Safety and tolerability of linaclotide for the treatment of chronic idiopathic constipation and irritable bowel syndrome with constipation: pooled Phase 3 analysis

Background: Linaclotide is approved for treating irritable bowel syndrome with constipation (IBS-C; 290 µg QD) and chronic idiopathic constipation (CIC; 145 µg or 72 µg QD). These analyses aimed to assess linaclotide safety in a large, pooled Phase 3 population.

Methods: In six randomized controlled trials (RCTs), patients received linaclotide (72 µg, 145 µg, 290 µg) or placebo daily for 12–26 weeks; in two long-term safety (LTS) studies, patients received open-label linaclotide for ≤78 additional weeks. Laboratory values, vital signs, and treatment-emergent adverse events (TEAEs) were assessed.

Results: Overall, 3853 patients received ≥1 dose of linaclotide. The most common TEAE was diarrhea (majority [90.5% in RCTs] mild/moderate). Linaclotide patients experienced 1.1 diarrhea TEAE per patient-year in the RCTs (0.2 in placebo), and 0.3 in the LTS studies. In RCTs, 6.9% linaclotide and 3.0% placebo patients discontinued due to any adverse event (AE); 4.0% linaclotide and 0.3% placebo patients discontinued due to diarrhea. In LTS studies, 9.4% patients discontinued due to any AE, and 3.8% due to diarrhea. Serious AEs (SAEs) were rare and similar across treatment groups; there were no SAEs of diarrhea.

Conclusion: These pooled analyses of patients treated for ≤104 weeks confirm linaclotide’s overall safety.     

P-Glycoprotein and transporter MRP1 reduce HIV protease inhibitor uptake in CD4 cells: potential for accelerated viral drug resistance?

BACKGROUND: The multidrug transporters P-glycoprotein (P-gp) and MRP1 are functionally expressed in several subclasses of lymphocytes. HIV-1 protease inhibitors interact with both; consequently the transporters could reduce the local concentration of HIV-1 protease inhibitors and, thus, influence the selection of viral mutants. OBJECTIVES: To study the effect of the expression of P-gp and MRP1 on the transport and accumulation of HIV-1 protease inhibitors in human lymphocytes and to study the effects of specific P-gp and MRP1 inhibitors. METHODS: The initial rate and the steady-state intracellular accumulation of radiolabelled ritonavir, indinavir, saquinavir and nelfinavir was measured in three human lymphocyte cell lines: control CEM cells, CEM-MDR cells, which express 30-fold more P-gp than CEM cells, and CEM-MRP cells, which express fivefold more MRP1 protein than CEM cells. The effect of specific inhibitors of P-gp (GF 120918) and MRP1 (MK 571) was also examined. RESULTS: Compared with CEM cells, the initial rates of uptake and the steady-state intracellular concentrations of all protease inhibitors are significantly reduced in CEM-MDR cells. The intracellular concentrations of the protease inhibitors are increased upon co-administration with GF 120918, in some cases to levels approaching those in CEM cells. The intracellular concentrations of the protease inhibitors are also significantly reduced in CEM-MRP cells. Co-administration with MK -571 can partially overcome these effects. CONCLUSIONS: The overexpression of multidrug transporters significantly reduces the accumulation of protease inhibitors at this major site of virus replication, which, potentially, could accelerate the acquisition of viral resistance. Targeted inhibition of P-gp may represent an important strategy by which this problem can be overcome.     

The diagnosis and management of allergic reactions in patients sensitized to non-specific lipid transfer proteins

Sensitization to one or more non-specific lipid transfer proteins (nsLTPs), initially thought to exist mainly in southern Europe, is becoming accepted as a cause of allergic reactions to plant foods across Europe and beyond. The peach nsLTP allergen Pru p 3 is a dominant sensitizing allergen and peaches a common food trigger, although multiple foods can be involved. A frequent feature of reactions is the requirement for a cofactor (exercise, alcohol, non-steroidal anti-inflammatory drugs, Cannabis sativa) to be present for a food to elicit a reaction. The variability in the food and cofactor triggers makes it essential to include an allergy-focused diet and clinical history in the diagnostic workup. Testing on suspected food triggers should also establish whether sensitization to nsLTP is present, using purified or recombinant nsLTP allergens such as Pru p 3. The avoidance of known trigger foods and advice on cofactors is currently the main management for this condition. Studies on immunotherapy are promising, but it is unknown whether such treatments will be useful in populations where Pru p 3 is not the primary sensitizing allergen. Future research should focus on the mechanisms of cofactors, improving diagnostic accuracy and establishing the efficacy of immunotherapy.     

Antimicrobial Susceptibility Trends of Streptococcus pneumoniae by Age Groups Over Recent 10 Years in a Single Hospital in South Korea

PurposeStreptococcus pneumoniae (S. pneumoniae) causes respiratory tract infections. Its non-vaccine serotypes and multidrug-resistant pneumococcal diseases have increased during the post-pneumococcal vaccination era. Therefore, it is important to understand the regional and age-related antimicrobial susceptibility of S. pneumoniae to select appropriate empirical antimicrobials.Materials and MethodsWe retrospectively studied trends in the antimicrobial resistance of S. pneumoniae to commonly prescribed antibiotics in patient groups of various ages at a single teaching hospital in Jeju Island from 2009 to 2018.ResultsIn total, 1460 S. pneumoniae isolates were obtained during the study period. The overall antimicrobial resistance rates of S. pneumoniae to penicillin, erythromycin, ceftriaxone, levofloxacin, and vancomycin were 16.2%, 84.7%, 25.9%, 3.3%, and 0.0%, respectively, and the MDR rate was 6.7%. Erythromycin and ceftriaxone resistance rates increased by years; however, they were significantly reduced in adult groups. Levofloxacin resistance and MDR rates were also higher in adult groups. Overall, the MDR rate significantly increased during the recent 10 years, as well as in patients with a history of hospitalization within 90 days [odds ratio (OR)=3.58, 95% confidence interval (CI)=1.91–6.71] and sinusitis (OR=4.98, 95% CI=2.07–11.96).ConclusionErythromycin and ceftriaxone resistance rates and the MDR rate of S. pneumoniae significantly increased during the recent 10 years; the trends in individual antimicrobial resistance rates significantly differed between the age groups. This study indicates the need for caution when using ceftriaxone as an empirical antimicrobial against pneumococcal infections.     

A review of staging chest CT in trunk and extremity soft tissue sarcoma

Objectives:To determine the incidence of pulmonary metastases on chest CT in trunk and extremity soft tissue sarcoma based on two size criteria, and to identify factors associated with metastases.Methods:Retrospective review of chest CT studies in patients with trunk and extremity soft tissue sarcoma over an 18-month period. Data collected included patient age/sex, tumour location, size and relationship to fascia. All chest CTs were reviewed for the presence of metastases which were diagnosed according to two size criteria: multiple nodules > 5 mm in size or multiple nodules > 10 mm in size. Follow-up CT studies were reviewed in cases initially considered indeterminate.Results:127 males and 73 females were included (mean age 57.1 years; range 10–90 years). 147 (73.5%) tumours were deep to the fascia and 53 (26.5%) superficial. Tumour size classified according to the 12 AJCC 2019 criteria was: T1 = 52, T2 = 76, T3 = 39, T4 = 33. Based on nodule size >5 mm, 73 (36.5%) patients had no metastases, 42 (21%) had metastases, while 85 (42.5%) studies were indeterminate. Based on nodule size >10 mm, 73 (36.5%) patients had no metastases, 28 (14%) had metastases, while 99 (49.5%) studies were indeterminate. Larger maximum dimension of the primary tumour was a risk factor for pulmonary metastases using both size criteria.Conclusion:The incidence of pulmonary metastases at presentation in trunk and extremity soft tissue sarcoma is 14–21%. 42.5–49.5% of chest CTs were indeterminate.Advances in knowledge:The incidence of pulmonary metastases at presentation in trunk and extremity soft tissue sarcoma is 14–21%. Indeterminate pulmonary nodules are also very common.     

Effects of Organic Light-Emitting Diodes on Circadian Rhythm and Sleep

ObjectiveOrganic light-emitting diodes (OLEDs) emit less blue light than traditional light-emitting diodes (LEDs), and we previously found that early-night OLED light exposure (LE) delays the melatonin phase by less than LED at a color temperature of 4,000 K. As a follow-up study, we investigated the effects of OLED and LED at a different color temperature (3,000 K) on melatonin profile, sleep, and vigilance. Methods24 healthy subjects (27.5±5.1 years) were exposed to three light conditions [OLED, LED, and dim light (DL)] from 17:30 to 24:00, in a random order and with a 1-week interval. Saliva samples for melatonin were taken every hour from 18:00 to 24:00. Polysomnography (PSG) and a psychomotor vigilance test (PVT) were performed. ResultsMelatonin onset time was significantly delayed under OLED and LED compared with DL, with no significant difference between OLED and LED. The mean melatonin level at 24:00 under LED was lower than that under DL, but there was no significant difference between OLED LE and DL. The percentage of slow wave sleep (N3) in LED was significantly lower than in OLED. ConclusionExposure to light in the evening can suppress melatonin secretion late at night and disturb deep sleep, and those effects are slightly worse under LED than OLED.     

Postobturation Pain Associated with Tricalcium Silicate and Resin-based Sealer Techniques: A Randomized Clinical Trial

IntroductionThe incidence of immediate postobturation pain associated with 2 sealer techniques was compared and potential prognostic factors identified.MethodsPatients referred for endodontic treatment were recruited with informed consent. Root canals were debrided and teeth rendered asymptomatic before random allocation to receive TotalFill BC (FKG Dentaire SA, La Chaux-de-Fonds, Switzerland) or AH Plus sealer (Dentsply Maillefer, Ballaigues, Switzerland). Patients blinded to the sealer reported their postobturation pain experience 1, 3, and 7 days after treatment. Blinded and calibrated assessors independently reviewed treatment quality, sealer extrusion, and radiographic data under standardized conditions.ResultsOne hundred sixty eligible patients (163 teeth, 95.3%) returned their pain diary. No postobturation pain difference was found between the 2 sealers (P > .05), although the AH Plus sealer technique was significantly associated with extrusion beyond the apex (P < .05; odds ratio [OR] = 3.02; 95% confidence interval [CI], 1.39–6.57). Thirty-three (20.6%) patients reported pain on day 1 (median 1 = very mild pain), 16 (10.0%) on day 3 (median 1 = very mild pain), and 9 (5.6%) on day 7 (median 2 = mild pain). The prognostic factors were as follows:(1) moderate/severe preoperative pain (OR = 4.41; 95% CI, 1.42–13.76 on day 3 and OR = 5.16; 95% CI, 1.17–22.78 on day 7),(2) provoked preoperative pain (OR = 4.24; 95% CI, 1.40–12.78 on day 3 and OR = 5.35; 95% CI, 1.27–22.51 on day 7),(3) pulpless tooth (OR = 0.11; 95% CI, 0.02–0.57 on day 3), and(4) sonic activation during treatment (OR = 3.02; 95% CI, 1.39–6.57 on day 1 and OR = 3.01; 95% CI, 1.05–8.59 on day 3).ConclusionsThere was no significant difference in pain experience between teeth filled using AH Plus or TotalFill BC Sealer 1, 3, and 7 days after obturation. Patient- and treatment-related factors could influence postobturation pain.     

Are Irregular Hypoechoic Breast Masses on Ultrasound Always Malignancies?: A Pictorial Essay

Irregular hypoechoic masses in the breast do not always indicate malignancies. Many benign breast diseases present with irregular hypoechoic masses that can mimic carcinoma on ultrasonography. Some of these diseases such as inflammation and trauma-related breast lesions could be suspected from a patient''s symptoms and personal history. Careful ultrasonographic examination and biopsy could help to differentiate these from malignancies.