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Non-healing wounds are one of the chronic complications of diabetes and have remained a worldwide challenge as one of the major health problems. Hyperbaric oxygen (HBO) therapy is proven to be very successful for diabetic wound treatment, for which the molecular basis is not understood. Adipocytes regulate multiple aspects of repair and may be therapeutic for inflammatory diseases and defective wound healing associated with aging and diabetes. Endothelial cell-derived extracellular vesicles could promote wound healing in diabetes. To study the mechanism by which HBO promotes wound healing in diabetes, we investigated the effect of HBO on fat cells in diabetic mice. A diabetic wound mouse model was established and treated with HBO. Haematoxylin and eosin (H&E) staining and immunofluorescence were used for the analysis of wound healing. To further explore the mechanism, we performed whole-genome sequencing on extracellular vesicles (EVs). Furthermore, we conducted in vitro experiments. Specifically, exosomes were collected from human umbilical vein endothelial cell (HUVEC) cells after HBO treatment, and then these exosomes were co-incubated with adipose tissue. The wound healing rate in diabetic mice treated with HBO was significantly higher. HBO therapy promotes the proliferation of adipose precursor cells. HUVEC-derived exosomes treated with HBO significantly promoted fat cell browning. These data clarify that HBO therapy may promote vascular endothelial cell proliferation and migration, and promote browning of fat cells through vascular endothelial cells derived exosomes, thereby promoting diabetic wound healing. This provides new ideas for the application of HBO therapy in the treatment of diabetic trauma.
Pressure ulcers including heel ulcers remain a global healthcare concern. This study comprehensively evaluates the biomechanical effectiveness of the market-popular ALLEVYN® LIFE multilayer dressing in preventing heel ulcers. It focuses on the contribution of the frictional sliding occurring between the non-bonded, fully independent layers of this dressing type when the dressing is protecting the body from friction and shear. The layer-on-layer sliding phenomenon, which this dressing design enables, named here the frictional energy absorber effectiveness (FEAE), absorbs approximately 30%–45% of the mechanical energy resulting from the foot weight, friction and shear acting to distort soft tissues in a supine position, thereby reducing the risk of heel ulcers. Introducing the novel theoretical FEAE formulation, new laboratory methods to quantify the FEAE and a review of relevant clinical studies, this research underlines the importance of the FEAE in protecting the heels of at-risk patients. The work builds on a decade of research published by our group in analysing and evaluating dressing designs for pressure ulcer prevention and will be useful for clinicians, manufacturers, regulators and reimbursing bodies in assessing the effectiveness of dressings indicated or considered for prophylactic use.
Diabetic Foot Ulcers (DFUs) are a major complication of diabetes, often leading to amputation. Understanding the relationship between haematological inflammatory markers and the incidence of amputation in DFU patients with infectious complications is crucial for improving management and outcomes. This retrospective study, conducted from May 2020 to October 2022, involved 109 patients with DFUs, categorised into amputation (AM) and non-amputation (NAM) groups. Patients were evaluated for various factors, including demographic data, DFU duration, and blood parameters such as haemoglobin A1c (HbA1c), haemoglobin (Hb), albumin (ALB), white blood cell count (WBC), erythrocyte sedimentation rate (ESR), procalcitonin (PCT), C-reactive protein (CRP), platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), and lymphocyte-to-monocyte ratio (LMR). Statistical analyses were performed using independent sample t-tests, Mann–Whitney U test and logistic regression. The univariate analysis showed no significant difference in BMI, DM duration or DFU duration between groups. However, significant differences were noted in PCT, Hb, ESR, ALB, HbA1c and WBC levels, and in inflammatory ratios (NLR, PLR and LMR). Multivariate logistic regression identified CRP, NLR and PLR as independent risk factors for amputation. The study highlights CRP, PLR and NLR as key independent risk factors for amputation in patients with DFUs. These easily obtainable markers from routine blood tests can effectively aid in predicting the risk of osteomyelitis and amputation, enhancing clinical decision making and patient care strategies.
The study explores the impact of predictive nursing interventions on pressure ulcers (PUs) in elderly bedridden patients. A total of 120 elderly bedridden patients from the Central Hospital of Enshi Tujia and Miao Autonomous Prefecture between August 2019 and August 2023 were selected as the subjects of the study and were randomly divided into an observation group and a control group using a random number table method. The control group received conventional nursing care, while the observation group received predictive nursing interventions. The study compared the incidence of PUs, Braden scale scores, the onset time of PUs, self-rating anxiety scale (SAS) scores, self-rating depression scale (SDS) scores, and nursing satisfaction between the two groups. In elderly bedridden patients, the application of predictive nursing interventions significantly reduced the incidence of PUs (p < 0.001), significantly lowered the SAS and SDS scores (p < 0.001), and also significantly increased Braden scale scores (p < 0.001) and delayed the onset time of PUs (p < 0.001). Additionally, it improved patients' nursing satisfaction (p = 0.008). Predictive nursing interventions in elderly bedridden patients have good application effects, reducing the occurrence of PUs, delaying the time of onset in patients, improving patients' negative emotions and enhancing nursing satisfaction rates. It is worthy of widespread use.
To gain a greater understanding of how compression therapy affects quality of life, this systematic review appraised existing published studies measuring the impact of compression therapy on health quality of life (HRQoL), and pain, among people with venous leg ulcers (VLU).
Five databases were searched, and two authors extracted data and appraised the quality of selected papers using the RevMan risk of bias tool. Due to heterogeneity in the types of compression and instruments used to evaluate HRQoL, meta-analysis was not appropriate; thus, a narrative synthesis of findings was undertaken.
Ten studies were included, 9 RCTs and one before-after study. The studies employed nine different HRQoL tools to measure the impact of a variety of compression therapy systems, with or without an additional exercise programme, versus other compression systems or usual care, and the results are mixed. With the use of the Cardiff Cardiff Wound Impact Schedule, the SF-8 and the SF-12, study authors found no differences in QoL scores between the study groups. This is similar to one study using QUALYs (Iglesias et al., 2004). Conversely, for studies using EuroQol-5D, VEINES-QOL, SF-36 and CIVIQ-20 differences in QoL scores between the study groups were noted, in favour of the study intervention groups. Two further studies using QUALYs found results that favoured a two-layer cohesive compression bandage and the TLCCB group, respectively. Results for the five studies that assessed pain are also mixed, with one study finding no difference between study groups, one finding that pain increased over the study period and three studies finding that pain reduced in the intervention groups. All studies were assessed as being at risk of bias in one or more domains.
Results were varied, reflecting uncertainty in determining the impact of compression therapy on quality of life and pain among people with a venous leg ulcer. The heterogeneity of the compression systems and the measures used to evaluate HRQoL make it a challenge to interpret the overall evidence. Further studies should strive for homogeneity in design, interventions and comparators to enhance both internal and external validity.
This study evaluated the effectiveness of a multi-disciplinary diabetic limb salvage programme in improving clinical outcomes and optimising healthcare utilisation in 406 patients aged ≥80 years with diabetic foot ulcers (DFUs), compared to 2392 younger patients enrolled from June 2020 to June 2021 and against 1716 historical controls using one-to-one propensity score matching. Results showed that elderly programme patients had lower odds of amputation-free survival (odds ratio: 0.64, 95% CI: 0.47, 0.88) and shorter cumulative length of stay (LOS) compared to younger programme patients (incidence rate ratio: 0.45, 95% CI: 0.29, 0.69). Compared to the matched controls, participating in the programme was associated with 5% higher probability of minor lower extremity amputation, reduced inpatient admissions and emergency visits, shorter LOS but increased specialist and primary care visits (all p-values <0.05). The findings suggest that the programme yielded favourable impacts on the clinical outcomes of patients aged≥80 years with DFUs. Further research is needed to develop specific interventions tailoring to the needs of the elderly population and to determine their effectiveness on patient outcomes while accounting for potential confounding factors.
Our objective was to evaluate normative data for near-infrared spectroscopy (NIRS) in 110 healthy volunteers by Fitzpatrick skin type (FST) and region of the foot. We obtained measurements of the dorsum and plantar foot using a commercially available device (SnapshotNIR, Kent Imaging, Calgary Canada). On the dorsum of the foot, people with FST6 had significantly lower oxygen saturation compared to FST1-5 (p < 0.001), lower oxyhaemoglobin compared to FST2-5 (p = 0.001), but there was no difference in deoxyhaemoglobin. No differences were found on the plantar foot. When comparing dorsal and plantar foot, there was higher oxyhaemoglobin (0.40 ± 0.09 vs. 0.51 ± 0.12, p < 0.001) and deoxyhaemoglobin (0.16 ± 0.05 vs. 0.21 ± 0.05, p < 0.001) on the plantar foot, but no differences in oxygen saturation (dorsal 70.7 ± 10.8, plantar 70.0 ± 9.5, p = 0.414). In 6.4% of feet, there were black areas, for which no NIRS measurements could be generated. All areas with no data were on the dorsal foot and only found in FST 5–6. People with FST6 had significantly larger areas with no data compared to FST 5 (22.2 cm2 ± 20.4 vs. 1.9 cm2 ± 0.90, p = 0.007). These findings should be considered when using NIRS technology. Skin pigmentation should be evaluated in future NIRS studies.
The process of wound healing in the dental pulp is characterized by intricate interplay of signalling cascades, cellular responses, and extracellular matrix (ECM). The objective of this research was to examine the intricate interaction between signalling cascades, cellular responses, and extracellular matrix (ECM) dynamics that comprise the wound healing process of dental pulp. We conducted a controlled laboratory analysis of transcriptomic landscape of dental pulp tissues, including both healthy and inflamed samples, utilizing single-cell RNA sequencing. We identified significant change in cellular composition under carious conditions by analysing samples from 50 patients. Specifically, the proportion of immune cells increased from 25% to 40%, while the proportion of fibroblasts decreased from 20% to 10%. A transition towards ECM remodelling and fibrosis was indicated by this change. In addition, substantial increase inexpression of critical genes including COL1A1, FN1, IL-1B, IL-6 and TNC was detected, indicating that the extracellular matrix (ECM) was actively remodelled and that a robust inflammatory response was present, both of which are vital for tissue repair. Increased cell–cell interactions among B cells, plasma cells, macrophages and MSCs, and fibroblasts were highlighted in our study, demonstrating the intricate cellular dynamics that occur in response to dental pulp injury. The knowledge gained regarding the cellular and molecular processes underlying pulp wound healing contributed to the advancement of knowledge regarding pulp pathology and regeneration. Moreover, it established a foundation for creation of targeted therapeutic interventions that seek to maximize pulp repair and regeneration. This study represented noteworthy achievement in the field of dental surgery, establishing a solid groundwork for subsequent investigations into regenerative medicine, wound healing, and dental tissue restoration.
Cleansing is a vital component of effective wound hygiene and biofilm management, often accomplished through vigorous mechanical action or through soaking with moistened gauze. In the present study, a quantitative comparison of the effectiveness of different cleansing techniques and solutions in removing bacteria was conducted on 71 chronic wounds using bacterial fluorescence imaging as a real-time diagnostic for moderate to high bacterial loads. Vigorous gauze cleansing for 30 s proved most effective by reducing bacterial fluorescence by 33.99%, surpassing 10-min soaking in bacterial reduction (13.24%). Among different cleansers, no statistically significant differences in effectiveness were observed, but povidone-iodine showed the strongest trend towards bacterial reduction. Sub-analysis highlighted the superiority of antiseptic cleansers over saline and gentle soap (−33.30% vs. −1.80% bacterial reduction respectively). Five percent acetic acid was also shown to be more effective in removing specific bacterial strains (Pseudomonas aeruginosa). Findings from studies like this contribute to refining wound hygiene guidelines and clinical algorithms for bacterial and biofilm management.
To review the application of telehealth guidelines developed by Bondini et al for clinicians to determine patient suitability for telehealth in an outpatient Chronic Wound Service, including the proportion of patients suitable for telehealth, type and mode of telehealth encounters. Retrospective, random convenience sample of patients attending the Chronic Wound Service in 2021. Fifty-six patients were included, most with leg/foot wounds (93%), median age 74 [54–84], 64% male. Four patients at admission and 19 patients at review met criteria for telehealth. Six percent of encounters were telehealth; phone-only (82%), unscheduled nursing reviews (77%) in patients with healing wounds. Thirty patients (54%) received at least one telehealth encounter. Telehealth occurred 35.6 days later in the admission than face-to-face encounters (p < 0.05, 95% CI 14.9–56.3). There was a significant relationship between patients receiving telehealth and meeting telehealth suitability criteria on reviews (X 2 (1) = 19.6*, p < 0.001). Eighteen percent of patients required wound-related hospitalisation during their outpatient admission. Telehealth guidelines identified patients suitable for telehealth, although the proportion of patients was small. Telehealth was mostly utilised for nurse-led telephone calls in patients with improving wounds. Future research into use of telephone review for clinical standards of wound care is warranted.
The extraction of wisdom teeth with mandibular impact frequently results in complications including damage to the inferior alveolar nerve (IAN) and malformations of the bone. The objective of this research endeavour was to assess the efficacy of low-level laser therapy and concentrated growth factor (CGF) in facilitating nerve recovery and wound healing in such instances. A total of thirty-one patients (mean age 27.52 ± 5.79 years) who presented with IAN injury after extraction were randomly assigned to one of three groups: control group (which received oral mecobalamin), CGF group (which received CGF gel applied to the extraction sockets) and laser group (which received low-level lasers (808 nm, 30 mW, 10 J/cm2)) at the extraction site. Patients' recovery from IAN paresthesia was evaluated seven times over the course of 14 days utilizing visual analogue scale (VAS) and the pinprick test (PP). At multiple intervals following surgery, periodontal probing and bone level measurements were utilized to assess the recovery of both soft and hard tissues. The findings revealed that, compared with the control group, both the CGF and laser treatment groups exhibited a markedly greater improvement in VAS scores and wound healing of soft tissues, as well as in PP results (p < 0.001), indicating enhanced wound healing processes. Despite these improvements, there was no significant difference in wound healing outcomes between the CGF and laser groups. Notably, the CGF group showed a statistically significant improvement in healing bone defects at 30 and 90 days post-treatment compared with the control group (p = 0.003 and p = 0.004, respectively), underscoring its effectiveness in bone healing as a critical aspect of the overall wound healing process. However, in terms of other wound healing comparisons, no significant differences were observed. CGF and laser therapy significantly enhanced the healing of wounds, including soft tissue and bone recovery, in addition to accelerating the recovery of IAN injuries following mandibular wisdom tooth extraction. Although both treatments were equally effective in nerve recovery, CGF notably excelled in promoting bone healing, suggesting its pivotal role in comprehensive wound healing. This highlights that both CGF and laser therapy are viable options for not only nerve recovery but also for overall wound healing in such dental procedures.
Surgical site infection (SSI) is a common cause of post-operative morbidity. According to the latest report announced by CDC, the SSI accounts for 20% of healthcare-associated infection with a high risk of mortality up to twofold to 11-fold increase with high economic burden for the prolonged hospital stay. Port site infection (PSI) is a subgroup of SSI occurring at the ports of laparoscopy. We tried to determine the efficacy of polyglactin 910 suture coated with triclosan in lowering the rate of PSI in some of the clean-contaminated wound surgeries. This study included 480 individuals eligible for laparoscopic cholecystectomy, appendicectomy or sleeve operations. Polyglactin 910 sutures coated with triclosan were used in one port site incision while polyglactin 910 sutures were used in the other port sites incisions. In patients who underwent laparoscopic cholecystectomy and appendicectomy, the incidence of PSI was significantly lower in the triclosan-coated sutures. In sleeve gastrectomy patients, although a lower number of triclosan-coated sutures developed PSI, there was no statistically significant difference between triclosan and non-triclosan-coated sutures. This study showed that using sutures coated with antiseptics like triclosan has clinical benefits to prevent SSIs in most of the laparoscopic surgeries.
The purpose of this meta-analysis is to determine if the application of stitching in the closed area of the knee arthroplasty remains significantly superior to that of the staples. Data sources: EMBASE, Cochrane Libraryand, publications, and the Web of Science. Patients were treated with staples for closure of their wounds, or with conventional stitches for closure of wounds. The main findings were surgical site infection, wound dehiscence, and cutting time. The secondary results were the time to completion, the duration of the hospitalization, and the time to discharge. We incorporated the SIX trial into the meta-analyses with Review Manager V.5.3. The hazard ratio was computed as a therapeutic outcome with respect to the heterogeneity. For more than 50% of heterogeneous samples, we employed a stochastic effect model. The results showed that there was no significant difference in the degree of infection, the degree of dehiscence, the length of the cut and the degree of satisfaction of the wound. But the time to close the wound and the time to operate were significantly different. The time needed to close the wound was shorter than that of the suture (OR, −227. 22; 95% CI, −238. 74, −215. 69 p < 0. 0001); The time taken to replace the knee was also significantly lower among those who had been stapled sutures (OR, −5.46; 95% CI, −10. 43, −0.49 p = 0. 03). Wound closing materials are an afterthought for many orthopaedic surgeons. Together, the findings from a number of comparative studies indicate that the selection of wound closure materials might affect the outcome of the surgery. The evidence, however, is weak because of the heterogeneous approach adopted in earlier research. This study program is intended to provide guidance on how to select the best wound closure material for the purpose of identifying if there is any difference in the incidence of injuries among traditional stitches and staples.
We investigated the healing effect of a new dehydrated amnion/chorion membrane with a spongy layer over a 30-month period in 32 patients with 53 chronic non-healing wounds of different aetiologies. Wounds with <40% surface reduction after 4 weeks of best wound treatment underwent weekly allograft application by a certified wound specialist based on national guidelines and a standardised protocol until complete healing or definite treatment interruption. The main outcome measure was the percentage of wound surface reduction from baseline calculated using digital planimetry follow-up photographs. Overall, 38 (71.7%) wounds presented a favourable outcome (70%–100% area reduction), with 35 (66%) completely healing over a median time of 77 days (range 29–350 days). Favourable outcomes were observed in 75% of traumatic wounds, surgical wounds, venous leg ulcers and pressure injuries, as well as in 50% of ischaemic wounds. Wounds being present <12 months were significantly more likely to have a favourable outcome than more long-standing wounds (χ2 = 7.799; p = 0.005; OR = 3.378; 95% CI, 1.410–8.092). Thus, treatment with dehydrated amnion/chorion membrane with a spongy layer improves the outcome of non-healing wounds of different aetiologies and, therefore, has to be considered early in the management of refractory wounds.
We investigated the inflammatory (IL-1 alpha) and thermal (infrared thermography) reactions of healthy sacral skin to sustained, irritating mechanical loading. We further acquired digital photographs of the irritated skin (at the visible light domain) to assess whether infrared imaging is advantageous. For clinical context, the skin status was monitored under a polymeric membrane dressing known to modulate the inflammatory skin response. The IL-1 alpha and infrared thermography measurements were consistent in representing the skin status after 40 min of continuous irritation. Infrared thermography overpowered conventional digital photography as a contactless optical method for image processing inputs, by revealing skin irritation trends that were undetectable through digital photography in the visual light, not even with the aid of advanced image processing. The polymeric membrane dressings were shown to offer prophylactic benefits over simple polyurethane foam in the aspects of inflammation reduction and microclimate management. We also concluded that infrared thermography is a feasible method for monitoring the skin health status and the risk for pressure ulcers, as it avoids the complexity of biological marker studies and empowers visual skin assessments or digital photography of skin, both of which were shown to be insufficient for detecting the inflammatory skin status.
A limited understanding of the pathology underlying chronic wounds has hindered the development of effective diagnostic markers and pharmaceutical interventions. This study aimed to elucidate the molecular composition of various common chronic ulcer types to facilitate drug discovery strategies. We conducted a comprehensive analysis of leg ulcers (LUs), encompassing venous and arterial ulcers, foot ulcers (FUs), pressure ulcers (PUs), and compared them with surgical wound healing complications (WHCs). To explore the pathophysiological mechanisms and identify similarities or differences within wounds, we dissected wounds into distinct subregions, including the wound bed, border, and peri-wound areas, and compared them against intact skin. By correlating histopathology, RNA sequencing (RNA-Seq), and immunohistochemistry (IHC), we identified unique genes, pathways, and cell type abundance patterns in each wound type and subregion. These correlations aim to aid clinicians in selecting targeted treatment options and informing the design of future preclinical and clinical studies in wound healing. Notably, specific genes, such as PITX1 and UPP1, exhibited exclusive upregulation in LUs and FUs, potentially offering significant benefits to specialists in limb preservation and clinical treatment decisions. In contrast, comparisons between different wound subregions, regardless of wound type, revealed distinct expression profiles. The pleiotropic chemokine-like ligand GPR15L (C10orf99) and transmembrane serine proteases TMPRSS11A/D were significantly upregulated in wound border subregions. Interestingly, WHCs exhibited a nearly identical transcriptome to PUs, indicating clinical relevance. Histological examination revealed blood vessel occlusions with impaired angiogenesis in chronic wounds, alongside elevated expression of genes and immunoreactive markers related to blood vessel and lymphatic epithelial cells in wound bed subregions. Additionally, inflammatory and epithelial markers indicated heightened inflammatory responses in wound bed and border subregions and reduced wound bed epithelialization. In summary, chronic wounds from diverse anatomical sites share common aspects of wound pathophysiology but also exhibit distinct molecular differences. These unique molecular characteristics present promising opportunities for drug discovery and treatment, particularly for patients suffering from chronic wounds. The identified diagnostic markers hold the potential to enhance preclinical and clinical trials in the field of wound healing.
Chronic wounds contribute to significant healthcare and economic burden worldwide. Wound assessment remains challenging given its complex and dynamic nature. The use of artificial intelligence (AI) and machine learning methods in wound analysis is promising. Explainable modelling can help its integration and acceptance in healthcare systems. We aim to develop an explainable AI model for analysing vascular wound images among an Asian population. Two thousand nine hundred and fifty-seven wound images from a vascular wound image registry from a tertiary institution in Singapore were utilized. The dataset was split into training, validation and test sets. Wound images were classified into four types (neuroischaemic ulcer [NIU], surgical site infections [SSI], venous leg ulcers [VLU], pressure ulcer [PU]), measured with automatic estimation of width, length and depth and segmented into 18 wound and peri-wound features. Data pre-processing was performed using oversampling and augmentation techniques. Convolutional and deep learning models were utilized for model development. The model was evaluated with accuracy, F1 score and receiver operating characteristic (ROC) curves. Explainability methods were used to interpret AI decision reasoning. A web browser application was developed to demonstrate results of the wound AI model with explainability. After development, the model was tested on additional 15 476 unlabelled images to evaluate effectiveness. After the development on the training and validation dataset, the model performance on unseen labelled images in the test set achieved an AUROC of 0.99 for wound classification with mean accuracy of 95.9%. For wound measurements, the model achieved AUROC of 0.97 with mean accuracy of 85.0% for depth classification, and AUROC of 0.92 with mean accuracy of 87.1% for width and length determination. For wound segmentation, an AUROC of 0.95 and mean accuracy of 87.8% was achieved. Testing on unlabelled images, the model confidence score for wound classification was 82.8% with an explainability score of 60.6%. Confidence score was 87.6% for depth classification with 68.0% explainability score, while width and length measurement obtained 93.0% accuracy score with 76.6% explainability. Confidence score for wound segmentation was 83.9%, while explainability was 72.1%. Using explainable AI models, we have developed an algorithm and application for analysis of vascular wound images from an Asian population with accuracy and explainability. With further development, it can be utilized as a clinical decision support system and integrated into existing healthcare electronic systems.
The purpose of the meta-analysis was to evaluate and compare the risk factors for neurosurgical surgical site infection (SSI) after craniotomy. Using dichotomous or contentious random or fixed effect models, the odds ratio (OR) and mean difference (MD) with 95% confidence intervals (CIs) were computed based on the examination of the meta-analysis results. Eighteen analyses, covering 11 068 craniotomies between 2001 and 2023, were included in the current meta-analysis. Subjects with SSIs had a significantly younger age (MD, −2.49; 95% CI, −2.95 to −2.04, p < 0.001), longer operation duration (MD, 10.21; 95% CI, 6.49–13.94, p < 0.001) and longer length of postoperative hospital stay (MD, 1.52; 95% CI, 0.45–2.60, p = 0.006) compared to subjects with no SSI with craniotomy. However, no significant difference was found between craniotomy subjects with SSIs and with no SSI in gender (OR, 0.90; 95% CI, 0.76–1.07, p = 0.23), and combination with other infection (OR, 3.93; 95% CI, 0.28–56.01, p = 0.31). The data that were looked at showed that younger age, longer operation duration and longer length of postoperative hospital stay can be considered as risk factors of SSI in subjects with craniotomy; however, gender and combination with other infections are not. Nonetheless, consideration should be given to their values because several studies only involved a small number of patients, and there are not many studies available for some comparisons.
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