Misleading localization by 18F-fluorocholine PET/CT in familial hypocalciuric hypercalcemia type-3: a case report.

BACKGROUND: Familial hypocalciuric hypercalcemia (FHH) is a heterogeneous autosomal-dominant disorder of calcium hemostasis that may be difficult to distinguish clinically from mild primary hyperparathyroidism. Loss-of-function mutations mainly involving Arg15 residue of the adaptor-related protein complex 2, sigma subunit 1 (AP2S1) cause a rarer, more recently recognized form of FHH, FFH type-3. Recently, 18F-fluorocholine positron emission tomography/computed tomography (FCH-PET/CT) showed superior sensitivity to conventional imaging in localizing parathyroid adenomas. We report a new FFH type-3 patient who underwent unnecessary parathyroidectomy in association with misleading FCH-PET/CT imaging. CASE PRESENTATION: A 29-year old woman was initially evaluated for parathyroid hormone (PTH)-dependent hypercalcemia in 2013. Medical history was positive only for chronic constipation and malaise with no personal or family history of hypercalcemia, kidney stones, or neck surgery. Over seven years, serum calcium level was 2.51-2.89 mmol/L with concomitant PTH level of 58.7-94.8 mmol/L. Serum phosphate levels were in the low/low normal range. Serum creatinine and magnesium levels were normal. 25-hydroxy vitamin D level was 13 nmol/L. 24-hour urine calcium level was 1.92 mmol/day but increased to 6.99 mmol/day after treatment with cholecalciferol 1000 IU daily. Bone mineral density and renal ultrasound were normal. Parathyroid ultrasound showed two hypoechoic nodules inferior to the left and right thyroid lobes; however, 99mtechnitium-sestamibi scans (2013, 2016, 2018) were negative. FCH-PET/CT (2019) showed focal uptake co-localizing with the nodule inferior to the left thyroid lobe. The patient underwent left inferior parathyroidectomy and pathology was consistent with parathyroid hyperplasia. However, postoperatively, serum calcium and PTH levels remained elevated and FCH-PET/CT and ultrasound showed persistence of the uptake/nodule. Whole exome sequencing showed Arg15Cys mutation in the AP2S1 gene characteristic of FHH type-3. CONCLUSIONS: In this new case of FHH type-3, FCH-PET/CT failed to localize to the hyperplastic parathyroid glands and localized instead to apparently a lymph node. This, together with increased urinary calcium after vitamin D supplementation, led to unnecessary parathyroidectomy. Given the increasingly lower cost of genetic testing and the cost of follow up and unnecessary surgery, it may prudent to include genetic testing for FHH early on in patients with mild PTH-dependent hypercalcemia.

Factors underlying surrogate medical decision-making in middle eastern and east Asian women: a Q-methodology study.

BACKGROUND: It is not clear how lay people prioritize the various, sometimes conflicting, interests when they make surrogate medical decisions, especially in non-Western cultures. The extent such decisions are perspective-related is also not well documented. METHODS: We explored the relative importance of 28 surrogate decision-making factors to 120 Middle-Eastern (ME) and 120 East-Asian (EA) women from three perspectives, norm-perception (N), preference as patient (P), and preference as surrogate decision-maker (S). Each respondent force-ranked (one to nine) 28 opinion-items according to each perspective. Items' ranks were analyzed by averaging-analysis and Q-methodology. RESULTS: Respondents' mean (SD) age was 33.2 (7.9) years; all ME were Muslims, 83% of EA were Christians. "Trying everything possible to save patient," "Improving patient health," "Patient pain and suffering," and/or "What is in the best interests of patient" were the three most-important items, whereas "Effect of caring for patient on all patients in society," "Effect of caring for patient on patients with same disease," and/or "Cost to society from caring for patient" were among the three least-important items, in each ME and EA perspectives. P-perspective assigned higher mean ranks to family and surrogate's needs and burdens-related items, and lower mean rank to "Fear of loss" than S-perspective (p<0.001). ME assigned higher mean ranks to "Medical facts" and "Surrogate own wishes for patient" and lower mean rank to "Family needs" in all perspectives (p<0.001). Q-methodology identified models that were relatively patient's preference-, patient's religious/spiritual beliefs-, or emotion-dependent (all perspectives); medical facts-dependent (N- and S-perspectives), financial needs-dependent (P- and S-perspectives), and family needs-dependent (P-perspective). CONCLUSIONS: 1) Patient's health was more important than patient's preference to ME and EA women; society interest was least important. 2) Family and surrogate's needs/ burdens were more important, whereas fear of loss was less important to respondents as patients than as surrogate decision-makers. 3) Family needs were more important to EA than ME respondents, the opposite was true for medical facts and surrogate's wishes for patient. 4) Q-methodology models that relatively emphasized various surrogate decision-making factors overlapped the ME and EA women' three perspectives.

Circumferential Negative Intermittent Pressure to the Midarm Does Not Impair Digital O2 Saturation: A Randomized Controlled Study.

BACKGROUND: Circumferential negative pressure wound therapy is commonly used to manage wounds and enhance the healing process. A theoretical concern was recently raised that circumferential negative pressure wound therapy may have a negative effect on perfusion distally. METHODS: In a randomized study, we applied circumferential negative pressure (125 mm Hg) to the midarm of 13 healthy volunteers through InfoV.A.C. Therapy Unit device. The pressure was applied intermittently (5 minutes on and 2 minutes off) for 9 hours. The same device without negative pressure was applied to the contralateral midarm as control. Bilateral index finger O2 saturation (SpO2) was measured every 30 minutes using digital pulse oximetry. RESULTS: Mean (SD) age of the volunteers was 32.2 (9.5) years, and 61.5% were male. Mean (SD) area under the curve from time 0 to 9 hours of SpO2 was 890.56 (6.69) and 889.71 (6.23) %xh in the intervention and control arms, respectively (P = 0.35). O2 saturation was ≥94% at all observation times in both arms, and no adverse events were identified. CONCLUSIONS: Circumferential negative intermittent pressure of 125 mm Hg applied to the midarm of healthy volunteers for 9 hours does not adversely affect digital SpO2.

Vitamin-D2 treatment-associated decrease in 25(OH)D3 level is a reciprocal phenomenon: a randomized controlled trial.

BACKGROUND: Vitamin-D2 (D2) treatment has been associated with a decrease in 25-hydroxy (25(OH)) vitamin-D3 (D3) level, suggesting that D3 treatment would be preferred to raise total 25(OH) vitamin-D (D) level. We postulated that D2 treatment-associated decrease in 25(OH)D3 level is related to the increase in 25(OH)D level rather than being D2-specific, and thus there would be a similar D3 treatment-associated decrease in 25(OH)D2 level. METHODS: Fifty volunteers were block-randomized to 50,000 IU D2 or placebo orally once (study-1) and fifty volunteers received 50,000 IU D2 orally once and 4 days later block-randomized to 50,000 IU D3 or placebo orally once (study-2). Interventions were concealed from volunteers and research coordinators and blindly-administered. Serum 25(OH)D2 and 25(OH)D3 levels were blindly-determined at baseline and days 14, 28, 42, and 56, post-randomization by high performance liquid chromatography assay. Results of 97 participants were analyzed. Primary outcome measure was day-28 D2-associated change in 25(OH)D3 level in study-1 and D3-associated change in 25(OH)D2 level in study-2, adjusted for baseline levels. RESULTS: Mean (95% confidence interval) difference between the active and placebo arms in the decrease in day-28 25(OH)D3 (study-1) and 25(OH)D2 (study-2) levels was 13.2 (9.7 to 16.6) and 9.8 (5.2 to 14.4) nmol/L, respectively. Corresponding differences at day-56 were 10.8 (6.8 to 14.8) and 1.7 (- 7.6 to 11.1) nmol/L, respectively. The difference between the placebo and active arms in area-under-the-curve at day-28 (AUC28) and day-56 (AUC56) were 262.3 (197.8 to 326.7) and 605.1 (446.3 to 784.0) for 25(OH)D3 (study-1) and 282.2 (111.2 to 453.3) and 431.2 (179.3 to 683.2) nmol.d/L for 25(OH)D2 (study-2), respectively. There were significant correlations between day-28 changes in 25(OH)D2 and 25(OH)D3 levels in study-1 (rho = - 0.79, p < 0.001) and study-2 (rho = - 0.36, p = 0.01), and between day-28 changes in 25(OH)D2 level and baseline 25(OH)D level in study-2 (rho = - 0.42, p = 0.003). CONCLUSIONS: Compared to placebo, D3 treatment is associated with a decrease in 25(OH)D2 level similar in magnitude to D2-treatment associated decrease in 25(OH)D3 level; however, the D3-placebo difference in 25(OH)D2 level is shorter-lasting. Changes in 25(OH)D2 and 25(OH)D3 levels are correlated with each other and with baseline 25 (OH) D levels, suggesting a common regulatory mechanism. TRIAL REGISTRATION: ClinicalTrial.gov identifier: NCT03035084 (registered January 27, 2017).

Prediction of life-story narrative for end-of-life surrogate's decision-making is inadequate: a Q-methodology study.

BACKGROUND: Substituted judgment assumes adequate knowledge of patient's mind-set. However, surrogates' prediction of individual healthcare decisions is often inadequate and may be based on shared background rather than patient-specific knowledge. It is not known whether surrogate's prediction of patient's integrative life-story narrative is better. METHODS: Respondents in 90 family pairs (30 husband-wife, 30 parent-child, 30 sibling-sibling) rank-ordered 47 end-of-life statements as life-story narrative measure (Q-sort) and completed instruments on decision-control preference and healthcare-outcomes acceptability as control measures, from respondent's view (respondent-personal) and predicted pair's view (respondent-surrogate). They also scored their confidence in surrogate's decision-making (0 to 4 = maximum) and familiarity with pair's healthcare-preferences (1 to 4 = maximum). Life-story narratives' prediction was examined by calculating correlation of statements' ranking scores between respondent-personal and respondent-surrogate Q-sorts (projection) and between respondent-surrogate and pair-personal Q-sorts before (simulation) and after controlling for correlation with respondent-personal scores (adjusted-simulation), and by comparing percentages of respondent-surrogate Q-sorts co-loading with pair-personal vs. respondent-personal Q-sorts. Accuracy in predicting decision-control preference and healthcare-outcomes acceptability was determined by percent concordance. Results were compared among subgroups defined by intra-pair relationship, surrogate's decision-making confidence, and healthcare-preferences familiarity. RESULTS: Mean (SD) age was 35.4 (10.3) years, 69% were females, and 73 and 80% reported ≥ very good health and life-quality, respectively. Mean surrogate's decision-making confidence score was 3.35 (0.58) and 75% were ≥ familiar with pair's healthcare-preferences. Mean (95% confidence interval) projection, simulation, and adjusted-simulation correlations were 0.68 (0.67-0.69), 0.42 (0.40-0.44), and 0.26 (0.24-0.28), respectively. Out of 180 respondent-surrogate Q-sorts, 24, 9, and 32% co-loaded with respondent-personal, pair-personal, or both Q-sorts, respectively. Accuracy in predicting decision-control preference and healthcare-outcomes acceptability was 47 and 52%, respectively. Surrogate's decision-making confidence score correlated with adjusted-simulation's correlation score (rho = 0.18, p = 0.01). There were significant differences among the husband-wife, parent-child, and sibling-sibling subgroups in percentage of respondent-surrogate Q-sorts co-loading with pair-personal Q-sorts (38, 32, 55%, respectively, p = 0.03) and percent agreement on healthcare-outcomes acceptability (55, 35, and 67%, respectively, p = 0.002). CONCLUSIONS: Despite high self-reported surrogate's decision-making confidence and healthcare-preferences familiarity, family surrogates are variably inadequate in simulating life-story narratives. Simulation accuracy may not follow the next-of-kin concept and is 38% based on shared background.

Evaluation of Omeprazole Limited Sampling Strategies to Estimate Constitutive Cytochrome P450 2C19 Activity in Healthy Adults.

BACKGROUND: Limited sampling strategy (LSS) is a validated method to estimate pharmacokinetic (PK) parameters from a reduced number of samples. Omeprazole is used to phenotype in vivo cytochrome P450 (CYP) 2C19 activity. This study examined an LSS using 2 estimation methods to determine apparent oral clearance (CL/F) and thus CYP2C19 activity. METHODS: Data from 7 previously published studies included healthy subjects receiving a single, oral dose of omeprazole with intensive PK sampling. CL/F was estimated using noncompartmental analysis (NCA) and population PK modeling. LSS was simulated by selecting the 1, 2, 4, and/or 6-hour postdose time points. Linear regression was performed to assess whether CL/F estimated from limited sampling could accurately predict CL/F from the full PK profile. RESULTS: Median CL/F was 23.7 L/h by NCA and 19.3 L/h by population PK modeling. In comparing the LSS NCA estimated versus observed CL/F, all evaluated linear regression models had unacceptable coefficients of determination (r, range: 0.14-0.81). With the population PK approach, 737 plasma concentrations (n = 71) and CYP2C19 genotype data were described with a 1-compartment structural model with mixed zero and first-order absorption and lag time. In comparing the population PK LSS estimated versus observed CL/F, all evaluated linear regression models had unacceptable r (range: 0.02-0.74). Post hoc comparison of CYP2C19 poor metabolizers versus CYP2C19 extensive metabolizers resulted in significantly lower CL/F in poor metabolizers versus extensive metabolizers. CONCLUSIONS: Omeprazole LSS performed poorly in estimating CL/F using 2 separate estimation approaches and does not seem to be a suitable method for determining CYP2C19 activity.

Differential effects of vitamin D2 and D3 supplements on 25-hydroxyvitamin D level are dose, sex, and time dependent: a randomized controlled trial.

BACKGROUND: Vitamin D (D) supplements are indispensable for its world-wide deficiency. Controversy continues on ergocalciferol (D2) and cholecalciferol (D3) relative potency as well as on dosing-schedule and sex role in raising 25-hydroxy D (25(OH)D) level, the best indicator of D status. METHODS: We randomized 279 adults to daily D2, D3, D2/D3, or placebo; 2-weekly D2 or D3; or 4-weekly D2 or D3 (250,000 IU over/140 days). Randomization sequence, stratified by body-mass-index (BMI) and sex, was concealed from study coordinators and participants who were then blinded to capsules' content. D2, D3, 25(OH)D2, and 25(OH)D3 Serum levels were determined blindly on days 0,1,2,3,4,7,14, and 2-weekly thereafter by high performance liquid chromatography assay. The results of 269 participants were available for analysis. Primary endpoint was area-under-the-curve (AUC) of 25(OH)D (25(OH)D2 + 25(OH)D3) adjusted for sex, BMI, and baseline 25(OH)D level. RESULTS: Mean(SD) age was 33.0(8.5) year, 41% were males, and 85% completed follow-up. Baseline 25(OH)D level was 39.8(11.9) and increased by 3.3(11.6) and 28.6(16.3) nmol/L, in the placebo and active-treatment groups, respectively. AUC from day 0 to 140 (AUC140) of 25(OH)D was 40% (D3 daily) to 55% (D3 2-weekly) higher with active-treatment than placebo (p < 0.001). 25(OH)D2 AUC140 was higher in daily than 2-weekly (17%, p = 0.006) and 4-weekly (20%, p = 0.001) D2-treated groups. 25(OH)D3 AUC140 was lower in daily than 2-weekly (11%, p = 0.002) and 4-weekly D3-treated groups (10%, p = 0.008). In D2-treated groups, there was 16.4 nmol/L decrease in 25(OH)D3 level that correlated (p < 0.001) with 25(OH)D2 level increase (r = 0.48) and baseline 25(OH)D level (r = 0.58), in one participant with measurable baseline 25(OH)D2 level, D3 caused a similar decrease in 25(OH)D2 level, while in the D2/D3-treated group, 25(OH)D3 level didn't increase. Incremental AUC from day 0 to 7 (AUC7) of D3 and 25(OH)D3 in D3-treated groups were 118-243% higher and 31-39% lower, respectively, than incremental AUC7 of D2 and 25(OH)D2 in D2-treated groups. Incremental AUC7 of D3 and 25(OH)D3 in D3-treated groups and D2 and 25(OH)D2 in D2-treated groups were higher in females than males (55, 13, 64, and 28%, respectively). Baseline 25(OH)D level predicted response to D2 and D3 (p < 0.001), whereas, BMI was significant predictor only for early response to D2. CONCLUSIONS: Effects of D2 and D3 supplements on 25 (OH)D level may be dosing-schedule and sex-dependent. D2-associated reduction in 25(OH)D3 level may be related to total 25(OH)D level rather than being D2-specific. D2 may be 25-hydroxylated faster than D3. TRIAL REGISTRATION: ClinicalTrial.gov identifier: NCT01170494 (registered July 25, 2010).

Does the placebo effect modulate drug bioavailability? Randomized cross-over studies of three drugs.

BACKGROUND: Medication effect is the sum of its drug, placebo, and drug*placebo interaction effects. It is conceivable that the interaction effect involves modulating drug bioavailability; it was previously observed that being aware of caffeine ingestion may prolong caffeine plasma half-life. This study was set to evaluate such concept using different drugs. METHODS: Balanced single-dose, two-period, two-group, cross-over design was used to compare the pharmacokinetics of oral cephalexin, ibuprofen, and paracetamol, each described by its name (overt) or as placebo (covert). Volunteers and study coordinators were deceived as to study aim. Drug concentrations were determined blindly by in-house, high performance liquid chromatography assays. Terminal-elimination half-life (t½) (primary outcome), maximum concentration (Cmax), Cmax first time (Tmax), terminal-elimination-rate constant (λ), area-under-the-concentration-time-curve, to last measured concentration (AUCT), extrapolated to infinity (AUCI), or to Tmax of overt drug (AUCOverttmax), and Cmax/AUCI were calculated blindly using standard non-compartmental method. Covert-vs-overt effect on drug pharmacokinetics was evaluated by analysis-of-variance (ANOVA, primary analysis), 90% confidence interval (CI) using the 80.00-125.00% bioequivalence range, and percentage of individual pharmacokinetic covert/overt ratios that are outside the +25% range. RESULTS: Fifty, 30, and 50 healthy volunteers (18%, 10%, and 6% females, mean (SD) age 30.8 (6.2), 31.4 (6.6), and 31.2 (5.4) years) participated in 3 studies on cephalexin, ibuprofen, and paracetamol, respectively. Withdrawal rate was 4%, 0%, and 4%, respectively. Eighteen blood samples were obtained over 6, 10, and 14 h in each study period of the three drugs, respectively. ANOVA showed no significant difference in any pharmacokinetic parameter for any of the drugs. The 90% CIs for AUCT, AUCI, Cmax, AUCOverttmax, and Cmax/AUCI were within the bioequivalence range, except for ibuprofen Cmax (76.66-98.99), ibuprofen Cmax/AUCI (77.19-98.39), and ibuprofen (45.32-91.62) and paracetamol (51.45-98.96) AUCOverttmax. Out of the 126 individual covert/overt ratios, 2.0-16.7% were outside the +25% range for AUCT, 2.0-4.2% for AUCI, 25.0-44.9% for Cmax, 67.3-76.7% for AUCOverttmax, and 45.8-71.4% for Tmax. CONCLUSIONS: This study couldn't confirm that awareness of drug ingestion modulates its bioavailability. However, it demonstrates the trivial effect of blinding in bioequivalence studies and the extent of bio-variability that would be expected when comparing a drug product to itself. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01501747 (registered Dec 26, 2011).

Drug*placebo interaction effect may bias clinical trials interpretation: hybrid balanced placebo and randomized placebo-controlled design.

BACKGROUND: Conventional randomized placebo-controlled study design assumes the absence of drug*placebo interaction. We hypothesized the presence of such an interaction and that conventionally estimated drug effect might be biased. The objectives of the study were to determine the drug*placebo interaction effect (main) and compare conventionally estimated and interaction model-estimated drug effects (secondary). METHODS: We used a hybrid of balanced placebo and randomized placebo-controlled designs. Four hundred eighty healthy volunteers were randomized to three groups. The first received hydroxyzine (25 mg) described as hydroxyzine or placebo, the second received placebo described as hydroxyzine or placebo, and the third received hydroxyzine and placebo described as unknown; each in a randomized crossover design. Seven participants failed to crossover. Group assignment was concealed from participants and study coordinators. Coordinators were blinded to group and intervention assignment. Participants and coordinators were deceived as to study objectives. Main outcomes were mean area-under-the-curve of drowsiness (therapeutic outcome) and mouth-dryness (adverse outcome), self-reported on 100 mm visual analog scale over 7 h. Drug, placebo, placebo + interaction, and total effects were estimated using analysis of covariance by comparing received hydroxyzine/told placebo to received placebo/told placebo, received placebo/told hydroxyzine to received placebo/told placebo, received hydroxyzine/told hydroxyzine to received hydroxyzine/told placebo, and received hydroxyzine/told hydroxyzine to received placebo/told placebo, respectively. Drug effect was also conventionally estimated in the third group. RESULTS: Mean (SD) age was 31.4 (6.6) years, 65% were males. There was significant difference between placebo + interaction effect and placebo effect for both drowsiness and mouth-dryness with a mean difference (95% confidence interval) of 35.1 (5.6 to 64.6) and 23.8 (2.4 to 45.2) mm*hr, respectively. Total effect was larger than the sum of drug and placebo effects for drowsiness (139.7 (109.8 to 169.6) vs. 99.1 (68.2 to 130.0) mm*hr) and mouth-dryness (63.6 (41.1 to 86.1) vs. 34.7 (11.1 to 58.4) mm*hr). Conventionally estimated drug effect was larger than interaction model-estimated drug effect for drowsiness (69.2 (45.5 to 92.8) vs. (58.3 (31.6 to 85.0) mm*hr) and mouth-dryness (19.9 (5.3 to 34.5) vs. 9.5 (-9.2 to 28.1) mm*hr). CONCLUSIONS: There is significant and important drug*placebo interaction effect that may bias conventionally estimated drug effect. TRIAL REGISTRATION: ClinicalTrial.gov identifier: NCT01501591 (registered December 25, 2011).

Case report of severe Cushing's syndrome in medullary thyroid cancer complicated by functional diabetes insipidus, aortic dissection, jejunal intussusception, and paraneoplastic dysautonomia: remission with sorafenib without reduction in cortisol concentration.

BACKGROUND: Normalization of cortisol concentration by multikinase inhibitors have been reported in three patients with medullary thyroid cancer-related Cushing's syndrome. Aortic dissection has been reported in three patients with Cushing's syndrome. Diabetes insipidus without intrasellar metastasis, intestinal intussusception, and paraneoplastic dysautonomia have not been reported in medullary thyroid cancer. CASE PRESENTATION: An adult male with metastatic medullary thyroid cancer presented with hyperglycemia, hypernatremia, hypokalemia, hypertension, acne-like rash, and diabetes insipidus (urine volume >8 L/d, osmolality 190 mOsm/kg). Serum cortisol, adrenocorticoitropic hormone, dehydroepiandrostenedione sulfate, and urinary free cortisol were elevated 8, 20, 4.4, and 340 folds, respectively. Pituitary imaging was normal. Computed tomography scan revealed jejunal intussusception and incidental abdominal aortic dissection. Sorafenib treatment was associated with Cushing's syndrome remission, elevated progesterone (>10 fold), normalization of dehydroepiandrostenedione sulfate, but persistently elevated cortisol concentration. Newly-developed proximal lower limb weakness and decreased salivation were associated with elevated ganglionic neuronal acetylcholine receptor (alpha-3) and borderline P/Q type calcium channel antibodies. CONCLUSION: Extreme cortisol concentration may have contributed to aortic dissection and suppressed antidiuretic hormone secretion; which combined with hypokalemia due cortisol activation of mineralocorticoid receptors, manifested as diabetes insipidus. This is the first report of paraneoplastic dysautonomia and jejunal intussusception in medullary thyroid cancer, they may be related to medullary thyroid cancer's neuroendocrine origin and metastasis, respectively. Remission of Cushing's syndrome without measurable reduction in cortisol concentration suggests a novel cortisol-independent mechanism of action or assay cross-reactivity. Normalization of dehydroepiandrostenedione sulfate and elevation of progesterone suggest inhibition of 17-hydroxylase and 21-hydroxylase activities by sorafenib.

Exploring end of life priorities in Saudi males: usefulness of Q-methodology.

BACKGROUND: Quality end-of-life care depends on understanding patients' end-of-life choices. Individuals and cultures may hold end-of-life priorities at different hierarchy. Forced ranking rather than independent rating, and by-person factor analysis rather than averaging may reveal otherwise masked typologies. METHODS: We explored Saudi males' forced-ranked, end-of-life priorities and dis-priorities. Respondents (n = 120) rank-ordered 47 opinion statements on end-of-life care following a 9-category symmetrical distribution. Statements' scores were analyzed by averaging analysis and factor analysis (Q-methodology). RESULTS: Respondents' mean age was 32.1 years (range, 18-65); 52% reported average religiosity, 88 and 83% ≥ very good health and life-quality, respectively, and 100% ≥ high school education. Averaging analysis revealed that the extreme five end-of-life priorities were to, be at peace with God, be able to say the statement of faith, maintain dignity, resolve conflicts, and have religious death rituals respected, respectively. The extreme five dis-priorities were to, die in the hospital, not receive intensive care if in coma, die at peak of life, be informed about impending death by family/friends rather than doctor, and keep medical status confidential from family/friends, respectively. Q-methodology classified 67% of respondents into five highly transcendent opinion types. Type-I (rituals-averse, family-caring, monitoring-coping, life-quality-concerned) and Type-V (rituals-apt, family-centered, neutral-coping, life-quantity-concerned) reported the lowest and highest religiosity, respectively. Type-II (rituals-apt, family-dependent, monitoring-coping, life-quantity-concerned) and Type-III (rituals-silent, self/family-neutral, avoidance-coping, life-quality & quantity-concerned) reported the best and worst life-quality, respectively. Type-I respondents were the oldest with the lowest general health, in contrast to Type-IV (rituals-apt, self-centered, monitoring-coping, life-quality/quantity-neutral). Of the extreme 14 priorities/dis-priorities for the five types, 29, 14, 14, 50, and 36%, respectively, were not among the extreme 20 priorities/dis-priorities identified by averaging analysis for the entire cohort. CONCLUSIONS: 1) Transcendence was the extreme end-of-life priority, and dying in the hospital was the extreme dis-priority. 2) Quality of life was conceptualized differently with less emphasize on its physiological aspects. 3) Disclosure of terminal illness to family/close friends was preferred as long it is through the patient. 4) Q-methodology identified five types of constellations of end-of-life priorities and dis-priorities that may be related to respondents' demographics and are partially masked by averaging analysis.

Information disclosure in clinical informed consent: "reasonable" patient's perception of norm in high-context communication culture.

BACKGROUND: The current doctrine of informed consent for clinical care has been developed in cultures characterized by low-context communication and monitoring-style coping. There are scarce empirical data on patients' norm perception of information disclosure in other cultures. METHODS: We surveyed 470 adults who were planning to undergo or had recently undergone a written informed consent-requiring procedure in a tertiary healthcare hospital in Saudi Arabia. Perceptions of norm and current practice were explored using a 5-point Likert scale (1 = strongly agree with disclosure) and 30 information items in 7 domains: practitioners' details, benefits, risks, complications' management, available alternatives, procedure's description, and post-procedure's issues. RESULTS: Respondents' mean (SD) age was 38.4 (12.5); 50.2% were males, 57.2% had ≥ college education, and 37.9% had undergone a procedure. According to norm perception, strongly agree/agree responses ranged from 98.0% (major benefits) to 50.5% (assistant/trainee's name). Overall, items related to benefits and post-procedure's issues were ranked better (more agreeable) than items related to risks and available alternatives. Ranking scores were better in post-procedure respondents for 4 (13.3%) items (p < 0.001 to 0.001) and in males for 8 (26.7%) items (p = 0.008 to <0.001). Older age was associated with better ranking scores for 3 (10.0%) items and worse for one (p < 0.001 to 0.006). According to current practice perception, strongly agree/agree responses ranged from 93.3% (disclosure of procedure's name) to 13.9% (lead practitioner's training place), ranking scores were worse for all items compared to norm perception (p < 0.001), and post-procedure status, younger age, and lower educational level were associated with better ranking scores for 15 (50.0%), 12 (40.0%), and 4 (13.3%) items, respectively (p < 0.001 to 0.009). CONCLUSIONS: 1) even in an overall high-context communication culture, extensive and more information than is currently disclosed is perceived as norm, 2) the focus of the desired information is closer to benefits and post-procedure's issues than risks and available alternatives, 3) male, post-procedure, and older patients are in favor of more information disclosure, 4) male, older, and more educated patients may be particularly dissatisfied with current information disclosure. The focus and extent of information disclosure for clinical informed consent may need to be adjusted if a "reasonable" patient's standard is to be met.

Patients' perceived purpose of clinical informed consent: Mill's individual autonomy model is preferred.

BACKGROUND: Although informed consent is an integral part of clinical practice, its current doctrine remains mostly a matter of law and mainstream ethics rather than empirical research. There are scarce empirical data on patients' perceived purpose of informed consent, which may include administrative routine/courtesy gesture, simple honest permission, informed permission, patient-clinician shared decision-making, and enabling patient's self decision-making. Different purposes require different processes. METHODS: We surveyed 488 adults who were planning to undergo or had recently undergone written informed consent-requiring procedures. Perceptions of informed consent purpose (from norm and current practice perspectives) were explored by asking respondents to rank (1 = most reflective) 10 randomly-presented statements: "meaningless routine", "courtesy gesture" "litigation protection", "take away compensation rights", "inform patient', "make sure patient understand", "document patient's decision", "discover patient's preferences", "have shared decision", and "help patient decide". RESULTS: Respondents' mean (SD) age was 38.3 (12.5); 50.4% were males, 56.8% had ≥ college education, and 37.3% had undergone a procedure. From the norm perspective, the least reflective statement was "meaningless routine" (ranked 1-3 by 2.6% of respondents) and the most reflective statements were "help patient decide", "make sure patient understand", and "inform patient" (ranked 1-3 by 65%, 60%, and 48% of respondents with median [25%,75%] ranking scores of 2 [1,5], 3 [2,4], and 4 [2,5], respectively). Compared to their counterparts, males and pre-procedure respondents ranked "help patient decide" better, whereas females and post-procedure respondents ranked "inform patient" better (p = 0.007 to p < 0.001). Age was associated with better ranking of "help patient decide" and "make sure patient understand" statements (p < 0.001 and p = 0.002, respectively), which were ranked 1-3 by only 46% and 42% of respondents from the current practice perspective (median ranking score 4 [2,6], p < 0.001 vs. norm perspective for both). CONCLUSIONS: 1) the informed consent process is important to patients, however, patients vary in their views of its purpose with the dominant view being enabling patients' self decision-making, 2) males, pre-procedure, and older patients more favor a self decision-making purpose, whereas females and post-procedure patients more favor an information disclosure purpose, and 3) more self decision-making and more effective information disclosure than is currently practiced are desired. An informed consent process consistent with Mill's individual autonomy model may be suitable for most patients.

Acute severe hypothyroidism is not associated with hyponatremia even with increased water intake: a prospective study in thyroid cancer patients.

BACKGROUND: Hypothyroidism, commonly induced in preparation for radioiodine treatment of differentiated thyroid cancer, is a text-book cause for hyponatremia. Nausea, stress, and increased fluid intake associated with the treatment are expected to exacerbate hyponatremia. METHODS: We prospectively studied 212 (80% females) consecutive thyroid cancer patients for the incidence of hypothyroidism-induced hyponatremia and associated risk factors. RESULTS: Mean(SD) age was 39.7(14.1) year, creatinine 82.0(20.8) µmol/l, TSH 141.6(92.0) mU/l, pre- and post-isolation sodium 139.5(2.3) and 137.8(3.0) mEq/l, respectively, and estimated fluid intake during isolation 9.7(6.2) L. Mild hyponatremia (≥130 mEq/l) was present in 18 patients (8.5%) and moderate hyponatremia (≥120 mEq/l) in 4(1.9%), 3 of the latter had elevated creatinine concentration and 2 were on diuretics. There was no significant correlation between post-isolation sodium concentration and TSH concentration (r = 0.03, p = 0.69) or estimated fluid intake (r = 0.10, p =0.17). There was significant correlation between post-isolation sodium concentration and age (r = -0.24, p < 0.0001) and creatinine concentration (r = -0.22, p = 0.001). Pre-post-isolation drop in sodium concentration was more in females (mean difference 1.21, p = 0.02). Compared to eunatremic patients, hyponatremic patients were more likely to have pre-isolation hyponatremia (9% vs. 0.5%, p = 0.03), elevated creatinine concentration (36% vs. 13%, p = 0.008), and to be on diuretics (23% vs. 1%, p = 0.0001). CONCLUSIONS: In the setting of acute severe hypothyroidism: 1) clinically-important hyponatremia is uncommon; sodium concentration may not need to be monitored unless patients have impaired renal function or are on diuretics, 2) age and female gender are associated with lower sodium concentration. Uncomplicated acute severe hypothyroidism didn't cause clinically-important hyponatremia/SIADH in this cohort of patients.

Consenting options for posthumous organ donation: presumed consent and incentives are not favored.

BACKGROUND: Posthumous organ procurement is hindered by the consenting process. Several consenting systems have been proposed. There is limited information on public relative attitudes towards various consenting systems, especially in Middle Eastern/Islamic countries. METHODS: We surveyed 698 Saudi Adults attending outpatient clinics at a tertiary care hospital. Preference and perception of norm regarding consenting options for posthumous organ donation were explored. Participants ranked (1, most agreeable) the following, randomly-presented, options from 1 to 11: no-organ-donation, presumed consent, informed consent by donor-only, informed consent by donor-or-surrogate, and mandatory choice; the last three options ± medical or financial incentive. RESULTS: Mean(SD) age was 32(9) year, 27% were males, 50% were patients' companions, 60% had ≥ college education, and 20% and 32%, respectively, knew an organ donor or recipient. Mandated choice was among the top three choices for preference of 54% of respondents, with an overall median[25%,75%] ranking score of 3[2,6], and was preferred over donor-or-surrogate informed consent (4[2,7], p < 0.001), donor-only informed consent (5[3,7], p < 0.001), and presumed consent (7[3,10], p < 0.001). The addition of a financial or medical incentive, respectively, reduced ranking of mandated choice to 7[4,9], p < 0.001, and 5[3,8], p < 0.001; for donor-or-surrogate informed consent to 7[5,9], p < 0.001, and 5[3,7], p = 0.004; and for donor-only informed consent to 8[6,10], p < 0.001, and 5[3,7], p = 0.56. Distribution of ranking score of perception of norm and preference were similar except for no-organ donation (11[7,11] vs. 11[6,11], respectively, p = 0.002). Compared to females, males more perceived donor-or-surrogate informed consent as the norm (3[1,6] vs. 5[3,7], p < 0.001), more preferred mandated choice with financial incentive option (6[3,8] vs. 8[4,9], p < 0.001), and less preferred mandated choice with medical incentive option (7[4,9] vs. 5[2,7], p < 0.001). There was no association between consenting options ranking scores and age, health status, education level, or knowing an organ donor or recipient. CONCLUSIONS: We conclude that: 1) most respondents were in favor of posthumous organ donation, 2) mandated choice system was the most preferred and presumed consent system was the least preferred, 3) there was no difference between preference and perception of norm in consenting systems ranking, and 4) financial (especially in females) and medical (especially in males) incentives reduced preference.

Sweat Cortisol and Cortisone Determination in Healthy Adults: UHPLC-MS/MS Assay Validation and Clinical Application.

A simple and effective ultra-high-performance liquid chromatography assay linked to tandem mass spectrometry (UHPLC-MS/MS) for measuring cortisol and cortisone levels in human sweat has been developed and validated. A noninvasive world standard sweat collecting equipment was utilized to collect samples. The samples were analyzed using an Atlantis dC18 (2.1 × 100 mm, 3 µm) column with a 2 mM ammonium acetate and acetonitrile (1 : 1, v : v) mobile phase. In an isocratic condition, the mobile phase was delivered at a flow rate of 0.3 ml/minute. A positive electrospray ionization interface with multiple-reaction monitoring mode was used to provide simultaneous quantification of cortisol, cortisone, and internal standard at transitions of 363.11 to 121.00, 361.18 to 163.11, and 367.19 to 121.24, respectively. The method was validated for cortisol and cortisone determination over a concentration range of 0.5-50 ng/mL The detection limits for cortisol and cortisone in human sweat were 0.3 and 0.2 ng/ml, respectively. The interday coefficients of variation of cortisol and cortisone were ≤8.5% and ≤10.01%, whereas bias was in the range from -7.9% to 2.1% and from -4.3% to 3.0%, respectively. The assay was successfully applied to evaluate the cortisol-to-cortisone ratio in sweat samples collected from healthy adult volunteers.

Disclosure of terminal illness to patients and families: diversity of governing codes in 14 Islamic countries.

BACKGROUND: The consistency of codes governing disclosure of terminal illness to patients and families in Islamic countries has not been studied until now. OBJECTIVES: To review available codes on disclosure of terminal illness in Islamic countries. DATA SOURCE AND EXTRACTION: Data were extracted through searches on Google and PubMed. Codes related to disclosure of terminal illness to patients or families were abstracted, and then classified independently by the three authors. DATA SYNTHESIS: Codes for 14 Islamic countries were located. Five codes were silent regarding informing the patient, seven allowed concealment, one mandated disclosure and one prohibited disclosure. Five codes were silent regarding informing the family, four allowed disclosure and five mandated/recommended disclosure. The Islamic Organization for Medical Sciences code was silent on both issues. CONCLUSION: Codes regarding disclosure of terminal illness to patients and families differed markedly among Islamic countries. They were silent in one-third of the codes, and tended to favour a paternalistic/utilitarian, family-centred approach over an autonomous, patient-centred approach.

Quality assessment of nine paracetamol 500 mg tablet brands marketed in Saudi Arabia.

OBJECTIVE: To evaluate in-vitro quality of paracetamol 500 mg tablet brands marketed in Saudi Arabia. RESULTS: Two reference (R1 and R2) and seven generic (G1-G7) brands were commercially available. Four brands were single-drug, containing paracetamol only (R1, G1-G3) and five contained additional active ingredients (R2, G4-G7). All brands were immediate-release. Weight variation (n = 20, range as percent difference from mean), active substance content (n = 20, mean (SD) as percent difference from label), breaking force (n = 10, mean (SD)), and friability (n = 20, as percent weight loss) ranged from 97 to 102%, 96.1% (2.9%) to 99.8% (1.1%), 9.9 (0.4) to 21.0 (0.9) kg, and 0.017% to 0.809%, respectively. Disintegration (water medium) time (n = 6, minute: second) ranged from 02:35-03:09 to 12:49-13:10. Dissolution (phosphate buffer, pH 5.8) profile showed a mean release at 30 min of 87% to 97% of label content, with seven brands passing stage-1 (≥ 85% for each of 6 test units) and two passing stage-2 (mean of 12 test units ≥ 85%) criteria. Despite statistically significant differences between R1 and R2 and some of their corresponding generic brands in active substance content, breaking force, and amount dissolved at 30 min, all nine brands met the pre-specified quality standards.

Which medical error to disclose to patients and by whom? Public preference and perceptions of norm and current practice.

BACKGROUND: Disclosure of near miss medical error (ME) and who should disclose ME to patients continue to be controversial. Further, available recommendations on disclosure of ME have emerged largely in Western culture; their suitability to Islamic/Arabic culture is not known. METHODS: We surveyed 902 individuals attending the outpatient's clinics of a tertiary care hospital in Saudi Arabia. Personal preference and perceptions of norm and current practice regarding which ME to be disclosed (5 options: don't disclose; disclose if associated with major, moderate, or minor harm; disclose near miss) and by whom (6 options: any employee, any physician, at-fault-physician, manager of at-fault-physician, medical director, or chief executive director) were explored. RESULTS: Mean (SD) age of respondents was 33.9 (10) year, 47% were males, 90% Saudis, 37% patients, 49% employed, and 61% with college or higher education. The percentage (95% confidence interval) of respondents who preferred to be informed of harmful ME, of near miss ME, or by at-fault physician were 60.0% (56.8 to 63.2), 35.5% (32.4 to 38.6), and 59.7% (56.5 to 63.0), respectively. Respectively, 68.2% (65.2 to 71.2) and 17.3% (14.7 to 19.8) believed that as currently practiced, harmful ME and near miss ME are disclosed, and 34.0% (30.7 to 37.4) that ME are disclosed by at-fault-physician. Distributions of perception of norm and preference were similar but significantly different from the distribution of perception of current practice (P < 0.001). In a forward stepwise regression analysis, older age, female gender, and being healthy predicted preference of disclosure of near miss ME, while younger age and male gender predicted preference of no-disclosure of ME. Female gender also predicted preferring disclosure by the at-fault-physician. CONCLUSIONS: We conclude that: 1) there is a considerable diversity in preferences and perceptions of norm and current practice among respondents regarding which ME to be disclosed and by whom, 2) Distributions of preference and perception of norm were similar but significantly different from the distribution of perception of current practice, 3) most respondents preferred to be informed of ME and by at-fault physician, and 4) one third of respondents preferred to be informed of near-miss ME, with a higher percentage among females, older, and healthy individuals.

Saudi views on consenting for research on medical records and leftover tissue samples.

BACKGROUND: Consenting for retrospective medical records-based research (MR) and leftover tissue-based research (TR) continues to be controversial. Our objective was to survey Saudis attending outpatient clinics at a tertiary care hospital on their personal preference and perceptions of norm and current practice in relation to consenting for MR and TR. METHODS: We surveyed 528 Saudis attending clinics at a tertiary care hospital in Saudi Arabia to explore their preferences and perceptions of norm and current practice. The respondents selected one of 7 options from each of 6 questionnaires. RESULTS: Respondents' mean (SD) age was 33 (11) years, 42% were males, 56% were patients, 84% had ≥ secondary school education, and 10% had previously volunteered for research. Respectively, 40% and 49% perceived that the norm is to conduct MR and TR without consent and 38% and 37% with general or proposal-specific consent; the rest objected to such research. There was significant difference in the distribution of choices according to health status (patients vs. companions) for MR (adjusted Kruskal-Wallis test P = 0.03) but not to age group, gender, education level, or previous participation in research (unadjusted P = 0.02 - 0.59). The distributions of perceptions of current practice and norm were similar (unadjusted Marginal Homogeneity test P = 0.44 for MR and P = 0.89 for TR), whereas the distributions of preferences and perceptions of norm were different (adjusted P = 0.09 for MR and P = 0.02 for TR). The distributions of perceptions of norm, preferences, and perceptions of current practice for MR were significantly different from those of TR (adjusted P < 0.009 for all). CONCLUSIONS: We conclude that: 1) there is a considerable diversity among Saudi views regarding consenting for retrospective research which may be related to health status, 2) the distribution of perceptions of norm was similar to the distribution of perceptions of current practice but different from that of preferences, and 3) MR and TR are perceived differently in regard to consenting.