The endocannabinoid system, cannabis, and cannabidiol: Implications in urology and men's health.

BACKGROUND: The endocannabinoid system is a neuromodulatory system responsible for partial regulation of cognitive and emotional processes in the human central nervous system such as behavior, mood disorders, and neurologic disorders such as epilepsy. The endocannabinoid system is also prevalent throughout the peripheral nervous system and human body and its receptors and signaling pathways are present and active in areas including the male and female reproductive tracts and organ systems such as the urologic and gastrointestinal system. SUMMARY: The purpose of this article is to provide the reader with a brief background on the endocannabinoid system and to discuss the implications of the endocannabinoid system in urology as it applies to the male reproductive system, risk of urologic malignancy, and impact on the lower urinary tract, voiding, and urologic pain. It also summaries and discusses the epidemiology and research on cannabis and cannabidiol products. KEY MESSAGE: The endocannabinoid system affects the urologic and reproductive systems. Cannabis products and inhibitors targeting endocannabinoid pathways are being studied for their potential use as treatments for lower urinary tract symptoms and other urologic symptoms. Cannabis use adversely affects spermatogenesis and semen parameters and may be a risk factor for testicular germ cell tumors, however, it may be useful as a potential treatment for urologic symptoms. Cannabidiol products are popular in the consumer marketplace but there is still a paucity of scientific data on their potential medicinal use.

Traditional Chinese herbal medicine-potential therapeutic application for the treatment of COVID-19.

Traditional Chinese Medicine (TCM) is a complete medical system that has evolved over millennia to include practices and procedures such as acupuncture, herbal medicine, manual therapies, nutrition, and mind-body therapies such as qi gong. In modern-day China and other Asian countries, TCM is a medical subspecialty utilized alongside western biomedicine. During the current Coronavirus Disease 19 (COVID-19) pandemic, TCM and TCM herbal medicine is being used and a number of single herbs and combination formulas have significant bioactivity and therapeutic potential. The purpose of this paper is to highlight the use of TCM in the treatment of COVID-19. This commentary provides the reader with a concise background on COVID-19 and summarizes TCM concepts including identification, pattern diagnosis, and treatment principles commonly used for the treatment of viral influenza-like diseases. It also highlights some of the challenges and potential for using TCM in an integrated medical setting.

A Randomized, Double-Blind, Sham-Controlled Study Assessing Electroacupuncture for the Management of Postoperative Pain after Percutaneous Nephrolithotomy.

INTRODUCTION: Percutaneous nephrolithotomy (PCNL) is the gold standard procedure for large renal calculi but postoperative (PO) pain remains a concern. Modifications of the PCNL technique and intraoperative and PO strategies have been tested to reduce pain. PO pain control reducing risk of long-term pain medication and narcotic use is of considerable importance. Acupuncture is a common medical procedure shown to alleviate PO pain. Some benefits are that it is nonpharmacologic, easy to administer, and safe. The purpose of this study was to evaluate the effects of electroacupuncture (EA) on PO pain in patients undergoing PCNL. MATERIALS AND METHODS: This was a randomized, double-blind, sham-controlled study. The study was Institutional Review Board approved and performed under standard ethical guidelines. Fifty-one patients undergoing PCNL by a single surgeon were randomized to one of the three groups: true EA (n = 17), sham EA (SEA, n = 17), and no acupuncture (control, n = 17). The EA and SEA were performed by a single licensed acupuncturist <1 hour before operation. PCNL was performed without the use of intraoperative nerve block(s) or local anesthetic. Pain scores (visual analog scale [VAS]), narcotic use (morphine equivalents), and side effects were recorded at set intervals postoperatively. RESULTS: Mean VAS scores for flank and abdomen pain were lower at all time periods in the EA compared with the SEA and control groups. Mean cumulative opioid usage was lower in the EA group immediately postoperatively compared with both SEA and control groups. Two patients in the EA group did not require any PO narcotics. No differences between groups were found for PO nausea and vomiting. No adverse effects of EA or SEA were noted. CONCLUSIONS: EA significantly reduced PO pain and narcotic usage without any adverse effects after PCNL. This promising treatment for managing PO pain warrants further investigation.

Effect of Acupuncture vs Sham Acupuncture or Waitlist Control on Joint Pain Related to Aromatase Inhibitors Among Women With Early-Stage Breast Cancer: A Randomized Clinical Trial.

Importance: Musculoskeletal symptoms are the most common adverse effects of aromatase inhibitors and often result in therapy discontinuation. Small studies suggest that acupuncture may decrease aromatase inhibitor-related joint symptoms. Objective: To determine the effect of acupuncture in reducing aromatase inhibitor-related joint pain. Design, Setting, and Patients: Randomized clinical trial conducted at 11 academic centers and clinical sites in the United States from March 2012 to February 2017 (final date of follow-up, September 5, 2017). Eligible patients were postmenopausal women with early-stage breast cancer who were taking an aromatase inhibitor and scored at least 3 on the Brief Pain Inventory Worst Pain (BPI-WP) item (score range, 0-10; higher scores indicate greater pain). Interventions: Patients were randomized 2:1:1 to the true acupuncture (n = 110), sham acupuncture (n = 59), or waitlist control (n = 57) group. True acupuncture and sham acupuncture protocols consisted of 12 acupuncture sessions over 6 weeks (2 sessions per week), followed by 1 session per week for 6 weeks. The waitlist control group did not receive any intervention. All participants were offered 10 acupuncture sessions to be used between weeks 24 and 52. Main Outcomes and Measures: The primary end point was the 6-week BPI-WP score. Mean 6-week BPI-WP scores were compared by study group using linear regression, adjusted for baseline pain and stratification factors (clinically meaningful difference specified as 2 points). Results: Among 226 randomized patients (mean [SD] age, 60.7 [8.6] years; 88% white; mean [SD] baseline BPI-WP score, 6.6 [1.5]), 206 (91.1%) completed the trial. From baseline to 6 weeks, the mean observed BPI-WP score decreased by 2.05 points (reduced pain) in the true acupuncture group, by 1.07 points in the sham acupuncture group, and by 0.99 points in the waitlist control group. The adjusted difference for true acupuncture vs sham acupuncture was 0.92 points (95% CI, 0.20-1.65; P = .01) and for true acupuncture vs waitlist control was 0.96 points (95% CI, 0.24-1.67; P = .01). Patients in the true acupuncture group experienced more grade 1 bruising compared with patients in the sham acupuncture group (47% vs 25%; P = .01). Conclusions and Relevance: Among postmenopausal women with early-stage breast cancer and aromatase inhibitor-related arthralgias, true acupuncture compared with sham acupuncture or with waitlist control resulted in a statistically significant reduction in joint pain at 6 weeks, although the observed improvement was of uncertain clinical importance. Trial Registration: ClinicalTrials.gov Identifier: NCT01535066.

Integrating dietary supplements into cancer care.

Many studies confirm that a majority of patients undergoing cancer therapy use self-selected forms of complementary therapies, mainly dietary supplements. Unfortunately, patients often do not report their use of supplements to their providers. The failure of physicians to communicate effectively with patients on this use may result in a loss of trust within the therapeutic relationship and in the selection by patients of harmful, useless, or ineffective and costly nonconventional therapies when effective integrative interventions may exist. Poor communication may also lead to diminishment of patient autonomy and self-efficacy and thereby interfere with the healing response. To be open to the patient's perspective, and sensitive to his or her need for autonomy and empowerment, physicians may need a shift in their own perspectives. Perhaps the optimal approach is to discuss both the facts and the uncertainty with the patient, in order to reach a mutually informed decision. Today's informed patients truly value physicians who appreciate them as equal participants in making their own health care choices. To reach a mutually informed decision about the use of these supplements, the Clinical Practice Committee of The Society of Integrative Oncology undertook the challenge of providing basic information to physicians who wish to discuss these issues with their patients. A list of leading supplements that have the best suggestions of benefit was constructed by leading researchers and clinicians who have experience in using these supplements. This list includes curcumin, glutamine, vitamin D, Maitake mushrooms, fish oil, green tea, milk thistle, Astragalus, melatonin, and probiotics. The list includes basic information on each supplement, such as evidence on effectiveness and clinical trials, adverse effects, and interactions with medications. The information was constructed to provide an up-to-date base of knowledge, so that physicians and other health care providers would be aware of the supplements and be able to discuss realistic expectations and potential benefits and risks.

Zyflamend inhibits the expression and function of androgen receptor and acts synergistically with bicalutimide to inhibit prostate cancer cell growth.

BACKGROUND: Interference of androgen receptor (AR) signaling is a target for prostate cancer (CaP) chemoprevention and treatment. We hypothesize that Zyflamend (ZYF) assert its anti-cancer effect by disrupting AR signaling. We also hypothesize that it may act synergistically with the anti-androgen bicalutimde to inhibit CaP cell growth. METHODS: Western blotting, ELISA and reporter assays were done to test ZYF on AR signaling. Semi-quantitative RT-PCR and AR half-life were also examined. Potential synergism between ZYF and bicalutimide were tested via cytotoxicity, colony formation assays, flow cytometry, and Western blotting in the human CAP line, LNCaP and 22RV1. RESULTS: ZYF reduced AR protein, mRNA and protein stability levels in LNCaPs. ZYF also reduced both full-length AR protein and truncated AR protein in the 22Rv1 cell line. Nkx3.1 and PSA were also reduced at the mRNA level. PSA promoter activity and secretion were lower after treatment of cells with ZYF. DHT induction of cell proliferation and AR responsiveness revealed reduction of AR, Nkx3.1, and PSA protein were demonstrated with ZYF treatment. Co-treatment with bicalutimide reducing cell growth, induced apoptosis, and reduced Bcl-2 and BclxL, caspase-3 and PARP. Co-treatment also reduced Nkx3.1 and PSA protein. CONCLUSIONS: These data indicate that ZYF suppresses cell growth mediated by AR signaling, and suggests that the co-treatment with the anti-androgen bicalutimide and ZYF may be a promising approach for cancer therapy and may demonstrate the mechanism of action of ZYF.

Two case reports on the use of genistein combined polysaccharide (GCP) against bladder cancer recurrence.

We followed two subjects with resected stage Ta superficial transitional cell carcinoma (TCC) of the bladder who had not received intravesicle bacillus Calmette-Guerin (BCG) and received supplementation with the agent Genistein Combined Polysaccharide (GCP) in an IRB approved study. The observation period was 12 months for both cases. After the yearly oral dosage of GCP, there was no recurrence in either of the subjects as determined by cytoscopy, urine cytology, and fluorescence in-situ hybridization analysis of urine (UrovysionTM FISH Assay). The intravenous pyelogram (IVP), obtained at baseline and after 12 months, was also negative. There were no adverse events over the course of treatment and had full patient compliance and tolerability of the GCP agent in both cases.

Acupuncture in the oncology setting: clinical trial update.

Acupuncture, the insertion of sterile needles into acupuncture points of traditional meridians on the body, is a common and effective treatment for a number of supportive care issues in oncology including acute chemotherapy-induced nausea and vomiting. In the Integrative Oncology setting, acupuncture and Traditional Oriental Medicine have become more visible and many oncology clinics, academic health centers and comprehensive cancer centers recommend and administer acupuncture treatment. Continued basic studies on the physiologic mechanisms of acupuncture and recent clinical trials of acupuncture for cancer patients are enhancing our knowledge and informing our guidelines. While debates on methodological problems confronting the study of acupuncture remain, the most recent research demonstrates that acupuncture is safe, tolerable and effective for a range of side effects resulting from conventional cancer treatments.

Randomized, blinded, sham-controlled trial of acupuncture for the management of aromatase inhibitor-associated joint symptoms in women with early-stage breast cancer.

PURPOSE Women with breast cancer (BC) treated with aromatase inhibitors (AIs) may experience joint symptoms that can lead to discontinuation of effective therapy. We examined whether acupuncture improves AI-induced arthralgias in women with early-stage BC. METHODS We conducted a randomized, controlled, blinded study comparing true acupuncture (TA) versus sham acupuncture (SA) twice weekly for 6 weeks in postmenopuasal women with BC who had self-reported musculoskeletal pain related to AIs. TA included full body/auricular acupuncture and joint-specific point prescriptions, whereas SA involved superficial needle insertion at nonacupoint locations. Outcome measures included the Brief Pain Inventory-Short Form (BPI-SF), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and Modified Score for the Assessment of Chronic Rheumatoid Affections of the Hands (M-SACRAH) obtained at baseline and at 3 and 6 weeks. Results Of 51 women enrolled, 43 women were randomly assigned and 38 were evaluable. Baseline characteristics were comparable between the two groups. Our primary end point was the difference in mean BPI-SF worst pain scores at 6 weeks, which was lower for TA compared with SA (3.0 v 5.5; P < .001). We also found differences between TA and SA in pain severity (2.6 v 4.5; P = .003) and pain-related interference (2.5 v 4.5; P = .002) at 6 weeks. Similar findings were seen for the WOMAC and M-SACRAH scores. The acupuncture intervention was well-tolerated. CONCLUSION Women with AI-induced arthralgias treated with TA had significant improvement of joint pain and stiffness, which was not seen with SA. Acupuncture is an effective and well-tolerated strategy for managing this common treatment-related side effect.

Zyflamend in men with high-grade prostatic intraepithelial neoplasia: results of a phase I clinical trial.

Subjects diagnosed with high-grade prostatic intraepithelial neoplasia (HGPIN) at biopsy are at increased risk for developing prostate cancer (CaP). A prospective clinical trial was done to determine the safety and tolerability of a novel herbal amalgam, Zyflamend (New Chapter, Inc., Brattleboro, VT), with various dietary supplements in subjects with HGPIN. Men ages 40 to 75 years with HGPIN were eligible. Subjects were evaluated for 18 months. Every 3 months, standard blood chemistries and prostate-specific antigen (PSA) were monitored. Rebiopsy was done every 6 months. Tissue was evaluated for HGPIN or CaP and stained for cyclooxygenase-2, nuclear factor kappaB (NF-kappaB), interleukin-6, and thromboxane. Twenty-three subjects were evaluable. The median age was 64.1 years (range 46-75 years), and the mean (+/- SD) PSA level was 6.13 +/- 3.56 ng/mL. Side effects, when present, were mild and gastrointestinal in nature. There were no reported serious adverse events or toxicities. No significant changes in blood chemistries, testosterone, or cardiac function were noted. Forty-eight percent of subjects demonstrated a 25 to 50% decrease in PSA after 18 months. Of subjects who had the 18-month biopsy, 60% (9 of 15) had benign tissue, 26.7% (4 of 15) had HGPIN in one core, and 13.3% (2 of 15) had CaP at 18 months. A reduction in serum C-reactive protein was observed (95% confidence interval [CI] 0.7-1.7, p = .045). Immunoreactive staining demonstrated a reduction in NF-kappaB in the 18-month samples (95% CI 0.8-3.0, p = .017). Zyflamend alone and in combination with various dietary supplements is associated with minimal toxicity and no serious adverse events when administered orally for 18 months. Further studies are warranted to evaluate these agents in patients who are at risk for CaP.

beta-carboline alkaloid-enriched extract from the amazonian rain forest tree pao pereira suppresses prostate cancer cells.

Bark extracts from the Amazonian rain forest tree Geissospermum vellosii (pao pereira), enriched in alpha-carboline alkaloids have significant anticancer activities in certain preclinical models. Because of the predominance of prostate cancer as a cause of cancer-related morbidity and mortality for men of Western countries, we preclinically tested the in vitro and in vivo effects of a pao pereira extract against a prototypical human prostate cancer cell line, LNCaP. When added to cultured LNCaP cells, pao pereira extract significantly suppressed cell growth in a dose-dependent fashion and induced apoptosis. Immunodeficient mice heterotopically xenografted with LNCaP cells were gavaged daily with pao pereira extract or vehicle control over 6 weeks. Tumor growth was suppressed by up to 80% in some groups compared with tumors in vehicle-treated mice. However, we observed a striking U-shaped dose-response curve in which the highest dose tested (50 mg/kg/d) was much less effective in inducing tumor cell apoptosis and in reducing tumor cell proliferation and xenograft growth compared with lower doses (10 or 20 mg/kg/d). Although this study supports the idea that a pao pereira bark extract has activity against human prostate cancer, our in vivo results suggest that its potential effectiveness in prostate cancer treatment may be limited to a narrow dose range.

Treatment of chronic pelvic pain in men and women.

Chronic pelvic pain syndrome (CPPS) is a common condition that is encountered by a variety of healthcare professionals. Unfortunately, physicians often misdiagnose this problem or recommend inappropriate and sometimes dangerous treatments that offer little hope of successful outcome. In addition, CPPS is typically a multifaceted disorder, simultaneously compromising psychological, peripheral nerve, autonomic, central nervous, visceral, connective tissue, hormonal and other systems. Thus, solo practitioners who may correctly diagnose CPSS are often ill-equipped to provide adequate comprehensive, multidisciplinary treatment. This article is intended as an overview of the most recent literature in support of various treatment modalities for chronic pelvic pain in men and women. We advocate a team-oriented approach in the treatment of CPPS, which employs the coordinated efforts of multiple practitioners, ideally in a subspecialty care setting.

A pilot study on acupuncture for lower urinary tract symptoms related to chronic prostatitis/chronic pelvic pain.

BACKGROUND: The etiology and treatment of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) remain poorly understood. Pain, lower urinary tract voiding symptoms and negative impact on quality of life (QOL) are the most common complaints. Acupuncture, which has been widely used to treat painful and chronic conditions, may be a potential treatment to alleviate the constellation of symptoms experienced by men with CP/CPPS. The purpose of our study was to assess the impact of standardized full body and auricular acupuncture in men refractory to conventional therapies and collect pilot data to warrant further randomized trials. METHODS: Ten men diagnosed with category IIIA or IIIB CP/CPPS >6 months, refractory to at least 1 conventional therapy (antibiotics, anti-inflammatory agents, 5-alpha reductase inhibitors, alpha-1 blockers) and scoring >4 on the pain subset of the NIH-CPSI were prospectively analyzed in an Institutional Review Board (IRB) approved, single-center clinical trial (Columbia University Medical Center IRB#AAAA-7460). Standardized full body and auricular acupuncture treatment was given twice weekly for 6 weeks. The primary endpoints were total score of the NIH-CPSI and assessment of serious adverse events. The secondary endpoints were individual scores of the NIH-CPSI and QOL questionnaire scores of the short-form 36 (SF-36). RESULTS: The median age of the subjects was 36 years (range 29-63). Decreases in total NIH-CPSI scores (mean +/- SD) after 3 and 6 weeks from baseline (25.1 +/- 6.6) were 17.6 +/- 5.7 (P < 0.006) and 8.8 +/- 6.2 (P < 0.006) respectively and remained significant after an additional 6 weeks of follow-up (P < 0.006). Symptom and QOL/NIH-CPSI sub-scores were also significant (P < 0.002 and P < 0.002 respectively). Significance in 6 of 8 categories of the SF-36 including bodily pain (P < 0.002) was achieved. One regression in the SF-36 vitality category was observed after follow-up. There were no adverse events. CONCLUSION: The preliminary findings, although limited, suggest the potential therapeutic role of acupuncture in the treatment of CP/CPPS. Data from this and previous studies warrant randomized trials of acupuncture for CP/CPPS and particular attention towards acupuncture point selection, treatment intervention, and durability of acupuncture.

Pilot study of acupuncture for the treatment of joint symptoms related to adjuvant aromatase inhibitor therapy in postmenopausal breast cancer patients.

INTRODUCTION: Aromatase inhibitors (AIs) have become the standard of care for the adjuvant treatment of postmenopausal, hormone-sensitive breast cancer. However, patients receiving AIs may experience joint symptoms, which may lead to early discontinuation of this effective therapy. We hypothesize that acupuncture is a safe and effective treatment for AI-induced arthralgias. METHODS: Postmenopausal women with early-stage breast cancer who had self-reported musculoskeletal pain related to adjuvant AI therapy were randomized in a crossover study to receive acupuncture twice weekly for 6 weeks followed by observation or vice-versa. The intervention included full body and auricular acupuncture, and a joint-specific point prescription. Outcome measures included the Brief Pain Inventory-Short Form (BPI-SF), Western Ontario and McMaster Universities Osteoarthritis (WOMAC) index, the Functional Assessment of Cancer Therapy-General (FACT-G) quality of life measure, and serum levels of inflammatory markers, IL-1 beta and TNF-alpha. RESULTS: Twenty-one women were enrolled and two discontinued early. From baseline to the end of treatment, patients reported improvement in the mean BPI-SF worst pain scores (5.3 to 3.3, p = 0.01), pain severity (3.7 to 2.5, p = 0.02), and pain-related functional interference (3.1 to 1.7, p = 0.02), as well as the WOMAC function subscale and FACT-G physical well-being (p = 0.02 and 0.04, respectively). No adverse events were reported. DISCUSSION/CONCLUSIONS: In this pilot study, acupuncture reduced AI-related joint symptoms and improved functional ability and was well-tolerated. IMPLICATIONS FOR CANCER SURVIVORS: Musculoskeletal side effects are common among breast cancer survivors on adjuvant AI therapy, therefore, effective treatments are needed for symptom relief and to improve adherence to these life-saving medications.

What patients take without telling you: holistic approach for BPH.

The use of botanicals and supplements have markedly increased in men that are seeking increased protection against the potential onset and symptomatic relief of lower urinary tract symptoms that are commonly experienced with benign prostatic hyperplasia (BPH). While this implies a positive trend and considers that men are taking a more active role in health and prevention, dialog between the patient and the clinician is often deficient. This may be due to a number of factors including both the patients' inability to report about the use of certain agents and the clinicians' inability to ask. Moreover, the sense that natural agents may lack side effects coupled with ineffective communication between the doctor and patient could result in potential adverse interactions. We have performed a comprehensive search of articles published from 1990 to 2005 using the Medline databases in order examine clinical data on the most commonly researched herbs for BPH. We provide a brief update on the state of the research.

The use of herbal and over-the-counter dietary supplements for the prevention of prostate cancer.

Having a high probability of experiencing prostate cancer during their lifetime, men are increasingly seeking protection against this disease with the use of over-the-counter dietary supplements containing herbs, vitamins, or plant-derived biochemical agents. The use of these agents for prostate cancer prevention is driven by epidemiology supporting the idea that regional diets and consumption of specific dietary components (certain herbs, vitamins, isoflavones, and polyphenols) are associated with a lower risk for prostate cancer, in conjunction with basic research that is defining molecules within food substances that kill or suppress growth of cultured human prostate cancer cells. Moreover, there is a sense that these dietary agents lack side effects, although this assumption often is faulty. Unfortunately, at this time, there is insufficient clinical evidence to support the widespread use of these dietary supplements for chemoprevention of prostate cancer, although ongoing clinical trials of the most promising vitamins and minerals are approaching conclusion.

The use of herbal and over-the-counter dietary supplements for the prevention of prostate cancer.

Having a high probability of experiencing prostate cancer during their lifetime, men are increasingly seeking protection against this disease with the use of over-the-counter dietary supplements containing herbs, vitamins, or plant-derived biochemical agents. The use of these agents for prostate cancer prevention is driven by epidemiology supporting the idea that regional diets and consumption of specific dietary components (certain herbs, vitamins, isoflavones, and polyphenols) are associated with a lower risk for prostate cancer, in conjunction with basic research that is defining molecules within food substances that kill or suppress growth of cultured human prostate cancer cells. Moreover, there is a sense that these dietary agents lack side effects, although this assumption often is faulty. Unfortunately, at this time, there is insufficient clinical evidence to support the widespread use of these dietary supplements for chemoprevention of prostate cancer, although ongoing clinical trials of the most promising vitamins and minerals are approaching conclusion.

Complementary and alternative medicine for chronic prostatitis/chronic pelvic pain syndrome.

To discuss challenges concerning treatment for chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) and review complementary and alternative medical (CAM) therapies being evaluated for this condition, we performed a comprehensive search of articles published from 1990-2005 using the PubMed, Medline databases. Data from the articles were abstracted and pooled by subject. Keywords cross-searched with CP/CPPS included: complementary, alternative, integrative, therapies, interventions, nutrition, antioxidants, herbs, supplements, biofeedback and acupuncture. Listed articles with no abstracts were not included. Various CAM therapies for CP/CPPS exist including biofeedback, acupuncture, hyperthermia and electrostimulation. Additionally, a variety of in vitro and in vivo studies testing herbal and nutritional supplements were found. Saw palmetto, cernilton and quercetin were the most frequently tested supplements for CP/CPPS. Although many CAM therapies demonstrate positive preliminary observations as prospective treatments for CP/CPPS, further exploratory studies including more randomized, controlled trials are necessary for significant validation as treatment options for this complex disorder.