Cysteine-binding adjuvant enhances survival and promotes immune function in a murine model of acute myeloid leukemia.

ABSTRACT: Therapeutic vaccination has long been a promising avenue for cancer immunotherapy but is often limited by tumor heterogeneity. The genetic and molecular diversity between patients often results in variation in the antigens present on cancer cell surfaces. As a result, recent research has focused on personalized cancer vaccines. Although promising, this strategy suffers from time-consuming production, high cost, inaccessibility, and targeting of a limited number of tumor antigens. Instead, we explore an antigen-agnostic polymeric in situ cancer vaccination platform for treating blood malignancies, in our model here with acute myeloid leukemia (AML). Rather than immunizing against specific antigens or targeting adjuvant to specific cell-surface markers, this platform leverages a characteristic metabolic and enzymatic dysregulation in cancer cells that produces an excess of free cysteine thiols on their surfaces. These thiols increase in abundance after treatment with cytotoxic agents such as cytarabine, the current standard of care in AML. The resulting free thiols can undergo efficient disulfide exchange with pyridyl disulfide (PDS) moieties on our construct and allow for in situ covalent attachment to cancer cell surfaces and debris. PDS-functionalized monomers are incorporated into a statistical copolymer with pendant mannose groups and TLR7 agonists to target covalently linked antigen and adjuvant to antigen-presenting cells in the liver and spleen after IV administration. There, the compound initiates an anticancer immune response, including T-cell activation and antibody generation, ultimately prolonging survival in cancer-bearing mice.

(How) ChatGPT-Artificial Intelligence Thinks It Can Help/Harm Physiatry.

ABSTRACT: ChatGPT is a chatbot that is based on the generative pretrained transformer architecture as an artificial inteligence-based large language model. Its widespread use in healthcare practice, research, and education seems to be (increasingly) inevitable. Also considering the relevant limitations regarding privacy, ethics, bias, legal, and validity, in this article, its use as a supplement (for sure not as a substitute for physicians) is discussed in light of the recent literature. Particularly, the "opinion" of ChatGPT about how it can help/harm physiatry is exemplified.

Enhanced serum levels of tumor necrosis factor-α, interleukin-1ß, and -6 in sarcopenia: alleviation through exercise and nutrition intervention.

BACKGROUND: Limited research has been conducted on the post-intervention inflammatory status in sarcopenic patients, despite previous studies revealing elevated pro-inflammatory markers. This study aimed to investigate the potential elevation of specific pro-inflammatory cytokines in sarcopenic patients and evaluate the effects of exercise and nutritional support interventions on these cytokine levels. METHODS: In this post-hoc analysis of a randomized controlled trial (RCT), 57 individuals with sarcopenia from the RCT and 57 non-sarcopenic participants from the same geriatric community cohort that did not participate in the RCT were enrolled. Grip strength and body composition measurements were recorded. Tumor necrotizing factor (TNF)-α, interleukin (IL)-1ß, IL-6, and IL-15 levels were assessed at baseline for both groups and after a 12-week intervention consisting of resistive exercise and supplementation with branched-chain amino acids, calcium, and vitamin D3 in the patients with sarcopenia. RESULTS: The sarcopenic group demonstrated significantly lower body weight, body mass index, grip strength, and skeletal muscle mass index. Moreover, sarcopenic patients exhibited higher levels of TNF-α (p=0.007), IL-1ß (p<0.001), and IL-6 (p<0.001), while no significant difference was observed in IL-15 (p=0.345) between participants with and those without sarcopenia. Following the intervention, the sarcopenic group experienced significant improvements in grip strength and skeletal muscle mass index with a notable reduction in TNF-α (p=0.003), IL-1ß (p=0.012) and IL-6 (p=0.001) levels. CONCLUSIONS: Sarcopenic patients exhibit elevated levels of TNF-α, IL-1ß, and IL-6, which declined after nutrition support and exercise interventions. However, further research is necessary to evaluate the long-term impact of these interventions on cytokine levels.

Limited Relevance of the Very Low Risk Prostate Cancer Classification in the Modern Era: Results from a Large Institutional Active Surveillance Cohort.

Although the American Urological Association recently dropped the very low-risk (VLR) subcategory for low-risk prostate cancer (PCa) and the European Association of Urology does not substratify low-risk PCa, the National Comprehensive Cancer Network (NCCN) guidelines still maintain this stratum, which is based on the number of positive biopsy cores, tumor extent in each core, and prostate-specific antigen density. This subdivision may be less applicable in the modern era in which imaging-targeted prostate biopsies are common practice. In our large institutional active surveillance cohort of patients diagnosed from 2000 to 2020 (n = 1276), the number of patients meeting NCCN VLR criteria decreased significantly in recent years, with no patient meeting VLR criteria after 2018. By contrast, the multivariable Cancer of the Prostate Risk Assessment (CAPRA) score effectively substratified patients over the same period and was predictive of upgrading on repeat biopsy to Gleason grade group ≥2 on multivariable Cox proportional-hazards regression modeling (hazard ratio 1.21, 95% confidence interval 1.05-1.39; p < 0.01), independent of age, genomic test results, and magnetic resonance imaging findings. These findings suggest that the NCCN VLR criteria are less applicable in the targeted biopsy era, and that the CAPRA score or similar instruments are better contemporary risk stratification tools for men on active surveillance. PATIENT SUMMARY: We investigated whether the National Comprehensive Cancer Network classification of very low risk (VLR) for prostate cancer is relevant in the modern era. We found that in a large group of patients on active surveillance, no man diagnosed after 2018 satisfied the VLR criteria. However, the Cancer of the Prostate Risk Assessment (CAPRA) score discriminated patients by cancer risk at diagnosis and was predictive of outcomes on active surveillance, and thus may be a more relevant classification scheme in the modern era.

Efficacy of Acupuncture, Intravenous Lidocaine, and Diet in the Management of Patients with Fibromyalgia: A Systematic Review and Network Meta-Analysis.

Introduction: This network meta-analysis aimed to assess the efficacy of acupuncture, intravenous lidocaine, and diet compared with other comparators such as physiotherapy and sham/placebo in fibromyalgia patients. Materials and Methods: We searched Embase, PubMed, Scopus, and Web of Science for relevant studies till September 2021. The included studies were randomized controlled clinical trials. For the network meta-analysis, we used the R software. Results: There were 23 included RCTs. The total sample size was 1409 patients. Compared with the sham/placebo group, the network analysis showed the highest improvement in the quality of life in the acupuncture group standardized mean difference (SMD) = -10.28, 95%-CI [-14.96; -5.59]), and then in the physiotherapy group (SMD = -7.48, 95%-CI [-14.72; -0.23]). For the pain, there was a significant reduction with acupuncture (SMD = -1.69, 95%-CI [-2.48; -0.89]), compared with sham/placebo. Regarding depression, it showed a significant reduction with acupuncture (SMD = -9.64, 95%-CI [-16.13; -3.14]) compared with sham/placebo. Finally, for stiffness, it showed no significant differences in the stiffness between acupuncture (SMD = -8.52, 95%-CI [-20.40; 3.36]), fluoxetine (SMD = -6.52, 95%-CI [-29.65; 16.61]), and physiotherapy (SMD = -4.64, 95%-CI [-22.83; 13.54]) compared with sham/placebo. Conclusions: The acupuncture showed a significant effect in the management of fibromyalgia patients. It reduced pain, depression, and enhanced the quality of life. While physiotherapy showed a significant improvement in the quality of life only. In contrast, intravenous lidocaine and diet showed no significant differences when compared with sham/placebo.

A role for substance P and acid-sensing ion channel 1a in prolotherapy with dextrose-mediated analgesia in a mouse model of chronic muscle pain.

ABSTRACT: Prolotherapy is widely used in pain control and tissue repair in pain medicine. The classical mode is injection with hypertonic dextrose in muscle or perimysium. However, the analgesic mechanism is still not known. Here, we successfully established dextrose-mediated antinociception in a mouse model of fibromyalgia. The antinociceptive effects of dextrose injections were evaluated in a mouse model of fibromyalgia, in which bilateral chronic mechanical hyperalgesia was induced by unilateral intramuscular acid injection. The injectant (dextrose), dose (≥5%), and volume (>10 µL), but not osmolarity, were essential for the prolotherapy. Further studies showed that the activation of acid-sensing ion channel 1a (ASIC1a), neural activation, and the release of substance P from muscle afferents were required in the dextrose-induced reduction of mechanical hypersensitivity. Both pharmacological blockade and genetic deletion of ASIC1a or substance P as well as lidocaine abolished the dextrose-induced antinociception in mice with chronic hyperalgesia. Moreover, intramuscular dextrose injection induced phosphorylated extracellular signal-regulated kinase expression in dorsal root ganglion neurons expressing substance P; the phosphorylated extracellular signal-regulated kinase expression was inhibited by the ASIC1a antagonist PcTx1. The optimal settings for prolotherapy in fibromyalgia-like pain are dextrose dependent and volume dependent, and the peripheral antinociception involves ASIC1a and substance P signaling in muscle afferents. This study suggests a possible mechanism of action of dextrose prolotherapy in noninflammatory muscle pain such as fibromyalgia and provides insights into treating other types of chronic pain.

Diagnosing sarcopenia: Functional perspectives and a new algorithm from the ISarcoPRM.

Sarcopenia is an important public health problem, characterized by age-related loss of muscle mass and muscle function. It is a precursor of physical frailty, mobility limitation, and premature death. Muscle loss is mainly due to the loss of type II muscle fibres, and progressive loss of motor neurones is thought to be the primary underlying factor. Anterior thigh muscles undergo atrophy earlier, and the loss of anterior thigh muscle function may therefore be an antecedent finding. The aim of this review is to provide an in-depth (and holistic) neuromusculoskeletal approach to sarcopenia. In addition, under the umbrella of the International Society of Physical and Rehabilitation Medicine (ISPRM), a novel diagnostic algorithm is proposed, developed with the consensus of experts in the special interest group on sarcopenia (ISarcoPRM). The advantages of this algorithm over the others are: special caution concerning disorders related to the renin-angiotensin system at the case finding stage; emphasis on anterior thigh muscle mass and function loss; incorporation of ultrasound for the first time to measure the anterior thigh muscle; and addition of a chair stand test as a power/performance test to assess anterior thigh muscle function. Refining and testing the algorithm remains a priority for future research.

Effectiveness of early versus delayed exercise and nutritional intervention on segmental body composition of sarcopenic elders - A randomized controlled trial.

BACKGROUND & AIMS: Although resistance training with nutritional support is considered the best treatment option for sarcopenia, the importance of home-based exercise should not be overlooked. For managing sarcopenia, a fundamental issue is whether home-based exercise or a supervised training program should be administered first. Therefore, the present trial aimed to compare the effect of early versus delayed exercise intervention with nutritional support on the physical performance and body composition of sarcopenic elders. METHODS: The study was a randomized controlled trial using a parallel-group design. Each group received two therapeutic periods lasted 12 weeks with an interval of 2 weeks in between. Physical performance and body composition were assessed at baseline and immediately following the end of the first and second phases. One phase included hospital-based resistance training and nutritional support (amino acid, calcium, and vitamin D3), whereas the other phase included home-based exercise. In the early intervention group, supervised exercise and nutrition supplementation were administered first followed by home-based exercise, whereas the sequence was reversed in the delayed intervention group. The influence of intervention sequence on the outcome variables was examined using a 3∗2 repeated-measures analysis of variance. The primary endpoints were defined as changes in lean mass and related physical function (grip strength and gait speed) over 12 and 26 weeks of interventions. RESULTS: A total of 57 sarcopenic elders were randomly assigned to the early (n = 29) and delayed (n = 28) intervention groups. Among the primary endpoints, the only significant group-time interaction was recognized on the changes of lower extremity lean mass (p = 0.039). The early intervention was associated with an earlier increase in lower extremity lean mass (770.8 g, 95% confidence interval (CI), 564.8 g-976.9 g) than delayed intervention (294.2 g, 95% CI, -42.13 to 630.5 g) which was evident from the between-group comparison between baseline and the 1st follow-up (p = 0.016). No significant effect of group-time interaction was observed on the physical performance and other components of body composition. CONCLUSIONS: Early exercise and nutritional intervention may be helpful in an earlier restoration of lower extremity muscle mass but not physical function in sarcopenic elders. When designing a rehabilitation program for patients with sarcopenia, resistance training with nutrition support can be prescribed first for the rapid enlargement of the muscle volume, and structuralized home-based exercise can be administered subsequently to preserve the prior intervention effect. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02779088).

Expression of Telomeric Repeat-Containing RNA Decreases in Sarcopenia and Increases after Exercise and Nutrition Intervention.

Sarcopenia is defined as aging-related loss of muscle mass and function. Telomere length in chromosomes shortens with age and is modulated by telomeric repeat-containing RNA (TERRA). This study aimed to explore the impact of aging and sarcopenia on telomere length and TERRA expression, and changes following strengthening exercise and nutrition intervention (supplement of branched-chain amino acids, calcium and vitamin D3) for 12 weeks in the sarcopenic population. Older adults (≥65 years old) were divided into non-sarcopenic controls (n = 36) and sarcopenic individuals (n = 36) after measurement of grip strength and body composition. The relative telomere length of leukocytes in all research participants was evaluated using the T/S ratio (telomere/single copy gene), and relative TERRA expression of leukocytes was determined by reverse-transcription qPCR (RT-qPCR). Generalized estimating equation (GEE) was used to analyze the influence of sarcopenia and intervention on the outcomes. There was no significant difference in telomere length between control subjects and participants with sarcopenia. TERRA expression was lower in sarcopenic participants compared to that in non-sarcopenic controls (5.18 ± 2.98 vs. 2.51 ± 1.89; p < 0.001). In the sarcopenic group, intervention significantly increased TERRA expression, but not telomere length. The GEE analysis demonstrated that TERRA expression was negatively associated with sarcopenia (ß coefficient = -2.705, p < 0.001) but positively associated with intervention (ß coefficient = 1.599, p = 0.023). Sarcopenia is associated with a decrease in TERRA expression in leukocytes. Rebound TERRA expression (returning to the level similar to the non-sarcopenic controls) was observed in the sarcopenic group after exercise and nutrition intervention. Future studies are warranted to examine the potential of TERRA as a biomarker for sarcopenia and its subsequent responses to intervention.

'Scientific Strabismus' or two related pandemics: coronavirus disease and vitamin D deficiency.

The WHO has announced the novel coronavirus disease (COVID-19) outbreak to be a global pandemic. The distribution of community outbreaks shows seasonal patterns along certain latitude, temperature and humidity, that is, similar to the behaviour of seasonal viral respiratory tract infections. COVID-19 displays significant spread in northern mid-latitude countries with an average temperature of 5­11°C and low humidity. Vitamin D deficiency has also been described as pandemic, especially in Europe. Regardless of age, ethnicity and latitude, recent data showed that 40 % of Europeans are vitamin D deficient (25-hydroxyvitamin D (25(OH)D) levels <50 nmol/l), and 13 % are severely deficient (25(OH)D < 30 nmol/l). A quadratic relationship was found between the prevalences of vitamin D deficiency in most commonly affected countries by COVID-19 and the latitudes. Vitamin D deficiency is more common in the subtropical and mid-latitude countries than the tropical and high-latitude countries. The most commonly affected countries with severe vitamin D deficiency are from the subtropical (Saudi Arabia 46 %; Qatar 46 %; Iran 33·4 %; Chile 26·4 %) and mid-latitude (France 27·3 %; Portugal 21·2 %; Austria 19·3 %) regions. Severe vitamin D deficiency was found to be nearly 0 % in some high-latitude countries (e.g. Norway, Finland, Sweden, Denmark and Netherlands). Accordingly, we would like to call attention to the possible association between severe vitamin D deficiency and mortality pertaining to COVID-19. Given its rare side effects and relatively wide safety, prophylactic vitamin D supplementation and/or food fortification might reasonably serve as a very convenient adjuvant therapy for these two worldwide public health problems alike.

EURO-MUSCULUS/USPRM Global Report on Musculoskeletal Ultrasound Publications.

The developments in technology have improved access to the use of musculoskeletal ultrasound (MSUS) in different clinical settings. Accordingly, MSUS has been applied to a wide range of musculoskeletal problems including inflammatory and degenerative diseases, sport injuries, and regional pain syndromes both for clinical practice and research. In this report, the authors aimed to globally examine the publications on MSUS among different specialties, countries, and topics. Sixteen reviewers under the umbrella of the European Musculoskeletal Ultrasonography Society Group and the Ultrasound Study Group of International Society of Physical and Rehabilitation Medicine have evaluated approximately 15,000 publications on MSUS. The authors believe that the results of this comparative analysis may provide a holistic snapshot with regard to the utility of MSUS, not only for clinicians/academicians but also for the industry. Accordingly, while aiming to further increase their awareness, this article would possibly guide future investments as well.

Comparative Effectiveness of Botulinum Toxin Injection for Chronic Shoulder Pain: A Meta-Analysis of Randomized Controlled Trials.

Botulinum toxin (BoNT) injection is regarded as a promising treatment for musculoskeletal pain. However, its efficacy for treating chronic shoulder pain remains unclear. We investigated the effectiveness of BoNT injections for chronic shoulder pain by conducting a systematic search of electronic databases up to March 2020 for randomized control trials (RCTs) that used BoNT injections for chronic shoulder pain treatment. The primary outcome was the between-group comparison of pain reduction, quantified by the standardized mean difference (SMD). Nine RCTs comprising 666 patients were included and divided into two groups: one group with shoulder joint pain (n = 182) and the other group with shoulder myofascial pain (n = 484). Regarding shoulder joint pain, the efficacy of BoNT injections was similar to that of the reference treatment (SMD: -0.605, 95% confidence level [CI]: -1.242 to 0.032 versus saline; SMD: -0.180, 95% CI: -0.514 to 0.153 versus corticosteroids) at one month post-intervention, and was superior (SMD: -0.648, 95% CI: -0.1071 to -0.225 versus corticosteroids) between one and three months. Likewise, in terms of shoulder myofascial pain, the effectiveness of BoNT injections did not differ from the reference treatment (SMD: -0.212, 95% CI: -0.551 to 0.127 versus saline; SMD: 0.665, 95% CI: -0.260 to 1.590 versus dry needling and SMD: 1.093; 95% CI: 0.128 to 2.058 versus lidocaine) at one month post- intervention, and appeared superior (SMD: -0.314, 95% CI: -0.516 to -0.111 versus saline) between one and three months. Our meta-analysis revealed that BoNT injections could be a safe and effective alternative for patients with chronic shoulder pain.

P/Q and N-type Voltage-gated Calcium Channel Binding Antibodies Associated with Paraneoplastic Chorea and Mixed Invasive Ductal and Lobular Carcinoma of the Breasts in an Elderly Patient.

Paraneoplastic neurologic syndromes are a group of immune-mediated, cancer-associated disorders affecting the nervous system. While these syndromes are not understood fully, they are reportedly caused by an immune response against common antigens expressed by the cancer and nervous system. We describe the course of a patient who suffered paraneoplastic chorea before being diagnosed with breast cancer. A 70-year-old female presented with complaints of "shaking" movements of her head. History, physical exam findings, and preliminary workup ruled out the hereditary, metabolic, and infectious causes of chorea while brain computed tomography (CT) ruled out chorea due to a basal ganglia lesion. A paraneoplastic antibody panel identified N-type and P/Q-type voltage-gated (V-G) calcium channel binding antibodies. Subsequent age-appropriate cancer screening, which included a colonoscopy and screening mammograms, identified breast cancer. The patient had bilateral total mastectomies. Histopathology confirmed mixed invasive ductal and lobular carcinoma that was estrogen receptor positive, progesterone receptor positive, and human epidermal growth factor receptor 2 negative. In addition to mastectomies, the patient received adjuvant anastrozole. The appearance of choreiform movements before the diagnosis of breast cancer and the presence of paraneoplastic antibodies indicated that the chorea was most likely paraneoplastic in nature. Our patient continues to have choreiform movements despite undergoing bilateral mastectomies and receiving anastrozole, prednisone, and rituximab. We suspect the mastectomies and immune modulating therapies have not had an effect on her chorea because her P/Q and N-type V-G calcium channel binding antibodies may be intracellular. This case of paraneoplastic chorea associated with breast cancer is unusual. To the best of our knowledge, only one other case of paraneoplastic chorea associated with breast cancer has been reported in the English literature.

ACR Appropriateness Criteria® Colorectal Cancer Screening.

This review summarizes the relevant literature regarding colorectal screening with imaging. For individuals at average or moderate risk for colorectal cancer, CT colonography is usually appropriate for colorectal cancer screening. After positive results on a fecal occult blood test or immunohistochemical test, CT colonography is usually appropriate for colorectal cancer detection. For individuals at high risk for colorectal cancer (eg, hereditary nonpolyposis colorectal cancer, ulcerative colitis, or Crohn colitis), optical colonoscopy is preferred because of its ability to obtain biopsies to detect dysplasia. After incomplete colonoscopy, CT colonography is usually appropriate for colorectal cancer screening for individuals at average, moderate, or high risk. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

Comparative effectiveness of dextrose prolotherapy versus control injections and exercise in the management of osteoarthritis pain: a systematic review and meta-analysis.

BACKGROUND: Increasing evidence has supported the use of dextrose prolotherapy for patients with osteoarthritis. However, the real benefits may be affected by differences in injection protocols, comparative regimens, and evaluation scales. METHODS: PubMed and Scopus were searched from the earliest record until February 2016. One single-arm study and five randomized controlled trials were included, comprising 326 participants. We estimated the effect sizes of pain reduction before and after serial dextrose injections and compared the values between dextrose prolotherapy, comparative regimens, and exercise 6 months after the initial injection. RESULTS: Regarding the treatment arm using dextrose prolotherapy, the effect sizes compared with baseline were 0.65 (95% confidence interval [CI], 0.14-1.17), 0.84 (95% CI, 0.40-1.27), 0.85 (95% CI, 0.60-1.10), and 0.87 (95% CI, 0.53-1.21) after the first, second, third, and fourth or more injections, respectively. The overall effect of dextrose was better than control injections (effect size, 0.36; 95% CI, 0.10-0.63). Dextrose prolotherapy had a superior effect compared with local anesthesia (effect size, 0.38; 95% CI, 0.07-0.70) and exercise (effect size, 0.71; 95% CI, 0.30-1.11). There was an insignificant advantage of dextrose over corticosteroids (effect size, 0.31; 95% CI, -0.18 to 0.80) which was only estimated from one study. CONCLUSION: Dextrose injections decreased pain in osteoarthritis patients but did not exhibit a positive dose-response relationship following serial injections. Dextrose prolotherapy was found to provide a better therapeutic effect than exercise, local anesthetics, and probably corticosteroids when patients were retested 6 months following the initial injection.

Comparative effectiveness of autologous blood-derived products, shock-wave therapy and corticosteroids for treatment of plantar fasciitis: a network meta-analysis.

OBJECTIVE: To compare the efficacy of autologous blood-derived products (ABPs), CSs and shock-wave (SW) therapy in the treatment of plantar fasciitis. METHODS: Electronic databases were searched for studies that compared ABPs, CSs and SW therapy for the treatment of plantar fasciitis, published up to June 2014. The primary and secondary outcomes were reduction in visual analogue scale (VAS) score at 3 and 6 months and odds ratio of treatment success, respectively. Groups were compared by traditional pair-wise meta-analysis and by network meta-analysis. RESULTS: Seven randomized controlled trials and three quasi-experimental studies that included 604 patients were enrolled. Pair-wise meta-analysis indicated a trend favouring ABPs over CSs regarding VAS reduction at 3 months; this benefit was significant in a subgroup analysis of platelet-rich plasma (PRP) vs CSs. There were no significant between-group differences in VAS reduction at 6 months and in treatment success. Network meta-analysis showed that ABPs had the highest probability of being the best treatment at 3 months, but ABPs were slightly inferior to SW for VAS reduction at 6 months. Although SW therapy had the highest likelihood of treatment success, the between-group differences in probabilities were less remarkable than those for pain reduction at 3 and 6 months. CONCLUSION: ABPs, followed by CSs, were best in providing relief from pain at 3 months. SW therapy and ABPs had similar probabilities of providing pain relief at 6 months, and were better than CSs at that time. Subgroup analysis indicated that an ABP regimen consisting of platelet-rich plasma improves treatment efficacy.