Comparison of clinical safety between standard versus extended interval dosing of immune checkpoint inhibitors: a real-world retrospective cohort study.

BACKGROUND: Extended interval dosing (ED) for inhibitors of programmed cell death protein 1 (anti-PD-1) (nivolumab, pembrolizumab) or its ligand (anti-PD-L1) (durvalumab) were recently approved based on pharmacokinetic model results that predicted a benefit-risk profile comparable with the standard dosing (SD) regimen. However, safety data in real-world condition of use are lacking. The objective was to compare the incidence and the risk factors of serious immune-related adverse events (irAEs) and any-grade irAEs between the SD and ED regimens in patients treated with anti-PD-1 or anti-PD-L1. MATERIALS AND METHODS: IrAEs were assessed from medical records in all new users of nivolumab, pembrolizumab, or durvalumab between 1 January 2019 and 31 December 2020 across two oncology centers in France. The incidence of irAEs was compared between both dosing regimens using Cox proportional hazards models adjusting for the main available confounders. RESULTS: Among 686 patients included, 63% were new users of an SD regimen, 14% of ED regimen, and 23% started with SD and switched to ED regimen during follow-up. Overall, 34.6% of patients experienced at least one irAE of any grade and 11.4% presented at least one serious grade ≥3 irAE. No statistical difference was found between the SD and ED regimen on the risk of grade ≥3 irAEs [adjusted hazard ratio (HR) 1.40, 95% confidence interval (CI) 0.71-2.76] but our results suggest an increased risk of any-grade irAEs with the ED regimen (adjusted HR 1.46, 95% CI 1.00-2.12, P = 0.048). IrAEs resolved without sequelae in 46.4% of cases, and they were fatal for three patients (0.4%). Autoimmune pre-existing condition was confirmed as a risk factor for grade ≥3 irAEs (HR 2.56, 95% CI 1.53-4.27) and for all-grade irAEs (HR 1.60, 95% CI 1.17-2.20). CONCLUSIONS: In a real-world setting, according to the regimen chosen by the oncologist based on clinical characteristics, we did not observe an increase in grade ≥3 irAE incidence between the SD and ED regimens.

Usability, accuracy, and cost-effectiveness of a medical software for early pregnancies: a retrospective study.

STUDY QUESTION: Can early pregnancies be accurately and cost-effectively diagnosed and managed using a new medical computerized tool? SUMMARY ANSWER: Compared to the standard clinical approach, retrospective implementation of the new medical software in a gynaecological emergency unit was correlated with more accurate diagnosis and more cost-effective management. WHAT IS KNOWN ALREADY: Early pregnancy complications are responsible for a large percentage of consultations, mostly in emergency units, with guidelines becoming complex and poorly known/misunderstood by practitioners. STUDY DESIGN, SIZE, DURATION: A total of 780 gynaecological emergency consultations (446 patients), recorded between November 2018 and June 2019 in a tertiary university hospital, were retrospectively encoded in a new medical computerized tool. The inclusion criteria were a positive hCG test result, ultrasonographical visualization of gestational sac, and/or embryo corresponding to a gestational age of 14 weeks or less. Diagnosis and management suggested by the new computerized tool are named eDiagnoses, while those provided by a gynaecologist member of the emergency department staff are called medDiagnoses. PARTICIPANTS/MATERIALS, SETTING, METHODS: Usability was the primary endpoint, with accuracy and cost reduction, respectively, as secondary and tertiary endpoints. Identical eDiagnoses/medDiagnoses were considered as accurate. During follow-up visits, if the updated eDiagnoses and medDiagnoses became both identical to a previously discrepant eDiagnosis or medDiagnosis, this previous eDiagnosis or medDiagnosis was also considered as correct. Four double-blinded experts reviewed persistent discrepancies, determining the accurate diagnoses. eDiagnoses/medDiagnoses accuracies were compared using McNemar's Chi square test, sensitivity, specificity, and predictive values. MAIN RESULTS AND THE ROLE OF CHANCE: Only 1 (0.1%) from 780 registered medical records lacked data for full encoding. Out of the 779 remaining consultations, 675 eDiagnoses were identical to the medDiagnoses (86.6%) and 104 were discrepant (13.4%). From these 104, 60 reached an agreement during follow-up consultations, with 59 medDiagnoses ultimately changing into the initial eDiagnoses (98%) and only one discrepant eDiagnosis turning later into the initial medDiagnosis (2%). Finally, 24 remained discrepant at all subsequent checks and 20 were not re-evaluated. Out of these 44, the majority of experts agreed on 38 eDiagnoses (86%) and 5 medDiagnoses (11%, including four twin pregnancies whose twinness was the only discrepancy). No majority was reached for one discrepant eDiagnosis/medDiagnosis (2%). In total, the accuracy of eDiagnoses was 99.1% (675 + 59 + 38 = 772 eDiagnoses out of 779), versus 87.4% (675 + 1 + 5 = 681) for medDiagnoses (P < 0.0001). Calculating all basic costs of extra consultations, extra-medications, extra-surgeries, and extra-hospitalizations induced by incorrect medDiagnoses versus eDiagnoses, the new medical computerized tool would have saved 3623.75 Euros per month. Retrospectively, the medical computerized tool was usable in almost all the recorded cases (99.9%), globally more accurate (99.1% versus 87.4%), and for all diagnoses except twinning reports, and it was more cost-effective than the standard clinical approach. LIMITATIONS, REASONS FOR CAUTION: The retrospective study design is a limitation. Some observed improvements with the medical software could derive from the encoding by a rested and/or more experienced physician who had a better ultrasound interpretation. This software cannot replace clinical and ultrasonographical skills but may improve the compliance to published guidelines. WIDER IMPLICATIONS OF THE FINDINGS: This medical computerized tool is improving. A new version considers diagnosis and management of multiple pregnancies with their specificities (potentially multiple locations, chorioamnionicity). Prospective evaluations will be required. Further developmental steps are planned, including software incorporation into ultrasound devices and integration of previously published predictive/prognostic factors (e.g. serum progesterone, corpus luteum scoring). STUDY FUNDING/COMPETING INTEREST(S): No external funding was obtained for this study. F.B. and D.G. created the new medical software. TRIAL REGISTRATION NUMBER: NCT03993015.

A regional strategy to decrease the time to thrombectomy in patients with low probability of treatment by thrombolysis.

BACKGROUND AND PURPOSE: The best transportation strategy for patients with suspected large vessel occlusion (LVO) is unknown. Here, we evaluated a new regional strategy of direct transportation to a Comprehensive Stroke Center (CSC) for patients with suspected LVO and low probability of receiving intravenous thrombolysis (IVT) at the nearest Primary Stroke Center (PSC). METHODS: Patients could be directly transported to the CSC (bypass group) if they met our pre-hospital bypass criteria: high LVO probability (i.e., severe hemiplegia) with low IVT probability (contraindications) and/or travel time difference between CSC and PSC<15 minutes. The other patients were transported to the PSC according to a "drip-and-ship" strategy. Treatment time metrics were compared in patients with pre-hospital bypass criteria and confirmed LVO in the bypass and drip-and-ship groups. RESULTS: In the bypass group (n=79), 54/79 (68.3%) patients met the bypass criteria and 29 (36.7%) had confirmed LVO. The positive predictive value of the hemiplegia criterion for LVO detection was 0.49. In the drip-and-ship group (n=457), 92/457 (20.1%) patients with confirmed LVO met our bypass criteria. Among the 121 patients with bypass criteria and confirmed LVO, direct routing decreased the time between symptom discovery and groin puncture by 55 minutes compared with the drip-and-ship strategy (325 vs. 229 minutes, P<0.001), without significantly increasing the time to IVT (P=0.19). CONCLUSIONS: Our regional strategy led to the correct identification of LVO and a significant decrease of the time to mechanical thrombectomy, without increasing the time to IVT, and could be easily implemented in other territories.

Teledentistry and forensic odontology: Cross-sectional observational comparative pilot study.

Forensic dentistry is the branch of forensic science concerned with the study of teeth and jaws. To facilitate the work of experts, new comparative identification tools are emerging, with digital techniques such as the intra-oral camera, which are revolutionising current techniques in forensic dentistry. OBJECTIVE: The aim of this study is to evaluate the diagnostic quality of the post-mortem odontogram carried out remotely via a video of the oral cavity using an intra-oral camera. The gold standard is the post-mortem odontogram obtained via the standard identification technique during the clinical examination. MATERIALS AND METHODS: 25 deceased patients were included in the study and the data were collected in the Forensic Medicine and Thanatology Department at the University Hospital of Montpellier. The protocol was divided into three stages: the gold standard consultation, the recording of videos with the Soprocare® camera, and the remote analysis of the images obtained. The gold standard consultation and the remote analysis were carried out by two separate dental surgeons responsible for completing a clinical file, used to establish the odontogram of the deceased patient. RESULTS: The study was carried out on 25 deceased subjects, between 13 May and 12 June 2019. Our sample was composed of 68% men and 32% women. A sensitivity threshold of 0.97 was observed for the performance of the odontogram, i.e., for all the teeth actually present in the mouth for all subjects in the study, 97% of them were identified with the videos taken using the intraoral camera. The examination with the intra-oral camera demonstrated a good diagnostic performance in the detection of missing teeth with a PPV of 97.9% and a NPV of 98.2%. Practitioner became more skilled at recording the videos with the intra-oral camera. One can therefore note an ease in the handling of this digital tool, which gradually improved with the number of subjects included in the study CONCLUSIONS: The Soprocare® intraoral camera has an acceptable diagnostic validity in establishing the odontogram of the deceased. It enables fundamental elements to be detected with optimal efficiency. However, several points still need to be improved, in order to make the use of the camera during data collection as easy and efficient as possible.

Optimal Duration of MRI Follow-up to Safely Identify Middle Ear Residual Cholesteatoma.

BACKGROUND AND PURPOSE: Previous studies have demonstrated the usefulness of non-EPI DWI for detection of residual cholesteatoma. However, limited data are available to determine the suitable duration of imaging follow-up after a first MR imaging with normal findings has been obtained. The present study aimed to determine the optimal duration of non-EPI DWI follow-up for residual cholesteatoma. MATERIALS AND METHODS: A retrospective, monocentric study was performed between 2013 and 2019 and included all participants followed up after canal wall up tympanoplasty with at least 2 non-EPI DWI examinations performed on the same 1.5T MR imaging scanner. MR images were reviewed independently by 2 radiologists. Sensitivity and specificity values were calculated as a function of time after the operation. Receiver operating characteristic curves were analyzed to determine the optimal follow-up duration. RESULTS: We analyzed 47 MRIs from 17 participants. At the end of the individual follow-up period, a residual cholesteatoma had been found in 41.1% of cases. The follow-up duration ranged from 20 to 198 months (mean, 65.9 [SD, 43.9] months). Participants underwent between 2 and 5 non-EPI DWI examinations. Analyses of the receiver operating characteristic curves revealed that the optimal diagnostic value of non-EPI DWI occurred 56 months after the operation when the first MR imaging performed a mean of 17.3 (SD, 6.8) months after the operation had normal findings (sensitivity = 0.71; specificity = 0.7, Youden index = 0.43). CONCLUSIONS: Repeat non-EPI DWI is required to detect slow-growing middle ear residual cholesteatomas. We, therefore, recommend performing non-EPI DWI for at least the first 5 years after the initial operation.

[Hydrochlorothiazide use and risk of skin cancers: A systematic review]. / Risque de cancers cutanés sous hydrochlorothiazide : revue systématique.

The risk of skin cancer induced by photosensiting drugs is well known. An association between hydrochlorothiazide use and skin cancer has been recently published in some epidemiological studies. A systematic review of case-control or prospectives cohorts showed an increased risk of cutaneous squamous cell carcinoma even if some confusing factors such as tobacco smoking was not analysed. Results are more conflicting for basal cell carcinoma or melanoma. These results do not modify the benefit/risk ratio but should lead to propose preventive mesures: identification of high risk population, avoidance of this drug if possible in immunocompromised patients or with previous skin cancer, regular skin examination in case of long term use of hydrochlorothiazide.

[Functional MRI by general radiologists in prediction of side-specific extracapsular extension after radical prostatectomy: what value in daily practice?]. / IRM fonctionnelle par des radiologues généralistes, dans la prédiction de l'extension extracapsulaire lobe spécifique après prostatectomie radicale : quelle valeur en pratique quotidienne ?

OBJECTIVE: To evaluate the performance of functional MRI (FMRI) performed by general radiologists (GR) in detection of side-specific extracapsular extension (SSECE) prostate cancer (PCa). METHODS: We retrospectively analyzed 79 patients who underwent FMRI with pelvic phased array coil before radical prostatectomy (RP) performed at University Hospital (UH) of Nîmes. Twelve GR (including three from UH) interpreted the images during their daily practice. FMRI results were dichotomized as positive or negative and confronted to pathological reports for SSECE and side-specific seminal vesicle invasion (SSSVI), with calculation of diagnostic values. The influence of interval between biopsy and FMRI, diffusion-weighted sequence (DWS) and intensity of FMRI, on the diagnostic performance were assessed by Fisher's exact test. RESULTS: A SSECE and a SSSVI were observed at FMRI and pathology respectively on 14 (8.8%) and 38 (24.1%) prostate lobes, and on six (3.8%) and seven (4.4%) prostate lobes. The sensitivity, specificity, positive and negative predictive values of FMRI for SSECE were respectively 24%, 96%, 64% and 80%; and for SSSVI were 14%, 97%, 17% and 96% respectively. The time between biopsy and FMRI, intensity of FMRI and DWS, did not influence the sensitivity and specificity of fMRI at Fisher test. CONCLUSION: This study found that preoperative prostate FMRI performed by GR has good specificity but poor sensitivity in predicting SSECE on pathological reports.

Breast diseases in adolescents.

Fibroadenomas and breast growth disorders are the most common breast diseases in adolescent women. Assessment of breast disorders in this age group generally involves clinical evaluation through history and physical examination and when is needed ultrasonography. Due to the absence of breast cancer in adolescent women, it is easy to reassure women at the first consultation. Breast growth disorders can lead great psychological and physical embarrassment. Treatment consists of surgical procedures when the cosmetic defect is severe. According to the ANDI classification, small fibroadenomas are normal, clinical fibroadenomas are a mild aberration of the normal processes, and giant or multiple fibroadenomas are placed to the disease end of the spectrum. Fibroadenomas can be treated conservatively provided diagnosis is confident. Giant fibroadenomas are treated by surgical enucleation. Breast abscess is mainly due to the duct ectasia. In adolescence, ectasia has been described as an exaggeration of sinus duct development and can be considered as a variant of normality. Diseases of the adolescent breast are usually benign and their management are simple using medical strategy and more rarely surgical therapy.

Effects of growth reduction therapy using high-dose 17beta-estradiol in 26 constitutionally tall girls.

OBJECTIVE: The efficacy and safety of height-limiting therapy with high-dose 17beta-oestradiol in girls with constitutionally tall stature (CTS) are controversial. We evaluated the effectiveness of high-dose 17beta-oestradiol in premenarchal girls with CTS treated until their bone age reached 14 years. DESIGN: We retrospectively reviewed the medical records of the girls managed between 1989 and 2000 with high-dose 17beta-estradiol for CTS with a predicted final height greater than +3SDs. PATIENTS: Twenty-six girls met our inclusion criteria. At baseline, mean chronological age was 12.06 +/- 1.51 years and mean height was 171.1 +/- 6.5 cm with a height standard deviation score of 4.5 +/- 0.24, and mean predicted final height was 183.0 +/- 4.2 cm. Treatment was stopped when bone age reached 14 years; mean treatment duration was 1.62 +/- 0.76 years. MEASUREMENTS: The following were obtained at 6-month intervals: height, body weight, Tanner stage, bone age, plasma cholesterol and triglycerides, plasma glucose and side effects. A mailed questionnaire on final height and satisfaction was sent 2 years after treatment discontinuation (response rate, 24/26). Results Final height was significantly (P < 0.001) reduced, by 2.4 +/- 3.2 cm, as compared to predictions. High-dose 17beta-estradiol therapy decreased growth velocity and significantly increased skeletal maturation (P < 0.001). Linear growth after treatment discontinuation was 3.3 +/- 1.9 cm. No serious side effects were recorded. Most of the patients were satisfied with the treatment. CONCLUSION: High-dose 17beta-estradiol was moderately effective in reducing final height and should probably be reserved for selected patients, particularly as knowledge on potential long-term side effects is lacking.

Breast inflammatory gigantomastia in a context of immune-mediated diseases.

CONTEXT: Localized breast lesions have been described in lupic or diabetic patients. However, the description of breast gigantomastia in women presenting with autoimmune diseases has not been reported. SETTING: The study took place within the Department of Endocrinology and Reproductive Medicine, Necker Hospital, Paris, France. PATIENTS: We describe eight patients with inflammatory gigantomastia, occurring in a context of immune-mediated diseases: myasthenia, chronic arthritis, or thyroiditis. MAIN OUTCOME MEASURES: Together with hormonal, immunological, and breast magnetic resonance imaging (MRI) evaluation, breast histology enabled us to perform immunocytochemical and indirect immunofluorescence studies. Control sera were obtained from patients with (n = 10) and without (n = 7) antinuclear antibodies. RESULTS: Six of the eight patients developed gigantomastia either at puberty or during pregnancy. Neither a hormonal oversecretion nor a specific immunological pattern was observed. All patients except one presented antinuclear antibodies. Histological study revealed a diffuse, stromal hyperplasia and a severe atrophy of the lobules. A rarefaction of adipocytes was also noted, as previously suggested on MRI. There was a perilobular lymphocytic infiltrate made of CD3+ lymphocytes. Study of sera from five of six cases of gigantomastia showed a nuclear immunofluorescence pattern in normal mammary ductal and lobular glandular epithelium, as well as in kidney and intestine epithelial cells. In control sera, a nuclear signal was observed only when antinuclear antibodies were present. CONCLUSIONS: We suggest that breast tissue may be a target tissue in autoimmune diseases, this process being favored by the hormonal milieu. However, the precise mechanism of such association is not individualized. The fact that stromal hyperplasia is the main histological feature justifies the search for the involvement of growth factors in such a process.

[Genital bleeding secondary to chemotherapy in adolescent girls]. / Métrorragies de l'adolescente au cours des chimiothérapies responsables de thrombopénies sévères.

UNLABELLED: Severe genital bleeding during adolescence can occur in the event of thrombocytopenia related to chemotherapy. Preventive hormonal treatment to induce therapeutic amenorrhea is recommended by some clinicians. Nevertheless, the adverse effects of oestroprogestative treatment, such as thromboembolic risk or hepatic toxicity, could potentialize the adverse effects of some chemotherapies. AIM OF THE STUDY: To assess retrospectively the risk of genital bleeding associated with thrombocytopenia secondary to chemotherapy in a population of adolescent girls for whom therapeutic amenorrhea was induced or not. PATIENTS AND METHODS: Among 140 girls, 12 to 18 years old, who were subjected to chemotherapy between 1991 and 1998, 24 girls presented at least one thrombocytopenic event (platelet level < 20 x 10(9) l(-1)) and were included. RESULTS: Six out of 24 adolescent girls received hormonal therapy to induce amenorrhea. Only one bleeding event was observed, in a girl who had not received preventive oestroprogestative treatment. Vital prognosis was preserved. Furthermore, spontaneous amenorrhea occurring before chemotherapy was observed in 33% of the patients and permanent secondary ovarian insufficiency in 17% of the patients. CONCLUSION: The risk of genital bleeding among adolescent population at risk of chemotherapy-induced thrombocytopenia is low. The high frequency of amenorrhea, secondary to weight loss or to chemotherapy toxicity, should raise questions as to the usefulness of preventive oestroprogestative treatment.

Follow up of precocious pseudopuberty associated with isolated ovarian follicular cysts.

The clinical outcomes of seven girls presenting with pseudosexual precocity caused by isolated autonomous ovarian follicular cysts are presented. Six of the seven girls, aged 11 months to 6.9 years, had a unilateral ovarian cyst detected by ultrasound at the first acute episode. Plasma oestradiol was raised in only five of the cases, but all had a low response to luteinising hormone releasing hormone stimulation. Follow up lasted for up to eight years with recurrent episodes of variable frequency and severity in all seven patients. Evidence of McCune-Albright syndrome appeared later in only three patients. It could not be predicted from the initial symptoms or the clinical course. Mutations of the G(s)alpha protein leading to activation were investigated in the lymphocytes and ovarian and bone tissues of four patients. Only one patient showed a mutation in bone tissue. Close follow up with repeated searches for skeletal lesions remains necessary since the distribution of somatic mutations cannot be assessed by molecular studies. Most patients with recurrent ovarian cysts require a conservative approach.

1,25-Dihydroxycholecalciferol regulates rat intestinal calbindin D9k posttranscriptionally.

To determine whether calbindin D9k (CaBP) is subject to posttranscriptional control, 6-wk-old Sprague Dawley-derived rats were fed one of three purified diets, 1.5% Ca and 3.0% Ca, mostly as carbonate, and 2.9% Ca, mostly as gluconate. Two weeks later, 5-cm segments of duodenum, jejunum, ileum, cecum and colon were obtained and analyzed for CaBP and CaBP-mRNA. Analysis of the steady-state distribution of CaBP-mRNA and of CaBP revealed a statistically significant (r = 0.95; P < 0.01) linear relationship between CaBP-mRNA and CaBP. When, however, animals that had been fed the 1.5% Ca diet received by intrajugular injection 1.2 nmol 1,25-dihydroxycholecalciferol [1.25-(OH)2-D3] and their CaBP-mRNA and CaBP were analyzed as a function of time after 1,25-(OH)2-D3 administration, the kinetic response of the two molecules differed. The CaBP-mRNA increased linearly by approximately 68% for 4 h after administration and then declined over the next 6 h to a concentration below the preinjection value. Thus, appearance and disappearance of CaBP-mRNA approximated 17% x h(-1). The CaBP, however, increased steeply to 80% above preinjection concentration until 2 h postinjection, i.e., at a rate of 40% x h(-1). Thereafter, CaBP decreased to 35% above the preinjection value between 5 and 10 h postinjection (2.5% x h(-1)). These findings are consistent with a 1,25-(OH)2-D3-mediated posttranscriptional regulation of CaBP concentrations, because the 1,25-(OH)2-D3-mediated increase in CaBP-mRNA is not reflected in an immediately changed CaBP level.

Calcium solubility, intestinal sojourn time and paracellular permeability codetermine passive calcium absorption in rats.

To investigate the nonsaturable, paracellular pathway of intestinal Ca absorption, the luminal contents of 12-cm segments of the intestine of 8-wk-old male Sprague-Dawley rats were analyzed for pH, sojourn time and soluble and insoluble Ca over a 24-h period. The rats had been fed one of two high Ca diets for 2 wk: 1.5% Ca (diet group 3a) and 3.1% (diet group 5a). The pH of the small intestine increased from < 6.6 to > 8.0 from duodenum to ileum; transit time increased from 2.5 min in the duodenum to 58 min in the distal ileum, with the entire ileum accounting on the average for 74% of the transit time of 3 h. The amount of Ca solubilized throughout the intestine was 32 +/- 3.3 mumol in diet group 3a and 53 +/- 5.3 mumol in diet group 5a, i.e., 2.7% and 2.0% of the total luminal Ca. Because absorption by diet group 3a was 1.45 +/- 0.23 mmol/d and that by diet group 5a was 2.50 +/- 0.18 mmol/d, the amounts absorbed were 45.3 and 47.1 times greater than present in the lumen in soluble form at any one time. Thus, over a 24-h period, an average of 3.2% (46.2/1440) of the soluble Ca present in the lumen at any time was absorbed per min. Calculations involving the gradient between luminal and plasma Ca show that the rate of Ca diffusion from lumen to blood is < 2% of what it would be if the paracellular path were unrestricted. Thus, intestinal sojourn time, Ca solubility and mucosal permeability to Ca are factors that determine the rate of passive Ca absorption.

Solubility and intestinal transit time limit calcium absorption in rats.

Six-week-old male rats were placed on two high calcium regimens: one with calcium carbonate and monobasic calcium phosphate, with calcium content increased via calcium carbonate; and another with calcium phosphate and calcium gluconate, with calcium gluconate the source of increased calcium. Animals fed the gluconate-containing diets absorbed 29% of the ingested calcium over the entire calcium intake range, whereas those fed the calcium carbonate diets absorbed 25% over an intake range of 225 to 450 mg Ca/d, but at calcium intakes above 450 mg Ca/d their absorption reached a plateau at approximately 109 mg/d. Active calcium transport decreased with increased calcium intake in both the calcium carbonate- and calcium gluconate-fed groups. Nonsaturable transport was unchanged as a result of increasing calcium intake and did not differ among the diet groups. Because the absorptive processes were unaffected by the calcium source, events in the lumen must have been responsible for the observed differences. Because phosphate is nearly 18 times more soluble than carbonate, very little calcium of calcium carbonate origin can have been solubilized in the presence of phosphate and this, we conclude, accounts for the limit on calcium absorption observed in diets high in calcium carbonate. Moreover, when intake is expressed as soluble calcium, absorption approaches 50%, the value expected when intestinal transit time (approximately 3 h) is multiplied by 16%/h, the experimental value of nonsaturable absorption.