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Biomedical subjects

D Bush

Publications and source records attributed to D Bush.

At least 19 recordsLinked to original sources
PubMed2002

Reproducibility and normal ranges for gastric emptying in normal volunteers using a test meal designed for post-operative patients.

Scintigraphy is the current gold standard for the quantification of gastric emptying; however, results vary with meal composition. We modified a dual phase meal for administration to patients in the early post-operative period and aimed to test the reproducibility of the method, to obtain normal ranges and to compare these with previous data. Twenty healthy volunteers (10 male, 10 female), studied prospectively, were compared with 10 historical male volunteers. Each volunteer was studied twice (Test 1 at day 0 and Test 2 at day 7-10). After an overnight fast, subjects had Meal A consisting of a 60 g pancake labelled with 3 MBq of non-absorbable 99mTc-ion exchange resin and 100 ml of water labelled with 0.5 MBq of non-absorbable 111In-diethylenetriamine pentaacetic acid (111In-DTPA). Anterior and posterior gamma camera images of the stomach were obtained every 20 min for 3 h. The time for 50% emptying (T50) was derived from time-activity curves. Data obtained for males were compared with historical data using a similar technique with Meal B, consisting of two pancakes and a 200 ml milkshake labelled with identical amounts of radioisotopes. The mean (95% CI) T50 values for solid phase emptying for males and females using Meal A, and for historical males using Meal B, were 51.1 min (44.1-58.1), 58.6 min (52.7-64.5) and 128.9 min (112.8-145.1), respectively. Corresponding figures for the liquid phase were 33.2 min (26.1-40.3), 50.2 min (38.4-62.1) and 30.7 min (21.4-39.9). Bland-Altman plots for each phase showed good agreement between Tests 1 and 2 for Meal A. The modified test meal gave reproducible results in healthy volunteers; however, solid phase emptying was significantly faster than that of the bulkier test meal in historical subjects.

Adult↗
PubMed2001

Comparative scintigraphic assessment of the intragastric distribution and residence of cholestyramine, Carbopol 934P and sucralfate.

It has been demonstrated that orally administered cholestyramine is distributed throughout the stomach and provides prolonged gastric residence via mucoadhesion. Gamma scintigraphy was used to compare the gastric emptying and residence of this resin with two formulations known to exhibit retentive or bioadhesive properties, Carbopol 934P and sucralfate. Fasted normal subjects received a single radiolabelled dose and gastrointestinal transit was monitored for 6 h. The subjects were fed after 4 h to determine the effects of inducing a fed pattern of motility on the retention of the formulations. Initial gastric emptying was similar (Mean T50+/-S.E.M.: cholestyramine=66.93+/-9.39 min; Carbopol=56.57+/-11.96 min; sucralfate=48.33+/-11.07 min; P=0.548: n=10), however, the emptying of cholestyramine slowed beyond 2 h. This resulted in greater residence for cholestyramine (Mean AUC0-6+/-S.E.M. (relative units)=11516+/-686 versus 7657+/-1170 versus 6170+/-998; cholestyramine versus Carbopol versus sucralfate; P=0.004: n=10), with approximately 25% remaining in the stomach at 6 h compared to 3.84 and 2.65% of Carbopol and sucralfate, respectively. Cholestyramine was also distributed widely throughout the stomach whereas Carbopol and sucralfate were concentrated in the body and antrum. Thus, as cholestyramine had a comparable emptying time to Carbopol and sucralfate but greater gastric residence and wider distribution, it could provide a potential mucoadhesive drug delivery system targeting the gastric mucosa for treatment of conditions such as Helicobacter pylori infection.

Acrylic Resins↗
PubMed2001

Analysis of amino acids and catecholamines, 5-hydroxytryptamine and their metabolites in brain areas in the rat using in vivo microdialysis.

In vivo microdialysis, using dialysis probes inserted into discrete brain areas and subsequent analysis of neurotransmitters and related substances in the dialysates (usually with HPLC), has yielded a great deal of important information about the actions of psychotropic drugs and endogenous neurotransmitter systems and about the functional interactions between various brain areas. This paper reviews the principles involved in in vivo microdialysis, its advantages and disadvantages, and recent innovations in methodology and applications. The first section includes brief discussions of principles and applications of dialysis, use of anesthetized versus conscious freely moving animals, and methods used to determine the neural origin of neurotransmitters in the dialysate. The subsequent sections provide detailed descriptions, based largely on our own studies in rats, of stereotaxic surgery, in vivo microdialysis, and dialysate analysis, with an emphasis on amino acids and biogenic amines and their metabolites. A discussion of methodological problems which may be encountered in the analysis of amino acids and biogenic amines is also included.

Amino Acids↗
PubMed2001

Medical care use by treated and untreated substance abusing medicaid patients.

Medicaid reimbursement costs for county residents at least 18 years old who used a treatment service (n = 1043) and residents who were Medicaid enrollees with a substance abuse diagnosis but who did not receive treatment (n = 2125) were compared. Untreated patients were more likely to be male (47% vs. 39%), white (56% vs. 45%), and older (39.7 yrs. +/- 13 SD vs. 35.5 yrs +/- 10 SD). The average monthly Medicaid costs ($257) for the untreated were higher in the year prior to identification than were costs ($207) for the treated. The monthly costs in the six months following identification were $761 for the untreated and $373 for the treated. The costs in the next six months returned to near the original for the treated ($224), while those for the untreated remained higher at $340. Medicaid enrollees with untreated substance abuse pose a significant cost to the Medicaid system.

Adult↗
PubMed2001

Effects of proton and combined proton/photon beam radiation on pulmonary function in patients with resectable but medically inoperable non-small cell lung cancer.

STUDY OBJECTIVES: We evaluated the effects on pulmonary function of irradiating lung cancer with protons alone or protons combined with photons. DESIGN: Prospective phase I/II study. SETTING: University medical center. PATIENTS AND INTERVENTIONS: Ten patients with stage I-II non-small cell lung cancer (NSCLC) and FEV(1) < or = 1.0 L were irradiated with protons to areas of gross disease only, using 51 cobalt gray equivalents (CGE) in 10 fractions (protocol 1). Fifteen patients with stage I-IIIA NSCLC and FEV(1) > 1.0 L received 45-Gy photon irradiation to the primary lung tumor and the mediastinum, plus a 28.8-CGE proton boost to the gross tumor volume (protocol 2). MEASUREMENTS: Pulmonary function was evaluated prior to treatment and 1 month, 3 months, and 6 to 12 months following irradiation. RESULTS: In patients receiving protocol 1, no significant changes in pulmonary function occurred. In patients receiving protocol 2, at 6 to 12 months, the diffusion capacity of the lung for carbon monoxide had declined from 61% of predicted to 45% of predicted (p < 0.05), total lung capacity had declined from 114% of predicted to 95% of predicted (p < 0.05), and residual volume had declined from 160% of predicted to 132% of predicted (p < 0.05). Airway resistance increased from 3.8 to 5.2 cm H(2)O/L/s (p < 0.05). No statistically significant changes occurred in vital capacity, FEV(1), or PaO(2). CONCLUSIONS: Our observations indicate that it is feasible to apply higher-than-conventional doses of radiation at a higher-than-conventional dose per fraction without excess pulmonary toxicity when conformal radiation techniques with protons are used.

Aged↗
PubMed2001

Comparison of cesarean section rates in fee-for-service versus managed care patients in the Ohio Medicaid population, 1992-1997.

OBJECTIVE: To examine changes over time in the cesarean section rates for fee-for-service (FFS) beneficiaries versus enrollees of managed care programs (MCPs) in the Ohio Medicaid population. STUDY DESIGN: Cross-sectional study using linked Ohio birth certificates and Medicaid files. PATIENTS AND METHODS: Study patients were Medicaid-enrolled residents of urban counties who had singleton, live births from 1992 through 1997 (n = 86,459). Changes in primary and repeat cesarean section rates were analyzed in the FFS and MCP groups. The test of homogeneity of odds ratios was used to measure the statistical difference between unadjusted odds ratios. Logistic regression analysis was conducted to adjust for risk factors. RESULTS: From 1992 to 1997, the difference in the rates of primary and repeat cesarean sections between FFS and MCP patients decreased. The unadjusted odds ratio (OR) increased from 0.66 to 0.81 (P = .06) for primary cesarean sections and from 0.67 to 1.04 (P = .03) for repeat cesarean sections; this indicated that the likelihood of undergoing a cesarean section increased over time for MCP enrollees compared with FFS beneficiaries. The results of the multivariate analysis indicated that the interaction term of payment source by year was not significant for primary cesarean sections (adjusted OR = 0.93; 95% confidence interval = 0.83, 1.04), but was highly significant for repeat cesarean sections (adjusted OR = 0.53; 95% confidence interval = 0.44, 0.64). CONCLUSION: We observed a reduction in the difference between the rates of both primary and repeat cesarean sections in FFS and MCP patients over time. The reduction was not statistically significant for primary cesarean sections. For repeat cesarean sections, however, we observed a convergence of the rates for FFS and MCP patients.

Adult↗
PubMed2000

Effect of resin surface charge on gastric mucoadhesion and residence of cholestyramine.

Previous studies performed on excised gastric tissue and in healthy volunteers revealed that the ion exchange resin, cholestyramine, exhibits mucoadherent behaviour. This study was designed to elucidate whether surface charge affected this behaviour. Gamma scintigraphy was performed on fasted normal subjects following oral administration of cholestyramine or the cationic exchanger Amberlite(R) IRP-69, either uncoated or polymer-coated to mask their charge. Subjects were fed after 4 h. The initial gastric emptying of all formulations was similar (T(50) values (mean+/-S.E.M.): cholestyramine=85.86+/-9.16 min; IRP-69=76.09+/-9.23 min; polymer-coated cholestyramine=72.0+/-12.64 min; polymer-coated IRP-69=70.25+/-10.57 min: P=0.724). However, after 3 h the emptying pattern of cholestyramine was slower than that of IRP-69. This resulted in greater retention times than IRP-69 (AUC(0-6) values (relative units)=15,200+/-1093 versus 9452+/-811; cholestyramine versus IRP-69: P=0.0004). This effect was reduced by polymer-coating the cholestyramine. Serial images showed that cholestyramine was trapped in the oropharyngeal region and subsequently displaced by the meal, resulting in higher levels of activity remaining at 6 h. Thus, cholestyramine exhibited prolonged gastric residence via mucoadhesion and was distributed throughout the stomach. The surface charge of the resin was found to have a contributory role. These materials may have potential for the delivery of drugs in the topical treatment of the gastric mucosa, for example in the eradication of Helicobacter pylori.

Adolescent↗
PubMed2000

Determination of baseline human nasal pH and the effect of intranasally administered buffers.

The nose is becoming a common route of drug administration, however, little is known about the pH of the human nasal cavity. Local pH may have a direct effect on the rate and extent of absorption of ionizable compounds and hence this study was performed to investigate normal pH values and whether pH could be manipulated by various buffers. Twelve healthy volunteers participated in a study to measure pH in the anterior and posterior sites of the nasal cavity. Miniature pH electrodes were placed 3 cm apart in the nasal cavity and a baseline was recorded for 30 min once the pH had stabilized. One hundred microlitres of isotonic solution was sprayed into the nostril and the pH was measured for 4 h post-dose. The following five formulations were tested: formulation A--sodium chloride (0.9%) at pH 7.2; formulation B--sodium chloride (0.9%) at pH 5.8; formulation C--Sorensens phosphate buffer (0.06 M) at pH 5. 8; formulation D--Sorensens phosphate buffer (0.13 M) at pH 5.8 and formulation E--formulation as (c) but adjusted to pH 5.0. Each formulation also contained saccharin sodium (0.5%) as a taste marker for nasal clearance. The time at which each subject detected the taste of saccharin was noted. The 30-minute baseline recording prior to administration of the nasal spray formulation demonstrates that there was both considerable intersubject and intrasubject variation in nasal pH. The average pH in the anterior of the nose was 6.40 (+0. 11, -0.15 S.D.) when calculated from H(+) values. The pH in the posterior of the nasal cavity was 6.27 (+0.13, -0.18 S.D.). The overall range in pH was 5.17-8.13 for anterior pH and 5.20-8.00 for posterior pH. Formulation A caused the pH in the anterior part of the nasal cavity to reach a maximum of 7.06 in 11.25 min from the baseline of pH 6.14 (P<0.05). The mean baseline pH was 6.5 for the posterior part of the nose which did not change over the recording period. Formulation B caused the anterior pH to increase from pH 6. 60 to 7.25 within the first minute. This fell back to a mean pH of 7.07 over the first hour which was still significantly above the baseline. It remained at this value for the remainder of the recording period. The initial average posterior pH was 6.32 and again this did not significantly change over the recording period. Formulation C produced a sustained increase in anterior nasal pH from a baseline pH of 6.57-7.12. A small transient decrease was observed in the pH in the posterior of the nose but baseline pH of 6. 6 was re-established within 15 min post dose. Formulation D significantly reduced anterior nasal pH from 6.30 to 5.87 by 30 min reaching a pH of 5.95 by 90 min where it remained for the remainder of the recording period. The posterior baseline pH was 6.3 and introduction of the pH 5.8 buffer caused a slow increase over 90 min to pH 6.6. Formulation E increased anterior pH from 6.1 to 6.7 for the remainder of the recording period. It had an insignificant effect on posterior nasal pH. The mean (+/-S.D.) time to taste saccharin for formulations A to E was 13.42+/-10.21, 14.67+/-8.37, 11.67+/-8.08, 10.08+/-7.6, 9.80+/-6.73 min, respectively. There was no significant difference between the clearance times for the different formulations. In conclusion, average baseline human nasal pH is approximately 6.3. Nasal anterior pH can be decreased when buffers of 0.13 M and above are used. Mildly acidic solutions produce an increase in pH presumably due to reflux bicarbonate secretion. Posterior nasal pH was not altered by administration of any buffer except the 0.13 M buffer at pH 5.8. This produced a rise in posterior pH.

Administration, Intranasal↗
PubMed2000

The effect of nasal patency on the clearance of radiolabeled saline in healthy volunteers.

PURPOSE: The objective of this study was to investigate the effect of nasal cavity patency on the penetration, deposition, and clearance of an aqueous isotonic saline solution. METHODS: The study was carried out as a single center, open, randomized, 2-way cross-over in healthy volunteers. Nasal patency was assessed using misting patterns on a cold metal surface at the beginning and end of study. 100 microl of technetium-99m radiolabeled saline solution was introduced into either the most or least patent nasal cavity using a purpose designed spray device. The distribution and residence time of the radiolabel was followed for 2 hours using gamma scintigraphy. RESULTS: The mean times to 50% clearance were 34+/-7 and 28+/-12 minutes (+/- s.d.) for the side view of the least and most patent nasal cavity respectively. Total clearance of the radiolabelled saline from the nose was not affected by patency. Between 7 and 35% of the radiolabelled saline solution remained in the nasal cavity at the end of imaging. Using endoscopy to track the clearance of an aqueous solution of food dye using the same delivery procedure, identified this region as hair in the nasal vestibule. The dye was seen to dry in this region along with the mucus. CONCLUSIONS: Nasal patency affects the initial, but not total clearance of solutions, however, the remaining solution may not be available for drug delivery.

Adolescent↗
PubMed2000

Gastric response to increased meal viscosity assessed by echo-planar magnetic resonance imaging in humans.

Normal meals are highly viscous, and viscosity is a key factor in influencing gastric emptying of food. However, the process of meal dilution and mixing is difficult to assess with the use of conventional methods. The aim of this study was to validate an in vivo, novel, noninvasive, echo-planar magnetic resonance imaging (EPI) technique, capable of monitoring the viscosity of a model meal, and to use this to investigate the effects of viscosity on gastric emptying, meal dilution and satiety. Healthy volunteers (n = 8) ingested 500 mL of locust bean gum (0.25, 0.5, 1.0 or 1.5 g/100 g), nonnutrient, liquid meals of varying viscosities, and labeled with a nonabsorbable marker, phenol red. Meal viscosity was calibrated against the water proton transverse relaxation rate (T(2)(-1)) in vitro before ingestion, thus viscosity was measured in vivo via EPI measurements of T(2)(-1). Viscosity and dilution were also measured directly using nasogastric aspirates. Gastric volumes as measured by EPI, fullness, appetite and hunger were also assessed serially. Before ingestion, the log of initial meal viscosity was linearly related to T(2)(-1) (n = 8, r(2) = 0.95). Similarly, T(2)(-1) measured in vivo was also linearly related to the viscosity of the aspirates (r(2) = 0.88). All meals underwent rapid dilution, leading to a reduction in viscosity, which was greatest for the most viscous meal (P < 0.01). Surprisingly, despite the fact that the initial meal viscosity varied 1000-fold, there was only a small delay in gastric emptying (P for trend < 0.05). The area under the curve for satiety increased with initial meal viscosity, whereas that for hunger decreased (P < 0.05). In conclusion, the viscosity of a meal in vivo can be measured noninvasively using EPI. The stomach responds to meal ingestion by rapid intragastric dilution, causing a reduction of meal viscosity, and gastric emptying is minimally delayed. However, increased viscosity is associated with more prolonged satiety.

Adult↗
PubMed1999

Twenty-four hour ambulatory nasal pH monitoring.

The nasal delivery of drugs, both for systemic and local use, is an expanding field with many drugs being delivered by this route. It is known that changes in pH can affect drug absorption but there is no data regarding intranasal pH over time. We present the results of 24-h ambulatory nasal pH monitoring in four subjects, each of whom had monitoring on two separate occasions. The apparatus consisted of a pH monitor with two electrodes, thus enabling us to take readings from 1 and 4 cm behind the anterior end of the inferior turbinate. Measurements were recorded every 6 s by the posterior electrode and every 30 s by the anterior electrode. The recording apparatus was worn around the subjects waist. Analysis of the results showed that there was no diurnal variation and no significant differences between the subjects. The mean pH from the anterior electrode was higher than that from the posterior (7.1 versus 6.6). The pH did not fluctuate with daily activities such as eating, drinking or sleeping. The results are interesting and may be of importance with regard to the design of formulations for nasal drug delivery systems.

Activities of Daily Living↗
PubMed1999

Dual pH probe monitoring versus single pH probe monitoring in infants on milk feeds: the impact on diagnosis.

OBJECTIVES: Oesophageal pH monitoring is the gold standard technique for the detection of gastro-oesophageal reflux in adults and children. A standard parameter used to define "abnormal" reflux is the percentage of recording time for which the gastric pH is < 4. This study investigated the relevance of this measure in infants on regular milk feeds whose gastric contents and refluxate will be neutral for most of the recording time. METHODS: Simultaneous oesophageal and gastric pH monitoring was carried out on all infants who were milk fed exclusively and admitted to hospital for suspected gastro-oesophageal reflux. In vitro studies were performed to establish the buffering capacities of the fruit juice, Dioralyte (a glucose electrolyte solution), breast milk, and milk formula feeds available on the paediatric wards. RESULTS: Complete sets of data were obtained from 30 babies with a mean age of 4 months. Gastric pH was </= 4 for a mean (SEM) of 42.4 (4.9)% of the recording time. The mean (SEM) percentage time that oesophageal pH was < 4 for the total recording period was 6.89 (0.92)%. Recalculation of the percentage of time that the gastric pH was > 4 increased this value to 17.81 (2. 46)%. Using a cut off point of 10%, 11 of the 30 babies would have been diagnosed positive for reflux using the conventional method; however, recalculation by ignoring the time for which gastric pH was high doubled this to 22 positive for reflux. CONCLUSION: Combined oesophageal and gastric pH monitoring greatly increases the number of positive results from tests in infants on regular milk feeds.

Animals↗
PubMed1998

Anticoagulation for nonvalvular atrial fibrillation: effects of type of practice on physicians' self-reported behavior.

BACKGROUND: This study examines whether social and economic factors affect physician practice and attitude with regard to warfarin anticoagulation in patients with nonvalvular atrial fibrillation. METHODS: We identified physicians in Baltimore City, Baltimore County, and Prince George's County who (1) had written one or more prescriptions for a digitalis compound during the preceding year, and (2) were classified as general practitioners, family practice specialists, internists, or cardiologists. All 358 physicians fulfilling these criteria were surveyed by questionnaire. RESULTS: The overall response rate was 43%. Physicians who wrote 15% or more of their digitalis prescriptions for Medicaid patients said they used warfarin at significantly lower rates for patients with nonvalvular AF than other (66% versus 79%, P <0.01). The opposite pattern was seen with regard to aspirin. There were no significant differences in practice pattern between physicians located in urban vs. suburban counties. CONCLUSION: In our sample, self-reported anticoagulant practices for patients with nonvalvular AF were associated with the percentage of digitalis prescriptions written for Medicaid patients. In this metropolitan area, anticoagulant therapy was reportedly prescribed for approximately 75% of patients with nonvalvular atrial fibrillation.

Anticoagulants↗
PubMed1998

Patterns of food and acid reflux in patients with low-grade oesophagitis--the role of an anti-reflux agent.

BACKGROUND: Food and acid have been shown to be refluxed independently of each other in healthy volunteers, and anti-reflux agents decrease the reflux of both parameters. Until now this phenomenon had not been studied in patients with low-grade oesophagitis, who are the group most likely to use anti-reflux medication. AIM: To assess patterns of gastro-oesophageal reflux of acid and food in 12 ambulant patients with endoscopically proven oesophagitis of between grades I and II, but who were otherwise healthy. Also to assess the effectiveness of a single dose of an alginate-containing anti-reflux agent in controlling food and acid reflux in this patient group. METHODS: Oesophageal pH monitoring and external ambulatory gamma detection were used to study food and acid reflux. A pH electrode was positioned 5 cm above the cardia and the gamma detector was positioned externally over the pH electrode. The patients then received a technetium-99m labelled meal designed to provoke reflux. Thirty minutes later the patients were given a 20 ml dose of alginate (Liquid Gaviscon), or 20 ml of tap water. Incidence of reflux was monitored for approximately 4 h from the end of the meal. Allocation to treatment group was randomized, with patients receiving the alternative treatment on the second study day after approximately a 7-day washout period. RESULTS: The mean percentage time oesophageal pH remained below 4 was 16.3 min for the control group and 5.4 min for the treatment group (P = 0.03). Food reflux was detected 23.7% of the time in the control group compared to 12% of the time in the treatment group (P = 0.02). The anti-reflux agent was also successful in decreasing the number of events, but the duration of the reflux events was not significantly different. CONCLUSIONS: Patients with grades I and II oesophagitis reflux food and acid independently, and are predominantly either food refluxers or acid refluxers, but not both. Liquid alginate decreases the number of both food and acid reflux events, but does not change their duration.

Adult↗
PubMed1998

A hirudin-sensitive, growth-related proteinase from human fibroblasts.

We have identified a hirudin-sensitive proteinase from human fibroblasts. Inhibition of this enzyme results in partial inhibition of cell growth in culture. The enzyme has a molecular weight of about 38000, and can be isolated by affinity chromatography with a hirudin-agarose matrix. The enzyme is apparently not closely related to thrombin, but does show a high level of amino acid sequence homology with fragments of a protein isolated from the synovial fluid of rheumatoid arthritis patients, which acts as a mitogen for human T lymphocytes.

Amino Acid Sequence↗
PubMed1997

A nested case-control study of non-Hodgkin lymphoma and serum organochlorine residues.

BACKGROUND: The steady worldwide increase in the incidence of non-Hodgkin lymphoma during the past few decades remains mostly unexplained. Several studies suggest that there may be an association between the agricultural use of the organochlorine 1,1,1-trichloro-2,2'bis(p-chlorophenyl)ethane (DDT) and increased risk of non-Hodgkin lymphoma. We have investigated the association between risk of non-Hodgkin lymphoma and body burden of selected organochlorines in the general population in a nested case-control study. METHODS: We measured prediagnostic serum concentrations of DDT, its metabolites, and other organochlorines, including polychlorinated biphenyls (PCBs), in 74 cases of non-Hodgkin lymphoma and 147 matched controls identified from a prospective cohort of 25,802 adults, established in 1974 in Washington County, Maryland, USA. We report results for total lipid-corrected serum concentrations of DDT and total PCBs. FINDINGS: There was a strong dose-response relation between quartiles of total lipid-corrected serum PCB concentrations and risk of non-Hodgkin lymphoma overall (odds ratios by quartile: 1.0; 1.3 [95% CI 0.5-3.3]; 2.8 [1.1-7.6]); and 4.5 [1.7-12.0]; p for trend = 0.0008) and separately in men and in women. There was also evidence suggesting that seropositivity for the Epstein-Barr virus early antigen potentiated the effects of serum PCBs. By contrast, total lipid-corrected serum concentrations of DDT were not associated with risk of non-Hodgkin lymphoma. INTERPRETATION: These results should be regarded as hypothesis-generating. Before causal inferences can be made about exposure to PCBs and increased risk of non-Hodgkin lymphoma, our findings require replication and the biological plausibility of the association needs further investigation.

Adult↗