Cutaneous findings in patients with acromegaly and its relationship with concomitant endocrinopathies.

OBJECTIVES: Skin changes in acromegaly are often the first sign of the disease. The aim of this study was to describe the cutaneous findings in patients with acromegaly. In addition, a secondary aim was to investigate the possible association of these findings with remission status and concomitant endocrinopathies. DESIGN, PATIENTS, AND MEASUREMENTS: In this prospective multicenter study, 278 patients over the age of 18 years with acromegaly who were followed up in 14 different tertiary healthcare institutions were included. These patients, who were followed up by the Endocrinology Department, were then referred to a dermatologist for dermatological examination. The frequency of skin lesions was investigated by detailed dermatologic examination. Dermatological diagnosis is reached by clinical, dermatological and/or dermoscopic examination, and rarely skin punch biopsy examinations in suspicious cases. The possible association of the skin findings between remitted and nonremitted patients and with concomitant endocrinopathies were evaluated. RESULTS: The most common skin findings in patients with acromegaly in our study were skin tags (52.5%), cherry angiomas (47.4%), seborrhoea (37%), varicose veins (33%), acneiform lesions (28.8%), hyperhidrosis (26.9%) and hypertrichosis (18.3%). Hypertrichosis was significantly more prevalent in patients nonremitted (p: .001), while xerosis cutis was significantly more prevalent in patients remitted (p: .001). The frequency of diabetes mellitus and hypothyroidism was significantly higher in patients with varicose veins and seborrhoeic keratosis than those without. Additionally, the coexistence of hypothyroidism, hyperthyroidism and galactorrhea was significantly higher in patients with Cherry angioma than in those without Cherry angioma (p-values: .024, .034 and .027, respectively). The frequency of hypogonadism in those with xerosis cutis was significantly higher than in those without (p: .035). CONCLUSIONS: Cutaneous androgenization findings such as skin tag, seborrhoea, acne and acanthosis nigricans are common in patients with acromegaly. Clinicians should be aware that skin findings associated with insulin resistance may develop in these patients. It can be said that the remission state in acromegaly has no curative effect on cutaneous findings. Only patients in remission were less likely to have hypertrichosis. This may allow earlier review of the follow-up and treatment of acromegaly patients presenting with complaints of hypertrichosis. Additionally, it can be said that patients with skin findings such as cherry angioma may be predisposed to a second endocrinopathy, especially hypothyroidism. Including dermatology in a multidisciplinary perspective in acromegaly patient management would be beneficial to detect cutaneous findings earlier.

Iatrogenic Shapiro syndrome: a case report.

OBJECTIVES: Shapiro's syndrome (SS) is a rare condition characterized by spontaneous periodic hypothermia. The underlying pathophysiological mechanisms and etiology of this syndrome remain controversial, and fewer than 100 cases have been reported to date. The objective of this case report is to present a unique iatrogenic case of SS and contribute additional insights into the underlying etiology of this rare disorder. METHODS: We conducted an analysis of existing medical literature and described a clinical case of SS secondary to a neurosurgical procedure. RESULTS: To our knowledge, we present the first iatrogenic case of SS in a 53-year-old woman who underwent a partial right parieto-occipital lobectomy in 2003 as a treatment for refractory epilepsy. Several years after the surgical procedure, she began experiencing recurrent episodes of hypothermia. Brain magnetic resonance imaging (MRI) revealed the absence of the splenium of the corpus callosum (CC) and pituitary hyperplasia. After ruling out other potential causes of hypothermia, a diagnosis of SS was made. DISCUSSION: The most plausible mechanism to explain the recurrent hypothermia associated with SS in our patient is a probable disruption of the pathways involved in thermoregulation through the CC as a consequence of the surgical procedure. This case report provides further insights into the etiology of this rare disorder.

Aquagenic wrinkling of the palms in a cohort of Greek children diagnosed with cystic fibrosis: Associated clinical parameters.

BACKGROUND: Aquagenic wrinkling of the palms (AWP) is an excessive and early palmar wrinkling occurring after brief immersion to water (BIW), and has been reported as a frequent finding among Cystic Fibrosis (CF) patients. OBJECTIVES: To investigate any associations of CF patients presenting AWP with other disease characteristics and explore the pathomechanism of AWP phenomenon. METHODS: We evaluated AWP in CF patients and assessed the AWP parameters of palmar wrinkling, oedema, papules, pruritus and pain at 3, 7 and 11 min after a BIW test with other disease characteristics. Statistical analyses explored the associations of AWP with genotype, lung function, pancreatic insufficiency, hyperhidrosis, personal and family history of atopy and sweat chloride levels. RESULTS: One hundred CF patients (mean age 10.4 years) were included in the analysis. The genotypic distribution was ΔF508/ΔF508: 47%, ΔF508/other: 41% and other/other: 12%. Statistically significant associations of Kaplan-Meier curves of the AWP parameters with various disease characteristics and personal/family history were detected. Wrinkling was associated with history of atopy, hyperhidrosis and levels of sweat chloride test. The time to presentation of oedema and the appearance of papules were associated with history of hyperhidrosis and age at diagnosis. Finally, time to appearance of pruritus was related to history of atopy and of hyperhidrosis. Regarding TEWL regression analysis showed significant associations with age at diagnosis (p = 0.024), sweat chloride test levels (p = 0.005), history of hyperhidrosis (p = 0.033), history of atopy (p = 0.002) and hepatic-pancreatic involvement (p = 0.027). CONCLUSIONS: The existence of a statistically significant association between AWP and the history of hyperhidrosis, atopy, sweat chloride levels and hepatic-pancreatic function in CF patients was detected. A strong association between AWP and CF was detected. AWP after BIW could be elicited easily and possibly can be used as an initial screening tool to diagnose an individual with symptoms and signs that raise the likelihood of CF.

Anatomical proposal of local anesthesia injection for median nerve block in treating hyperhidrosis with botulinum neurotoxin.

INTRODUCTION: Hyperhidrosis, causing excessive sweat, can be treated with Botulinum neurotoxin injection. Botulinum toxin, an effective and safe treatment for hyperhidrosis, unfortunately involves significant pain due to multiple injections. This study aims to propose a more efficient and less painful approach to nerve blocks for relief, by identifying optimal injection points to block the median nerve, thereby enhancing palmar hyperhidrosis treatment. METHODS: This study, involving 52 Korean cadaver arms (mean age 73.5 years), measured the location of the median nerve relative to the transverse line at the pisiform level to establish better nerve block injection sites. RESULTS: In between the extensor carpi radialis and palmaris longus, the median nerve was located at an average distance of 47.39 ± 6.43 mm and 29.39 ± 6.43 mm from the transverse line at the pisiform level. DISCUSSION: To minimize discomfort preceding the botulinum neurotoxin injection, we recommend the optimal injection site for local anesthesia to be located 4 cm distal to the transverse line of the pisiform, within the tendons of the palmaris longus and flexor carpi radialis muscles.

Idiopathic Harlequin Syndrome in a Patient from Ethiopia: A Case Report.

Background: Harlequin syndrome is a rare disorder caused by autonomic nervous system dysfunction. It manifests as asymmetric facial flashing and sweating with contralateral anhidrosis. It may be primary (idiopathic) with a benign course or can occur secondary to structural abnormalities or iatrogenic factors. To our knowledge, there has been no report of idiopathic Harlequin syndrome published from Ethiopia. We are reporting this case since it signifies the existence of idiopathic Harlequin syndrome in our setting and the need to properly diagnose this condition. Case Presentation: We are reporting a 29-year-old female from Addis Ababa, Ethiopia, who presented with a complaint of left hemifacial hyperhidrosis of 8 years which worsen after routine household activities and exercise. Physical examination revealed left hemifacial hyperhidrosis with right-side anhidrosis. She was diagnosed with idiopathic Harlequin syndrome after an appropriate investigation revealed a nonremarkable finding. Symptomatic treatment showed no significant improvement and the patient was also counseled on the disease entity. Conclusions: The patient described here signifies an idiopathic Harlequin syndrome in an Ethiopian woman. This case highlights the existence of idiopathic Harlequin syndrome within our setting and the need to properly diagnose this condition.

The differentiating effect of COVID-19-associated stress on the morbidity of blood donors with symptoms of hidradenitis suppurativa, hyperhidrosis, or psoriasis.

PURPOSE: The burden of different skin diseases may vary leading individuals to have different sensitivity to stress. Therefore, we compared the health-related quality of life (HRQoL) and stress before and during the universal stress from the severe acute respiratory syndrome coronavirus-2-pandemic in individuals with and without hyperhidrosis, hidradenitis suppurativa, or psoriasis. METHODS: The study cohort was the Danish Blood Donor Study. Overall, 12,798 participants completed a baseline questionnaire before the pandemic, in 2018-2019, and a follow-up questionnaire during the pandemic, in 2020. Regression determined the association between the skin diseases and outcomes. Outcomes were the physical and mental component summary (MCS, PCS, respectively), which assess the mental and physical HRQoL, and the perceived stress scale, which assesses stress in the past four weeks. RESULTS: Overall, 1168 (9.1%) participants had hyperhidrosis, 363 (2.8%) had hidradenitis suppurativa, and 402 (3.1%) had psoriasis. At follow-up, the participants with hyperhidrosis had worse MCS (coefficient -0.59 [95% confidence interval (CI) -1.05, -0.13]) and higher odds of moderate-to-severe stress (odds ratio 1.37 [95% CI 1.13, 1.65]) and the participants with hidradenitis suppurativa worse PCS (coefficient -0.74 [95% CI -1.21, -0.27]) than the control groups. The associations were independent of baseline HRQoL, stress, the Connor-Davidson Resilience scale, and other covariables. Psoriasis was not associated with the outcomes. CONCLUSION: Individuals with hyperhidrosis or hidradenitis suppurativa experienced worse mental or physical well-being and individuals with hyperhidrosis also had higher stress during the pandemic compared to healthy individuals. This suggests that individuals with these skin diseases are particularly susceptible to external stress.

Concurrence of Hyperhidrosis and Hypohidrosis in Ross Syndrome.

Ross Syndrome is a rare disorder characterized by tonic pupils, hyporeflexia, and abnormal segmental sweating. The pathophysiology of the disease remains unclear, with either hypohidrosis or hyperhidrosis reported in individual patients. We present the case of a man, aged 57 years, who presented with hyperhidrosis in his right extremities, anhidrosis in the left extremities, and changes in his pupils. The disease was not associated with markers of autoimmune disease, which supports recent research findings on the role of neurodegeneration. The patient's son was exhibiting similar symptoms, which implicates genetic inheritance in the process. A multidisciplinary approach is crucial for the diagnosis and ultimate management of patients with Ross Syndrome.

Axillary Cutaneous Hemosiderosis in a Patient With Hyperhidrosis, After Intravenous Iron Infusion.

ABSTRACT: Hemosiderosis consists of an iron deposit in tissues, which does not cause organic damage to them. However, in the case of the skin, being an organ exposed to sight, siderosis can produce a brownish coloration that is aesthetically discomforting for the individual. Most cutaneous sideroses are because of venous insufficiency with hemorrhagic extravasation. There is also a group secondary to iron extravasation in the injection site of the transfusion. However, there are very few cases in which an intravenous injection of an iron preparation has produced diffuse siderosis in extensive areas of the skin. We present the case of a 31-year-old woman with hyperhidrosis, who was transfused as a result of postpartum hemorrhage and, shortly after receiving an intravenous iron infusion, developed extensive hyperpigmentation in both axillae.

Pharmacovigilance-based drug repurposing: searching for putative drugs with hypohidrosis or anhidrosis adverse events for use against hyperhidrosis.

BACKGROUND: Drug repurposing refers to the application of existing drugs to new therapeutic indications. As phenotypic indicators of human drug response, drug side effects may provide direct signals and unique opportunities for drug repurposing. OBJECTIVES: We aimed to identify drugs frequently associated with hypohidrosis or anhidrosis adverse reactions (that is, the opposite condition of hyperhidrosis) from the pharmacovigilance database, which could be potential candidates as anti-hyperhidrosis treatment agents. METHODS: In this observational, retrospective, pharmacovigilance study, adverse event reports of hypohidrosis or anhidrosis in the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) were assessed between January 2004 and December 2021 using reporting odds ratio (ROR) estimates and categorized by the World Health Organization Anatomical Therapeutic Chemical (ATC) classification code. The onset time of drug-associated hypohidrosis or anhidrosis was also examined. RESULTS: There were 540 reports of 192 drugs with suspected drug-associated hypohidrosis or anhidrosis in the FAERS database, of which 39 drugs were found to have statistically significant signals. Nervous system drugs were most frequently reported (187 cases, 55.82%), followed by alimentary tract and metabolism drugs (35 cases, 10.45%), genitourinary system and sex hormones (28 cases, 8.36%), and dermatologicals (22 cases, 6.57%). The top 3 drug subclasses were antiepileptics, drugs for urinary frequency and incontinence, and antidepressants. Taking disproportionality signals, pharmacological characteristics of drugs and appropriate onset time into consideration, the main putative drugs for hyperhidrosis were glycopyrronium, solifenacin, oxybutynin, and botulinum toxin type A. Other drugs, such as topiramate, zonisamide, agalsidase beta, finasteride, metformin, lamotrigine, citalopram, ciprofloxacin, bupropion, duloxetine, aripiprazole, prednisolone, and risperidone need more investigation. CONCLUSIONS: Several candidate agents among hypohidrosis or anhidrosis-related drugs were identified that may be redirected for diminishing sweat production. There are affirmative data for some candidate drugs, and the remaining proposed candidate drugs without already known sweat reduction mechanisms of action should be further explored.

Squamous Cell Carcinoma of the Lung Presenting Unilateral Thoracic Hyperhidrosis: A Case Report and Review of Literature.

Unilateral hyperhidrosis is an uncommon manifestation, and the majority of cases have been attributed to neurological diseases. There are few cases of unilateral hyperhidrosis associated with thoracic malignant tumors. We herein report a 74-year-old Japanese man with squamous cell carcinoma of the lung who presented with unilateral hyperhidrosis in the right thoracic area as one of the first clinical manifestations. We should consider the possibility of pleural diseases, including metastatic lung cancer, when encountering patients presenting with unilateral thoracic hyperhidrosis.

Parental report of dental pain and discomfort in preschool children is associated with sleep disorders: a cross-sectional study in Brazilian families.

PURPOSE: To evaluate the prevalence of sleep disorders in Brazilian preschool children and its associations with parental report of dental pain and discomfort. METHODS: This cross-sectional study involved 604 Brazilian preschoolers (4-5 years old). Sleep disorders (SD) and the parental report of dental pain and discomfort (DPD) were evaluated using the Brazilian versions of the Sleep Disturbance Scale for Children (SDSC) and the Dental Discomfort Questionnaire (DDQ-B), respectively. Bivariate and multivariate Poisson regression analyses with robust variance were performed to analyze the association between SDSC and DP. RESULTS: Prevalence of SD ranged from 7 to 21%. 7.9% of the children had DPD indicating the need for more invasive dental procedures (DDQ-B ≥ 5). Significant associations were found between DPD and the following SDSC domains: sleep hyperhidrosis (p = 0.024; PRa = 1.38; 95% CI: 1.04-1.83), disorders of initiating and maintaining sleep (p < 0.001; PRa = 1.41; 95% CI: 1.15-1.73), parasomnias (p < 0.001; PRa = 1.82; 95% CI: 1.39-2.37), and sleep-wake transition disorders (p = 0.018; PRa = 1.28; 95% CI: 1.04-1.58). Children with higher prevalence of DPD presented 20% higher prevalence of SD than children lower prevalence of DPD (p = 0.039; PRa = 1.20; 95% CI: 1.01-1.44). CONCLUSION: Preschool children with higher prevalence of DPD are more likely to have SD, such as hyperhidrosis, disorders of initiating and maintaining sleep, parasomnias, and sleep-wake transition.

Hyperhidrosis in sleep disorders - A narrative review of mechanisms and clinical significance.

Hyperhidrosis is characterized by excessive sweating beyond thermoregulatory needs that affects patients' quality of life. It results from an excessive stimulation of eccrine sweat glands in the skin by the sympathetic nervous system. Hyperhidrosis may be primary or secondary to an underlying cause. Nocturnal hyperhidrosis is associated with different sleep disorders, such as obstructive sleep apnea, insomnia, restless legs syndrome/periodic limb movement during sleep and narcolepsy. The major cause of the hyperhidrosis is sympathetic overactivity and, in the case of narcolepsy type 1, orexin deficiency may also contribute. In this narrative review, we will provide an outline of the possible mechanisms underlying sudomotor dysfunction and the resulting nocturnal hyperhidrosis in these different sleep disorders and explore its clinical relevance.

The presence and co-incidence of geriatric syndromes in older patients with mild-moderate Lewy body dementia.

INTRODUCTION: Geriatric symptoms are common in dementia cases, while few studies have focused on these symptoms in Lewy body dementia (LBD). The purpose of this study is to investigate the distributions of Apolipoprotein E (APOE) ε4 and geriatric symptoms, and explore their associaitons in Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD). METHODS: A retrospective study with 185 mild-moderate probable DLB (n = 93) and PDD (n = 92) patients was assigned. Demographic and clinical characteristics, neuropsychological assessments, and APOE genotypes were recorded. Description, correlation and logistic regression models were used to analyze the presence of geriatric symptom complaints and their associations with APOE ε4. RESULTS: DLB patients displayed more frequency of fluctuating cognition, visual hallucination, rapid eye movement sleep behavior disorder, delusion, depression, anxiety, apathy, and loss of appetite, whereas the PDD cases had constipation, fear of falling, and insomnia more frequently. The APOE ε4 allele was more common in DLB than PDD (29.9% vs. 7.0%, p < 0.001), and the patients with DLB + APOE ε4 (+) were presented more delusions (p = 0.005) and apathy (p = 0.007) than patients with PDD + APOE ε4 (+). We also found that the APOE ε4 allele was significantly associated with hyperhidrosis (OR = 3.472, 95%CI: 1.082-11.144, p = 0.036) and depression (OR = 3.002, 95%CI: 1.079-8.353, p = 0.035) in DLB patients, while there were no significant associations between APOE ε4 allele and the age at visit, the age at onset, scores of MDS-UPDRS III, H&Y stage, ADL, MMSE, MOCA and NPI, as well as the presences of fluctuating cognition, VH, parkinsonism and RBD in both groups. CONCLUSION: The presence and co-incidence of geriatric symptoms are common in patients with mild-moderate LBD. The presence of APOE ε4 allele is associated with hyperhidrosis and depression, but not global cognition, activitives of daily life, motor function and other neuropsychitric symptoms in DLB. These findings improve the awareness of geriatric symptoms, and contribute to the healthcare management of mild-moderate DLB and PDD.

Association between early and current gastro-intestinal symptoms and co-morbidities in children and adolescents with Angelman syndrome.

BACKGROUND: Angelman syndrome (AS) is a neurogenetic disorder that causes severe intellectual disability, expressive language deficits, motor impairment, ataxia, sleep problems, epileptic seizures and a happy disposition. People with AS frequently experience gastrointestinal (GI) symptoms. METHOD: This study used data from the Global Angelman Syndrome Registry to explore the relationship between early and current GI symptoms and co-morbidity in children and adolescents with AS (n = 173). Two groups that experienced a high (n = 91) and a low (n = 82) frequency of GI symptoms were examined in relation to feeding and GI history in infancy, sleep and toileting problems, levels of language and communication and challenging behaviours. Predictors of GI symptoms were then investigated using a series of logistic regressions. RESULTS: This analysis found that constipation and gastroesophageal reflux affected 84% and 64%, of the sample, respectively. The high frequency of GI symptoms were significantly associated with: 'refusal to nurse', 'vomiting', 'arching', 'difficulty gaining weight', gastroesophageal reflux, 'solid food transition', frequency of night-time urinary continence and sleep hyperhidrosis during infancy. GI symptoms were not significantly associated with sleep, toileting, language or challenging behaviours. Significant predictors of high frequency GI symptoms were gastroesophageal reflux and sleep hyperhidrosis. CONCLUSIONS: Future research needs to investigate the association between AS and GI co-morbidity in adults with AS.

Hyperhidrosis in Parkinson's disease: a 3-year prospective cohort study.

BACKGROUND: Although hyperhidrosis is a common symptom in patients with Parkinson's disease (PD), no study has yet examined it longitudinally. OBJECTIVES: We conducted a 3-year prospective cohort study to investigate the development, evolution and correlates of hyperhidrosis in patients with PD. METHODS: A total of 224 patients with early-stage PD were enrolled at baseline and followed up annually for three consecutive years. Hyperhidrosis was assessed using hyperhidrosis question (item 30) of the Non-Motor Symptoms Scale (NMSS). The generalized estimating equations model was applied to investigate the correlates of both presence and severity of hyperhidrosis. RESULTS: The frequency of hyperhidrosis in PD had an overall increasing tendency from 24.1% at baseline to 34.4% after 3 years, although hyperhidrosis was not always persistent in all patients over the 3-year study period. The presence of hyperhidrosis was found to be associated with dyskinesia (OR 2.27 [1.02-5.04], P = 0.045), the sexual function domain subscore of the NMSS (OR 1.04 [1.01-1.07], P = 0.016), the Hamilton Anxiety Rating Scale (HARS) score (OR 1.08 [1.03-1.13], P = 0.001) and the Unified Parkinson's Disease Rating Scale part III score (OR 1.02 [1.00-1.04], P = 0.036). Only the HARS score was associated with the severity of hyperhidrosis (B 0.08 [0.03-0.12], P = 0.001). CONCLUSIONS: Hyperhidrosis is common in PD, and its frequency increases along with disease duration. Hyperhidrosis in PD is associated not only with motor severity and motor complication such as dyskinesia, but also with non-motor symptoms such as sexual dysfunction and anxiety.

Sub-macroscopic skin presentation of acromegaly and effect of pituitary tumor surgery: A study using dermatoscopy and ultra-high-frequency ultrasound.

Objective: Excessive growth hormone and insulin-like growth factor 1 contribute to cutaneous changes in acromegaly. We investigated the sub-macroscopic skin manifestation of acromegaly patients and explored its reversibility upon hormone reduction after pituitary adenoma surgery. Design: Prospectively cohort study. Methods: We enrolled 26 patients with acromegaly and 26 patients with non-functioning pituitary adenomas undergoing pituitary adenomectomy at Peking Union Medical College Hospital from July 2021 to March 2022. Skin presentations were evaluated by dermatoscopy and ultra-high-frequency ultrasound before and after surgery. Results: Skin thickening, follicular plugs, perifollicular pigmentations, perifollicular orange haloes, red structureless areas, increased hair shafts, honeycomb-like pigmentations, widened dermatoglyphics, dilated appendage openings, excessive seborrhea, hyperhidrosis, enlarged pores, and acne-like lesions were commonly occurring in acromegaly patients, and their incidences were higher than the controls (P<0.05). At 3-month follow-up after surgery, the thickness of skin reduced (4.0 ± 0.4 to 3.7 ± 0.4, P=0.007), the incidences of hyperhidrosis (92.3% to 69.2%, P=0.035) and acne-like lesions (53.8% to 26.9%, P=0.048) declined, and the severity of multiple cutaneous lesions improved. Patients with surgical endocrine remission (53.8%) had greater declines in the thickness of skin than those without remission. Patients with improvement of >1 skin lesions were younger (P=0.028) and had higher baseline GH levels (P=0.021) than those with improvement of ≤1 skin lesion. Conclusions: Dermatoscopy and ultra-high-frequency ultrasound provided augmented visual examination of the cutaneous changes in acromegaly. Some of the skin lesions could improve or reverse after pituitary surgery. Baseline GH levels, age, and endocrine remission were correlated with skin improvement at 3-month follow-up.

A questionnaire study on sleep disturbances associated with Prader-Willi syndrome.

Background This study aimed to investigate the presence of sleep disturbances in children with Prader-Willi syndrome (PWS) using the Sleep Disturbance Scale for Children (SDSC). Methods The SDSC, which was designed to identify the presence and severity of different sleep disorders, was applied to 50 patients with PWS and 112 controls. Results Patients with PWS achieved worse scores in the sleep-disordered breathing and disorders in initiating and maintaining sleep in the SDSC questionnaire as compared with controls. We also observed that patients with PWS were more prone to having hyperhidrosis. We did not observe significant differences in the presence of other types of sleep disorders (such as hypersomnolence) between the PWS and control groups. Conclusions The results obtained with the SDSC questionnaire showed that children with PWS have more sleep breathing disorders and disorders in initiating and maintaining sleep as compared to controls. Additionally, we demonstrated that patients with PWS associates significantly with the presence of hyperhidrosis during sleep. However, SDSC was not reliable to identify the excessive daytime somnolence in patients with PWS, as previously reported in the literature.