Safety of tapentadol compared with other opioids in chronic pain treatment: network meta-analysis of randomized controlled and withdrawal trials.

OBJECTIVE: To assess the relative safety of oral tapentadol PR and other opioid analgesics for moderate or severe chronic pain in adults, we conducted a systematic review and network meta-analysis (NMA). METHODS: A systematic review was conducted to identify randomized controlled trials (RCTs) and randomized withdrawal trials of tapentadol with other WHO stage II and III opioid analgesics in patients with moderate or severe chronic pain. Searches were conducted in MEDLINE, EMBASE, PubMed, Cochrane databases and trial registries. Feasibility assessment evaluated the trials' suitability for NMA. Outcomes assessed were overall AEs, overall serious adverse events, constipation, nausea, dizziness, somnolence, headache, and discontinuation due to AEs. Randomized withdrawal trials were analyzed separately to other RCTs. RESULTS: Searches conducted in April 2019 identified 16,604 records. Following screening and feasibility assessment, 29 RCTs and 19 randomized withdrawal trials were identified and included in the NMA. Consistent with existing research, evidence from RCTs suggested that tapentadol is associated with relatively lower odds of adverse events occurring than most active comparators. The withdrawal trial data were less clear, with higher uncertainty around the results, and results that appear to contradict the RCT evidence. There are a number of trial design factors that may be affecting these results. CONCLUSIONS: RCT evidence suggests that tapentadol can be a useful treatment option for patients suffering from chronic pain and in need of an opioid analgesic. Opioids should be prescribed by a qualified physician only after other analgesics have been considered, taking side effects and misuse risk into account.

Mepilex Border Sacrum and Heel Dressings for the Prevention of Pressure Ulcers: A NICE Medical Technology Guidance.

Mepilex Border Sacrum and Heel dressings are self-adherent, multilayer foam dressings designed for use on the heel and sacrum aiming to prevent pressure ulcers. The dressings are used in addition to standard care protocols for pressure ulcer prevention. The National Institute for Health and Care Excellence (NICE) selected Mepilex Border Sacrum and Heel dressings for evaluation. The External Assessment Centre (EAC) critiqued the company's submission. Thirteen studies (four randomised controlled trials and nine nonrandomised comparative studies) were included. The majority of studies compared Mepilex Border Sacrum dressings (plus standard care) with standard care alone. Comparative evidence for Mepilex Border Heel dressings was limited. A meta-analysis indicated a non-statistically significant difference in favour of Mepilex Border Sacrum dressings for pressure ulcer incidence [RR 0.51 (95% CI 0.22-1.18)]. The company produced a de novo cost model, which was critiqued by the EAC. After the EAC updated input parameters, cost savings of £19 per patient compared with standard care alone for pressure ulcer prevention were estimated with Mepilex Border dressings predicted to be cost saving in 57% of iterations. The Medical Technologies Advisory Committee reviewed the evidence and judged that, although Mepilex Border Heel and Sacrum dressings have potential to prevent pressure ulcers in people who are considered to be at risk in acute care settings, further evidence is required to address uncertainties around the claimed benefits of the dressings and the incidence of pressure ulcers in an NHS acute-care setting. After a public consultation, NICE published this as Medical Technology Guidance 40.

Unexplained positive/elevated maternal serum alpha-fetoprotein associated with placenta increta. A case report.

Maternal serum alpha-fetoprotein (MSAFP) is a regularly utilized antenatal screening test for the identification of pregnancies at increased risk for a variety of genetic and nongenetic abnormalities. Complete mid-trimester evaluation of the patient with a positive screening test may fail to reveal an etiology for a positive MSAFP value. This case report concerns an unexplained positive/elevated MSAFP screening test for a patient found at delivery to have abnormal placentation.

Obstetric ultrasonography in a tertiary military medical referral center.

Antenatal ultrasonography is an integral component of diagnostic tests available to the practicing obstetrician. Periodic assessment of sonographic services offered and their diagnostic reliability is necessary for good patient care and quality assurance/risk management (QA/RM) documentation. We report the findings from a 1-year review of antenatal ultrasonographic services provided in a military referral center serving the Department of Defense in the southeastern United States. During the study period, 1627 obstetric scans were done by our Department of Radiology. Most of the examinations (139 [85%]) were done on patients served on a continuing basis by USAF Medical Center, Keesler; 236 (15%) studies were done on patients referred by other military hospitals throughout the region. Of all scans available for review, 1529 were normal, whereas 98 (6%) revealed clinically significant abnormalities. We address herein the results of this periodic assessment, as well as implications for referral among Department of Defense hospitals.

Acute postdisaster psychiatric disorders: identification of persons at risk.

This study examined the prevalence of four psychiatric disorders--posttraumatic stress disorder, major depression, generalized anxiety disorder, and alcohol abuse/dependence--in survivors of a jet plane crash into a hotel. Forty-six subjects were interviewed with the Diagnostic Interview Schedule/Disaster Supplement within 4-6 weeks of the event. More than half of the subjects met criteria for a psychiatric disorder after the disaster. More than two-thirds of the cases of acute postdisaster psychiatric disorders were predicted by identifying the subjects who had predisaster psychiatric histories. Predisaster psychiatric disorder predicted postdisaster psychopathology with a sensitivity of 72% and a specificity of 90%.

T-cell hybridoma production of macrophage activation factor (MAF) I. Separation of MAF from interferon gamma.

A T cell hybridoma was developed that produced macrophage activation factor (MAF) but no gamma interferon (IFN gamma). Hybridoma MAF was produced after stimulation with either concanavalin A (Con A) or phytohemagglutinin (PHA). Dose-response experiments showed that 1.5 microgram/ml Con A provided maximum MAF production with equivalent levels of MAF produced at Con A concentrations up to 6 microgram/ml. Time-course studies showed that maximum MAF activity was observed 48 hours after mitogen stimulation, and titration of MAF-containing supernatants showed that maximal MAF activity was observed at 1:4 dilutions with significant activity present at dilutions as great as 1:64. No IFN gamma activity was detectable at any supernatant dilution.

Optimum conditions for the reproducible measurement of concanavalin A-activated suppressor cell activity.

The reproducibility of the measurement of concanavalin A (Con A)-inducible suppressor cell activity in human peripheral blood lymphocytes was examined. Suppressor cells were activated for 24, 48, or 72 hr with 3, 6, and 12 micrograms of Con A (Con A in concentrations greater than 12 micrograms/ml was toxic to the lymphocytes) per ml and suppression of the proliferative response of autologous lymphocytes to varying concentrations of Con A (3, 6, and 12 micrograms/ml) was measured. No single set of conditions consistently produced optimal suppression. Assays performed concurrently using lymphocytes from the same subject produced comparable suppressor cell activity; however, considerable variability in suppressor cell activity was observed under all conditions tested when five normal subjects were examined on as many as four separate occasions. The variability was reduced but not eliminated by reporting the data for each assay in terms of a peak suppression value determined from multiple sets of conditions. The results suggest that small differences in suppressor cell activity between patient groups may be masked by the intrinsic variability of the assay system.

gamma-Interferon induced by S. aureus protein A augments natural killing and ADCC.

Staphylococcus aureus produces a protein identified as protein A (SpA) with a molecular weight of 41,000 (ref. 1) which binds to the Fc region of many types of mammalian IgG2, activates complement, blocks opsonins and is both chemotactic and mitogenic. SpA has been used for various immunological purposes including removal of immune complexes, arming effector cells with antibody, distinguishing between antibody-dependent cell-mediated cytotoxicity (ADCC) and natural killing (NK), and exerting anti-tumor activity. We have now demonstrated that SpA induces the production of gamma interferon (IFN-gamma) in nonadherent, T lymphocyte-depleted (E-), Fc receptor-bearing (FcR+) human peripheral blood lymphocytes. Our data also suggest that IFN-gamma is a potent stimulator of both NK and ADCC activity.

Current management of iatrogenic splenic injuries in children.

Recent clinical observations indicate that children who have undergone splenectomy for trauma have a significantly increased incidence (about 2 per cent) of subsequent fata sepsis, particularly with pneumococcus organisms. Some protection against fatal sepsis may be afforded by immunization with the newly developed pneumococcal vaccine in children more than 2 years old or by the use of prophylactic penicillin. However, splenectomy should be avoided whenever possible. The vast majority of iatrogenic splenic injuries that occur during renal operations in children are usually minor capsular lacerations that can be managed conservatively, using suturing techniques and drainage, and do not require splenectomy.

Role of antibody in cytotoxicity by lymphocytes armed against 253J bladder cancer line.

The role of antibody-dependent cell-mediated cytotoxicity (ADCC) in cytotoxicity mediated by antibody-armed effector cells was examined. Cytotoxicity mediated by unsensitized human peripheral blood mononuclear cells (MNC) directed against the human bladder cancer cell line, 253J, was significantly enhanced when MNC were preincubated with a rabbit anti-253J serum and then washed free of unbound antibody. Nonadherent, Fc receptor positive MNC were the effector cells and the arming antibody was IgG. Supernatants of 24-hour cultures and armed MNC exhibited antibody activity in ADCC assays, suggesting the ADCC was in part responsible for the arming phenomenon.

Induction of human gamma interferon by protein A from Staphylococcus aureus.

Protein A from Staphylococcus aureus (SpA) has been observed to stimulate the production of human gamma interferon (HuIFN gamma) by peripheral blood mononuclear cells (MNC). Dose-dependent experiments showed donor-to-donor variation in the concentration of SpA required for maximum IFN production although 50 micrograms/ml consistently produced near peak IFN gamma titers for each donor. Kinetic studies revealed that peak IFN gamma production occurred 24 hr after SpA stimulation. Physicochemical and antigenic characterization showed that SpA-induced IFN possessed the characteristics of IFN gamma in that it was inactivated by treatment at pH 2, heating at 56 C and anti-HuIFN gamma serum but not by anti-HuIFN alpha serum. Further studies showed tha maximum IFN gamma production could be achieved by stimulating 5 x 10(6) MNC/ml and IFN gamma could be harvested for 3 successive days by removing IFN gamma-containing supernatant fluids and adding fresh medium to stimulated MNC cultures. Preliminary cell fractionation studies suggest that the mononuclear cell that produces IFN gamma after SpA stimulation is a nonadherent lymphocyte that lacks high affinity receptors for sheep erythrocytes and expresses Fc receptors for IgG. Moreover, unlike other mitogen inducers, SpA appears to be less dependent on the presence of macrophages for IFN gamma production.

Concanavalin A-activated suppressor cell activity in peripheral blood lymphocytes of urologic cancer patients.

Concanavalin A (Con A)-inducible suppressor cell activity in peripheral blood lymphocytes (PBL) of urologic cancer patients and of appropriate controls with benign urologic disorders was measured concurrently. Although the proliferative responses to Con A of the cancer patients were significantly lower than those of controls, no difference in Con A-induced suppressor cell activity was demonstrated between cancer patients and controls when tested under a variety of conditions. Moreover, regression analysis revealed no correlation between the proliferative response to Con A and suppressor cell activity in either cancer patients or controls. The results indicated that Con A-inducible suppressor cell activity was unaltered in urologic cancer patients and suggested that suppressor cells of the type that can be activated by Con A were not involved in the general immunologic impairment frequently associated with urologic cancer.

Characterization of cell-mediated cytolytic mechanisms against human transitional cell carcinoma line, 253J.

We examined the nature of effector cells that mediate antibody-dependent cell-mediated cytotoxicity (ADCC) and spontaneous cell-mediated cytotoxicity (SCMC) against the 253J human bladder transitional cell carcinoma cell line. Fractionation of peripheral blood lymphocytes (PBL) showed that ADCC and SCMC against the 253J targets were mediated by non-adherent, surface immunoglobulin-negative lymphocytes lacking or having only weak affinity for sheep erythrocytes. Macrophages were not cytotoxic against 253J cells in 18 h culture, as removal of macrophages by glass adherence or treatment with silica particles did not reduce ADCC or SCMC, and macrophage-enriched effector cell preparations were only weakly cytotoxic.

Concanavalin A-inducible suppressor cells in regional lymph nodes of cancer patients.

Regional tumor-draining lymph nodes of 11 of 14 patients with urological tumors and one of four controls studied contained suppressor cell precursors that could be activated by concanavalin A (Con A) to suppress the proliferative response of autologous lymphocytes to Con A. In contrast, no suppression of lymphocyte proliferation by lymph node cells that were not activated with Con A was observed in four patients tested. The suppressive effect was not due to decreased viability or increased release of cold thymidine by Con A-activated cells nor to alteration in the time course of the proliferative response of Con A-activated cells. Mitomycin C treatment of lymph node cells 24 hr after activation did not abrogate their suppressive activity. Peak suppression was observed after 72 hr in culture. The amount of suppression measured could be maximized by treatment of suppressor cells with mitomycin C 24 hr after activation and by washing the cells immediately before pulse labeling with tritiated thymidine. The concentration of Con A required to produce peak suppression varied from patient to patient with optimal doses ranging from 5 to 25 microgram/ml.

Antibody-dependent and spontaneous lympholysis in urologic cancer patients.

To evaluate cytotoxic function mediated by killer lymphocytes and macrophages in urological cancer patients, we examined antibody-dependent and spontaneous lympholysis of chicken erythrocyte target cells, which is mediated by macrophages. Our results demonstrate a discordance between cytotoxic mechanisms in cancer patients, killer-cell function being impaired whilst macrophage-mediated cytotoxicity was increased.