Median age of the study population was 37 years , and 51/135 (37.8%) of the patients were female. Seventeen (12.6%) of the 135 bAVM patients were considered pediatric (18 years old or younger) at the time of the operation. In the literature review, 79 of 1739 (4.5%) of surgically treated patients later developed a recurrence with a mean delay of 3.1 years until diagnosis of recurrence. Young surgically treated bAVM patients with a hemorrhagic presentation at initial diagnosis are at a relatively high risk of bAVM recurrence. Follow-up imaging should be arranged for these patients in order to prevent rupture from a recurrent bAVM and subsequent morbidity.Treatment for arteriovenous malformations of the brain (bAVMs) aims to achieve complete removal or occlusion of the lesion in order to eradicate the risk of rupture and subsequent morbidity associated with these lesions. Despite initially successful treatment, bAVMs may carry a risk of recurrence especially in younger patients. We studied the rate of recurrence of surgically treated bAVMs at Kuopio University Hospital (KUH) in 1981–2021. The study population was collected retrospectively from KUH databases and presented a cohort of 135 surgically treated bAVMs with complete occlusion of the lesion. We also performed a systematic literature review on this topic. In our series, 6 out of 135 (4.4%) patients with angiographically confirmed removal of the lesion later developed a recurrent bAVM with a median time to diagnosis of recurrence of 7.46 years. In pediatric patients, the rate was 5 out of 17 (29.4%). bAVM recurrence was associated with age ( Arteriovenous malformations of the brain (bAVMs) are rare lesions with an incidence of approximately 1 per 100,000 person-years in unselected populations  and, dueWhile the tendency for bAVMs to grow, especially in pediatric patients, was first brought to attention by Olivecrona et al. , bAVM reKUH bAVM registry was created by a systematic search of the KUH hospital discharge registry for ICD-10 diagnosis codes Q28.0–28.3, complemented by a retrospective review of operating room log books ranging to year 1981. Following this, the medical records and imaging studies of all identified patients were reviewed. Confirmed bAVM cases were entered into the registry, and for them the date of diagnosis, date of treatment, age at first treatment, gender, and neurological symptoms were recorded as described in the patient’s medical records at the time of diagnosis or leading to the diagnosis. Additionally, the given treatments, dates of interventions, and possible dates of ruptures and recurrence as well as postoperative neurological condition were recorded. Post-treatment clinical outcome was assessed according to Glasgow Outcome Scale (GOS), the occurrence of new neurological symptoms, and the patient’s ability to return to work.For this study, we collected all surgically treated patients from the KUH bAVM registry.In our institution, bAVM patients are managed on a case-by-case basis with treatment recommendations being provided by a multidisciplinary team consisting of neurosurgeons and neuroradiologists. The patients in our registry come from multiple eras with different treatment and follow-up protocols, with the oldest having been initially treated in 1981. Complete removal of the lesion was always confirmed with postoperative DSA. Follow-up imaging was performed if the patient’s neurological condition deteriorated or if the patient presented new symptoms. More recently, long-term follow-up imaging with MRI at approximately 5 and 10 years after treatment has been performed for patients under 40 years of age. We examined our patient follow-up in three different ways. First, we looked at imaging follow-up which covers the period of time from surgical excision of the lesion to recurrence or the latest MRI or DSA imaging performed on the patient. Second, we looked at clinical follow-up which covers the period of time from surgical excision to recurrence or the latest clinical visit or call to either our neurosurgical or neurological clinic. Third, we looked at follow-up based on patient records which covers the period of time from surgical excision of the lesion to the day on which patient records were examined, or the date of death, or the last clinical visit in our hospital if the patient has moved away from the KUH catchment area, or detection of recurrence, whichever comes first. KUH is the only neurosurgical care provider for its catchment population , and all patients experiencing symptoms warranting neurosurgical attention are referred to our clinic.http://www.cebm.brown.edu/openmeta/). Outcomes across studies were pooled using a random-effects model and reported with a 95% confidence interval (CI). Heterogeneity was assessed with Cochran’s Q test and I2 statistic.In order to compare our experience and results with those reported by others, we performed a systematic search in the Pubmed-database for surgical series and case reports which assessed bAVM recurrence by using the search terms “ AND surgery,” “de novo AND AVM,” “acquired and AVM,” and “AVM AND brain AND case.” All studies which presented the bAVM rate of recurrence in surgically treated patients with occlusion confirmed by digital subtraction angiography (DSA) were included and classified according to the age distribution of their patient population. Case reports of AVM recurrences after surgical excision were also recorded. Surgical series with five or less patients were ignored. Bibliographies were cross-referenced to make sure that all suitable studies were included. A forest plot was created using the OpenMeta[Analyst] software  software.For this study, 146 patients with 147 surgically treated AVMs in 1981–2017 were reviewed. Out of these 147 AVMs, 52 (35.3%) were also treated with preoperative endovascular embolization. Three (2.0%) patients were treated with radiosurgery after surgical resection failed to remove the entire lesion. Surgical occlusion was achieved in 135/147 (91.8%) of AVMs, and these patients formed the basis of the study. Median age of the study population was 37 years , and 51/135 (37.8%) of the patients were female. Seventeen (12.6%) of the 135 bAVM patients were considered pediatric (18 years old or younger) at the time of the operation. These 135 patients were clinically followed up for a median of 1.27years . Fifty-six patients had imaging follow-up spanning longer than 3 months with a median imaging follow-up of 3.39 years . In the pediatric subgroup, the median clinical follow-up was 3.67 years . For the 9 pediatric patients with imaging follow-up spanning longer than 9 months, median imaging follow-up was 5.51 years . Median clinical follow-up for non-pediatric patients was 1.24 years . For the 47 non-pediatric patients with imaging follow-up spanning longer than 3 months, median imaging follow-up was 2.67 years . Median follow-up from patient records was 18.56 years . Patients treated after 2018 were not included in the study due to lack of sufficient possible follow-up (less than 5 years at the time of writing). The demographics and clinical presentation of the studied patients with complete surgical removal of the lesion are presented in Table Six out of 135 (4.4%) patients with DSA-confirmed complete removal of the lesion were later diagnosed with a recurrent lesion for a rate of one recurrence in 89.55 patient-years of clinical follow-up or one recurrence in 64.07 patient-years of imaging follow-up. Out of the 17 pediatric (18 years or younger) patients in our study, 5 (29.4%) later developed a recurrent bAVM for a rate of one recurrence in 19.16 years of clinical follow-up or one recurrence in 12.58 years of imaging follow-up. For non-pediatric patients, 1 (0.85%) out of 118 patients later developed a recurrence for a rate of one recurrence in 441.5 years of clinical follow-up or 321.52 years of imaging follow-up. The mean delay from initial surgical removal of the bAVM to the diagnosis of a recurrent lesion was 7.46 years . In our series, no patient was intended to be treated solely with embolization.Two out of 6 recurrent bAVMs were found with follow-up imaging, while one was diagnosed after the patient reported increasing numbness of the left leg. The other 3 presented with intracranial hemorrhage years after the initial surgical removal. One out of 3 hemorrhages from a recurrent bAVM led to a permanent neurological deficit which impairs the patient’s ability to work. Four patients had their recurrent lesions surgically resected, while one patient was treated with radiosurgery and another with combined endovascular embolization and radiosurgery. Occlusion was achieved with all recurrent lesions. Further detail on these patients with recurrent bAVMs is provided in Table p = 0.001), and they tended to present more often with intracranial or subarachnoid hemorrhage . Half of the (3/6) bAVMs which recurred drained into the deep venous system at the first clinical presentation before surgery. For 5/6 patients, the presence of venous deep drainage after recurrence did not change from the bAVM’s initial presentation, while for one patient this could not be assessed due to the patient living abroad during the diagnosis of a recurrence and thus the imaging being unavailable. Further demographic comparison between patients experiencing a recurrent lesion and the rest of the study population is provided in Table Patients with later bAVM recurrence were significantly younger at first treatment than those without recurrence . Among those surgical series in which suitable information could be gathered, 44 out of 50 (88%) recurrent bAVMs had their primary lesion initially present with a hemorrhage. Further information on these studies is presented in Table We studied the rate of bAVM recurrence after angiographically confirmed, seemingly complete surgical resection. Our results show that bAVM recurrence is a relatively common phenomenon in pediatric patients.The mechanics behind the development of an AVM or a recurrence are still unknown, although several theories have been created in an attempt to explain the development of the lesion. Pellettieri at al. suggested that in a minority of AVMs, angiographically unfilled compartments exist alongside the angiographically visible lesion. Hemodynamic changes could induce blood flow into these compartments, filling the “hidden compartments” and resulting in the growth or recurrence of an AVM in angiography . Others The overall hemorrhage risk of an unruptured, untreated AVM has been estimated to be 1–3% per year , with thOur review and own patient cohort support the notion of AVM recurrence being quite common in pediatric patients. The duration and frequency of imaging follow-up vary greatly in the literature, and the exact prevalence of recurrence varies between 0 and 33%. It is likely that the risk of recurrence has, thus far, been underestimated and that more vigorous follow-up schemes would result in a higher observed rate of recurrence. In our own patient cohort with a defined, relatively homogenic population, the delay from AVM occlusion to diagnosis of recurrence was quite high, yet prevalence of recurrence was also higher than generally reported in the literature. It is possible that other population-based factors may also factor into the prevalence of recurrence. While our patient cohort agrees with current literature on the increased prevalence of hemorrhage at initial bAVM presentation in recurrent lesions, unlike Morgan et al. , we did While recurrent AVMs, as reported in the literature, are far more likely to develop in pediatric patients, they may also present themselves in older patients. Our study demonstrates an AVM patient who was 28 years old at initial surgery and 43 years old during the diagnosis of a recurrence. While quite old in comparison to the general population of recurrent AVMs, he is not the oldest as Morgan et al.  report aThese older patients create a dilemma: what are the criteria with which we should subject our surgically treated AVM patients to follow-up imaging, and how should one go about designing that follow-up? In addition to the golden standard, digital subtraction angiography (DSA), magnetic resonance imaging (MRI) has been used to follow-up on AVM patients. While the most accurate method of imaging when it comes to AVMs, DSA is an invasive procedure which exposes patients to ionizing radiation and procedural complications with approximately 2.6% experiencing a neurological event within 24 h of the procedure . The proThe main issue with MRI is its accuracy, which is lacking in comparison to DSA; 4D MRA performed at 3T has been demonstrated to have a sensitivity of 73.7% and specificity of 100% in comparison to DSA in detecting residual lesions after radiosurgery , while iThere is likely selection bias included in our patient cohort. Extensive imaging follow-up was not always carried out in our patient cohort, and median clinical follow-up in our patient cohort is relatively short. However, median follow-up from patient records was 18.56 years and given that our institution is the sole neurosurgical care provider for the population of eastern Finland, it is reasonable to assume that patients with a symptomatic bAVM recurrence have been referred to our clinic. The real rate of recurrence for bAVMS may be higher than what is presented in this study.BAVMs may recur after complete angiographic cure in a fairly high percentage of pediatric bAVM patients. Since the bAVM recurrence may lead to a debilitating hemorrhage, long-term follow-up of treated bAVMs, especially pediatric ones, is recommended even after complete angiographic cure.


To describe our experience with the use of a novel iodized Polyvinyl Alcohol Polymer liquid agent (Easyx) in type II endoleak treatment with translumbar approach.Our case series is a retrospective review of patients with type II endoleak (T2E) treated with Easyx from December 2017 to December 2020. Indication for treatment was a persistent T2E with an increasing aneurysm sac ≥5 mm on computed tomography angiography (CTA) over a 6-month interval. Technical success was defined as the embolization of the endoleak nidus with reduction or elimination of the T2E on sequent CTA evaluation. Clinical success was defined as an unchanged or decreased aneurysm sac on follow-up CTA. Secondary endpoints included the presence of artifacts in the postprocedural cross-sectional tomographic imaging and post and intraprocedural complications.Ten patients were included in our retrospective analysis. All T2E were successfully embolized. Clinical success was achieved in 9 out of 10 patients (90%). The mean follow-up was 14 3–20 months. No beam hardening artifact was observed in follow-up CT providing unaltered imaging.Easyx is a novel liquid embolic agent with lava-like characteristics and unaltered visibility on subsequent CT examinations. In our initial experience, Easyx showed to have all the efficacy requisites to be an embolization agent for type II EL management. Its efficacy, however, should be evaluated in more extensive studies and eventually compared with other agents. Although literature lacks RCTs  and there is no consensus about the best embolic agent, few comparative studies reported a reduction of reintervention with NBC   and the with NBC  and Onyxwith NBC  rather tpuncture . Moreovepuncture .Our series aims to describe our preliminary experience and to review the existing literature about translumbar embolization of persistent T2E with a novel iodized liquid Polyvinyl Alcohol (PVA) polymer agent . This new embolic agent  consists of a PVA Polymer in liquid form which forms a solid cast when the solvent (Dimethyl sulfoxide—DMSO) dissipates in contact with the bloodstream. This liquid agent has no adhesive capacity, and it is covalently bonded with iodine, which provides its intrinsic opacity.2.2.1.In our case series, we retrospectively analyzed patients who underwent translumbar T2E embolization with Easyx alone or in combination with coils between December 2017 and January 2020. Patient data was obtained through the review of imaging reports and medical records. According to institutional statutes, no ethical clearance for such retrospective analysis is required.Procedure indication, patient selection, and the easier approach  were discussed by interventional radiologists and vascular surgeons during a multidisciplinary team meeting. All patients had a persistent T2E with an increase of the aneurysm sac ≥5 mm on at least one out of 2 axial diameters measured on CTA in a minimum interval of 6 months. All CT scans were performed on the same machine  and included a non-enhanced, arterial, and venous phase. Images were analyzed with the integrated PACS software  by a radiologist with at least 5 years experience in vascular imaging.Technical success was defined as the embolization of the endoleak nidus with reduction or elimination of the T2E on sequent CTA evaluation. Clinical success was defined as an unchanged or decreased aneurysm sac on a follow-up CTA made during the follow-up, with the first one made after 6 months.2.2.All embolization procedures were performed in the same angio suite  under local anesthesia by one interventional radiologist and one vascular surgeon .Sedation was reserved for especially anxious patients in order to reduce movements, and analgesic drugs were administered to control back pain in some patients.Written consent was obtained from the patient before each procedure. We standardized the procedure in order to have stable access into the sac with an introducer sheath: in this way, we could both navigate the feeders with different catheter shapes and safely inject the DMSO through a distally placed compatible microcatheter. We used a tapered 4 French introducer system with radiopaque marker and a coaxial system including the coaxial dilator with metallic stiffening cannula  which facilitates over-the-wire translumbar placement. The aneurysm sac was punctured on the left side at the level of the T2E nidus with a 21 Gauge, 15 cm long needle with stylet under fluoroscopic and cone beam CT (CBCT) guidance with the patient lying in a prone position . A 0.18 At the end of the procedure, the coaxial system was removed, and gentle compression was applied at the entry point for 5 min. Post-procedure CBCT was not performed systematically. After embolization, patients were admitted to the vascular surgery department and monitored for at least 24 h before discharge. A follow-up CTA was scheduled at 6 months for all the patients.2.3.Patient and procedure data have been retrospectively collected in a database. Descriptive statistical analysis of significant clinical data was performed on the dataset using Microsoft Excel 2011 . Most representative data are reported with mean and range.3.Between December 2017 and December 2020, we performed 13 embolization procedures for persistent T2E. Three patients treated with transarterial approach were excluded (2 through the inferior mesenteric artery and one through the iliolumbar artery) in order to focus our study only to direct percutaneous sac puncture. We eventually selected 10 consecutive patients  reported in 2 . The mean follow-up was 14 months .Technical success was achieved in all 10 cases (100%). Clinical success was achieved in 9/10 patients (90%): one patient had a reduced but persistent T2E and eventually underwent open conversion with endograft resection 3 months later, after a CTA re-evaluation. In this case, the indication for open conversion was persistent back pain without neurological or musculoskeletal cause, which was therefore attributed to the still pressurized aneurysm sac (10.8 cm). After surgical correction, back pain resolved, and the patient was still alive at follow-up. In one patient we fluoroscopically observed a small amount of embolic material adjacent to the aneurysm sac. This was later drained into the vena cava and subsequently caused a small subsegmental lung embolism. The embolism was asymptomatic and required no additional treatment.The mean total procedure time was 93 min (min-max 41–130), and fluoroscopic duration was 28 min (min-max 15–54). The mean Dose Area Product was 50.892 µGymTwo patients were lost to follow-up at 6 and 12 months without evidence of T2E at the control CTA. Three patients (30%) experienced back pain related to the prolonged prone position, which resolved at the end of the procedure. No beam hardening artifacts were observed in the follow-up CTAs .4.via translumbar, transcaval  and in particular Onyx . The other EVOH agent  use is only reported among different peripheral use  4 out o and inclAt our institution, we use the transarterial or the direct translumbar puncture approach, the easiest route is chosen according to the operator and each case is evaluated individually during a multidisciplinary meeting. Since its introduction into the market in 2017, we have used Easyx in different clinical settings  and as the preferred liquid embolic agent for T2E embolization.The reason is mainly due to a combination of beam hardening artifact absence on follow-up CTA, “lava like” consistency, and the intrinsic non-adhesive nature of the liquid PVA as reported by Kulcsár et al. . In theiOn the other side, fluoroscopic visibility provided by iodine is slightly inferior to other agents containing tantalum  especialSince then, we have not observed any further non-target embolization in any procedure  with Easyx. Therefore, we think that this complication is not related to the embolic material itself but rather to the operator learning curve and to the microcatheter malpositioning. The material radiopacity was adequate to promptly recognize the non-target embolization and immediately stop the injection.Finally, we did not observe any microcatheter entrapment even after prolonged injection from the microcatheter submerged into the embolic cast . The absThis study is limited by the small cohort of patients and by its retrospective and observational nature. It is therefore limited by the fact it's monocentric and could be influenced by operator bias. Some of the shortcomings of the study could be overcome by larger and randomized studies comparing this agent with the others present on the market. The limited mean follow-up is mainly due to the recent introduction of this embolization agent in the market.5.Our preliminary experience with this new embolic agent in the T2E procedure has been positive in terms of technical and short-term clinical success. Non-artifacted follow-up CT certainly adds value to the comprehension of T2E evolution after the embolization procedure.Easyx-DMSO overdiluition in the microcatheter hub must be carefully avoided in order to prevent non-target embolization. Given the small number of patients, the limited follow-up, and the retrospective nature of this work, larger studies will be required in order to better assess the efficacy of this agent in this and other types of embolic procedures.


To successfully treat a periprosthetic infection, successful bacteria eradication and successful wound closure are mandatory. Despite adequate surgical débridement in the deep, persistence of wound drainage and subsequent persistence of periprosthetic infection may occur, especially in patients with compromised soft tissue conditions. This study presents a transcutaneous compression suture technique with iodine gauze that was used in patients with persistent wound secretion in therapy-resistant periprosthetic shoulder infections in order to achieve successful infection control and wound healing.All patients with persistent periprosthetic or implant-associated shoulder joint infections despite correct previous surgical and antibiotic therapy attempts were included in the study. In all patients, in addition to repeat deep surgical débridement, a transcutaneous “iodine-gauze-compression-suture” was performed with postoperative antibiotic therapy. The primary endpoint was infection control; the secondary endpoint was wound healing rate; and the third endpoint was complication rate after index surgery.Ten consecutive patients with a mean age of 74 (±7.6) years and a mean follow-up of 14 (±2) months were included. All ten patients showed infection control and successful wound healing, with no need for further revision surgery. In 8 out of 10 patients, the wound healing was fast and completely uncomplicated. Two out of 10 patients showed delayed wound healing with fibrin coatings for 3 and 4 weeks, respectively. No additional intervention was necessary in both patients.Transcutaneous iodine gauze compression sutures were used to achieve successful infection control without additional revision surgery in 10 out of 10 patients who previously underwent surgery with failed infection control. This wound closure technique is a reliable adjunctive therapy method in the treatment of implant-associated infections of the shoulder in patients with fragile wound conditions. All patients, who met International Consensus Meeting (ICM) shoulder groupIn addition to the repeated deep radical wound débridement with intraoperative sampling (5 tissue cultures and 1 histology) taken in every case, if necessary, cement spacer insertion or spacer exchange, a so-called IGCS technique was additionally used for wound closure. The surgeries were all performed by the same surgeon (F.G). For the compression suture technique, an iodine-soaked gauze was placed on each side of the wound and then secured onto the skin with Donati stitches using a 2 polydioxanone suture (PDS) suture. The gauze was soaked in a nonalcoholic iodine standard solution . The first lateral stitches of the Donati stitch were deep stitches through the skin, subcutaneous fat layer, and deep fascial layer. The medial stitches were superficially placed to bring the wound edges of the skin close together. By pulling and knotting the PDS suture, pressure was created between the superficial gauze and the deep fascia, which reduced the dead space volume in the subcutaneous fat layer. The interposed superficial gauze is to protect the skin, which without the gauze could be strangulated and damaged by the powerful knotting that is needed for the compression suture. .Figure 1The compression suture was left in place for 14 days. All patients were immobilized in a sling for 6 weeks. The gauze of the compression suture was soaked in iodine daily to avoid contamination of the gauze. Wound care was performed by either an outpatient wound care service or the nursing staff at a rehabilitation facility. All patients were treated with intravenous antibiotic drugs between 3 and 7 days until the first results of the tissue cultures were obtained followed by oral antibiotic therapy for 6 to 12 weeks depending on the intraoperative cultures. The antibiotic therapy was determined by the Department of Infectious Diseases at our hospital.The primary outcome parameter was the infection control rate after the index surgery. Infection control was defined as successful wound closure in the absence of wound drainage and absence of elevated C-reactive protein, erythrocyte sedimentation rate, or white blood count. The primary endpoint parameter was assessed by the operating surgeon (F.G.) together with an infectious disease specialist (I.U.) during the 6- and 12-week postoperative visits. All patients and their infection status  were discussed at weekly infection disease rounds between the orthopedic and infection disease department. The reoperation rate, including all surgeries performed for wound revision or infection treatment was the second outcome parameter assessed during the 6- and 12-month postoperative visits. Postoperative complications were assessed using the Clavien–Dindo classification score and recorded as the third outcome parameterA total of 10 consecutive patients, who all fulfilled the ICM criteria for PSJI with an average age of 74 years (SD 7.6 years) with a mean follow-up of 14 (±2) months (minimum follow-up of 12 months) were included in the study. Of the 4 women and 6 men, 8 patients (80%) had undergone previous surgeries at external hospitals and were referred to our clinic for further treatment of the therapy-resistant periprosthetic or implant-associated shoulder joint infection. The number of previous surgeries performed for infection control or wound closure varied between 1 and 3 in eight patients and 8 and 9 in two patients – see Removal of the arthroplasty, débridement, and implantation of an antibiotic-loaded cement spacer in the setting of a two-stage approach in 6 cases; removal of the arthroplasty, débridement, and reimplantation of a new implant in the setting of a one-stage approach in 2 cases; and removal of the plate, débridement, cement spacer implantation, and negative pressure wound therapy in two cases.The IGCS was combined in 5 cases with an antibiotic spacer exchange, and in another 5 cases, the compression suture was combined with the removal of the implant or the humeral head and implantation of a new antibiotic-loaded cement spacer.Most patients were severely ill with an American Society of Anesthesiologists score of III (n = 4) or IV (n = 5) and accordingly had significantly reduced general health status.Staphylococcus aureus in 5 cases (2x MRSA), Corynebacterium acnes in 2 cases, Staphylococcus epidermidis in 1 case, Streptococcus mitis/oralis in 1 case, and Pseudomonas aeruginosa in 1 case.The pathogens were Infection control: all wounds were dry at postoperative day 3 and all patients showed successful wound healing after removal of the compression suture with no signs of infection. In all patients, the infection laboratory values were normal at the 6 and 12-week follow-up, with no evidence of a persistent infection. The infection control rate was therefore 100%.Revision surgery: no patient needed a revision surgery to achieve infection control. After acheiving infection control, 7 patient underwent a reimplantation of a shoulder arthroplasty  to improve shoulder function or shoulder pain. In all 7 patients, the tissue cultures and histology (minimum 5 tissue cultures and 1 histology) during the reimplantation were negative, so infection eradication was proven in these cases. The three patients, in whom the cement spacer was left in place had no or little pain and were not limited in their quality of life; therefore, reimplantation of a shoulder prosthesis was not indicated. In these 3 patients, the cultures were negative when the spacer was inserted and the compression suture was applied, additionally, the last CRP and leucocyte levels were within normal limits, so that infection eradication is very likely – Complications: In two patients, fibrin deposits were observed for 3 and 4 weeks postoperatively, respectively. These fibrin deposits were managed with dry dressings, and both patients achieved spontaneous wound healing without requiring additional interventions. However, these two fibrin deposits were classified as wound healing problems and graded as Clavien–Dindo grade II complications, as additional wound check appointments were required.In addition to adequate surgical and medical treatment of deep implant-associated joint infections, adequate treatment of superficial soft tissues including wound closure is an essential component of successful infection treatment.,In these 10 consecutively treated patients, prior surgeries in which radical débridement and removal of the arthroplasty/implant were performed did not achieve infection control. This consecutive patient cohort demonstrates that adequate “deep” surgical débridement alone including débridement with implant removal combined with spacer implantation or one-stage exchange, is sometimes not sufficient to achieve successful infection control. In the surgical treatment of PJI, which affects typically elderly patients with multiple comorbidities, it is essential to optimize soft tissue management. The compression suture seemed to be safe and helpful in this patient series to achieve wound closure and infection control. The hypothesis behind the compression suture technique is that the developed compression between the incorporated gauze and the deep fascial layer decreases dead space volume in the subcutaneous fat layer and therefore reduces the risk for hematoma or seroma formation, which are risk factors for persistent wound drainage and wound infections.The radical deep débridement of the infection with removal of all infected implants and infected bone fragments is a prerequisite for successful infection control, and the compression suture should only be considered an adjuvant therapy to optimize the soft tissue situation. It cannot in any way replace deep infection eradication.After the compression suture was successfully and without complications used in the shoulder area, it was also used in other joint areas  with comparable successful wound healing rates.Limitations: This is a retrospective analysis of a small patient series without a control group, in which a conventional suture technique would have been applied. However, it should be noted that in all patients, prior surgical interventions, including débridement and implant removal, failed to achieve infection control. In this situation, generating a control group that would theoretically undergo the same surgical intervention with the same wound closure that was unsuccessful in the previous surgery would not be justifiable. The definition of infection eradication in this study can be debated. Objectively, only the blood values of ESR, CRP, and white blood count were evaluated, which per se are not reliable markers. The laboratory values alone are only part of the evaluation. An essential part is the clinical evaluation of the wound by the orthopedic and infection disease department as well as the absence of pain. In all patients, the wound was dry and without evidence of persistent infection  after 14 days. In addition, all patients were pain-free. Laboratory values were also within the normal range in almost all patients. Based on these clinical and laboratory results, the infections were classified as eradicated both from the orthopedic side and from the infection disease side. In our opinion, invasive diagnostic procedures such as puncture,biopsy, or even arthroscopic sampling are scientifically interesting but clinically not indicated. For this reason, these procedures were not indicated in asymptomatic patients. To increase the size of the study, other centers that treat such severely ill patients with therapy-resistant implant-associated joint infections could have been included.The compression suture described in this study contributed to successful infection control in all 10 predominantly severely ill patients. None of the affected patients required further infection control surgery after the application of the compression suture. The described wound closure technique is safe and has no significant complications.Funding: No funding was disclosed by the authors.Conflicts of interest: Karl Wieser receives payments as a consultant for Zimmer Biomet, Arthrex, Inc. and Karl Storz SE & Co KG not related to this work. The other authors, their immediate families, and any research foundation with which they are affiliated have not received any financial payments or other benefits from any commercial entity related to the subject of this article.


Parkinson’s disease (PD) is a common neurodegenerative disease. No disease-modifying treatment is available, and therapy is symptomatic. The histopathologic hallmark is the loss of dopaminergic neurons and accumulation of α-synuclein (α-syn) in surviving neurons, but the underlying pathophysiology is unclear. Inflammatory mechanisms seem to play a prominent role, with an imbalance of immune functions and neurotoxicity caused by reactive oxygen species (ROS). Involvement of peripheral adaptive immunity, with an imbalance in T cell subpopulations and in the expression of transcriptional factors in CD4+ T cells, has also been reported. Although clinical presentation is defined by motor symptoms, patients also report non-motor symptoms, often before the onset of a clinically established disease. Etiopathogenesis of PD is unknown, but an initial aggregation of α-syn in the gut, with subsequent propagation along the vagus nerve to the brain has been hypothesised. Interestingly, in an α-syn overexpressing murine model, the absence of gut microbiota prevented both microglia activation and motor impairment, thus pointing to a fundamental role of microbiota in the development of PD. Magistrelli et al. showed that in peripheral blood mononuclear cells of PD patients, probiotics modulate the in vitro production of cytokines toward an anti-inflammatory profile and reduce the production of ROS.This is a pilot randomised placebo-controlled clinical trial protocol for a 12-week treatment with probiotics. At least 80 patients affected by PD will be recruited and randomly allocated to either the treatment or placebo group in a 1:1 ratio. General inclusion criteria will be the onset of PD 2 to 5 years before the trial and absence of autoimmune comorbidities or immunomodulating therapy. Our primary endpoint is the assessment of changes in extracellular cytokine levels (Interferon (IFN)-γ, tumour necrosis factor (TNF)-α, interleukin (IL)-4, and IL-10) and ROS production. Secondary outcomes include changes in lymphocyte subpopulations and transcriptional factors mRNA levels.This study is designed to highlight the potential beneficial role of probiotics administration on peripheral immunity through the modulation of gut microbiota. Explorative outcomes will be evaluated to assess variations in motor and non-motor symptoms and the possible correlation with probiotics administration.ClinicalTrials.gov ID NCT05173701. Registered 08 November 2021 Parkinson’s disease (PD) is a common neurodegenerative disease, affecting up to 1–2 people in 1000. Prevalence increases with age and is estimated at 1% in people over 65 . InflammFurther evidence highlights the involvement of peripheral adaptive immunity in PD , 8, repoEtiopathogenesis of PD is unknown, but work by Braak et al. hypothesised an initial aggregation of α-syn in the gut with subsequent propagation along the vagus nerve to the brain, finally reaching the substantia nigra in the mesencephalon .Interestingly, in an α-syn overexpressing murine model of PD, the absence of gut microbiota prevented both microglia activation and motor impairment , thus poIn a recent paper, Magistrelli et al. showed that in peripheral blood mononuclear cells (PMBCs) of a cohort of PD patients, probiotics were able to modulate the production of cytokines toward an anti-inflammatory profile and to reduce the production of reactive oxygen species (ROS) . The cliIn the light of this evidence, we designed a pilot randomised placebo-controlled clinical trial to test the potential of probiotics therapy in modulating the inflammatory phenotype, to possibly normalise the gut-brain-microbiota axis, decreasing peripheral inflammation to finally affect disease progression in a cohort of PD patients. Feasibility objectives will be evaluated in the pilot clinical trial, including recruitment, acceptance, and dropout rates. The measurement of possible changes in intracellular and extracellular cytokine levels , ROS production, transcriptional factors mRNA levels, and lymphocyte subpopulations will be used for the selection of appropriate primary outcomes for the following main trial.The aim of this pilot study protocol is to assess the feasibility of a randomised controlled trial to assess the effects of a 3-month probiotics therapy in a cohort of Parkinson’s disease patients. Specific feasibility objectives will be assessed to define the feasibility of the proposed clinical trial, including recruitment, acceptance and dropout rate, and outcome identification, as listed in the following Table 1) Cytokines production , as already tested in vitro, to confirm the immune-modulating potential of probiotics.2) Assessment of CD4+ and CD8+ T naïve/memory cells, CD4+ T helper subsets, CD4+ regulatory T cells, monocytes, and NK cells to test the immunomodulating effects of probiotics administration on the immune profile.3) Monitoring of motor and non-motor symptoms of PD, including gut function, and subjective quality of life during the trial period.Data collected during this pilot study will include the following assessments to evaluate possible outcome measures for the definitive randomised controlled trial:This pilot randomised, double-blind, placebo-controlled trial will recruit Parkinson’s disease patients. This is a prospective, exploratory, interventional study. Enrolled subjects will be equally randomised (1:1) in the placebo or intervention group.Patients will be enrolled at Azienda Ospedaliero-Universitaria Maggiore della Carità di Novara, where all visits will be scheduled. The setting of the study is a centre of care and research and an academic hospital.All included patients will have a diagnosis of Parkinson’s disease with a disease duration between 2 and 5 years at baseline. Exclusion criteria for this study are listed in the following Table Patients will be required to report any proposed modification in their medical therapy. Patients who will need substantial changes in antiparkinsonian therapy will be dropped from the trial. The use of laxative or prokinetic drugs will be recorded and is not an exclusion criterion per se, but the introduction of these medications or posology variations should be avoided during the trial.Since the trial is primarily aimed at confirming the immunomodulating properties of probiotic treatment, any intercurrent and symptomatic infections, inflammatory episodes, or other medical conditions will be recorded. Evaluation by clinical staff for potential patient dropout will be based on the severity and temporal proximity of the event to scheduled visits and blood withdrawal. All participants will be advised to maintain a constant dietary intake and a regular physical activity during the trial. A daily report including quality of life aspects will be requested and evaluated using appropriate clinical scales. Informed consent will be obtained by clinicians after the eligibility assessment and during the first visit. All subjects or their legal representatives will be given all relevant information about the study structure and objectives. Additional consent will be requested for the use of collected data and biological specimens in ancillary studies.This is a placebo-controlled trial. The intervention group will be treated with a daily dose of probiotics, while the control group will be given identical packages containing maltodextrin only, used as a bulking agent in the probiotics’ formulation for the intervention group. In this pilot study, our aim is to assess the potential of probiotics therapy to modify the peripheral immune system profile and function in a cohort of PD subjects. In this pilot trial, the potential immunomodulating effects of probiotics will be tested. Placebo treatment was chosen as a comparator for this new approach to immunomodulation in PD.During the enrolment visit, the medical and neurological examination will assess the need for immediate variations in medical therapy for each participant. Within 2 weeks, any therapy modification will be completed, and a baseline visit will be scheduled.During the baseline visit (T0), physical and neurological examinations will be repeated to confirm the subject’s conditions and persistence of inclusion criteria, a baseline blood withdrawal will be performed, and all clinical evaluation scales will be completed to set baseline scores. Each participant, after the subscription of an appropriate informed consent, will be randomised and given a treatment box, containing single-dose sachets with 2.7g of powder of the allocated formulation. Patients will be instructed to take daily doses at home every morning before breakfast for 12 weeks, mixing the content of one sachet in about 125 ml of fresh water or other cold, non-carbonated drink. Participants will be instructed to keep unused or empty packaging for recollection and compliance evaluation.Product compositions per dose  for the treatment and placebo compounds are listed in the following Table Follow-up visits will be scheduled at 6 weeks after T0 (T1) and at 12 weeks after T0 (T2). At T1, physical and neurological examination will be repeated, and all clinical scales administered again, except for Bristol Stool Form Chart and MOCA. At T2, all assessments performed at T0 will be carried out again, including blood withdrawal.Participants will be advised to report any suspected adverse reaction and new or worsening symptoms. Every report will be recorded, and a thorough evaluation will be performed by neurologists in the clinical staff in collaboration with the subject’s primary care doctor. Feedback will be provided to the participant as well as indications on continuing or stopping treatment administration. In accordance with the Declaration of Helsinki by the World Medical Association, every participant can freely request to be removed from the study at any moment. All participants will be requested to record daily treatment usage and keep empty packaging or unused doses for recollection after the trial completion. One courtesy call will be scheduled during treatment to reduce compliance issues. The use of immunomodulating drugs or antibiotic therapy is an exclusion criterion and patients starting such therapy during the trial period will be dropped from the study. Dose adjustments in antiparkinsonian therapy are permitted but should be avoided and substantial modifications to said therapies will cause dropping out from the study.Every participant will be evaluated at enrolment by a clinical neurologist, who will assess needed adjustments in antiparkinsonian therapy that will be completed within two weeks from enrolment and before treatment administration to minimise the need for medical therapy modifications during the trial. The use of laxative or prokinetic drugs will be recorded and is not an exclusion criterion per se, but the introduction of these medications or posology variations should be avoided during the trial.To assess the feasibility of the proposed clinical trial, we defined different feasibility objectives, as previously listed in Table More in detail, we will evaluate the potential recruitment rate for the clinical trial by recording the number of eligible outpatients who scheduled a neurological examination in the proposed clinical setting during the pilot trial. The acceptance rate will also be evaluated, by recording the fraction of identified eligible subjects who will be willing to participate in the proposed clinical trial. Both assessments together will allow for an initial estimate of the needed duration for the main clinical trial, once an appropriate sample size will be defined based on the pilot trial results. During the pilot trial, the dropout rate will also be recorded to adjust the predicted trial duration based on the fraction of dropped-out subjects during the trial period.Reported reasons for subject drop-out will also be recorded and further analysed to confirm the safety of both the treatment and placebo administration to enrolled subjects. Collected data during the pilot trial will be analysed to assess whether a significant variation in any recorded parameter will occur between the two trial branches. This will allow to accordingly select one or more appropriate primary outcomes for the main trial, among collected immune profile data. Secondary outcomes for the main trial will be selected in the same way, among parameters who will show a remarkable variation.More in detail, in our previous in vitro study , we demonstrated that probiotics modulate ROS and cytokine production by driving an anti-inflammatory profile. Therefore, we will test whether these properties are confirmed in vivo. Particularly, in our study, we want to analyse whether probiotics may modulate cytokines production, such as IFN-γ, TNF-α, IL-4, IL-10, and ROS production.In order to investigate possible changes in immune phenotype, we plan to deepen the profile of both innate and adaptive immunity by means of a cytofluorimetric evaluation, according to the strategy described by Kustrimovic et al. (2018) and with additional panels specifically dedicated to innate immunity. The following cell subsets of the adaptive immune system will be assessed: CD4+ and CD8+ T naïve/memory cells, CD4+ T helper subsets , and CD4+ regulatory T cells . Moreover, for innate immunity, monocytes , and NK cells (NK CD56 dim and CD56 bright) will be also assessed. We will compare pre-treatment and post-treatment analysis and compare our intervention group with the placebo group at T0 and T2.A significant variation in scores resulting from appropriate questionnaires and scales will be evaluated as an outcome measure for exploratory and patient-centred endpoints (variations in motor and non-motor symptoms from T0 to T1 and T2).The timeline of the proposed study is summarised in the following Table The design of this pilot study is explorative and equally randomised to treatment with probiotics or placebo. Due to the exploratory nature of the proposed study, a formal sample size calculation is not strictly required . In our We thus used data from the said study to estimate sample sizes for the in vitro effect of all tested probiotic strains and a sample size of 80 subjects allows for the determination of most tested cytokines variations with an expected power greater than 80%, setting our threshold for statistical significance at 0.05.As previously stated, the drop-out rate of this pilot study will also be recorded and used to determine an appropriate sample size increase for the main study.Recruitment will occur in Azienda Ospedaliero-Universitaria Maggiore della Carità di Novara. Enrolment will be proposed to eligible subjects by clinical neurologists during routine visits and given their recorded consent to receive information about ongoing research and recruiting trials. Patients will be recruited continuously until reaching the desired sample size and will start the trial period asynchronously. The recruitment period will be limited in time to avoid seasonal diet modifications as a confounding factor for some of the trial outcomes.Participants will be assigned to the two intervention arms using the minimisation method, with a 1:1 allocation ratio. Codes for the two arms of the study will be different, but investigators, clinical, and laboratory staff will not know which code is assigned to the placebo or intervention group. This assignation method will minimise predictable differences between the two groups . Packages for the treatment formulation and placebo will be identical and although treatment and placebo packages will be differently coded, participants, clinicians, and all laboratory operators will be blinded to the coding scheme.Trial participants, care providers, outcome assessors, and data analysts will be blinded to treatment allocation. Only the provider of the treatment and placebo packages will know the coding schemes for the corresponding packages and will not disclose this information until after trial completion.No unblinding procedure is needed. Participants will be advised to report any suspected adverse reaction and new or worsening symptoms. Every report will be recorded, and a thorough evaluation will be performed by clinical staff. Feedback will be provided to the participant as well as indications on continuing or stopping treatment administration, without unblinding the subject’s allocation.Collected data will include clinical scales and questionnaires, administered by trained clinical neurologists at baseline visit T0, visit T1, and visit T2, and data from analyses carried out by trained technicians and laboratory staff on faecal samples and whole blood samples collected at T0 and T2.Blood specimen processing protocols are available from the corresponding author upon request. Follow-up visits will be scheduled at 6 weeks after T0 (T1) and at 12 weeks after T0 (T2). At T1, physical and neurological examination will be repeated, and all clinical scales administered again, except for Bristol Stool Form Chart and MOCA. At T2, all assessments performed at T0 will be carried out again, including blood withdrawal.At T0 and T2, withdrawal of 40 ml venous blood will be performed after a fasting night, between 8:00 and 10:00 am, in EDTA-coated tubes (BD Vacutainer). Tubes will be subsequently coded and stored at room temperature until processing, which will occur within 24 h after collection. A complete blood count with differential analysis will be conducted on separate blood samples.The possible influence of probiotic treatment on the inflammatory profile will be evaluated by measuring at T0 and T2 the plasma levels of pro  and anti-inflammatory cytokines . To this end, at each visit time, plasma aliquots from every sample will be separated and stored for cytokines assays . Two milliliters of fresh blood will be centrifuged at 1400g for 10 min at room temperature and two plasma aliquots of 350 µL each will be stored in 1.5mL vials to assay extracellular cytokines levels.6 cells/30 min, using an extinction coefficient of 21.1 mM. RPMI 1640 without phenol red and FBS will be used for incubating cells in order to avoid any spectrophotometric interference.The production of ROS will be assessed using the superoxide dismutase-sensitive cytochrome C reduction assay, as nmol of reduced cytochrome C/10For FACS assays of immune phenotype, 5 mL of the peripheral venous blood will be collected, and 100 or 150 µL aliquots of whole blood samples will be incubated with a cocktail of anti-human antibodies (ab) specific for each evaluated cell subset. For naïve-memory cell subset, samples will be stained with anti-human CD45, CD3, CD4, CD8, CD45RA, and CCR7 ab for the identification of naïve (CD45RA+CCR7+), central memory , effector memory , and effector memory RA+  on CD3+CD4+ and CD3+CD8+ lymphocytes. CD4+ T helper subsets will be assessed by staining the whole blood sample with a cocktail of anti-human CD45, CD3, CD4, CXCR3, CCR4, and CCR6 ab for the identification of Th1 cells (CD3+CD4+CXCR3+CCR4-CCR6-), Th2 cells (CD3+CD4+CXCR3-CCR4+CCR6-), Th17 cells (CD3+CD4+CXCR3-CCR4+CCR6+), and Th1-Th17 cells (CD3+CD4+CXCR3+CCR4-CCR6+).Total CD4+ regulatory T cells  and naïve , activated  Treg will be evaluated by incubating whole blood with the following ab: CD45, CD3, CD4, CD25, CD127, and CD45RA. The aliquot of the blood for the evaluation of monocytes will be incubated with a cocktail of anti-human CD45, HLA-DR, CD14, and CD16 ab for the identification of classical (HLA-DR+CD14highCD16-), non-classical (HLA-DR+CD14lowCD16high), and intermediate (HLA-DR+CD14highCD16+) monocytes. Finally, another aliquot of whole blood samples will be stained with a cocktail of anti-human CD45, CD3, CD56, and CD57 for the identification of total NK cells (CD3-CD56+) and their two main subsets: CD56dim (CD3-CD56dimCD16bright) and CD56bright (CD3-CD56brightCD16dim), together with the evaluation of the maturation marker CD57. The acquisition will be performed on a BD FACS Celesta flow cytometer  with BD FACS Diva software (version 8.0.1.1) and data will be analysed with FlowJo software (version 10.7.1).3 1.0, EDTA 0.0368). Cells will be washed twice in PBS by the addition of 10 mL of PBS, then centrifuged at 300 g for 10 min at RT and resuspended in 10 mL of RPMI/10% FBS. A manual cell count will then be performed to set CD4 separation reagent quantities. Typical PBMC preparations will contain at least 80% lymphocytes. CD4+ T cells will then be isolated from PBMC by means of Dynabeads CD4-Positive Isolation kit. At least 50,000 separated CD4+ T cells will then be resuspended in PerfectPure RNA lysis buffer , and the total RNA will be extracted by PerfectPure RNA Cell Kit™. Reverse-transcription will be performed on the resulting mRNA using a random primer and a high-capacity cDNA RT kit. Real-Time PCR reactions will be performed with 1 μM cDNA. Amplification of cDNA will allow for the analysis of mRNA levels of the transcription factor genes TBX21, STAT1, STAT3, STAT4, STAT6, RORC, GATA3, FOXP3, and NR4A2.According to our previous studies , we aim to investigate whether probiotic treatment is also able to modify the mRNA levels of the main transcriptional factors in CD4+ T lymphocytes. To this end, CD4-positive cells will be obtained by PBMC, which will be separated from whole blood using Ficoll-Paque Plus density gradient centrifugation. After resuspension, any residual contaminating erythrocytes will be lysed by the addition of 10 mL of lysis buffer ((g/L) NH4Cl 8.248, KHCOThe clinical evaluation will be completed by the administration of forms and questionnaires. In particular, every participant will fill out the forms and questionnaires listed in the following Table Participants will be contacted by phone to timely schedule T1 and T2 visits. Any intercurrent health issue will be recorded and evaluated by clinical neurologists, who will assess the need to drop the subject from the study protocol. Any previously collected data will be kept after dropout and used as appropriate in statistical analyses.Data for all participants will be recorded by clinical staff at the enrolment location at scheduled visits. Every entry will be double-checked by at least two different investigators and data will be monitored upon collection to evaluate the consistency and promote early identification of abnormal outliers.Personal information about trial participants will be strictly confidential and managed by clinical staff at the enrolment location. Investigators who will manage collected specimens and perform data analyses will be blinded to the subjects’ identity. Every collected sample will be assigned a unique code, which will be used by all non-clinical investigators for specimen identification. Clinical staff will ensure the confidentiality of participants’ data.All laboratory analyses will be executed after storage of specimens at −80°C, performing batches of sample analyses. Every sample in storage journals will be identified with an anonymised code.To assess the main trial feasibility, the drop-out rate will be reported as the absolute number and percentage of total participants for both the intervention and placebo arms and will be accounted for when assessing an appropriate sample size for the main study. Feasibility will also be evaluated by recording all drop-out reasons and accordingly estimating an increase of the foreseen sample size.n, with n indicating the number of observations. The normality of data distribution will be analysed by means of D’Agostino-Pearson omnibus normality test. Mann–Whitney U test, Wilcoxon test, and Kruskal-Wallis tests will be used to assess differences in the distribution of non-parametric data. Paired and unpaired t tests will be used, as appropriate, to compare means and standard deviations for parametric data in the two treatment groups. Wilcoxon signed ranks test will be used to compare measures taken at T0 with the corresponding measures at T1 and T2 in the assessment of primary and secondary outcomes. When appropriate, efficacy outcomes will be reported as estimates with 95% confidence intervals. Statistical significance for correlations will be set at p<0.05. Commercial software  will be used for data analyses and graph plotting.Collected results will be reported as mean ± standard deviation (SD) of the mean, or median ± 25th and 75th percentile, as appropriate, and No interim analyses will be performed on collected data. Enrolment in the study will proceed sequentially, and each participant will immediately start administration of the assigned intervention, so data from each participant will be collected independently and even a partial dataset will not be available for interim analyses until the trial will be in an advanced stage of completion. No subgroup or other additional analyses will be performed. Non-adherent patients and dropouts will be excluded from the study and related data will not be collected.The full protocol and used and/or analysed during the current study will be provided by the corresponding author upon request.Trial management on a day-to-day basis will be carried out by clinical staff at the coordinating centre and by staff at the Center for Research in Medical Pharmacology. Neurological and clinical assessment, enrolment, and data collection will be performed by neurologists, postgraduate students in neurology, and medical students at the trial centre. Postgraduate students in Clinical Pharmacology and Toxicology and staff at the Center for Research in Medical Pharmacology will receive collected data and manage data storage at the University of Insubria, where data analysis will be performed by academic staff.The trial steering committee will include academic staff from the University of Insubria and the University of Piemonte Orientale, who will monitor recruitment and timely data collection, oversee results reporting and publication. The committee will meet on a regular basis to monitor the regular course of the trial and ensure successful completion.The institutional review board explicitly approved the described trial protocol, for which the appointment of a Data Monitoring Committee was not requested, as no interim analyses will be performed besides subjective questionnaires. Appropriate safety monitoring will be performed directly on a per-subject basis by clinical staff. Furthermore, this pilot study protocol specifically excludes subjects with unstable or critical clinical conditions, and treatment with placebo or probiotics, during a relatively short period, is not expected to interfere with currently prescribed medical therapies.All potential adverse events will be recorded by clinical staff and participants will be encouraged to report any new or worsening symptom, which will timely and thoroughly be evaluated for possible correlations with the administered treatment.No auditing will be performed for this trial.No protocol modifications are planned within the trial. Possible amendments will be communicated to the local ethics committee before the enrolment of participants.The involvement of the immune system in the development and progression of Parkinson’s disease makes it a promising target for a disease-modifying therapy. This clinical trial will test the ability of probiotics therapy in modulating the peripheral immune system, which in turn is expected to have beneficial effects on disease progression and patients’ quality of life. If this trial shows a potential beneficial role of probiotics in immunomodulating peripheral immunity in PD patients, a trial with a larger cohort could be designed and disease progression could be monitored over a longer period to assess the disease-modifying potential of this intervention.The possibility to use probiotics as adjuvant therapy in Parkinson’s disease could also help in reducing necessary drugs for the treatment of disease-related symptoms such as laxatives, prokinetics, and others . The results of this study will also point further research in a disease-modifying direction. If further research shows a potential disease-modifying effect of probiotics, treatment could be proposed to all PD patients without any specific risks and increasing the quality of life in these patients.In our mono-centric setting and considering rigorous exclusion criteria, one possible problem will be the recruitment of a large enough number of subjects. Enrolment will therefore be proposed to all eligible subjects by clinical neurologists during routine visits and given their recorded consent to receive information about ongoing research and recruiting trials. This will help in reaching the maximum number of possible participants, while ensuring strict adherence to inclusion/exclusion criteria, since participation will be only proposed to eligible patients by their neurologist and after a thorough medical evaluation.All participants will be contacted during the trial to assess adherence to the assigned treatment and prevent dropouts whenever possible. Considering the current pandemic by SARS-CoV-2 and related vaccination campaigns, we will also record the vaccination status of all participants, so as to identify any possible interactions with clinical and laboratory data gathered for this trial. Since every participant will start the trial in a different time frame, we plan to schedule each participant’s agenda to minimise interactions with possible vaccine administrations or medical therapy variations. Such information will be gathered and, if needed, used at the best of our possibilities to assess potential biases in randomisation or data analyses.This protocol is based on the protocol published on ClinicalTrials.gov with ID: NCT05173701 and unique protocol ID: PROB-PD. The last update on said protocol was submitted on 18 February 2022. Recruitment for the trial began on 22 November 2021, and 40 subjects have already been recruited at the time of this writing.


Benign paroxysmal positional vertigo (BPPV) and bilateral vestibulopathy (BVL) are two completely different forms of vestibular disorder that occasionally occur in the same patient. We conducted a retrospective review searching for that coincidence in our database of the patients seen over a 15-year period and found this disorder in 23 patients, that is 0.4%. More frequently they occurred sequentially (10/23) and BPPV was diagnosed first. Simultaneous presentation occurred in 9/23 patients. It was subsequently studied, but in a prospective manner, in patients with BPPV on all of whom a video head impulse test was performed to search for bilateral vestibular loss; we found it was slightly more frequent (6/405). Both disorders were treated accordingly, and it was found that the results follow the general trend in patients with only one of those disorders. The major categories of vestibular symptoms are vertigo, dizziness, vestibular-visual and postural. All were recently arranged in a taxonomy based on triggers and situational occurrence broad enough to cover most of what is clinically recorded during anamnesis, being purely phenomenological and avoiding topo-diagnostic implications . Benign paroxysmal positional vertigo (BPPV) is an episodic vestibular syndrome triggered by head motion when performing positional changes. It is one of the most common diagnoses at outpatient clinics, and its frequency depends on the clinical context or specialty . The criThis finding is not restricted to BPPV and MD or Vestibular migraines. Previous authors have considered that different vestibular disorders are highly interrelated in 3.7% of the patients who receive at least two diagnoses to better define their clinical status .Bilateral vestibulopathy or bilateral vestibular loss (BVL) is an untriggered chronic vestibular syndrome and, contrary to BPPV, is infrequent, representing less than 5% of the diagnosis at specialized clinics . RecentlThe study aimed to analyze the prevalence of both disorders in a retrospective and prospective study. We were interested in not restricting the diagnosis of BPPV to posterior semicircular canalithiasis alone and in the amount of vestibular asymmetry found in these patients.This is a review work of the experience at one institution at two different centers (Pamplona and Madrid). The information in this paper pertaining to BVL was previously published but in a broader study on bilateral vestibulopathy ; no dataThis was carried out on all patients and included ocular motility (saccades and smooth-pursuit), spontaneous nystagmus with and without visual fixation (the latter with Frenzel goggles), the post-head-shake nystagmus or the skull-vibration induced nystagmus; positional tests: head-hanging or hyperextension in a supine position, head-roll to right and left in a supine position, and the Dix-Hallpike test to the right and left sides. Other tests were performed in accordance with clinical characteristics or ongoing findings during examination.As this study was carried out partially with patients seen in a period before the current criteria were published , we chec−1. This result was first confirmed with the ice water test in which when using water at 4 °C no response was obtained from each ear . In 10 patients the first diagnosis was BPPV, in 4 BVL and, in 9 both were simultaneously done. When BPPV was first diagnosed the second diagnosis (BVL) was done 51 months (CI95 32–108) after and, when BVL was first diagnosed the second diagnosis (BPPV) was done 18 months (CI95 12–29) after. Those periods of time between diagnoses were significantly different .The affected side with BPPV was the right in 13 (56.5%) patients and the left in 10 (43.5%). The affected canal was the posterior in 16 (69.6%) patients, the horizontal in 5 (21.8%) patients, the superior in 1 (4.3%), and, multiple canals in another 1 (4.3%) patient. According to physiopathology 20 were due to canalithiasis and 3  to cupulolithiasis. In patients with BPPV, the mean gain of the VOR in the affected canal was 0.52 ± 0.16 while in the corresponding co-planar (and other ear) canal was 0.44 ± 0.23; differences were not significant (p = 0.006).The specific PRM was performed immediately after diagnosis. The number of treatments performed to achieve a negative diagnostic test was only 1 in 13 patients; 1 additional PRM was performed in 5 patients and the rest, 5, needed 2.9 ± 1.1 PRM. There was an association between the initial diagnosis and recurrence such that in 8/10 of those first diagnosed with BPPV and then subsequently of BVL there was at least 1 recurrence that needed a new PRM. Recurrences were significantly lower when the first diagnosis was BVL or both (BVL and BPPV) simultaneous  but only in 6 (1.48%) a diagnosis of BVL was done.a priori paradoxical situation occasionally found in clinical work as one of them, BVL, should mean the other was impossible, that is, BPPV, by making the vestibular receptor insensitive to any otoconial debris freely floating in the canal or adhered to the cupula. This review was prompted when examining a patient with a recent onset BPPV who was previously diagnosed with BVL after treatment with non-monitored systemic gentamicin due to renal disease. This is not an impossible situation but is infrequent as it represents 1% of those with BPPV (in the prospective search that number was 1.8%) and 10% of those with BVL.In this work we were interested in analyzing an This finding firstly alerts on the need to perform a complete vestibular examination, in other words, the head impulse test  must be part of the vestibular examination in case of a suspected BPPV, and the Dix Hallpike test in a case of suspected BVL.The rationale for the performance of the head-impulse test or its video-based method  in patients with suspected BPPV  has been questioned by the results. Previous authors have not found any significant difference in patients with idiopathic BPPV between the gain of the VOR in the affected semicircular canal or in the asymmetry of VOR gain for co-planar canal pairs and, in none of the patients did they find refixation saccades when stimulating the affected canal . On the In the case of BVL, the rationale for the performance of positional testing is well supported by previous works. BPPV has been found commonly among older adults with dizziness, including those not seeking medical care. According to different studies, 25% of these patients (>70 years old) mention unsteadiness or imbalance and not properly vertigo . The resWe have found that BPPV can affect different canals irrespective of the diagnosis of BVL. This suggests that not only the Dix–Hallpike test but complete positional testing should be performed when BVL is suspected in order to verify whether positional nystagmus and vertigo could be part of the problem. The different forms of BPPV found in our work reflect what is found in other neurotology units where posterior canalithiasis is the most frequent finding . In our sine qua non for BPPV and nystagmus to occur. Post head-shake nystagmus [We have found that BPPV and nystagmus occur in cases of moderate vestibular deficit and in our series most probably as coincidental diseases. It is not clear how much vestibular function must be preserved to induce a consistent nystagmus in examination, but, according to our findings, normal vestibular function is not the ystagmus  and skulystagmus  are alsoystagmus . The vHIystagmus . When thystagmus . Sacculaystagmus .Patients were treated following the usual methodology for each disorder and no specific or different procedure was considered, which also supports the idea of purely coincidental disorders. Taking into consideration the limitations of BPPV treatment in this particular elderly population , the resIn conclusion, our findings support the need for a comprehensive bedside vestibular examination in patients irrespective of a suspected diagnosis or when the clinical follow-up shows a significant change in any given patient or only slight in the elderly. When BPPV and BVL are seen together, they should be managed as when seen alone. When chronic dizziness is the main clinical manifestation after PRM in patients with BPPV, it is important to consider BVL in the differential diagnosis.


Cervical cancer is the most common malignancy affecting South African women aged 15–44 years, with a higher prevalence among women living with HIV (WLWH). Despite recommendations for a screening target of 70%, the reported rate of cervical cancer screening in South Africa is 19.3%.To investigate the adherence of healthcare workers to cervical cancer screening guidelines in a tertiary-level HIV clinic.A retrospective cross-sectional record audit of women attending the Charlotte Maxeke Johannesburg Academic Hospital HIV Clinic over a 1-month period.P = 0.046) and had a longer time since diagnosis of their HIV  compared to women who had not undergone screening. There was no significant difference in CD4 count or viral suppression between women who had and had not undergone screening.Out of 403 WLWH who attended the clinic, 180 (44.7%) were screened for cervical cancer in the 3 years prior to the index consultation. Only 115 (51.6%) of those women with no record of prior screening were subsequently referred for screening. Women who had undergone screening in the previous 3 years were significantly older (47 years vs 44 years, The rate of cervical cancer screening in our institution is below that recommended by the World Health Organization and the South African National Department of Health. What this study adds: This study highlights the low rate of cervical cancer screening among women living with HIV.2Despite being a preventable disease, cervical cancer is the second most common malignancy affecting South African women, second only to breast cancer, and is the most common malignancy in women aged between 15 and 45 years. Approximately 11 000 women are diagnosed with and 5900 women die from cervical cancer annually in South Africa.3Southern Africa has the highest incidence of HIV worldwide, with the overall prevalence in South Africa being 13.9%. However, this percentage is considerably higher in South Africa’s female population with current statistics showing that 24.1% of women of childbearing age are living with HIV.4 Furthermore, WLWH are more likely to progress to more advanced stages of cervical cancer at a younger age compared to women who are HIV-negative. In a cohort of patients in the early stages of the HIV pandemic, it was shown that WLWH presented with invasive cervical cancer up to 10 years earlier than women without HIV infection.5Women living with HIV (WLWH) are six times more likely to develop cervical cancer compared to HIV-negative women, and the malignancy is classified as an AIDS-defining illness.6 Although the increased risk of cervical cancer seen in WLWH is most likely multifactorial, severe immunosuppression and higher rates of coinfection with high-risk strains of human papillomavirus (HPV) are key factors.7 Therefore, important strategies in preventing cervical malignancies in WLWH include regular cervical cancer screening followed by appropriate management of abnormal results, HPV vaccination and HIV viral suppression using antiretroviral treatment (ART) with resultant immune reconstitution.8Data from the Charlotte Maxeke Johannesburg Academic Hospital (CMJAH) postnatal clinic showed that 47% of WLWH who had a Papanicolaou (Pap) smear done in the postnatal period had an abnormal smear.10 South Africa has set itself the same target of 70% screening coverage; however, this target was not met for the period 2000–2004, nor for the period 2005–2014 according to the National Health Laboratory Service (NHLS) national cytology statistics.12 Furthermore, it has been shown that coverage of cervical cancer screening in South Africa may be as low as 19.3%.2The World Health Organization (WHO) has estimated that to prevent 62 million deaths from cervical cancer over the next 100 years, and effectively eliminate the disease, a cervical cancer screening target of 70% needs to be met by 2030 (in addition to HPV vaccination and treatment targets of 90%).13The South African Society of Obstetricians and Gynaecologists (SASOG) currently recommends that in WLWH cervical cancer screening should start at the time of HIV diagnosis and continue three-yearly in low-resource settings, or annually in high-resource settings, and continue throughout the woman’s lifetime. The South African national guidelines recommend three-yearly screening from the time of HIV diagnosis.Considering the association between HIV and cervical cancer we aimed to investigate the adherence of healthcare workers to nationally recommended cervical cancer screening guidelines in a tertiary-level HIV clinic.We conducted a retrospective cross-sectional record audit of all female adult patients attending the CMJAH HIV Clinic from 01 October 2020 to 31 October 2020. The CMJAH HIV Clinic is a large tertiary-level HIV clinic that acts as a referral centre for people living with HIV from urban Johannesburg and surrounds. Approximately 10 000 patients are seen per year, 60% of whom are women. A minimum of 214 files needed to be audited to achieve a 95% confidence level with a 5% of margin error. Male patients were excluded from the study as were female patients under the age of 18, and those who had undergone a total hysterectomy.Data, including demographic data, date of last cervical screening, result of previous cervical screening, record of referral for cervical screening, time since HIV diagnosis, most recent CD4 count, HIV viral load (VL) within the previous year and record of any previously abnormal cervical screening or previous hysterectomy, were captured directly from patient files using Google Forms  and subsequently exported into Microsoft Excel 16.67  for analysis. Data were not retrieved from the NHLS as the study was an audit of the clinic record. No patient identifying data were collected; however, files were marked once analysed to avoid duplicate data entry.P-value < 0.05 was considered statistically significant.Data were analysed using Microsoft Excel 16.67  and Prism 8.4 . Non-parametric statistical tests were used as data were non-normally distributed using the Shapiro-Wilk Normality test. Categorical variables, such as the number of women who had undergone a cervical smear, are presented as percentages and frequencies, and Pearson’s chi-square test was used to analyse differences in categorical data between groups. Continuous variables such as age, CD4 and HIV VL are presented as medians with interquartile ranges (IQRs), and the Mann-Whitney test was used to compare continuous variables between two groups. A Permission to conduct the study was granted by the Research Committee and Head of Internal Medicine at CMJAH. Ethical clearance was obtained from the University of the Witwatersrand Human Research Ethics Committee  with clearance certificate M2011107. The study was also registered on the National Health Research Database.During the period under audit, 430 WLWH were seen at the clinic. Twenty-six women had undergone a previous total hysterectomy and one was under the age of 18 years, resulting in a final cohort of 403 women. The median age of this cohort was 46 years (IQR: 39–52 years). The median time from diagnosis to the index consultation was 132 months (IQR: 84–176 months). Two hundred and thirty women (57%) had a known month and year of HIV diagnosis and the remainder, 173 (43%), only a known year of diagnosis. In the case of woman without a known month of diagnosis the month of diagnosis was assumed to be January for calculation purposes.3 (IQR: 345 cells/mm3 – 722 cells/mm3) and 36 women (8.9%) had a CD4 count of less than 200 cells/mm3 at the index consultation. HIV VL data was available for 402 women (99.8%) and most women , were virologically suppressed (VL < 50 copies/mL). Twenty-five women (6%) had an unsuppressed VL (> 1000 copies/mL).A CD4 count was available for 389 women. The median CD4 count for those with available data was 523 cells/mmConcerningly, only 180 women (44.7%) were noted to have undergone cervical cancer screening in the 3 years prior to the index consultation and 223 (55.3%) had no record of screening in the same period. Among women who had undergone cervical cancer screening in the preceding 3 years, 96 smears (53.3%) were reported as negative for intraepithelial malignancy (NILM), 16 (8.9%) as low-grade squamous intraepithelial lesion (LSIL), 6 (3.3%) as high-grade intraepithelial squamous lesion (HSIL) and 4 (2.2%) had lesions recorded as ‘other’. Fifty-eight (32.2%) women did not have a smear result recorded in their clinic file despite having undergone screening.P = 0.046) and had a longer time since diagnosis of their HIV  compared to women who had not undergone a cervical smear. There was no significant difference in CD4 count  nor rate of viral suppression  between women who had and had not undergone screening.The differences between screened and unscreened women are described in In the 223 women who had no record of previous cervical cancer screening only 115 (51.6%) women were noted to have been subsequently referred for screening, as shown in P = 0.496); however, women who were referred for a cervical smear had a median time since HIV diagnosis that was longer than those who were not referred for a smear . There was no significant difference in CD4 count  between the two groups; however, there was a significantly higher rate of viral suppression in women who were referred compared to those who were not .There was no significant difference in the age of women who had and had not been referred for a cervical smear  of the women seen during the study period had undergone screening for cervical cancer within the preceding 3 years. In a similar cross-sectional study among WLWH in Uganda, 44% of women had ever been screened for cervical cancer, with 16.1% having been screened in the preceding year.Women who had undergone screening for cervical cancer were significantly older than those who had not undergone screening. This may reflect adherence to national guidelines for women without HIV  and lack of knowledge of the HIV-specific guidelines. While this result is statistically significant it may not be clinically relevant; considering the median age in both groups was greater than 40 years.15 Individuals who are in HIV care for longer also have more opportunity to be referred for cervical cancer screening. Linked to this is the correlation between viral suppression and referral for cervical screening: clinicians may assess women who are virally suppressed as needing less HIV-related care, providing more time to discuss health promotional measures. Among those with no record of previous cervical cancer screening, just over half were subsequently referred for screening. Those who were referred for screening were more likely to be virologically supressed and had been living with HIV for longer, again suggesting that repeat and long-term contact with the healthcare system increases the likelihood of implementation of health promotional measures.We observed that women who had undergone screening were more likely to have been living with HIV for longer, suggesting that women in care for longer are more likely to be aware of the need for cervical cancer screening and may request referral or self-refer for screening. This is similar to a finding in an Ethiopian study where uptake of cervical cancer screening was significantly higher in women who had been living with HIV for 10 years or longer.7 Considering this, a further reflection is the lack of a ‘single-visit’ approach for both HIV care and cervical cancer screening. Women are required to attend a primary health clinic for their cervical screening, as noted above, placing an additional time and financial burden on them. Further studies are needed to evaluate if the establishment of a dedicated cervical screening service within our hospital for women at high risk would improve screening rates as it has in other studies.18 Considering the prevalence of HIV in South Africa and the known links between HIV and cervical cancer, an HIV clinic serves as an ideal site for cervical cancer screening. Alternatively, an organised referral system to a dedicated screening facility would greatly improve the number of women referred for screening – this could be initiated through utilisation of currently available gynaecology services in our hospital.It was not possible to assess reasons for lack of referral in this study as a formal assessment through staff interviews has not taken place. However, women requiring cervical screening are referred to their local (primary care) clinic and there is no standard form or referral letter in use for this. This may reflect an extra administrative burden where clinicians are required to write a referral letter for their patients to have cervical screening. Sigfrid and colleagues suggest that integrating HIV care and cervical cancer screening is both ‘feasible as well as acceptable to women living with HIV’.Finally, we are encouraged by the number of WLWH in our clinic who had a recent VL and by the rate of viral suppression among WLWH in our clinic.Our study was limited by its retrospective nature in that incomplete patient notes may have limited the amount of information captured from each file – women may have been referred for or undergone cervical cancer screening but not had this noted in their file. Additionally, the NHLS system was not checked when results were not recorded in the patient record, thus several patients may have been screened with the result not recorded in the patient record.Our study suggests poor adherence to guideline-recommended cervical cancer screening among WLWH in a single specialised centre. The care of people living with HIV is a complex and multifaceted task involving treatment of existing pathology and screening for co-morbid conditions, including cervical cancer. Although this study exhibited promising rates of viral suppression, that is not the only objective of HIV care. Our audit has highlighted substantial gaps in cervical cancer screening as part of the overall management of WLWH at a tertiary-level. This raises concerns for the cervical cancer screening programmes at other tertiary hospitals and, perhaps, more so at lower-level facilities. Furthermore, it highlights the challenges associated with a compartmentalised approach to HIV care with different tasks allocated to different facilities. This ultimately adds further time and financial burdens onto the patient and increases the risk of poor adherence. The reasons for these gaps in care are unclear; however, this audit may serve as a baseline reference to necessitate an intervention and prompt future investigation and quality improvement audits to improve overall care and patient outcomes.