Chronic Venous Disease: Pathophysiological Aspects, Risk Factors, and Diagnosis.

Chronic venous disease (CVD) is highly prevalent in the general population and encompasses a range of pathological and hemodynamic changes in the veins of the lower extremities. These alterations give rise to a variety of symptoms, with more severe forms resulting in venous ulceration, which causes morbidity and high socioeconomic burden. The origins and underlying mechanisms of CVD are intricate and multifaceted, involving environmental factors, genetics, hormonal factors, and immunological factors that bring about structural and functional alterations in the venous system. This review offers the latest insights into the epidemiology, pathophysiology, and risk factors of CVD, aiming to provide a comprehensive overview of the current state of knowledge. Furthermore, the diagnostic approach for CVD is highlighted and current diagnostic tools are described.

Identifying Key Drivers in the Pathogenesis of Martorell Hypertensive Ischaemic Leg Ulcer: A Comparative Analysis with Chronic Venous Leg Ulcer.

Martorell hypertensive ischaemic leg ulcer (Martorell HYTILU) is a rare but significant cause of distal leg ulcers. Although hypertension and diabetes are known factors in its development, the precise pathogenesis of Martorell HYTILU remains elusive. To reach a better understanding of Martorell HYTILU, transcriptomic analysis was conducted through RNA sequencing and immunohistochemical comparison of Martorell HYTILU (n = 17) with chronic venous ulcers (n = 4) and healthy skin (n = 4). Gene expression analysis showed a marked activation of immune-related pathways in both Martorell HYTILU and chronic venous ulcers compared with healthy skin. Notably, neutrophil activity was substantially higher in Martorell HYTILU. While pathway analysis revealed a mild downregulation of several immune pathways in Martorell HYTILU compared with chronic venous ulcers, keratinization, cornification, and epidermis development were significantly upregulated in Martorell HYTILU. Additionally, STAC2, a gene encoding for a protein promoting the expression of the calcium channel Cav1.1, was significantly upregulated in Martorell HYTILU and was detected perivascularly in situ (Martorell HYTILU n = 24; chronic venous ulcers n = 9, healthy skin n = 11). The high expression of STAC2 in Martorell HYTILU suggests that increased calcium influx plays an important role in the pathogenesis of the disease. Consequently, calcium channel antagonists could be a promising treatment avenue for Martorell HYTILU.

The Histopathology of Leg Ulcers.

Ulcerations of the lower extremities are a frequently encountered problem in clinical practice and are of significant interest in public health due to the high prevalence of underlying pathologies, including chronic venous disease, diabetes and peripheral arterial occlusive disease. However, leg ulcers can also present as signs and symptoms of various rare diseases and even as an adverse reaction to drugs. In such cases, correct diagnosis ultimately relies on histopathological examination. Apart from the macroscopic presentation, patient history and anatomic location, which are sometimes indicative, most ulcers have very distinct histopathological features. These features are found in different layers of the skin or even associated vessels. In this narrative review, we discuss and highlight the histopathological differences of several types of leg ulcers that can contribute to efficient and accurate diagnosis.

Dequalinium Chloride for the Treatment of Vulvovaginal Infections: A Systematic Review and Meta-Analysis.

OBJECTIVE/PURPOSE: Women at reproductive age frequently experience vulvovaginal infections and vaginitis. The most common etiologies are vulvovaginal candidiasis (VVC), bacterial vaginosis (BV), desquamative inflammatory vaginitis/aerobic vaginitis, and trichomoniasis. Various treatment options are available for these infections, such as specific antimicrobial or antiseptic agents. Dequalinium chloride (DQC) is a local antiseptic agent with a broad antimicrobial and antifungal spectrum. Multiple studies suggest that DQC is an efficient treatment for vaginal infections; however, it is not widely recommended as a first-line treatment. This systematic review and meta-analysis aims to evaluate the efficacy of DQC compared with that of standard treatment. METHODS: Our systematic review was conducted according to the PRISMA guidelines. PubMed/MEDLINE, EMBASE, CENTRAL, and clinicaltrials.org were searched to retrieve relevant reports up to October 2022. RESULTS: Four randomized controlled studies and 1 observational study were included in this review. Overall, DQC showed noninferiority to the reference treatments for BV and VVC, and to the evaluated treatment options for desquamative inflammatory vaginitis/aerobic vaginitis. For BV and VVC, this could also be confirmed in a meta-analysis including 3 randomized controlled studies. No serious adverse events were reported in any of these studies. CONCLUSIONS: Dequalinium chloride offers a safe, well-tolerated, and efficient treatment option for vulvovaginal infections of different etiologies. However, further studies are needed to confirm our findings and allow inclusion of DQC as a first-line treatment into guidelines.

Development of a localization-based algorithm for the prediction of leg ulcer etiology.

BACKGROUND: Diagnostic work-up of leg ulcers is time- and cost-intensive. This study aimed at evaluating ulcer location as a diagnostic criterium and providing a diagnostic algorithm to facilitate differential diagnosis. PATIENTS AND METHODS: The study consisted of 277 patients with lower leg ulcers. The following five groups were defined: Venous leg ulcer, arterial ulcers, mixed ulcer, arteriolosclerosis, and vasculitis. Using computational surface rendering, predilection sites of different ulcer types were evaluated. The results were integrated in a multinomial logistic regression model to calculate the likelihood of a specific diagnosis depending on location, age, bilateral involvement, and ulcer count. Additionally, neural network image analysis was performed. RESULTS: The majority of venous ulcers extended to the medial malleolar region. Arterial ulcers were most frequently located on the dorsal aspect of the forefoot. Arteriolosclerotic ulcers were distinctly localized at the middle third of the lower leg. Vasculitic ulcers appeared to be randomly distributed and were markedly smaller, multilocular and bilateral. The multinomial logistic regression model showed an overall satisfactory performance with an estimated accuracy of 0.68 on unseen data. CONCLUSIONS: The presented algorithm based on ulcer location may serve as a basic tool to narrow down potential diagnoses and guide further diagnostic work-up.

Peripartum Maternal Admission to the Intensive Care Unit: An Observational Study over a 15-Year Period at a Tertiary Center in Austria.

Peripartum maternal admission to the intensive care unit is challenging for anesthesiologists, obstetricians, and all personnel involved. An understanding of altered maternal physiology, fetal considerations, and acute peripartum emergencies is required to ensure adequate maternal and neonatal outcomes. In this study, we analyzed data of peripartum maternal admissions to the intensive care unit at our large tertiary referral center in order to define trends and changes over time. This study retrospectively analyzed maternal morbidity, admission diagnoses, treatments, and outcomes of women with peripartum admission to the intensive care unit at our tertiary care center over a 15-year period. We found that patient characteristics and admission diagnoses remained remarkably consistent over the observational period; however, there was a significant increase in postpartum hemorrhage (r = 0.200, p < 0.001) and cesarean hysterectomy (r = 0.117, p = 0.027) over time. Moreover, we found a reduction in preterm births (r = -0.154, p = 0.004) and a decreased peripartum neonatal intensive care unit admission rate (r = -0.153, p = 0.006) among women who were transferred to the intensive care unit. Based on our long-term observational data, there is consistent need for intensive care in obstetrics due to a small number of different etiologies. Specialized training for the predominant diagnoses involved as well as multidisciplinary care of the affected patients are both warranted.

Endovenous thermal ablation of superficial truncal veins and compression therapy result in symptom relief in venous valve aplasia.

Venous valve aplasia (or valvular rarefication) is a rare cause of chronic venous insufficiency. In the present report, we have described the case of a 33-year-old man with severe symmetric lower leg edema and heaviness and pain in both lower legs. Duplex ultrasound demonstrated severe venous insufficiency in the superficial and deep venous system of both legs. Further imaging examinations supported the diagnosis of venous valvular aplasia. Treatment consisted of endovenous thermal ablation of the great saphenous vein and small saphenous vein as well as consistent compression therapy, resulting in a marked reduction of his leg edema, heaviness, and pain.

German translation, cross-cultural adaption and validation of the Venous Clinical Severity and Venous Disability Scores.

BACKGROUND: The Venous Clinical Severity Score (VCSS) and the Venous Disability Score (VDS) represent assessment tools for chronic venous disease (CVD) combining physician and patient reported outcomes. To date, German versions are not available. The present study aimed at translating the VCSS and VDS into German and validating the questionnaires. METHODS: Translations of VCSS and VDS were compiled based on published guidelines considering potential differences in the use of German language in different countries. For validation, 33 patients with chronic venous disease and 5 healthy individuals were included in the pre-testing phase. Patients were examined twice by independent investigators to validate test-retest-validity culminating in 142 limb examinations. Internal consistency, inter-rater dependence and external reliability were subsequently evaluated. RESULTS: All assessed metrics showed good internal consistency. Intra-class correlation coefficients were .75 for the VDS, .98 for the VCSS of the right leg and .90 for the VCSS of the left leg, indicating inter-rater independence. Furthermore, VCSS scores showed a modest positive correlation with CEAP C class and both VCSS and VDS showed a negative correlation with the physical component of the SF-12, indicating adequate external reliability. CONCLUSION: A pan-cultural German version of both the VCSS and VDS was established and validated as reliable tools to evaluate the severity of CVD in German speaking countries.

Endovascular Repair of Penetrating Thoracic Aortic Ulcers Using Tubular Stent Grafts Versus Stent Grafts With a Proximal Scallop.

PURPOSE: In penetrating aortic ulcers (PAUs), limited data support tubular thoracic endovascular aortic repair (TEVAR) as a viable treatment option. For treatment of more proximal PAUs, hybrid approaches and-more recently-scalloped TEVAR (scTEVAR) have been advocated. Outcomes of scTEVAR specifically for PAUs have not yet been reported. This study reports long-term outcomes for tubular and scTEVAR in PAUs and compares the safety profile in both cohorts regarding the significantly more proximal landing zone (LZ) for scTEVAR. MATERIALS AND METHODS: This single-center retrospective cohort study includes all nonacute patients treated for complicated PAU with scTEVAR and tubular TEVAR. Patient and PAU characteristics as well as procedural success, complication and reintervention rates, and all-cause and aortic mortality were analyzed. RESULTS: Of 212 TEVAR procedures reviewed, 21 patients with tubular TEVAR and 19 patients with scTEVAR were included. Patient and PAU characteristics were similar, and LZ was significantly more proximal in the scTEVAR cohort (p=0.0001), with similar number and types of supra-aortic revascularization procedures. Clinical success was reached in all 40 patients (100%), and reintervention rate was 2/21 (9.5%) and 1/19 (5.3%), respectively. Over the mean follow-up of 63 (TEVAR) and 53 (scTEVAR) months, clinical success was stable in all patients with one (abdominal) aortic-related mortality in the scTEVAR cohort. CONCLUSION: Treatment of complicated PAUs with TEVAR as well as scTEVAR provides excellent and similar clinical success, stability of clinical success, and aortic survival with acceptable complication and reintervention rates. Scalloped TEVAR safely lengthens the proximal sealing zone to address more proximal pathologies. CLINICAL IMPACT: Treatment of asymptomatic complicated penetrating aortic ulcers (PAUs) with thoracic endovascular aortic repair (TEVAR) provides excellent clinical success and acceptable complication and reintervention rates. More patients become amenable to endovascular treatment by including scalloped TEVAR (scTEVAR) as a means to safely lengthen the proximal sealing zone to address more proximal pathologies.

Risk of fetal malformation, spontaneous abortion, and adverse pregnancy outcomes after gestational terbinafine exposure: a systematic review.

Fungal skin and nail infections are common health issues affecting an estimated 10%-20% of the world's population. The antifungal agent terbinafine shows broad-spectrum activity against a wide range of fungal species and is commonly prescribed as a first-line treatment for dermatomycoses and onychomycoses. However, owing to insufficient data regarding embryotoxicity and adverse pregnancy outcomes, treatment with terbinafine is currently not recommended in pregnancy and breastfeeding. This systematic review aimed to evaluate the effects of gestational terbinafine exposure on congenital malformations, spontaneous abortions, and adverse pregnancy outcomes. PubMed/MEDLINE, EMBASE, and clinicaltrials.org were searched to retrieve relevant reports up to March 2022. Two investigators independently screened the articles, extracted the data, and performed a quality assessment using the Newcastle-Ottawa Scale. Two cohort and two case-control studies were eligible for inclusion. Overall, the study showed the absence of an increased risk of congenital malformations, spontaneous abortion, preterm birth, small for gestational age, low birth weight, or stillbirth, following systemic or topical terbinafine exposure during pregnancy. In conclusion, the use of systemic and topical terbinafine during pregnancy can be regarded as safe for mothers and unborn children. The current recommendation concerning gestational terbinafine administration should be reconsidered.

Comparative analysis of endovenous laser ablation versus ultrasound-guided foam sclerotherapy for the treatment of venous leg ulcers.

Endovenous thermal and non-thermal therapeutic approaches have become standard of care for the treatment of venous insufficiency. However, comparative studies on its use in the population of venous leg ulcer patients are scarce. The present study aimed at a comparison of the efficacy of endovenous laser ablation (EVLA) and ultrasound-guided foam sclerotherapy (UGFS) for the treatment of venous leg ulcers (VUs). We retrospectively analyzed patient records of 68 patients with active VUs (C6 of the CEAP-classification), who underwent EVLA (n = 33) or UGFS (n = 35) between January 2001 and January 2021. In 68 patients, 97 venous segments (GSV: 43, SSV: 17, NSV: 37) were treated. Ulcer surface area at initial presentation did not differ significantly between both treatment groups (EVLA: 7.7 ± 10.7 vs. UGFS: 8.5 ± 16.3 cm2 ; p = 0.73). No significant difference regarding patient characteristics was found, with the exception of age, as patients receiving UGFS treatment were significantly older (EVLA: 61 ± 17 vs. UGFS: 70 ± 14 years; p = 0.018). The rate of ulcer resolution was not significantly different between EVLA and UGFS groups (97.0% vs. 85.7%; p = 0.20). Also, the mean time to complete ulcer healing after endovenous intervention was comparable (EVLA: 59 ± 37 vs. UGFS: 63 ± 41 days; p = 0.68). However, the relapse rate was significantly higher for UGFS than for EVLA treated patients (31.4% vs. 3.0%; p = 0.002). Taken together, rates of ulcer resolution and ulcer healing time after endovenous intervention were comparable between both treatment modalities. Nevertheless, a significantly higher relapse rate was observed in UGFS treated patients.

Topically administered purified clinoptilolite-tuff for the treatment of cutaneous wounds: A prospective, randomised phase I clinical trial.

In an ageing society, chronic ulcers pose an increasingly relevant healthcare issue associated with significant morbidity and an increasing financial burden. Hence, there is an unmet medical need for novel, cost-effective therapies that improve healing of chronic cutaneous wounds. This prospective, randomised, open-label, phase I trial investigated the safety and tolerability of topically administered purified clinoptilolite-tuff (PCT), mainly consisting of the naturally occurring zeolite-mineral clinoptilolite, in artificial wounds in healthy male volunteers compared to the standard of care (SoC). We found that topically administered PCT was safe for therapeutic application in acute wounds in healthy male volunteers. No significant differences in wound healing or wound conditions were observed compared to SoC-treated wounds. However, we found a significantly higher proportion of CD68-positive cells and a significantly lower proportion of α-smooth muscle actin-positive cells in PCT-treated wounds. Scanning electron microscopy revealed PCT particles in the restored dermis in some cases. However, these did not impede wound healing or clinical symptoms. Hence, purified PCT could represent an attractive, cost-effective wound treatment promoting the process of healing.

Raynaud's Phenomenon after COVID-19 Vaccination: Causative Association, Temporal Connection, or Mere Bystander?

Herein, we report a case of a new-onset Raynaud's phenomenon (RP), which occurred in an otherwise healthy 31-year-old Caucasian woman, who lacked any known risk factors and associations with possible causes for secondary RP. However, 2 weeks prior to the development of RP, the patient had received her first injection of the COVID-19 vaccine containing ChAdOx1-SARS-COV-2. The patient presented with well-demarcated, white-pale, cold areas involving the middle fingers of both hands and the ring finger of the right hand, which were triggered by exposure to cold environment and accompanied by a sensation of numbness. Infrared thermography revealed notable temperature differences of up to 10.9°C between affected and nonaffected fingers. Coagulation and immunological parameters, including cryoglobulins and pathological autoantibodies, were within the normal range and antibodies to the heparin/platelet factor 4 complex not detectable. It remains unclear if the development of RP in our patient is causally related to antecedent COVID-19 vaccination; however, the temporal connection to the vaccination, the complete absence of RP in her past medical history, and the lack of any risk factors and triggers raise the suspicion of a yet unknown association with the vaccine. Whether a clear association between the development of RP and COVID-19 vaccination exists or whether RP represents a bystander effect needs to be awaited in case observational reports on RP accumulate. Given the steadily rising numbers of people receiving COVID-19 vaccinations, physicians may remain alert to still unrecognized side effects.

Screening Pregnant Women for Bacterial Vaginosis Using a Point-of-Care Test: A Prospective Validation Study.

Bacterial vaginosis in early pregnancy is associated with an increased risk of preterm birth. The introduction of a simple screen-and-treat program into antenatal care was shown to significantly reduce the rate of preterm birth. The gold standard for diagnosing bacterial vaginosis is Gram staining, which is, however, time-consuming and requires laboratory facilities. The objective of this prospective study was to validate a point-of-care sialidase activity detection test (OSOM® BVBLUE® Test) for asymptomatic pregnant women and evaluate its accuracy as a screening tool. We enrolled 200 pregnant participants, 100 with Gram staining-confirmed bacterial vaginosis and 100 healthy controls. Compared to Gram staining, the point-of-care test showed a sensitivity of 81%, specificity of 100%, positive predictive value of 100%, and negative predictive value of 98.1%. In conclusion, we found that the OSOM® BVBLUE® Test was an accurate method for diagnosing bacterial vaginosis in asymptomatic pregnant women. This point-of-care test can therefore be considered a reliable and easy-to-use screening tool for bacterial vaginosis during pregnancy.

Differentiating Arteriolosclerotic Ulcers of Martorell from Other Types of Leg Ulcers Based on Vascular Histomorphology.

Clinical differential diagnosis of arteriolosclerotic ulcers of Martorell is challenging due to the lack of clearly affirmative instrument-based diagnostic criteria. The aim of this study was to develop vascular histomorphological diagnostic criteria differentiating Martorell ulcers from other types of leg ulcers. The histomorphology of patients diagnosed with arteriolosclerotic ulcers of Martorell (n = 67) was compared with that of patients with venous leg ulcers, necrotizing leukocytoclastic vasculitis, pyoderma gangrenosum, and non-ulcerative controls (n = 15 each). In a multivariable logistic regression model, the rates of arteriolar calcification (odds ratio (OR) 42.71, 95% confidence interval (CI) 7.43-443.96, p < 0.001) and subendothelial hyalinosis (OR 29.28, 95% CI 4.88-278.21, p <0.001) were significantly higher in arteriolosclerotic ulcers of Martorell. Arteriolar cellularity was significantly lower in Martorell ulcers than in controls (OR 0.003, 95 CI < 0.001-0.97, p = 0.05). However, the wall-to-lumen ratio was similar in all ulcers (OR 0.975, 95% CI 0.598-2.04, p =0.929). Based on the Youden index, a wall cellularity of < 0.24 cells/100 µm2 was determined as the optimum cut-off point (sensitivity 0.955, specificity 0.944). Thus, arteriolar calcification, subendothelial hyalinosis, and arteriolar cellularity revealed high discriminatory power for arteriolosclerotic ulcers of Martorell.

Validation of the SavvyCheck™ Vaginal Yeast Test for Screening Pregnant Women for Vulvovaginal Candidosis: A Prospective, Cross-Sectional Study.

Pregnant women have an increased risk of vulvovaginal candidosis. Recurrent candidosis is under debate as a contributor to preterm birth, and vertical transmission may cause diaper dermatitis and oral thrush in the newborn. Apart from cultural methods, the gold standard for diagnosing candidosis is Gram staining, which is time-consuming and requires laboratory facilities. The objective of this prospective study was to validate a point-of-care vaginal yeast detection assay (SavvyCheck™ Vaginal Yeast Test) and to evaluate it in asymptomatic pregnant women. We enrolled 200 participants, 100 of whom had vulvovaginal candidosis according to Gram stain (study group) and 100 were healthy pregnant controls (control group). Of these, 22 participants (11%) had invalid test results. The point-of-care test of the remaining 85 and 93 study participants in the study and control groups, respectively, showed a sensitivity of 94.1%, specificity of 98.9%, positive predictive value of 90.3%, and negative predictive value of 99.4% when compared with Gram stain. In conclusion, we found a high correlation between the SavvyCheck™ Vaginal Yeast Test and Gram-stained smears during pregnancy. This suggests a potential role of this point-of-care test as a screening tool for asymptomatic pregnant women in early gestation.

Microstructural comparative analysis of calcification patterns in calciphylaxis versus arteriolosclerotic ulcer of Martorell.

BACKGROUND: Calciphylaxis and the arteriolosclerotic ulcer of Martorell (ASUM) represent two entities of cutaneous calcific arteriolopathies. Their differential diagnosis can be challenging, given similarities in their clinical and histological presentation. Calcification patterns have been proposed as a possible discriminative histological criterion, however, a systematic microstructural comparative analysis is lacking. OBJECTIVES: The study aimed at a systematic comparative microstructural analysis of the calcification patterns in calciphylaxis versus ASUM. MATERIALS & METHODS: Skin biopsies of patients with leg ulcers due to calciphylaxis (20) and ASUM (69) diagnosed at three European wound care centres (Vienna, Bern, Zurich) were included. The extent of calcification, arteriolar calcification pattern and presence of extra-arteriolar calcification were assessed. RESULTS: All calciphylaxis and most ASUM patients (77%) presented with arteriolar calcification. Although the mean number of calcified vessels and the proportion of calcified area were significantly higher in calciphylaxis specimens (p = 0.003 and p = 0.0171), there was no significant difference in the pattern of arteriolar calcification (p = 0.177). Interestingly, extra-arteriolar calcification was detected in the majority of both calciphylaxis (93.3%) and ASUM samples (85.2%, p = 0.639). Notably, Alizarin Red S staining was superior to H&E for the detection of calcifications of both entities (p = 0.014 and p < 0.0001), and to von Kossa staining for ASUM samples (p = 0.0001). However, no differences could be observed between cases with uraemic and non-uraemic calciphylaxis or ulcerations located on the upper and lower leg. CONCLUSION: Our results indicate that extra-arteriolar calcification is not only present in calciphylaxis, but can also be detected in ASUM suggesting a lack of specificity for this finding. However, more specific calcification stains, such as Alizarin Red S, should be used in suspected cases, as calcifications may be overlooked using conventional H&E staining.

Global trends in clinical trials involving pluripotent stem cells: a systematic multi-database analysis.

Pluripotent stem cells (PSCs) hold great potential for novel therapeutic approaches to regenerate or replace functionally impaired tissues. Since the introduction of the induced pluripotent stem cell technology in 2006, the number of scientific publications on this topic has constantly been increasing. However, so far no therapy based on PSCs has found its way into routine clinical use. In this study, we examined research trends related to clinical trials involving PSCs based on data obtained from ClinicalTrials.gov, the ICTRP database from the World Health Organization, as well as from a search of all individual databases that are included in the ICTRP using a multistep search algorithm. Following a stringent inclusion/exclusion procedure 131 studies remained that could be classified as clinical trials involving PSCs. The magnitude of these studies (77.1%) was observational, which implies that no cells were transplanted into patients, and only a minority of studies (22.9%) were of an interventional study type. The number of clinical trials involving induced pluripotent stem cells (iPSCs, 74.8%) was substantially higher than the one involving embryonic stem cells (ESCs, 25.2%). However, the picture changes completely when focusing on interventional studies, where in the majority (73.3%) of cases ESCs were used. Interestingly, also the study duration was significantly shorter for interventional versus observational trials (p = 0.002). When focusing on the geographical study regions, it became obvious that the greatest part of all observational trials was performed in the USA (41.6%) and in France (16.8%), while the magnitude of interventional studies was performed in Asian countries (China 36.7%, Japan 13.3%, South Korea 10.0%) and in the field of ophthalmology. In summary, these results indicate that only a limited number of trials were focusing on the actual transplantation of PSCs into patients in a rather narrow field of diagnoses. The future will tell us, if the iPSC technology will ultimately overcome the current challenges and will finally make its way into routine clinical use.