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Background: Breakthrough infections after SARS-CoV-2 vaccination have been reported. Clinical outcomes in these persons are not widely known. Methods: We evaluated all vaccinated persons with breakthrough infection ≥14 days after the second vaccine dose and unvaccinated controls matched on age, sex, nationality, and reason for testing between December 23, 2020 and March 28, 2021 in Qatar. Our primary outcome was severe disease defined as hospitalization, mechanical ventilation, or death. Results: Among 456 persons cases of breakthrough infection and 456 unvaccinated matched controls with confirmed infection, median age was 45 years, 60.7% were males, and ≥1 comorbid condition was present in 61.2% of the vaccinated and 47.8% of the unvaccinated persons (P=0.009). Severe disease was recorded in 48 (10.5%) of the vaccinated and 121 (26.5%) of the unvaccinated group (P40–60 years, HR 2.32; >60–70 years, HR 4.34; >70 years, HR 5.43); presence of symptoms at baseline (HR 2.42, 95%CI 1.44-4.07); and being unvaccinated (HR 2.84, 95%CI 1.80-4.47). Conclusions: In persons with breakthrough SARS-CoV-2 infection, increasing age is associated with a higher risk of severe disease or death, while vaccination is associated with a lower risk. Presence of comorbidities was not associated with severe disease or death among persons with breakthrough infection.

Treating HCV infection reduces overall mortality and reduces the risk of multiple extrahepatic complications. Whether the reduction in mortality is primarily due to a reduction in liver-related causes or extrahepatic complications is unknown.We identified HCV-positive individuals treated for HCV, and propensity score-matched them to HCV-positive/untreated and HCV-uninfected individuals in ERCHIVES between 2002-2016. We extracted cause of death data from the National Center for Health Statistics' National Death Index. Viral hepatitis-associated liver-related mortality rates among treated and untreated HCV-infected persons were calculated by treatment and attainment of sustained virologic response (SVR).Among 50,674 HCV-positive/treated (Group A), 31,749 HCV-positive/untreated (Group B) and 73,526 HCV-uninfected persons (Group C), 8.6% in Group A, 35.0% in Group B, and 14.3% in Group C died. Among those who died, viral hepatitis-associated liver-related mortality rates per 100 patient-years (95% CI) were: 0.28 (0.27-0.30) for Group A; 1.44 (1.38-1.49) for Group B; and 0.06 (0.05-0.06) for Group C; (p0.0001 for both comparisons). Among HCV-positive/treated persons, rates were 0.06 (0.05-0.06) for those with SVR vs. 0.78 (0.74-0.83) for those without SVR. In competing risks Cox proportional hazards analysis, treatment with all-oral DAA regimens (adjusted hazard ratio 0.11; 95% CI 0.09-0.14) and SVR (adjusted hazard ratio 0.10; 95% CI 0.08-0.11) were associated with reduced hazards of liver-related mortality.Treatment for HCV is associated with a significant reduction in viral hepatitis-associated liver-related mortality, which is particularly pronounced in those treated with DAA regimens and those who attain SVR. This may account for a significant proportion of the reduction in all-cause mortality reported in previous studies.Treating hepatitis C virus (HCV) infection is known to reduce overall mortality. However, whether the reduction in mortality is primarily due to a reduction in liver-related causes or extrahepatic complications was previously unknown. Herein, we show that while treating HCV with direct-acting antiviral regimens has numerous extrahepatic benefits, a significant benefit can be attributed specifically to the reduction in liver-related mortality.

Summary Background Type 2 diabetes is affecting people at an increasingly younger age, particularly in the Middle East and in north Africa. We aimed to assess whether an intensive lifestyle intervention would lead to significant weight loss and improved glycaemia in young individuals with early diabetes. Methods This open-label, parallel-group, randomised controlled trial (DIADEM-I), done in primary care and community settings in Qatar, compared the effects of an intensive lifestyle intervention with usual medical care on weight loss and glycaemic outcomes in individuals with type 2 diabetes, aged 18–50 years, with a short diabetes duration (≤3 years), had a BMI of 27·0 kg/m2 or more, and who were from the Middle East and north Africa region. Participants were randomly allocated (1:1) either to the intensive lifestyle intervention group or the usual medical care control group by a computer-generated sequence and an online randomisation service. The intensive lifestyle intervention comprised a total diet replacement phase, in which participants were given formula low-energy diet meal replacement products followed by gradual food reintroduction combined with physical activity support, and a weight-loss maintenance phase, involving structured lifestyle support. Participants in the control group received usual diabetes care, which was based on clinical guidelines. The primary outcome was weight loss at 12 months after receiving the assigned intervention. Our analysis was based on the intention-to-treat principle. Key secondary outcomes included diabetes control and remission. The trial was registered with the ISRCTN registry, ISRCTN20754766, and ClinicalTrials.gov , NCT03225339 . Findings Between July 16, 2017, and Sept 30, 2018, we enrolled and randomly assigned 158 participants (n=79 in each group) to the study. 147 participants (70 in the intervention group and 77 in the control group) were included in the final intention-to-treat analysis population. Between baseline and 12 months, the mean bodyweight of participants in the intervention group reduced by 11·98 kg (95% CI 9·72 to 14·23) compared with 3·98 kg (2·78 to 5·18) in the control group (adjusted mean difference −6·08 kg [95% CI −8·37 to −3·79], p Interpretation Our findings show that the intensive lifestyle intervention led to significant weight loss at 12 months, and was associated with diabetes remission in over 60% of participants and normoglycaemia in over 30% of participants. The provision of this lifestyle intervention could allow a large proportion of young individuals with early diabetes to achieve improvements in key cardiometabolic outcomes, with potential long-term benefits for health and wellbeing. Funding Qatar National Research Fund.

Infection with hepatitis virus C (HCV) is associated with an increased risk of cardiovascular disease (CVD) events. It is not clear whether treatment with direct-acting antiviral (DAA) agents affects risk of CVD.We searched the Electronically Retrieved Cohort of HCV-Infected Veterans database for patients with chronic HCV infection (n = 242,680) and identified patients who had been treated with a pegylated interferon and ribavirin regimen (n = 4436) or a DAA-containing regimen (n = 12,667). Treated patients were matched for age, race, sex, and baseline values with patients who had never received treatment for HCV infection (controls). All subjects were free of any CVD event diagnosis of HCV infection at baseline. The primary outcome was incident CVD events, identified by International Classification of Diseases, Ninth Edition, Clinical Modification or International Classification of Diseases, Tenth Edition code, in the different groups and in patients with vs without a sustained virologic response to therapy.There were 1239 (7.2%) incident CVD events in the treated groups and 2361 (13.8%) events in the control group. Incidence rates were 30.9 per 1000 patient-years (95% CI 29.6-32.1) in the control group and 20.3 per 1000 patient-years (95% CI 19.2-21.5) in the treated groups (P.0001). Treatment with pegylated interferon and ribavirin (hazard ratio 0.78; 95% CI 0.71-0.85) or a DAA regimen (hazard ratio 0.57; 95% CI 0.51-0.65) was associated with a significantly lower risk of a CVD event compared with no treatment (controls). Incidence rates for CVD events were 23.5 per 1000 patient-years (95% CI 21.8-25.3) in the group treated with the pegylated interferon and ribavirin regimen, 16.3 per 1000 patient-years (95% CI 14.7-18.0) in the group treated with a DAA regimen, and 30.4 (95% CI 29.2-31.7) in the control group. A sustained virologic response was associated with a lower risk of incident CVD events (hazard ratio 0.87; 95% CI 0.77-0.98).In an analysis of a cohort of HCV-infected veterans, treatment of HCV infection was associated with a significant decrease in risk of CVD events. Patients treated with a DAA regimen and patients who achieved sustained virologic responses had the lowest risk for CVD events.

The pulsatile but not the continuous application of parathyroid hormone (PTH) increase bone mass in vivo. To study the effects of intermittent hormonal administration on bone-derived cells in vitro, we established a perifusion system using the human osteosarcoma cell line SaOS-2. Cells were grown in suspension culture attached to collagen beads and were then loaded into a 3 ml syringe for perifusion experiments. The application of PTH(1-34) resulted in a dose-dependent increase of cAMP release by SaOS-2 cells into the effluent medium. Cyclic AMP accumulation was rapidly desensitized by approx. 80% after 30 min of continuous exposure to PTH(1-34) (10(-7) M), while cells remained responsive to forskolin. The recovery of PTH responsiveness required at least 2 h of hormone-free perifusion. Desensitization in the experimental setting was dose-dependent (EC50 = 1 x 10(-10) M PTH(1-34)). Neither 8Br-cAMP (2 x 10(-4) M) nor PMA(1 x 10(-7) M) had an effect on the PTH(1-34)-induced desensitization of the adenylate cyclase. Radioreceptor assays showed that [125I]-[Tyr36]hPTHrP(1-36)amide binding to SaOS-2 cells was decreased by 60-70% by PTH(1-34) (1 x 10(-6) M), bPTH(1-84) (1.8 x 10(-6) M) and bPTH(3-34) (2 x 10(-6) M), whereas 8Br-cAMP (2 x 10(-4) M) had no effect on radioligand binding. PMA (1 x 10(-7) M) appeared to slightly increase [125I]PTHrP binding. This observation is consistent with a small (3-fold) increase in PTH-induced cAMP release as a result of PMA pre-treatment. Receptor internalization was dose-dependent EC50 = 3 x 10(-7) M PTH(1-34)). The maximal effect occurred after 10-30 min and was largely reversible within 2 h. Monensin (3 x 10(-5) M) inhibited the recovery from receptor internalization. We conclude that a perifusion system using SaOS-2 cells is a suitable model to study the effect of discontinuous application of PTH on cAMP release. A rapid, homologous desensitization of PTH(1-34) stimulated cAMP accumulation has been observed that does not appear to involve protein kinase A or C.

The renal PTH/PTHrP receptor is down-regulated in rats with chronic renal failure. Hypocalcemia, hyperphosphatemia, and resistance to the action of PTH are well characterized features in the setting of advanced chronic renal failure (CRF). Although the underlying mechanisms are ill-understood, clinical and experimental evidence points to both PTH receptor down-regulation and post-receptor abnormalities in their pathogenesis. In the present study we have examined the effect of advanced CRF in rats on the renal expression of PTH/PTHrP receptor (PTH-R). CRF was created by a standard two-step operation (5/6 nephrectomy). Four weeks thereafter, 19 uremic rats were compared with 23 sham-operated rats. Uremic rats had higher mean (± SD) plasma creatinine levels than control rats, 164 ± 107 µM versus 43 ± 5 µM, respectively. They also had higher plasma phosphorus and iPTH levels, 4.70 ± 1.71mM versus 2.59 ± 0.37mM and 561 ± 336 versus 27 ± 18 pg/ml, respectively. Mean plasma total calcium and blood ionized calcium were significantly lower in uremic than in control rats, 2.13 ± 0.06mM versus 2.61 ± 0.10mM and 1.07 ± 0.11 versus 1.31 ±0.06mM, respectively. Mean plasma calcitriol concentration was also significantly lower in uremic than in control rats, 39.8 ± 14.6 and 80.4 ± 15.2 pg/ml, respectively. Nine out of the 19 rats were examined for renal PTH-R gene expression. We show for the first time that the level of PTH-R mRNA in the kidney of uremic rats was markedly decreased compared with that of normal rats, the ratio PTH-R mRNA/β-actin mRNA being 0.47 ± 0.12 versus 0.99 ± 0.23, respectively, and the ratio PTH-R mRNA/28S being 8.9 ± 4.7 versus 19.6 ± 11.1, respectively. This decrease was associated with a marked reduction in PTH-sensitive adenylyl cyclase activity in crude renal membranes from uremic rats. The values of basal adenylyl cyclase activity and subsequently after stimulation by forskolin and NaF were also significantly reduced in comparison to that of normal rats. These data indicate that rats with severe CRF have reduced renal PTH-R expression, associated with diminished basal and PTH-sensitive adenylyl cyclase activity. These abnormalities could be important in the pathogenesis of the secondary hyperparathyroidism of CRF.

Corticotropin-releasing factor (CRF) stimulates adrenocorticotropin (ACTH) release via the adenylate cyclase/cAMP-dependent protein kinase system. Because calcium is necessary for receptor-mediated release of ACTH, we have examined the effect of CRF on 45 Ca 2+ uptake in a corticotroph cell line model, AtT-20. Treatment of AtT-20 cells with CRF (10 −9 − 10 −6 M) resulted in dose- and time-dependent increases in 45 Ca 2+ uptake, up to 2.2-fold above control values. The effect was statistically significant at 1 min and persisted for at least 10 min. Treatment with forskolin (1–30 μM), 8-Br-cAMP (0.5 mM), cholera toxin (CT, 100 ng/ml) and K + (20 mM) also increased cell-associated 45 Ca 2+ . The effect of K + was completely blocked by nifedipine (100 μM), whereas the effects of CRF (10 −8 M) were only partially inhibited by this calcium channel antagonist. These data suggested a role of voltage-dependent calcium channels in 45 Ca 2+ uptake. Short term pretreatment (1–2 h) of AtT-20 cells with CRF (10 −8 M) significantly desensitized both CRF-stimulated cAMP accumulation and ACTH release, but did not attenuate CRF-stimulated 45 Ca 2+ uptake. Pretreatment with CRF (10 −8 M) for 4 h did not alter CT- or forskolin-stimulated cAMP accumulation and ACTH release. This suggests that the molecular mechanisms of desensitization are proximal to adenylate cyclase. Conversely, long term pretreatment (24 h) of AtT-20 cells with CRF (10 −8 M) induced significant desensitization of CRF-stimulated 45 Ca 2+ uptake. These results indicate that CRF stimulates calcium uptake in AtT-20 cells via cAMP-dependent and cAMP-independent mechanisms, and that the cellular mechanisms involved in desensitization of cAMP accumulation and ACTH release and those involved in desensitization of calcium uptake are qualitatively different.

The potentiation of corticotropin-releasing factor (CRF)-stimulated cAMP production by vasopressin (VP) in the pituitary cell was investigated by studies on the interaction of CRF, VP, and the protein kinase C activator, phorbol 12-myristate 13-acetate (PMA) on cAMP, adenylate cyclase and phosphodiesterase. Addition of VP or PMA (0.01-100 nM) alone did not alter cellular cAMP content, but markedly increased the effect of 10 nM CRF with ED50 of about 1 nM. Treatment of the cells with 200 ng/ml pertussis toxin for 4 h increased CRF-stimulated cAMP accumulation by 3.2-fold, an effect that was not additive to those of VP and PMA. Incubation of pituitary cells with 2 mM 1-methyl-3-isobutylxanthine increased CRF-stimulated cAMP accumulation and decreased the relative effect of VP and PMA, suggesting that the actions of VP and PMA are partially due to inhibition of phosphodiesterase. This was confirmed by the demonstration of a 30% inhibition of the low-affinity phosphodiesterase activity in cytosol and membranes prepared from cells preincubated with VP or PMA. In intact cells, following [3H]adenine prelabeling of endogenous ATP pools, measurement of adenylate cyclase in the presence of 1-methyl-3-isobutylxanthine showed no effect of VP and PMA alone, but did show a 2-fold potentiation of the effect of CRF. Measurement of adenylate cyclase in pituitary homogenates by conversion of [alpha-32P]ATP to [32P]cAMP showed a paradoxical GTP-dependent inhibition by VP of basal and CRF-stimulated adenylate cyclase activity, suggesting that the VP receptor is coupled to an inhibitory guanyl nucleotide-binding protein. Pertussis toxin pretreatment of the cells prevented the VP inhibition of adenylate cyclase activity observed in pituitary cell homogenates. These findings indicate that besides inhibition of phosphodiesterase, VP has a dual interaction with the pituitary adenylate cyclase system; a direct inhibitory effect, manifested only in broken cells, that is mediated by a receptor-coupled guanyl nucleotide-binding protein, and a physiologically predominant indirect stimulatory effect in the intact cell, mediated by protein kinase C phosphorylation of one of the components of the CRF-activated adenylate cyclase system.