear, in general, reduced spasticity can allow improved intermuscular coordination and enhance walking, likely through reorganization of spinal circuits. This was shown in previous reports that noted improvements in inter-limb coordination during overground locomotion following SCES . OverallThe effects of different pharmaceuticals and rehabilitation intervention on spasticity after SCI is well studied . A previSince the mechanism by which EAW enhancement SCES produces these beneficial effects cannot be determined from this case report, a theoretical explanation must be proposed. Walking rehabilitation after SCI without SCES can benefit autonomic cardiovascular regulation , spasticIn summary, this case report shows that percutaneously-implanted SCES intended to yield rhythmic locomotor activity and enhance EAW performance resulted in beneficial off-target effects on cardiovascular autonomic function and spasticity in one individual with a chronic motor complete C8 SCI. The current case report may hold promising findings that applications of implanted percutaneous SCES may mitigate several of the chronic disorders after SCI. Furthermore, the use of simple rhythmic configuration may alleviate the burden of detailed mapping procedures, which may preclude feasibility of this approach in clinical settings. Future experimentation is warranted to determine if these results or other multi-use SCES configurations can be developed for other persons with SCI, and to determine the precise mechanisms by which these beneficial off-target effects are generated.In 2021, I had the spinal cord epidural stimulator implanted. The programs I have been using greatly help with spasticity and blood pressure. After about an hour with the stimulator on my spasms start to lessen and so on throughout the day until they are gone. My blood pressure is instantly taken to a normotensive level. I have hypotension so the stimulator is able to help drastically. Spasticity and blood pressure are the main effects of using my stimulator and it’s helps with my day-to-day life.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the McGuire Research Institute. The patients/participants provided their written informed consent to participate in this study.JG contributed to the data collection, data analysis, and manuscript drafting. AA assisted in the data collection. RT participated in the design of the study, the implantation of percutaneous leads, and managing the subject post-operative. AG participated in the design of the study, provided the funding, and contributed to the data collection, and manuscript drafting and editing. All authors contributed to the article and approved the submitted version.


Cardiac resynchronization therapy (CRT) via biventricular pacing (BiVP) is an established treatment for patients with left ventricular systolic heart failure and intraventricular conduction delay resulting in wide QRS. Seminal trials demonstrating mortality benefit from CRT were conducted in patients with wide left bundle branch block (LBBB) pattern on electrocardiogram (ECG) and evidence of clinical heart failure. The presence of conduction block was assumed to correlate with commonly applied criteria for LBBB. More recent data has challenged this assertion, revealing that LBBB pattern may include distinct underlying pathophysiology, including patients with complete conduction block, either at the left-sided His fibers or the proximal left bundle, intact Purkinje activation with wide LBBB-like QRS, and patients demonstrating both proximal block and distal delay. Currently, BiVP-CRT is indicated for all QRS duration ≥150 ms and may be considered for BBB patterns from 130 to 149 ms with robust clinical data to support its use. Despite this, however, there remains a significant number of non-responders to BVP. Conduction system pacing (CSP) has emerged as an alternative approach to deliver CRT and correct QRS in patients with conduction block. Newer hybrid approaches which combine CSP and traditional BiVP-CRT and may hold promise for patients with IP or mixed-level block. As various approaches to CRT continue to be studied, physiologic phenotyping of the LBBB pattern remains an important consideration. For over a century, left bundle branch block (LBBB) has been recognized as a clinical entity. The clinical significance of LBBB has changed over the years from being first perceived as a non-harmful electrocardiogram (ECG) finding to more recently being associated with poorer prognosis, particularly in patients with severe, symptomatic heart failure . CardiacMost definitions of LBBB are based on surface ECG patterns. The American Heart Association (AHA), American College of Cardiology (ACC), and Heart Rhythm Society (HRS) collaborated on the currently adopted definition in 2009 and was restated in 2018 . By theiIn 2011, the landmark Multicenter Automatic Defibrillator Implantation with Cardiac Resynchronization Therapy (MADIT-CRT) trial suggested that patients with reduced ejection fraction <30% and prolonged QRS >130 ms derived significant benefit in composite heart failure events and death from CRT-D compared to ICD if they had a LBBB pattern compared to non-LBBB  . Notablymid-QRS notching or slurring in at least two of the leads V1, V2, V5, V6, I, and aVL  dyssynchrony thus leading to unfavorable cardiac remodeling. Thus, transthoracic echocardiogram (TTE) has been used as a non-invasive tool to visually assess for LV dyssynchrony which are correlated with conduction block from complete LBBB. There are a number of TTE patterns which are indicative of this degree of LV dyssynchrony including septal flash or septal beak (the interventricular septum [IVS] rapidly and briefly moves leftward before or during ejection); septal systolic rebound stretch (IVS elongates during early systole); apical rocking ; LV lateral wall hypertrophy with late contraction; or short filling and ejection times with a longer isovolumic phase due to late aortic valve opening . ContracThere are several ‘mimics’ to LBBB induced LV dyssynchrony on TTE, particularly for septal flash. These ‘mimics’ include coronary artery disease, post-cardiac surgery, right ventricular dysfunction, severe mitral stenosis, pericardial disease, other conduction system abnormalities , or extra-cardiac posterior compression  . AdditioGiven the interest in accurately defining LBBB to identify patients who would benefit from CRT, there are several emerging modalities presently being explored. The use of ultra-high frequency ECG (UHF-ECG) has shown early promise in increasing accuracy of patient selection for CRT. UHF-ECG utilizes much higher acquisition frequencies to allow for a much more detailed understanding of electrical activity during ventricular depolarization  . The maiAnother area of active interest is the use of non-invasive body surface mapping to improve accuracy in identifying ventricular dyssynchrony beyond QRS duration and morphology. Ploux and collegues studied the use of non-invasive mapping in 2013 and found ventricular electrical uncoupling on body mapping predicted clinical CRT response better than presence of LBBB on standard surface ECG . SimilarAdvanced cardiac imaging technique have also been explored as non-invasive ways to better characterize LV dyssynchrony. Single photon emission computed tomography (SPECT) and 18F-fluorodeoxyglucose positron emission tomography (PET) studies have demonstrated that LBBB results in relative reduction in coronary flow to the septum and hyperperfusion to the lateral wall . Other tIntracardiac electroanatomic mapping in patients with LBBB patterns on surface ECG have found heterogenous activation sequences of His-Purkinje conduction, ranging from CCB to IVCD with IPA  Upadhya. CCB comCRT for patients with heart failure and LBBB is achieved through placement of both a right ventricular endocardial lead and a left ventricular epicardial lead that is located in the coronary sinus . BiVP isTaken together, these landmark clinical trials have firmly established CRT via BiVP as the standard of care for patients with poor systolic function and a wide QRS duration on surface ECG. This is reflected in multi-societal guidelines which give a class I indication for CRT in this subset of patients . CurrentCRT via CSP relies on inserting a LV lead into IVS to capture in the area of the His bundle  or to the left bundle of the Purkinje fibers  . CSP attMore recently, left bundle branch area pacing (LBBAP) was reported as a novel means to pursue CSP, with reduced procedural complexity and more stable capture thresholds than HBP . LBBAP aWhile the results of CSP appear promising, there remains a lack of high quality, large, randomized, control trials with blinded assessment of key endpoints and an emphasis on clinical outcomes. Notably, the majority of data reported on CSP have explored echocardiographic endpoints. Given the anatomic consideration of LBBB, it is also worth noting that CSP is likely not appropriate for patients with IPA. Upadhyay et al. found that no patients with IPA had correction of wide QRS duration with HBP . This haHybrid methods of pacing have been developed which use sequential or simultaneous fusion of CSP pacing with traditional coronary sinus leads. His-optimized cardiac resynchronization therapy (HOT-CRT) or left bundle branch optimized cardiac resynchronization therapy (LOT-CRT) use a LV epicardial lead with the addition of a His-bundle lead or a left bundle area lead, respectively, to achieve the shortest QRS width. The first experience of HOT-CRT was reported in 2019 by the HIS-Sync Investigators in patients whom successful QRS correction could not be achieved with HBP alone . HOT-CRTIntracardiac EP studies of patients with wide QRS duration and LBBB pattern on surface ECG have demonstrated three distinct entities: CCB, IVCD with IPA, or mixed blocks. The heterogeneity of the underlying pathophysiology of LBBB pattern on surface ECG has pushed investigators to study other forms of assessing LV dyssynchrony or CRT response such as intracardiac recordings, TTE, UHF-ECG, SPECT, and CMR. The highest quality data support CRT via BiVP for patients with clinical heart failure and wide QRS durations. Alternative pacing strategies such as CSP, HOT-CRT, and LOT-CRT show early clinical promise but have yet to show improvement in hard clinical outcomes compared to BiVP. CSP should be reserved for patients with CCB while hybrid models of pacing may be suitable for patients with IPA or mixed levels of conduction block.


Pacemaker-induced cardiomyopathy (PICM) is a rare but well-recognised phenomenon in patients requiring right ventricular (RV) pacing. It can be caused by single-chamber or dual-chamber pacemakers. We present a case of a 64-year-old female patient presenting to the pacemaker clinic with worsening shortness of breath and legs swelling. She was found to have atrial fibrillation and underwent atrioventricular node ablation followed by a dual chamber permanent pacemaker (PPM) implantation as part of a ‘pace and ablate’ strategy to treat refractory symptomatic atrial tachycardia, and the patient was entirely dependent on RV pacing. In the immediate two months following PPM implantation, the patient was seen in the clinic and reported shortness of breath that was attributed to interstitial lung disease. However, a month later her symptoms worsened, stimulating a referral for echocardiography, which demonstrated a fall in her left ventricular ejection fraction (LVEF) from 60% to 30% in just four months after the device implantation. The patient was diagnosed with PICM. The patient’s prognostic heart failure treatment was optimised and her device was upgraded to a cardiac resynchronisation (CRT) device with pacing functionality in an attempt to improve biventricular synchrony. The patient’s symptoms have improved significantly since and a repeat echocardiogram 2 months later showed significant improvement in LVEF to 45-50%. The number of patients living with permanent pacemakers (PPM) has risen rapidly, with one study finding prevalence trebling between 1995 and 2009 [A well-studied phenomenon, PICM is frequently characterised by a drop in left ventricular ejection fraction (LVEF) in the setting of high-burden RV pacing  -5. PatieA 64-year-old female with a background of rheumatoid arthritis, interstitial lung disease (ILD), obesity and obstructive sleep apnoea (OSA) had initially presented to cardiology services with symptomatic paroxysmal atrial fibrillation (PAF) and intermittent typical atrial flutter, refractory to first-line medication in September 2021. Regular medications include verapamil 240 mg once daily, amiodarone 200 mg once daily, digoxin 125 mcg once daily, allopurinol 100 mg twice daily, atorvastatin 20 mg once daily, calcium carbonate/cholecalciferol tablets twice daily, carbocysteine 750 mg capsules three time daily, furosemide 40 mg once daily, lisinopril 10 mg once daily, omeprazole 40 mg once daily, hydroxychloroquine 400 mg once daily, Fostair inhaler and prednisolone 5 mg once daily. Her heart was structurally normal on the echocardiogram, and LVEF was 60%. She underwent two acutely successful cryoablation pulmonary vein isolation and cavotricuspid isthmus (CTI) line ablation procedures in October 2021 and February 2022, both hampered by the early recurrence of palpitations impacting her quality of life. Two months later, in April 2022, the patient attended her local accident and emergency with symptomatic atrial tachycardia with rapid ventricular response despite being on verapamil, amiodarone, and digoxin, which the treating team were unable to chemically cardiovert or control  ablation and dual chamber PPM implantation in May 2022 (‘pace and ablate’), with one electrode placed in the right atrium and one in the right ventricle under general anaesthesia. The AVN was identified, and ablation was performed through an F-curve irrigated ablation catheter. Completed heart block (CHB) was achieved with a slow junctional escape rhythm and recovery of rhythm was not noticed after waiting for 15 minutes, hence PPM was implanted. The device was set to DDD mode, with atrial sensing and ventricular pacing and the backup rate was set to 80 beats per minute (bpm). The PPM leads  and RV) were active leads, with the RA lead positioned in the RA appendage and the RV lead in the mid-septum. The leads demonstrated stable trends throughout the follow-up period, with no change in sensitivity or impedance. The RV was paced 100% of the time. A post-PPM implant chest X-ray confirmed satisfactory lead positioning when compared to fluoroscopic images during the PPM insertion , this was felt to be secondary to normal pacemaker tracking of sinus node beats (max tracking rate of 130 beats per minute). In no instance were there reports of ischaemic chest pain. An echocardiogram was eventually arranged, demonstrating an LVEF of 30%, a 50% reduction in the 4 months following PPM implantation; the patient was significantly short of breath and was diagnosed with PICM  device with a pacing function in November 2022 with the introduction of a left ventricular lead via the coronary sinus Figure . The posWe present the case of a patient in her 60s with a diagnosis of PICM with high RV pacing dependency without ischaemic heart disease and a structurally normal heart prior to PPM insertion. Definitions vary widely, but in general, PICM is seen as a fall in LVEF in the context of high-burden RV pacing. This definition may result in inadequate capture of patients with PICM, and studies have shown that patients may suffer heart failure symptoms with reasonably preserved LVEF ,8. As inThe risk of PICM is thought to be greatest in male and older patients, those with increased native QRS duration, greater QRS duration following PPM insertion, a greater burden of RV pacing, and pre-PPM reduced LVEF . StudiesAs in our case, patients with PICM should have prognostic medications instituted and acute complications, such as pulmonary oedema managed appropriately . CardiacPICM is an infrequent but important complication of RV pacing and should be readily thought of when assessing any patient in the acute setting with symptoms of heart failure. This is particularly true when the patient presents soon after PPM insertion. Investigation of any patient with these symptoms should be investigated with echocardiography, and medical management of heart failure and its complications instituted. The patient should be referred for cardiology assessment and a potential upgrade to biventricular pacing.


Although depressive and anxious symptoms negatively impact musculoskeletal health and orthopedic outcomes, a gap remains in identifying modalities through which mental health intervention can realistically be delivered during orthopedic care. The purpose of this study was to understand orthopedic stakeholders’ perspectives regarding the feasibility, acceptability, and usability of digital, printed, and in-person intervention modalities to address mental health as part of orthopedic care.This single-center, qualitative study was conducted within the orthopedic department of a tertiary care center. Semi-structured interviews were conducted between January and May 2022. Two stakeholder groups were interviewed using a purposive sampling approach until thematic saturation was reached. The first group included adult orthopedic patients who presented for management of ≥ 3 months of neck or back pain. The second group included early, mid, and late career orthopedic clinicians and support staff members. Stakeholders’ interview responses were analyzed using deductive and inductive coding approaches followed by thematic analysis. Patients also performed usability testing of one digital and one printed mental health intervention.Patients included 30 adults out of 85 approached (mean (SD) age 59 (14) years, 21 (70%) women, 12 (40%) non-White). Clinical team stakeholders included 22 orthopedic clinicians and support staff members out of 25 approached (11 (50%) women, 6 (27%) non-White). Clinical team members perceived a digital mental health intervention to be feasible and scalable to implement, and many patients appreciated that the digital modality offered privacy, immediate access to resources, and the ability to engage during nonbusiness hours. However, stakeholders also expressed that a printed mental health resource is still necessary to meet the needs of patients who prefer and/or can only engage with tangible, rather than digital, mental health resources. Many clinical team members expressed skepticism regarding the current feasibility of scalably incorporating in-person mental health support into orthopedic care.Although digital intervention offers implementation-related advantages over printed and in-person mental health interventions, a subset of often underserved patients will not currently be reached using exclusively digital intervention. Future research should work to identify combinations of effective mental health interventions that provide equitable access for orthopedic patients.Not applicable. Depressive and anxious symptoms negatively impact physical function and recovery after a wide variety of orthopedic procedures –7. FurthThe primary purpose of this study was to understand orthopedic patients’ and clinical team members’ perspectives regarding the feasibility, acceptability, and usability of digital, printed, and in-person intervention modalities to address mental health as part of musculoskeletal care. A second purpose was to understand these stakeholders’ perspectives regarding the feasibility and acceptability of participating in mental health related research trials in the context of musculoskeletal care.This single-site qualitative study was approved by the Washington University IRB. Participants gave written or verbal consent, and they received a $40 stipend for participating. Participants were enrolled between January and May 2022, and data analysis was completed in September 2022.Participants from two stakeholder groups were recruited. The first group consisted of adult (18 years or older) patients who presented to a Washington University orthopedic specialist for treatment of ≥ 3 months of neck or back pain. This population was chosen because among patients who seek care for a musculoskeletal condition, people with chronic neck or back pain have a particularly high comorbid prevalence of depression and anxiety –27. PoteThe second participant group consisted of Washington University orthopedic clinical team members including clinicians and support staff. Purposive sampling was used to ensure the group included: 1) clinicians from all adult orthopedic subspecialties, 2) early, mid, and late career physicians, 3) operative and non-operative specialists, 4) members of all clinical support roles present in the clinic , and 5) team members who self-identified as women and with racial/ethnic minority groups. The study was introduced to team members via e-mail.After completing a demographic survey , 32, staThe interviews were informed by semi-structured interview guides that were drafted by the lead researcher (ALC) and then revised based on feedback from research team members including orthopedic surgeons and qualitative researchers  . The guides were pilot tested prior to the stakeholder interviews and were iteratively revised based on participant responses during the interviews.All stakeholders were asked to describe their preferences and perceptions of feasibility, acceptability, and usability regarding modality options for mental health interventions that could/should be offered in the context of orthopedic care. They were specifically asked to at least comment on digital, printed, and in-person options. They also provided feedback regarding specific examples of one digital and one printed intervention. The digital intervention, called Wysa for Chronic Pain, is an evidence-based mental health app that addresses the interplay between mental health and chronic pain , 13, 33.Patient stakeholders also completed usability testing for these digital and printed interventions. For the digital intervention, they were asked to complete onboarding and schedule a session with a counselor. For the printed intervention, they were asked to demonstrate how to engage with a resource on the guide which appealed to them. They provided qualitative feedback and rated each intervention on the System Usability Scale (SUS), which is scored 0-100 with higher scores being favorable and scores above 80.3 interpreted as receiving an “A” , 35. FinA preliminary codebook was developed by the lead researcher (ALC) using a deductive coding approach based on the dimensions of feasibility, acceptability, and usability. Next, using inductive coding, the codebook was refined and finalized by two team members (ALC and MAA (patient interviews), or ALC and AJL ) after they reviewed a sample of interview transcripts. All transcripts were independently coded by those two team members. Participant recruitment continued from each stakeholder group until thematic saturation was reached. Coding was completed with NVivo 12 software . Group discussion was used to resolve coding discrepancies and organize codes into final themes.Of 85 patients approached, 30 (35%) participated (mean (SD) age 59 (14) years, 21 (70%) women, 12 (40%) non-White, median (range) pain duration 3.3 (0.5–40) years) . Of 25 cClinical team members perceived delivery of a digital mental health intervention to be feasible and appealing . They esCompared to a digital intervention, team members expressed relatively greater feasibility to incorporate delivery of a printed mental health intervention into their existing clinic flow . PatientAlthough orthopedic patients and team members perceived that in-person mental health support would be the ideal intervention modality for some patients , many team members expressed skepticism regarding the current financial and logistical feasibility of providing in-person support as part of musculoskeletal care . If feasOrthopedic patients and team members expressed overall feasibility and acceptability of conducting randomized controlled trials of mental health interventions delivered in the orthopedic clinic setting . AlthougIn this study, we found that digital and printed modalities are both anticipated to be feasible and acceptable methods of delivering mental health intervention in the context of musculoskeletal care. Although implementation considerations slightly favored the printed modality, available evidence of intervention effectiveness currently favors the digital modality –38. TherIt is encouraging that orthopedic team members reported positive perceptions regarding the feasibility and acceptability of a digital intervention because: 1) this modality can provide at-home access to mental health tools when a patient’s mobility is limited due to a musculoskeletal condition, 2) there is growing evidence of effectiveness of digital mental health interventions, sometimes comparable to in-person mental health intervention , 40, andAlthough patients and team members expressed somewhat favorable feasibility and equity of a printed intervention compared to a digital intervention, there is currently weaker evidence regarding the clinical effectiveness of printed mental health interventions. So far, self-guided interventions have achieved small, yet still significant mean effects on mental health symptoms  of 6.4) , 47. A sAlthough our stakeholders also strongly favored the option of in-person, one-on-one mental health support for some patients, perceived financial and logistical barriers still substantially tamper enthusiasm for current feasibility. Orthopedic practices could circumvent clinic-facing financial barriers to in-person mental health support by developing a “preferred access” referral list to mental health clinicians in the community. However, due to restrictive third party payer policies and the nationwide shortage of mental health clinicians, patients would still face the same financial and wait-time barriers to accessing care that they currently face when independently seeking mental health support –52. One-A limitation of this study is that all stakeholders were recruited from a single institution in a single metropolitan region. Therefore, some of the mental health resources listed on the printed intervention that we tested may not be available elsewhere, although many of the included resources are widely available virtually. Similarly, the feasibility of incorporating in-person mental health support will somewhat vary based on regional resources, although the shortage of mental health clinicians is a widespread problem nationally and globally –52. Alsoand effective at improving mental and physical health outcomes in orthopedic patients.In this study, we found that orthopedic patients and clinical team members perceive distinct advantages and challenges related to integrating digital, printed, and in-person modalities of mental health intervention into the orthopedic care setting. Digital intervention may currently have a favorable balance of feasibility and evidence of effectiveness compared to the other modalities, but an important, often underserved, subset of patients will not currently be reached using exclusively digital intervention. To reach as many patients as possible and to particularly engage patients who are older, from rural communities, and/or otherwise cannot meaningfully engage with a digital intervention, we propose that mental health intervention in the orthopedic setting cannot be a one-size-fits-all approach. Multiple intervention modalities are needed. The next step will be to build on this stakeholder feedback and conduct rigorous clinical trials to identify interventions that are feasible, acceptable, scalable,


However, its role in spinal cord infarction (SCI) is less well-established. A few case reports describe the putative causative role of PFO in SCI. We present a case of a teenager with cryptogenic anterior SCI in the setting of a deep vein thrombosis and a high risk-PFO who underwent successful percutaneous closure.In patients with a patent foramen  The We describe the case of a 16-year-old male patient who presents to the emergency department with cervical pain radiating to both arms, followed by bilateral upper limb weakness and numbness, which began after performing a Valsalva maneuver . The paresthesias rapidly progressed to the abdomen and lower extremities, despite intact lower limb strength, and sphincter dysfunction developed. He denied having suffered a relevant trauma in the previous days.A comprehensive neurological exam revealed flaccid paralysis of both upper extremities, with muscle power of 2/5 on the Medical Research Council (MRC) scale in 3 upper right arm adduction and right forearm flexion and muscle power 3/5 in upper left arm adduction and left forearm flexion, downward drift of both outstretched arms (Barré test), bilateral bicipital hyperreflexia, and pain and temperature sensation impairment in both upper and lower extremities. Proprioception, lower extremity strength, and cranial nerve examination were normal.2) and had a right tibial fracture in the previous year, treated with osteosynthesis. There is familial history of venous thromboembolism and premature atherosclerotic disease.The patient is overweight  with positive anti-DFS70 autoantibodies, but the remainder of the autoimmune workup was negative, including antiphospholipid antibodies and high factor VIII levels (182%). The workup was otherwise normal, including hypercoagulability, vasculitis, infectious, and transverse myelitis workups were negative. Cerebrospinal fluid examination was unremarkable.T2-weighted sagittal MRI of the cervical spine disclosed a hyperintense lesion extending from C4 to D1 involving the anterior horns of the spinal cord, without signs of spinal cord compression and no apparent signs of acute vertebral artery dissection or intramural hematoma . Brain MChest and CT angiography of supra-aortic arteries failed to identify an etiology and excluded acute aortic syndrome or supra-aortic vessel dissection. Digital subtraction spinal and supra-aortic artery angiography excluded abnormalities of the spinal cord vascular system, namely, arteriovenous malformations and vessel dissection, despite a slow filling of the anterior spinal artery. Lower Extremity Venous Doppler Study revealed thrombotic occlusion of the left posterior tibial artery.Transcranial Doppler showed patency of major cerebral arteries, and saline bolus detected a right-to-left at-rest grade I shunt according to the Spencer grading scale during rest that increased with Valsalva maneuver. In order to evaluate for the presence of an intracardiac shunt, the patient underwent a transesophageal echocardiogram (TEE) that revealed the presence of a PFO with a tunnel length of 18 mm and an additional 2 mm ostium secundum atrial septal defect and an exuberant persisting Eustachian valve.Upon diagnosis of deep venous thrombosis, anti-Xa assay-guided low molecular weight heparin was started, requiring multiple dose adjustments due to subtherapeutic levels. The patient underwent successful physical rehabilitation.The patient was referred to our cardiac center for percutaneous closure (PC). Under general anesthesia and TEE guidance, a Cardia Ultrasept PFO 20 mm device was successfully implanted, with no residual leak Figures . The proDue to a probable underlying thrombophilia, it was decided to maintain anticoagulation.We report one of the first percutaneous closure of a PFO in a patient with a cryptogenic medullar infarction, involving the youngest patient described in literature.in situ thrombus formation, particularly in long-tunneled PFO with exuberant Eustachian valves. Recent randomized controlled trials (RCTs) [PFO affects about 25% of the adult population. It has a role in cryptogenic stroke in young adults, by providing a conduit to paradoxical embolism or by serving as a nidus for s (RCTs) –6 have dThe vast majority of strokes associated with PFO are of cortical pattern, and the major RCTs evaluating the efficacy and safety of its percutaneous closure excluded patients with strokes due to small-vessel occlusive disease. Spinal cord infarction (SCI) due to paradoxical embolism is rare, and a few recent case reports –12 have p = 0.0001) [We debated carefully the decision to close our patient's PFO. Contrary to closure, patients under 18 years old are largely underrepresented or have been excluded from the major RCTs –6; there 0.0001) . In the  0.0001) .Favoring closure, our patient presented with several features highly suggestive of a PFO-related paradoxical embolic event: the presence of lower limb deep venous thrombus; the temporal association between a Valsalva maneuver and symptom onset; the presence of high-risk characteristics associated with the PFO  , and, fiIn the short-term follow-up, the patient is doing well, with no additional neurological events.Our case describes the first percutaneous PFO closure in SCI in a young patient after a deep vein thrombosis and with a positive family history for venous thromboembolism. Due to the lack of randomized controlled trials on the management of SCI in the presence of PFO, the decision to close the PFO was not straightforward. However, the clinical context suggestive of paradoxical embolism, a probable underlying prothrombotic predisposition, the high-risk features of the PFO, and operator's experience played a role in the decision to close the PFO, despite patient's young age. Our work seeks to raise awareness to the role of right-to-left shunts and paradoxical embolism in cryptogenic ischemic spinal disorders.


Diabetic foot infection (DFI) management requires complex multidisciplinary care pathways with off-loading, debridement and targeted antibiotic treatment central to positive clinical outcomes. Local administration of topical treatments and advanced wound dressings are often used for more superficial infections, and in combination with systemic antibiotics for more advanced infections. In practice, the choice of such topical approaches, whether alone or as adjuncts, is rarely evidence-based, and there does not appear to be a single market leader. There are several reasons for this, including a lack of clear evidence-based guidelines on their efficacy and a paucity of robust clinical trials. Nonetheless, with a growing number of people living with diabetes, preventing the progression of chronic foot infections to amputation is critical. Topical agents may increasingly play a role, especially as they have potential to limit the use of systemic antibiotics in an environment of increasing antibiotic resistance. While a number of advanced dressings are currently marketed for DFI, here we review the literature describing promising future-focused approaches for topical treatment of DFI that may overcome some of the current hurdles. Specifically, we focus on antibiotic-impregnated biomaterials, novel antimicrobial peptides and photodynamic therapy. The International Diabetes Federation estimates that 537 million people were living with diabetes in 2021, representing 10% of the global population, which has increased by 1.2% in the past five years. It is predicted that this number will rise to 783 million by 2045 . NotablyDiabetic foot infection (DFI) is the commonest cause of hospitalisation among those with diabetes  and the Diabetes-associated peripheral neuropathy impairs the distal nerves of the limbs, resulting in reduced pain sensations and progressive numbness. As a consequence, diabetic foot ulcers may develop and progress unrecognised following relatively minor external traumas. Irregular plantar pressure and shear stress on the foot associated with reduced foot mobility and abnormal structural features such as hammer toe and Charcot deformity may further facilitate ulcer progression . Once a The symptoms of wound infection commonly include purulent exudate, odour, erythema, warmth, tenderness, oedema, pain, fever and elevated white cell count. However, these clinical signs of infection may not all be present in the immunocompromised patient, the patient with poor perfusion or the patient with a chronic wound. The latter three conditions are common among diabetic patients, making DFIs inherently complex to diagnose, categorise and manage—requiring a multidisciplinary care approach involving podiatrists, vascular surgeons, tissue viability experts and clinical microbiologists. Furthermore, multiple classification schemes for diabetic foot complications exist, of which infection is often a defined parameter in the broader classification of ulceration severity. However, because infection severity is a major contributor to poor clinical outcomes, the classification system recommended by the Infectious Diseases Society of America (IDSA) and the International Working Group of the Diabetic Foot (IWGDF) shows utility in a clinical setting as a predictor of lower limb amputation ,19. ThisThe emerging trend towards greater prominence of PAD among people with diabetes adds further complexity to the pathophysiology of foot wounds, meaning that such wound characteristics as contained within the PEDIS classification may all contribute to patient clinical outcomes and ought to be assessed while classifying DFIs. The Society for Vascular Surgery’s integrated system of classification of the lower extremity threatened limb is based on Wound, Ischaemia and Foot Infection (WIfI) to better predict amputation risk . RecentlIn the clinical management of DFUs, it is important to differentiate between colonisation and infection. Colonisation is defined as the presence of multiplying bacteria without an overt host immune response and is a feature of chronic wounds, usually involving bacteria of the normal flora . ApproxiStaphylococcus aureus, remain the most common bacterial pathogen isolated from DFIs, followed by aerobic Gram-negatives, mainly Pseudomonas aeruginosa , progressed to a phase IIb controlled trial for applications in the care of infected wounds, including DFI. While only a small study of eight patients, a statistically significant reduction in bacterial load (approximately 1 log immediately after PDT treatment) and a trend towards wound healing were observed. The authors reported that the treatment was well-tolerated with an obvious improvement in wound healing within the treatment group compared to the placebo group ,101. Impthe DFUs .Another group of molecules that offer exciting prospects for the application of antimicrobial PDT for wound applications are those with the 4,4-difluoro-4-bora-3a,4a-diaza-s-indance structure, commonly referred to as BODIPYs. They possess desirable photophysical properties including large molar extinction coefficients in the visible light region, long emission wavelength and photostability. In addition, their chemical versatility facilitates the structural modification of these molecules to increase their production of singlet oxygen species. This is achieved by introducing heavy atoms such as iodine or bromine into their structure to create a high-efficiency triplet excited state, which ensures the efficient production of singlet oxygen . This apmeso-Pyridinyl and methyl pyridinium or meso-pyridinium BODIPYs carrying hydrophobic head groups against S. aureus, Escherichia coli, Candida albicans and MRSA. Methyl-meso-(meta-pyridinium) BODIPY showed the highest phototoxicity against these pathogens with MICs ranging from 0.63 to 1.25 μM at a light dose of 81 J/cm2. This BODIPY group showed 3.59 to 7.05 log reduction in CFU/mL of S. aureus, including MRSA at concentrations from 0.31 to 5 µM, and 2.53 to 6.62 log reduction in CFU/mL of E. coli at concentrations from 1.25 μM to 5 μM. An in vivo aPDT study performed in a mouse S. aureus wound model using the methyl-meso-(meta-pyridinium) BODIPY formulated into a hydrogel to treat the infected area showed visible wound healing and significant reduction in bacterial load within 8 days.Lin et al. investigated structure–activity relationships of BODIPYs containing Reducing the bacterial burden of chronic ulcers helps to reduce the risk of infection but also removes a potential barrier to effective wound healing. Conventional antibiotics have limited efficacy due to poor tissue penetration, increasing bacterial resistance and the risk of allergic contact reactions with topical antibiotics. In contrast, aPDT can promote healing by modulating growth factors production even in the absence of any antimicrobial activity. Statius van Eps et al. showed that PDT in a vascular smooth muscle cell injury model, stimulated endothelial cell growth by inactivating transforming growth factor-beta (TGF-β). However, the authors cautioned that further work is required to establish optimal dosing, noting inhibition of mediators of wound healing with sub-therapeutic PDT . More reS. aureus using deuteroporphyrin (DP)-PDT with oxacillin but not with vancomycin, gentamicin, fusidic acid or rifampicin [S. aureus biofilms, its efficacy further increased by 3 log reduction when combined with oxacillin. The authors speculated that the impaired penicillin resistance among PDT survivors may reflect damage to plasmids that mediate beta-lactamase production based on earlier studies showing damage to supercoiled plasmid DNA in response to PDT [Interestingly, a synergy between PDT and penicillin antibiotics has been demonstrated in some studies, suggesting its potential as an adjunct to antibiotics. Iluz et al., using a checkerboard method, demonstrated synergistic antimicrobial activity against fampicin . Additioe to PDT .Photodynamic therapy has the potential to either reduce infection burden or eradicate infection completely. Its multiple bacterial targets may both abrogate existing resistance of pathogens to conventional antibiotics while limiting the development of new resistance mechanisms. The flexibility of feasible structural modifications within PS structures are also attractive for the future development of technologies towards wound healing applications for DFUs and other infected wound types. With well-designed clinical and preclinical studies, photodynamic therapy could be progressed into clinical practice for the treatment of multi-drug resistant wound infections. Perhaps the most appealing aspect of antimicrobial PDT is its potential for use in outpatient clinics at relatively low costs. Hospitalisation may not be required when using PDT, which reduces the cost of treatment by several orders of magnitude. It is also associated with the use of already available light sources and inexpensive photosensitisers.The management of infected DFUs is a critical component of the holistic management of the diabetic patient. Numerous approaches including antimicrobial peptides and peptide-based polymers, photodynamic therapy and antibiotics-impregnated biomaterials have been investigated in preclinical studies, with promising antimicrobial activity often against bacteria in biofilm growth modes. However, there is an urgent need to progress them into the clinic, through well-designed randomised controlled trials to generate much-needed evidence of clinical efficacy. These approaches present multimodal benefits of being applicable both as stand-alone therapies and as adjuncts to long-standing antibiotics, which have become less potent in the wake of rising antibiotic resistance. They also offer the advantage of being effective both as antimicrobial agents and promoters of wound healing—a benefit that cannot be overstated in the setting of diabetic foot infections.


Multiple sclerosis is a neurodegenerative disease characterized by an inflammatory demyelination of the central nervous system. The degenerative disease has been linked to numerous viral infections, geographical locations, and genetic predisposition. One link that has not been fully established is the relationship between West Nile virus infection and its role in the initiation of multiple sclerosis. This case study provides further evidence that the proinflammatory neurological processes induced by the West Nile virus may lead to systemic demyelination of neuronal axons, ultimately causing multiple sclerosis. Multiple sclerosis (MS) is a chronic, degenerative central nervous system (CNS) disease that is caused by an inflammatory demyelination of oligodendrocytic axons. The pathophysiology of MS involves the activation of autoreactive T-lymphocytes which induce inflammation and demyelination of CNS axons. Axonal loss causes CNS neurons to degenerate and accumulate into chronic plaques seen in the white matter of the brain. Although its etiology is not fully understood, activation and flares have largely been linked to genetic predisposition and can also commonly be triggered by viral infections. Previous studies have shown that there is an increased risk of developing MS in individuals with specific alleles in the major histocompatibility complex (MHC), specifically HLA-DRB1 . FurtherThe patient is a 20-year-old female with a past medical history of WNV meningoencephalitis diagnosed in 2017 with subsequent development of behavioral disinhibition consistent with Kluver-Bucy syndrome who presented to the Emergency Department for evaluation of recent onset left-sided upper extremity and lower extremity weakness. The patient stated that the weakness and paresthesia began approximately 5 to 7 days prior to admission, with symptoms worsening. Neurological examination presented with no focal motor deficits, but subjective paresthesia and decreased sensation specifically on the left upper extremity were noted. She had dysmetria and dysdiadochokinesia on the left upper and lower extremities. She was unable to walk unassisted. Upon admission, the patient had an MRI of the brain with contrast performed. MRI findings showed T2 hyperintensities located in the periventricular region, corpus callosum, right midbrain, and right brachium pontis. The cerebellum, pons, midbrain, and cerebral peduncles were noted to have normal signal intensity. The patient denied past history of weakness, paresthesia, urinary incontinence, transient vision loss, and other common sequelae of multiple sclerosis.Medical records were reconciled from an outside-hospital facility and reviewed. By review, the patient had an extensive hospital course for WNV meningoencephalitis in 2017 with slow recovery over a period of 1 year. Lumbar puncture (LP) was performed and confirmed active WNV infection. CT Head 2017 showed no focal findings. Repeat LP was performed in 2019 to assess for recurrent infection on outpatient follow-up. Cerebral spinal fluid (CSF) showed WNV IgG Ab (2.15), WNV IgM Ab (< 0.90), positive oligoclonal bands, myelin basic protein (< 2.0 mcg/L), lymphocytes (82%), monocytes/macrophages (12%), RBC (121 cells/mm3), WBC (1 cell/mm3), negative culture, segmental (6%)  signal hyperintensity involving the bilateral cerebral and cerebellar white matter, bilateral basal ganglia, thalami, and brainstem. By utilizing the modified McDonald criteria for MS, the patient met the criteria for MS with one clinical attack, greater than two lesions with objective clinical evidence. MRI comparison from 2019 to 2022 showed new-onset white-matter lesions on FLAIR sequences (Figure The patient refused repeat LP during the recent hospitalization. The patient was started on 125 mg of methylprednisolone every 6 hours and monitored over a six-day hospital course. Throughout the remainder of her hospital course, the patient reported a significant improvement in her left-sided weakness and paresthesia.WNV has been implicated in the induction of multiple auto-inflammatory neurological disease processes, but its link to MS has not been fully established.In a 2020 study, research on the pathophysiology of how WNV could induce neurological disease was tested in rodent models . It was A separate mechanism of action was assessed in a 2021 study. One neurological manifestation of WNV is acute flaccid paralysis. WNV can invade the CSF and causes inflammatory damage in the anterior horn of the gray matter in the spinal cord. These damaged nerves can present similarly to poliomyelitis with monoparesis, asymmetric paraparesis, or quadriparesis. Damage to the spinal cord gray matter can rarely manifest as acute transverse myelitis. A WNV case in Massachusetts showed “radiographic evidence displaying enhancement in 3 contiguous spinal cord segments as well as CSF analysis consistent with West Nile neuro-invasive disease” . This inMultiple sclerosis is the demyelination of oligodendrocyte axons that has been associated with genetics, environment, and numerous viral infections that induce proinflammatory states. The EBV has long been the key virus associated with triggering MS, but in this study, there is evidence that WNV is a different virus that can be associated with the onset of MS. The mechanism of demyelination in white matter spaces induced by the WNV ultimately provides insight into the pathophysiology of how the WNV can cause multiple sclerosis.


This will provide new insights into how root signals orchestrate associated microbes, will benefit agricultural production in the face of challenges posed by climate change, and will help to sustainably provide food for a growing global human population.Root exudates play a key role in mediating plant–plant and plant–rhizomicrobiome interactions, including regulating biochemical/physiological aspects of plant-associated microorganisms, to enhance host plant growth and resilience. Root exudates can act as signals to reduce the competition from neighboring plants and recruiting/choreographing a wide range of diverse rhizomicrobiome members to make the host plant a good fit with its immediate environment. Root exudate production is a dynamic and key process, but there is a limited understanding of the metabolites or metabolic pathways involved in the inter-organismal communications facilitated by them. Given the well-known symbiotic relationships between plants and associated rhizomicrobiome members, adding root exudates to microbial isolation media may allow some of the large segments of rhizomicrobiome members that are not currently culturable to be grown  Root exudate is part of the plant holobiont; its production varies with the surrounding circumstances.As a key aspect of root exudates, signal exchange is responsible for inter-organismal interactions such as plant–microbe, plant–kin, and neighbors in the rhizosphere and within the ecosystem.The combination of the advanced omics techniques is a promising approach to deeply explore and exploit the dynamics and abundance of root exudates.Plants recruit beneficial microbes through exudates to facilitate positive relationships and enhance plant development and resilience; specific elements of root exudates may also be required to allow growth of many phytomicrobiome members.via diffusion, ion channel pumping, and vesicle transport  and wild species (Z. mays subsp. parviglumis)  sibling, a cultivar with highly abundant dolabralexins in roots (Triticum aestivum L.) (Lotus and Arabidopsis.The belowground response to the root exudate composition mainly depends on soil conditions including nutrient availability and the rhizomicrobiome in rhizosphere . Plants iglumis) . A similiglumis) , pearl miglumis) , and spesalinity . In one in roots . The numivum L.) . A subseivum L.) . The quaivum L.) . Wippel via allelopathy exudates (Plant roots coordinate the aboveground (leaf and shoot) and belowground (microbiota in the rhizosphere) elements of the holobiont, thus regulating and balancing the critical physiological functions in the microbiota–root–shoot environment . Organicexudates . These cin vitro, finishing with considerations regarding future research required to understand the role of root exudates and their application to enhancement of agricultural productivity.While we know that root exudates have multiple functions, the inaccessibility of the root system has made it difficult to collect and characterize root exudates, resulting in limited understanding of the detailed mechanism(s) involved. In this paper, the role of root exudates in rhizospheric inter-organismal communications is introduced, including collection approaches and analysis techniques applied to root exudates, followed by a potential combination between root exudates and currently unculturable rhizomicrobiome members via signals including phytohormones and other secondary metabolites  pathogenic microbes [through root exudate signals: phenolic compounds, non-volatile terpenoids, volatile terpenes, and sulfurous compounds . In addition, high levels of organic acid anions released into soil by soybean and cowpea  improve P acquisition efficiency under P deficiency, and subsequently, organic P that accumulated in the previous legume crop residues contributes to enhance the following maize crop (4+ and amino acids) as a source of N for subsequent maize growth  hydroponic systems, (2) soil-hydroponic mixing systems, and (3) soil growth and sampling. Detailed description used to collect root exudates and the comparisons among improved methods are provided in Considering the interaction within all organisms, root exudate identification should not be separated from the rhizospheric organisms. In such situation, multi-omics approaches help to visualize the temporal–spatial distributions of root exudates and the associated microbiome. With regard to the beneficial aspects of each technique, genome sequences can firstly identify the specific traits of functional bacterial isolates involved in growth strategies, substrate uptake, and extracellular enzyme production related to fitness of host in the rhizosphere . Then, aFor structural elucidation of root exudate metabolites, collected exudate can also be fractionated by flash chromatography, purified by high-performance liquid chromatography–solid phase extraction (HPLC-SPE), and then subjected to nuclear magnetic resonance (NMR) analysis . To examin vitro make up only about 1%–5% of total microbes  production were detected under greenhouse growth (less rich methanogenic archaea) because methanogenic archaea cooperate with syntrophic partners to obtain H2 and formate for CH4 synthesis. In such cases, a novel genome-centric metatranscriptomics approach recently reported by In the aspect of microbes involving root exudation production, pre-collection of exudates could be a part of screening to identify microbes that interact regularly with signals from plant roots and other associated microbes. Traditionally, microbial screening has been conducted in artificial growth media under sterile laboratory conditions to select microbes with potential key holobiont bioactivities. Microbes that are easily grown and that readily colonize plant roots are generally chosen for further analysis. There have been promising laboratory results from work in artificial media provided with approximately 100-fold higher concentrations of nutrients than generally occurs in the rhizosphere under field conditions . Howevermicrobes . As the B. amyloliquefaciens NJN-6 , developed through endosymbiosis of prokaryotes leading to a rigid and completely obligatory mutualism interaction present in all terrestrial plants . Plant e systems .2 fixation mechanism (2 into what they need for their growth and development (2 levels of the near future. The composition of root exudates released by C3 and C4 plants may change, such as increases in organic acid production under higher atmospheric CO2 levels (2 (3 and C4 plants can be changed by the soil nutrient status, further affecting rhizosphere bacterial community structure (The establishment of microbial communities on plants is influenced by the plant compartment  and hostechanism . The phoelopment . Moreoveelopment , but a helopment . Thus, telopment . Prior selopment . However2 levels . For insevels (2 . Interestructure . Host sptructure . Therefotructure . The ratRoot exudate is a key element of plant homeostasis, in part through playing a key role in communication between aboveground and belowground elements of plants. Root signals affect interactions with the associated phytomicrobiome, leading to a functional and effective holobiont that benefits plant growth. However, there are certainly still unknown signals in inter-organismal communications, produced by both plants and microbes. Discovering and exploring more signals will extend our understanding of plant–plant and plant–microbe interactions. Moreover, exploiting new techniques for collecting plant metabolites will provide access to various inter-organismal signals on a large scale. In the long term, agricultural production will be able to take full advantage of the phytomicrobiome by manipulating plant root signal production. Importantly, plant C-fixation strategy is a major component driving rhizospheric development and maintenance. Evaluating the underground impact of biodesign programs leveraging C-fixation engineering in plants will thus be of great importance. All bioprospecting under laboratory conditions aims to identify the potential beneficial microbes that then could be efficiently employed as a sustainable strategy to improve crop plant resilience and overall crop productivity. One application of root exudates could be as bio-inoculants to trigger the signaling between plants and microbes and also recruit beneficial microbes, as well as remove contaminants from the soil, thus enhancing the crop yield and biomass. Thus, the identification of components of exudates and understanding the mechanisms by which they regulate rhizomicrobiome networks should be considered an important line of future research.in vitro? If so, are these specific root exudates spontaneous or are they induced?Are there one or more specific root exudate compounds/materials that cause/allow specific activities in plant-associated bacteria, including the ability to grow What are the effects of stressful growth conditions on root exudate production? To what extent is secondary metabolite production in other parts of plants changed with the root exudate?Were root exudates involved in the evolution of phytomicrobiome? If so, what does this tell us about the holobiont?DL gathered literature and prepared the manuscript. DS provided feedback and oversaw progression of the manuscript. All authors gave final approval for publication and agreed to be held accountable for the work contained therein.


Background: Decompression of the lumbar spine is one of the most common procedures performed in spine surgery. Hospital length of stay (LOS) is a clinically relevant metric used to assess surgical success, patient outcomes, and socioeconomic impact. This study aimed to investigate a variety of machine learning and deep learning algorithms to reliably predict whether a patient undergoing decompression of lumbar spinal stenosis will experience a prolonged LOS. Methods: Patients undergoing treatment for lumbar spinal stenosis with microsurgical and full-endoscopic decompression were selected within this retrospective monocentric cohort study. Prolonged LOS was defined as an LOS greater than or equal to the 75th percentile of the cohort . Unsupervised learning with K-means clustering was used to find clusters in the data. Hospital stay classes were predicted with logistic regression, RandomForest classifier, stochastic gradient descent (SGD) classifier, K-nearest neighbors, Decision Tree classifier, Gaussian Naive Bayes (GaussianNB), support vector machines (SVM), a custom-made convolutional neural network (CNN), multilayer perceptron artificial neural network (MLP), and radial basis function neural network (RBNN) in Python. Prediction accuracy and area under the curve (AUC) were calculated. Feature importance analysis was utilized to find the most important predictors. Further, we developed a decision tree based on the Chi-square automatic interaction detection (CHAID) algorithm to investigate cut-offs of predictors for clinical decision-making. Results: 236 patients and 14 feature variables were included. K-means clustering separated data into two clusters distinguishing the data into two patient risk characteristic groups. The algorithms reached AUCs between 67.5% and 87.3% for the classification of LOS classes. Feature importance analysis of deep learning algorithms indicated that operation time was the most important feature in predicting LOS. A decision tree based on CHAID could predict 84.7% of the cases. Conclusions: Machine learning and deep learning algorithms can predict whether patients will experience an increased LOS following lumbar decompression surgery. Therefore, medical resources can be more appropriately allocated to patients who are at risk of prolonged LOS. In patients over 65, lumbar spinal stenosis (LSS) is the most commonly occurring reason for spinal surgery, and decompression of the lumbar spine is among the most common surgical procedures . In theoAn important factor to consider when evaluating socioeconomic costs, surgical success, and patient outcomes is the length of stay (LOS). LOS is a measure that is frequently used to reduce healthcare costs, especially in light of escalating healthcare expenditures. When patients are undergoing spinal surgery, the length of stay variable is critical from the patient’s point of view and is a major factor in determining health care expenditures. It is estimated that each additional day in the hospital costs approximately 1000 USD , and inpPredictive analysis and machine learning have emerged as valuable tools for predicting patient outcomes based on pertinent feature characteristics variables . DevelopMany studies have already shown that certain characteristics are associated with a longer hospital stay following spinal surgery. A longer length of stay (LOS) was associated with an increase in operating time during adult spinal deformity surgery, according to Phan et al. . The autConsidering the socioeconomic impact of prolonged LOS, the present study sought to investigate various artificial intelligence-based algorithms that might be able to predict whether lumbar decompression surgery patients will experience a short or long LOS. Further, we aim to find the most relevant feature variables which are important to solve this classification task.We performed a retrospective cohort study including consecutive patients treated with microsurgical decompression or full-endoscopic interlaminar decompression of lumbar spinal stenosis between 2016 and 2021 at the Department of Spine Surgery, Loretto-Hospital Freiburg in Germany, an affiliated hospital of the University Medical Center Freiburg, Germany. This retrospective observational study was approved by the local Ethics Committee Freiburg, Germany [Number: 116/200]. Written informed consent to participate in observational studies was obtained from each patient.® system  was utilized for the endoscopic group. After collecting all data from patients fulfilling our inclusion criteria, we applied our exclusion criteria for filtering the initial dataset. Exclusion criteria included: <18-years-old patients, patients with tumors of the spine, patients having spinal fusion, and patients who have declined the usage of their data for research purposes.The main inclusion criterion involved patients with lumbar spinal stenosis treated with either microsurgical or full-endoscopic decompression in the aforementioned period. The iLESSYSPatients were collected from the in-house patient information system and extracted into a predefined datasheet. Data was pseudonymized utilizing a code generated with the “encode” command in Stata Statistical Software Release 15 . Variables were included in the study extraction form according to our previous study [n = 5), maximum tree depth of 3, minimum cases in parent node 10, and minimum cases in child node of 5, resulting in n = 19 nodes, n = 11 terminal nodes, and a depth of 3. Multiple imputations were applied utilizing linear regression for scale variables and logistic regression for categorical variables to impute missing values for the CHAID algorithm. Supervised machine learning and deep learning techniques were applied to predict the target LOS classes. The following algorithms were used: logistic regression, RandomForest classifier, stochastic gradient descent (SGD) classifier, K-nearest neighbors, Decision Tree classifier, Gaussian Naive Bayes (GaussianNB), support vector machines (SVM), a custom-made convolutional neural network (CNN), multilayer perceptron artificial neural network (MLP), and radial basis function neural network (RBNN). The hardware and software environment specifications were as follows:CPU: AMD Ryzen 9 5950X 16-Core Processor RAM: 64 GBGPU: NVIDIA Geforce RTX 3090 Python version: 3.10.4 (64-bit) OS: Windows 10 The target classes were classified as prolonged when hospital length of stay was ≥75% percentile and normal when <75% percentile (binary classification task) ,22. UnsuStatistical analyses were conducted in Python and SPSS v26 .p < 0.0001 for all comparisons)  as raw data type . The cluster analysis resulted in two clusters (74.5% in the high risk group and 25.5% in the low risk group) . The datarisons) . Overallp < 0.0001 for all comparisons) (p < 0.0001).The second cluster analysis was done with the hospital length of stay (LOS) as a binary class type utilizing the 75% percentile as the cut-off point. The cluster analysis resulted in two clusters (26.8% in cluster 1 and 73.2% in cluster 2) . The datarisons) . FurtherWe applied various machine learning and deep learning algorithms to predict the LOS classes in the next step. The AUC for the multilayer perceptron model reached the highest AUC with 0.873 . The feaThe AUC for the radial basis function neural network model (RBNN) reached an AUC of 0.847 . The MLPThe accuracies and AUC of the machine learning algorithms and the custom-made convolutional neural network (CNN) is shown in Finally, we developed a decision tree utilizing the CHAID growing method for simple interpretation in clinics . The algLower back pain (LBP) is reported to be one of the most serious diseases affecting both health and function, in addition to being among the most expensive to treat . There hBoth the patient and the healthcare system can be significantly affected by a longer LOS following lumbar decompression surgery ,29. A reEven though several risk factors have been identified for longer LOS following lumbar decompression surgery, no effective systematic model has been proposed to predict whether a patient will have a short or long LOS following this procedure. We only found one study applying machine learning techniques to predict prolonged LOS after lumbar spinal stenosis surgery . NeverthThis study found that all algorithms in this study were able to predict and discriminate between classes with AUC values of 0.675–0.873. In this study, the findings compared favorably with those from other studies examining machine learning in orthopedic subspecialties such as spine surgery. Prior research utilizing machine learning has used tree-based methods or neural networks to predict intraoperative blood loss, prolonged hospital stay, patient-reported outcomes, and discharge dispositions in the field with similar or inferior results ,36,37,38This risk assessment tool (RAPT) consists of six questions that have been validated for predicting outcomes of patients undergoing joint replacement surgery. In addition, it assists patients and physicians in identifying hurdles to discharge and can simplify the discharge process . LikewisOur results also indicate that preoperative CRP levels might be relevant for assessing the hospital length of stay in future prediction models. CRP is an acute-phase inflammatory cytokine that is released by the liver in response to interleukin-6 and other inflammatory factors . It bindDespite the strength of the algorithms presented, the novelty of the approach, and the promising predictive results, the study does have some potential limitations. The algorithms must be based on a sample that is representative of the population of patients receiving spinal decompression surgery in order to be therapeutically beneficial. Because our data comes from a single, small study, its applicability to other institutions may be limited. As a result, external validation of the models given is required. Furthermore, data were collected retrospectively, lowering the evidence grade because the data may not be as reliable as data collected prospectively. We were also unable to increase the selection of variables to include other possibly important variables that could improve the model further due to the retrospective methodology. However, based on what we found in our prior work and a search of the literature , we set Decompression of the lumbar spine is one of the most common procedures performed in spine surgery. The associated costs are highly dependent on the hospital length of stay. Patient-centered outcome prediction models to predict the length of stay can allow using the available societal healthcare resources effectively. This enables policymakers and providers to compare treatment strategies among different disciplines and to identify the relative priorities for optimal resource allocation among various interventions. Our results indicate that machine learning and deep learning techniques can effectively predict whether patients will have a prolonged length of stay. Implementing the provided algorithms into open-source software and external validation through large-scale prospective studies are warranted to introduce the provided prediction tools in clinics.