Taking culture seriously: Can we improve the developmental health and well-being of Australian Aboriginal children in out-of-home care?

BACKGROUND: Children in out-of-home care have well-documented health and developmental needs. Research suggests that Aboriginal children in care have unmet health and intervention needs. In metropolitan Sydney, Kari Aboriginal Resources Inc. (KARI), an Aboriginal organization, provides support to indigenous children in care, including clinical assessment and intervention. We wanted to determine the health and developmental needs of a subset of children in out-of-home care with KARI, who had been in stable care for at least a year. We wanted to identify child, carer, and intervention characteristics that contributed to children doing well. We also wanted to identify enablers and barriers to providing culturally competent intervention. METHODS: We used mixed methods. From the KARI clinic database over the past 3 years, we identified children who had been in stable care with KARI for >12 months. We compared clinical measures and outcomes for these children with results from previous audits. We carried out a group discussion and key informant interviews with therapists and caseworkers to identify risk and resilience factors for each child, as well as enablers and barriers to culturally competent intervention. RESULTS: The health and developmental profile of the 26 children identified as being in stable care was similar to that of previous audits. Most (88%) were getting speech pathology intervention; one third were getting occupational therapy and psychological intervention; most children and their carers attended cultural programmes. The majority of children (25/26) improved in their developmental health. Caseworkers and therapists identified risk and resilience factors related to child, carer, and home characteristics. They also identified elements of good practice; systemic issues prevented some interventions from being carried out. CONCLUSIONS: There are challenges delivering a trauma-informed, culturally respectful service to Aboriginal children in out-of-home care in an urban setting, but it can be done if attention is paid to culture and the enablers and barriers are identified.

Hearing in school-aged children with trisomy 21 - results of a longitudinal cohort study in children identified at birth.

OBJECTIVES: To report the prevalence of hearing problems and the hearing sequelae in school-aged children with trisomy 21 in a longitudinal study. DESIGN: All children with trisomy 21 were identified via schools, community-based child development centres, general practitioners, or the universal newborn hearing screen. Audiological data and otorhinolaryngological problems were prospectively entered in to the Audiological Surveillance Programme database from each visit. SETTING: Retrospective review of the Audiological Surveillance Programme database in the Glasgow area (United Kingdom) of all children reviewed between 2004 and 2012. PARTICIPANTS: All pre-teenaged children with trisomy 21 of school age (aged 5-12 years old). MAIN OUTCOME MEASURES: Hearing thresholds, aetiology of hearing loss and management of hearing loss was determined for the cohort of children. RESULTS: A total of 102 children were included. Fifty-four had normal hearing. Twenty-six had fluctuating otitis media with effusion; five had hearing in normal limits, six were managed with hearing aids, fourteen were managed conservatively, and one had ventilation tube insertion. Fifteen had persistent otitis media with effusion; four had ventilation tube insertion; and nine were managed with hearing aids. Seven had mixed hearing loss with four required hearing aids. CONCLUSIONS: Otitis media with effusion was the commonest cause of hearing impairment; effusions may fluctuate through the pre-teenaged years, and thus, hearing aids are beneficial. Ventilation tube insertion and bone-conducting hearing aids were useful when ear-level hearing aids were not tolerated. Mixed hearing loss occurred in later years as sensorineural hearing loss developed on a background of otitis media with effusion.

Effects of Ankle Position While Performing One- and Two-Leg Floor Bridging Exercises on Core and Lower Extremity Muscle Recruitment.

Given there are no known studies which have examined multiple lower extremity muscles between different ankle positions during bridging activities, the objective was to assess how employing two different ankle positions (PF versus DF) while performing five common bridging exercises (three bipedal and two unipedal) used in rehabilitation and athletic performance affect core and select lower extremity muscle EMG recruitment. Twenty healthy subjects performed a 5 s isometric hold during five two- and one-leg bridge exercises: (1) on right leg with left knee to chest (1LB-LFlex); (2) on right leg with left knee extended (1LB-LExt); (3) standard two-leg bridge (2LB); (4) two-leg bridge with resistance band around knees (2LB-ABD); and (5) two-leg bridge with ball between knees (2LB-ADD). Surface electromyographic (EMG) data were collected using a Noraxon Telemyo Direct Transmission System from fourteen muscles: (1) three superficial quadriceps (VM, VL, and RF); (2) three hip abductors (TFL, GMED, and GMAX); (3) medial hamstrings (ST) and lateral hamstrings (BF); (4) hip adductors (ADD); (5) erector spinae (ES); (6) latissimus dorsi (LATS); (7) upper rectus abdominis (RA); and (8) external oblique (EO) and internal oblique (IO). EMG data were normalized by maximum voluntary isometric contractions (MVICs). A paired t-test (p < 0.01) was used to assess differences in normalized mean EMG activities between DF and PF for each exercise. EMG activities were significantly greater in DF than PF for the (a) VM, VL, and RF during 1LB-LFlex; (b) ADD during 1LB-LFlex, 1LB-LExt; (c) EO during 1LB-LFlex; and (d) IO during 1LB-LFex. In contrast, EMG activities were significantly greater in PF than DF for ST and BF during all five bridge exercises. Bridging with PF (feet flat) was most effective in recruiting the hamstrings, while bridging with DF (feet up) was most effective in recruiting the quadriceps, hip adductors, and internal and external obliques.

Trough serum infliximab: a predictive factor of clinical outcome for infliximab treatment in acute ulcerative colitis.

BACKGROUND AND AIMS: Antibodies to infliximab reduce serum infliximab with loss of clinical benefit, but undetectable trough serum concentrations of infliximab may occur without antibody formation. The relationship between trough serum infliximab and clinical outcomes was evaluated in acute ulcerative colitis. METHODS: In a cohort of 115 patients with ulcerative colitis treated with three-dose induction followed by scheduled maintenance infliximab, rates of clinical remission, colectomy, antibodies to infliximab and trough serum infliximab were determined. RESULTS: Rates of remission were 32% at week 10 and 37% at week 54. Colectomy occurred in 40% of patients, at a median of 5.3 (IQR 1.9-12.1) months. Detectable trough serum infliximab was present in 39% of patients and, among patients with undetectable infliximab, 41% were antibody positive and 20% were antibody negative. For antibody-positive and antibody-negative patients, rates of remission (18% vs 14%), endoscopic improvement (25% vs 35%) and colectomy (52% vs 59%) were not different. A detectable serum infliximab was associated with higher rates of remission (69% vs 15%; p<0.001) and endoscopic improvement (76% vs 28%, p<0.001). An undetectable serum infliximab predicted an increased risk for colectomy (55% vs 7%, OR 9.3; 95% CI 2.9 to 29.9; p<0.001). Concurrent immunosuppression was not associated with clinical outcomes. CONCLUSIONS: For patients with ulcerative colitis treated with infliximab, a detectable trough serum infliximab predicts clinical remission, endoscopic improvement and a lower risk for colectomy. An undetectable trough serum infliximab, irrespective of antibody status, is associated with less favourable outcomes.

Angle grinder injuries in orthopedics: A case series and review of the literature.

Angle grinders are amongst the most dangerous tools used in industry and agriculture. Over 5000 documented injuries are related to their use each year which are commonly triggered by a shattering of the abrasive wheel. These injuries are often accompanied by suboptimal health and safety standards. The authors of this paper present three separate cases of accidental injuries presenting to our institution over a short time period. The authors main aim is to raise awareness surrounding the associated dangers of using such tools. A brief economic analysis also illustrates the significant costs involved in treating such preventable injuries.

30-Day postoperative COVID-19 outcomes in 398 patients from regional hospitals utilising a designated COVID-19 minimal surgical site pathway.

INTRODUCTION: Postoperative pulmonary complications and mortality rates during the COVID-19 pandemic have been higher than expected, leading to mass cancellation of elective operating in the UK. To minimise this, the Guy's and St Thomas' Hospital NHS Foundation Trust elective surgery hub and the executive team at London Bridge Hospital (LBH) created an elective operating framework at LBH, a COVID-19 minimal site, in which patients self-isolated for two weeks and proceeded with surgery only following a negative preoperative SARS-CoV-2 polymerase chain reaction swab. The aim was to determine the rates of rates of postoperative COVID-19 infection. METHODS: The collaboration involved three large hospital trusts, covering the geographic area of south-east London. All patients were referred to LBH for elective surgery. Patients were followed up by telephone interview at four weeks postoperatively. RESULTS: Three hundred and ninety-eight patients from 13 surgical specialties were included in the analysis. The median age was 60 (IQR 29-71) years. Sixty-three per cent (252/398) were female. In total, 78.4% of patients had an American Society of Anesthesiologists grade of 1-2 and the average BMI was 27.2 (IQR 23.7-31.8) kg/m2. Some 83.6% (336/402) were 'major' operations. The rate of COVID-19-related death in our cohort was 0.25% (1/398). Overall, there was a 1.26% (5/398) 30-day postoperative all-cause mortality rate. Seven patients (1.76%) reported COVID-19 symptoms, but none attended the emergency department or were readmitted to hospital as a result. CONCLUSION: The risk of contracting COVID-19 in our elective operating framework was very low. We demonstrate that high-volume major surgery is safe, even at the peak of the pandemic, if patients are screened appropriately preoperatively.

Effects of streptozotocin-induced long-term diabetes on parietal cell function and morphology in rats.

Gastric pathology is a common complication in diabetes mellitus. The aim of the study was to evaluate the functions and morphological changes of the parietal cells of the rat stomach after streptozotocin-induced diabetes. Diabetes mellitus was induced in Wistar rats by a single intraperitoneal injection of streptozotocin (60 mg/kg body weight). The rats were weighed weekly and sacrificed after 6 months. The glandular portion of the stomach was removed and processed for H(+)-K(+)-ATPase immunohistochemistry and light and electron microscopy studies. Acid secretion was measured in vivo. After 6 months of diabetes, the mean weight of the rats was significantly lower (P < 0.001) compared to control. The mean weight of the stomach to body weight percentage increased significantly (P < 0.001) compared to control. The blood glucose level in diabetic rats was significantly higher (P < 0.001) than in normal control. Diabetic rats showed significant (P < 0.001) decrease in basal and stimulated acid secretion when compared to control. Electron micrographs of the parietal cells of glandular stomach of diabetic rats revealed significant (P < 0.0002) reduction in the number of mitochondria and a small though not significant increase in the number of canaliculi in the parietal cells compared with normal. Immunohistochemistry showed reduced H(+)-K(+)-ATPase (P < 0.00001) compared to control. Long-term diabetes induces morphological as well as functional changes in gastric parietal cells. The decrease in the number of mitochondria accompanied by reduced in H(+)-K(+)-ATPase in parietal cells may explain the reduced acid secretion observed in diabetics.

Chromosomal abnormalities in leukocytes from LSD-25 users.

A significant increase of chromosomal abnormalities was found in leukocytes from LSD-25 users (six out of eight) compared to nonuser controls (one out of nine). The two LSD-25 users showing no damage reported the lowest estimated average dose. The subjects whose cells showed damage were tested between 1 day and 6 months after their last LSD-25 dose.

Pentylenetetrazol enhances memory function.

Pentylenetetrazol, in oral doses of 1 to 30 milligrams per kilogram of body weight, significantly facilitated one-trial learning and memory retention in CF1 mice, whether administered before or immediately after the initial trial. The effects appeared significantly greater than those observed in earlier studies with oral administration of strychnine or picrotoxin at 0.2 to 0.8 and 2.4 milligrams per kilogram, respectively.

The therapeutic alliance and family psychoeducation in the treatment of schizophrenia: an exploratory prospective change process study.

Although family psychoeducation has been shown to be highly efficacious in the treatment of schizophrenia, the mechanisms underlying the treatment's success are poorly understood. The therapeutic alliance in behavioral family management (BFM) was examined to determine whether the alliance plays a role in the efficacy of this treatment. One early BFM session (mean session = 6.5) involving 28 schizophrenia patients and their relatives who participated in the National Institute of Mental Health's Treatment Strategies in Schizophrenia study was coded using the System for Observing Family Therapy Alliances. Results indicated that when relatives developed a positive therapeutic alliance, patients were less likely to show prodromal signs of relapse and be rehospitalized over a 2-year follow-up period. When patients developed a positive alliance, relatives became less rejecting and were less likely to feel burdened over a 2-year period. The data suggest that the development of a positive therapeutic alliance within family psychoeducation may play an important role in preventing the escalation of psychotic symptoms and improving family relationships. (PsycINFO Database Record (c) 2008 APA, all rights reserved).

Unrecognised cognitive impairment in hospice patients: a pilot study.

The presence of cognitive impairment in patients who are receiving hospice care can affect numerous practical, ethical and legal aspects of their healthcare. A number of factors can contribute to cognitive impairment in these patients. Prevalence rates of cognitive impairment vary widely, but it remains under-recognised and under-treated. The aims of this pilot study were to evaluate the presence and nature of cognitive deficits in patients receiving inpatient hospice care who did not have a known current or past diagnosis of a cognitive disorder or any obvious cognitive impairments. A convenience sample of 30 patients receiving inpatient hospice care underwent bedside cognitive testing. A comprehensive battery of tests was used, including the Mini-Mental State Examination (MMSE) and standardised neuropsychological tests of pre-morbid intellectual functioning, immediate and delayed recall, digit span forward and backward, verbal reasoning and letter and category fluency. On average, subjects were impaired on the MMSE and on tests of learning, verbal reasoning and letter and category fluency. Furthermore, 12 of the 30 subjects met DSM-IV cognitive impairment criteria for dementia based on impaired performance in memory and at least one other cognitive domain on testing. The results of this pilot study suggest that a sizable proportion of patients receiving inpatient hospice care have undetected but clinically significant cognitive impairments. Assessing for and helping patients, families and caregivers deal with cognitive impairment might benefit patients' quality of life, relationships and overall care at the end of life. Future research in this population is needed to evaluate the causes and time course of cognitive impairment over time, as well as any relationship between cognitive impairment and decision-making capacity.

PHR1, a pH-regulated gene of Candida albicans, is required for morphogenesis.

Candida albicans, like many fungi, exhibits morphological plasticity, a property which may be related to its biological capacity as an opportunistic pathogen of humans. Morphogenesis and alterations in cell shape require integration of many cellular functions and occur in response to environmental signals, most notably pH and temperature in the case of C. albicans. In the course of our studies of differential gene expression associated with dimorphism of C. albicans, we have isolated a gene, designated PHR1, which is regulated in response to the pH of the culture medium. PHR1 expression was repressed at pH values below 5.5 and induced at more alkaline pH. The predicted amino acid sequence of the PHR1 protein was 56% identical to that of the Saccharomyces cerevisiae Ggp1/Gas1 protein, a highly glycosylated cell surface protein attached to the membrane via glycosylphosphatidylinositol. A homozygous null mutant of PHR1 was constructed and found to exhibit a pH-conditional morphological defect. At alkaline pH, the mutant, unlike the parental type, was unable to conduct apical growth of either yeast or hyphal growth forms. This morphological aberration was not associated with defective cytoskeletal polarization or secretion. The results suggest that PHR1 defines a novel function required for apical cell growth and morphogenesis.

The Effect of Interval From Completion of Short-Course Radiotherapy to Surgery on the Post-Operative Morbidity and Mortality of Patients with Rectal Cancer.

AIM: Surgery is the mainstay of treatment for invasive rectal cancer. Advances in surgical technique and radiotherapy over the past few decades have resulted in improved local control and survival.1-3 Some concern remains regarding the morbidity associated with performing surgery within a short window following radiotherapy. The current study assessed whether the interval between short-course radiotherapy and surgery influences all cause post-operative morbidity and mortality. METHODS: All patients who had undergone short-course radiotherapy for rectal cancer within the Belfast Health and Social Care Trust from 2005 to 2014 held on a prospective database were included (n=102). A retrospective review of patients' clinical records was performed and a comparison made of patients who had undergone surgery less than 4 days with those 4 or more days following completion of radiotherapy. Baseline patient and tumour characteristics, post-operative complications and readmission rates were compared. Statistical analysis was performed using SPSS ®, Version 22 (SPSS, Inc, Chicago, Illinois, USA). RESULTS: There was no significant difference in mortality or overall post-operative complications between groups, however, less serious complications were reduced in patients undergoing surgery less than 4 days following radiotherapy. Perineal wound complications were significantly more common in patients who had undergone surgery 4 or more days following radiotherapy. CONCLUSION: Our results support the existing data that post-operative complications may be more common with increasing interval to surgery from completion of radiotherapy. Perineal wound morbidity appears significantly more common in patients who undergo surgery 4 or more days following short-course radiotherapy. A larger study to look particularly at perineal wound morbidity and interval from completion of radiotherapy is warranted.

Family interactions and the course of schizophrenia in African American and White patients.

Relatives' critical and intrusive behavior with patients, patients' odd or unusual thinking with relatives, and the course of schizophrenia were examined. Seventy-one African American and White patients (each with 1 relative) completed 2 problem-solving discussions. Relatives' critical and intrusive behavior with patients and patients' odd or unusual thinking with relatives were assessed, and patients were followed for 2 years. For African American patients, high levels of relatives' critical and intrusive behavior were associated with better outcome. For White patients, low levels of both relatives' critical and intrusive behavior and patients' odd or unusual thinking with relatives were associated with better outcome. The results suggest that during family interactions, seemingly negative behaviors may be perceived as a sign of caring and concern by African Americans. For Whites, the combination of patients' odd or unusual thinking with relatives and relatives' critical and intrusive behavior toward patients may be especially predictive of an adverse course.

A sociocultural stress, appraisal, and coping model of subjective burden and family attitudes toward patients with schizophrenia.

A sociocultural stress, appraisal, and coping model was developed to understand relatives' burden of care and negative affective attitudes toward patients with schizophrenia. Ninety-two African American and 79 White patients and a significant other (80% mothers) completed 2 10-min family problem-solving discussions. In addition, the Kreisman Rejection Scale and a global self-report rating of family burden were administered to relatives, and a self-report rating of substance use was administered to patients. Results indicated that subjective burden of care and patients' odd and unusual thinking during the family discussion each independently predicted relatives' attitudes toward patients, suggesting that negative attitudes are based in part on both patients' symptoms and perceived burden of care. African American relatives' perceived burden was also predicted by patients' substance abuse. Finally, White family members were significantly more likely than African Americans to feel burdened by and have rejecting attitudes toward their schizophrenic relative suggesting that cultural factors play an important role in determining both perceived burden and relatives' attitudes toward patients.

Conjugation of benzo(a)pyrene 7,8-dihydrodiol-9,10-epoxide in infant Swiss-Webster mice.

Benzo(a)pyrene 7,8-dihydrodiol-9,10-epoxide (BPDE), accepted as the ultimate carcinogen of benzo(a)pyrene, has a very short half-life in aqueous solutions yet induces lung tumors when injected into infant mice. To evaluate the possibility that metabolites of BPDE, principally in the form of stable conjugates, contribute to binding to DNA in peripheral tissues, infant mice were injected i.p. with 39 nmol (+/- ) anti-BPDE. One h after injection, 5% of the dose was recovered in serum and appeared mostly as conjugated metabolites (54% as glucuronides and 16% as glutathione conjugates). Amounts of direct acting electrophiles in serum estimated by trapping with DNA comprised less than 0.02% of the injected dose. No more than 10% of the radioactivity in extracts of liver, lung, and kidney was recovered as BPDE. Glutathione conjugates predominated in the liver and lung, whereas glucuronides were the major metabolites in kidney. Radioactivity bound to DNA in liver, lung, and kidney was 21.5, 42.7, and 7.8 pmol/mg, respectively. Despite the rapid conversion of BPDE to stable conjugates, 32P-postlabeling profiles of DNA adducts in lung closely resembled that noted after addition of BPDE directly to lung homogenate. Thus, the reactive intermediate as well as stable conjugates of BPDE may be transported to target tissues where they initiate tumors.

Alterations in the rap1 signaling pathway are common in human gliomas.

Several inherited predisposition to cancer syndromes are associated with the development of nervous system tumors. Tuberous sclerosis complex (TSC) is an autosomal dominant disorder in which affected individuals are at risk for developing astrocytomas. One of the genes responsible for this disorder is TSC2, located on chromosome 16p, and encoding a 180 kDa protein (tuberin) that functions in part as a negative regulator of rap1. Previous studies from our laboratory demonstrated that 30% of sporadic astrocytomas have reduced or absent tuberin expression. In addition to loss of tuberin in sporadic astrocytomas, aberrant rap1 mediated signaling may also result from overexpression of rap1. In this study, we test the hypothesis that alterations in the rap1 signaling pathway are frequently observed in certain subsets of gliomas compared to other tumors of the nervous system. Analysis of sporadic astrocytomas and ependymomas demonstrated either increased rap1 or reduced/absent tuberin protein expression in 50-60% of different cohorts of these gliomas, compared to 30-33% of sporadic schwannomas and meningiomas and none of eight oligodendrocyte tumors. These results suggest that alterations in the rap1 signaling pathway are important in the development of certain sporadic human gliomas.

Interdomain binding mediates tumor growth suppression by the NF2 gene product.

The neurofibromatosis 2 (NF2) tumor suppressor gene encodes an intracellular membrane-associated protein, called merlin (or schwannomin), that belongs to the band 4.1 family of cytoskeleton-associated proteins. Inactivating NF2 mutations occur in several sporadic tumor types and have been linked to the NF2 disease, whose hallmark is the development of bilateral Schwann cell tumors (schwannomas) of the eighth cranial nerve. Two major alternatively spliced NF2 variants are expressed in normal tissues: 'NF2-17' lacking exon 16 and 'NF2-16' that contains exon 16 and encodes a merlin protein truncated at the C-terminus. We report that overexpression of NF2-17 in rat schwannoma cells inhibits their growth in vitro and in vivo, while NF2-16 fails to influence schwannoma growth. Tumor growth inhibition by merlin depends on an interdomain association occurring either in cis or in trans between the N- and C-termini. This association does not occur in the truncated NF2-16 protein nor in a mutant NF2-17 protein lacking C-terminal sequences. These data indicate that merlin has a unique mechanism of tumor suppression, inhibiting cell proliferation via self-association.

DNA specificity of the Cre recombinase resides in the 25 kDa carboxyl domain of the protein.

The Cre protein of bacteriophage P1 is a 38.5 kDa site-specific recombinase that belongs to the Int family of recombination proteins. Cre acts by binding specifically to a 34 base-pair sequence, lox, where it carries out recombination. A limited chymotryptic digest of Cre resulted in two fragments of sizes 25 and 13.5 kDa, respectively. The sequence of the amino terminus of the purified 25 kDa peptide demonstrates that this peptide represents the carboxyl-terminal portion of the Cre protein. A truncated version of the cre gene was constructed which produces only the 25 kDa peptide. The 25 kDa peptide is capable of specific binding to the lox site, but binds at lower affinity than does wild-type Cre. Footprinting with Fe-EDTA indicates that the 25 kDa peptide protects the inverted repeats of the lox site but shows only partial protection of the spacer region. This is in contrast to the footprint obtained with wild-type Cre which protects the entire spacer region.

Mechanisms of action of leptin in preventing gastric ulcer.

AIM: To investigate the effects of leptin (1-20 microg/kg) on acidified ethanol (AE)- and indomethacin (Indo)-induced gastric lesions in rats and compare it with ranitidine, lanso-prazole, and omeprazole and to determine its mechanisms of actions. METHODS: Gastric ulcers, which were approximately 1 mm in width, formed in the glandular portion of the gastric mucosa produced by oral administration of either AE or Indo were taken as ulcer index. The inhibitory effect of subcutaneous administration of leptin, two proton pump inhibitors (PPIs) lansoprazole and omeprazole, or H(2)-receptor antagonist ranitidine 30 min before AE or Indo was evaluated. A radioimmunoassay was used to determine the PGE(2) concentration in the homogenate of the glandular portion of the stomach. We performed histological study of the glandular stomach for the evaluation of total, acidic, and sulfated mucus content. RESULTS: Subcutaneous administration of leptin, two PPIs lansoprazole and omeprazole or H(2)-receptor antagonist ranitidine 30 min before AE or Indo produced a dose-dependent and reproducible inhibition of gastric ulcers (GUs). This inhibition was found to be more potent than other antagonists used. In N(G)-nitro L-arginine methyl ester (L-NAME)-pretreated animals, the ulcer prevention ability of leptin in AE-induced ulcer was significantly reduced, compared to rats without L-NAME pretreatment. However, the ulcer prevention ability of leptin was not altered by L-NAME treatment in Indo-induced ulcers. Leptin produced a dose-dependent increase in PGE(2) level in the gastric glandular tissues. Leptin also increased mucus secretion. CONCLUSION: The results of the present study show that leptin inhibits GU formation by AE or Indo in a dose-dependent and reproducible manner in rats. The results also suggest that leptin prevents ulcer formation by increasing the activities of the cyclo-oxygenase and/or nitric oxide pathways and by increasing mucus secretion.