Risks and benefits of oral modified-release compared with oral immediate-release opioid use after surgery: a systematic review and meta-analysis.

Prescription of modified-release opioids for acute postoperative pain is widespread despite evidence to show their use may be associated with an increased risk of adverse effects. This systematic review and meta-analysis aimed to examine the available evidence on the safety and efficacy of modified-release, compared with immediate-release, oral opioids for postoperative pain in adults. We searched five electronic databases from 1 January 2003 to 1 January 2023. Published randomised clinical trials and observational studies on adults who underwent surgery which compared those who received oral modified-release opioids postoperatively with those receiving oral immediate-release opioids were included. Two reviewers independently extracted data on the primary outcomes of safety (incidence of adverse events) and efficacy (pain intensity, analgesic and opioid use, and physical function) and secondary outcomes (length of hospital stay, hospital readmission, psychological function, costs, and quality of life) up to 12 months postoperatively. Of the eight articles included, five were randomised clinical trials and three were observational studies. The overall quality of evidence was low. Modified-release opioid use was associated with a higher incidence of adverse events (n = 645, odds ratio (95%CI) 2.76 (1.52-5.04)) and worse pain (n = 550, standardised mean difference (95%CI) 0.2 (0.04-0.37)) compared with immediate-release opioid use following surgery. Our narrative synthesis concluded that modified-release opioids showed no superiority over immediate-release opioids for analgesic consumption, length of hospital stay, hospital readmissions or physical function after surgery. One study showed that modified-release opioid use is associated with higher rates of persistent postoperative opioid use compared with immediate-release opioid use. None of the included studies reported on psychological function, costs or quality of life.

Natural history of occult hernias in adults at a safety-net hospital.

PURPOSE: Occult hernias, hernias seen on radiologic imaging but not felt on physical exam, are common. Despite their high prevalence, little is known about the natural history of this finding. Our aim was to determine and report on the natural history of patients with occult hernias including the impact on abdominal wall quality of life (AW-QOL), need for surgery, and risk of acute incarceration/strangulation. METHODS: This was a prospective cohort study of patients who underwent a computed tomography (CT) abdomen/pelvis scan from 2016 to 2018. Primary outcome was change in AW-QOL using the modified Activities Assessment Scale (mAAS), a hernia-specific, validated survey (1 = poor, 100 = perfect). Secondary outcomes included elective and emergent hernia repairs. RESULTS: A total of 131 (65.8%) patients with occult hernias completed follow-up with a median (IQR) of 15.4 (22.5) months. Nearly half of these patients (42.8%) experienced a decrease in their AW-QOL, 26.0% were unchanged, and 31.3% reported improvement. One-fourth of patients (27.5%) underwent abdominal surgery during the study period: 9.9% were abdominal procedures without hernia repair, 16.0% involved elective hernia repairs, and 1.5% were emergent hernia repairs. AW-QOL improved for patients who underwent hernia repair (+ 11.2 ± 39.7, p = 0.043) while those who did not undergo hernia repair experienced no change in AW-QOL (- 3.0 ± 35.1). CONCLUSION: When untreated, patients with occult hernias on average experience no change in their AW-QOL. However, many patients experience improvement in AW-QOL after hernia repair. Additionally, occult hernias have a small but real risk of incarceration requiring emergent repair. Further research is needed to develop tailored treatment strategies.

Enhancement of Mitochondrial Function by the Neurogenic Molecule NSI-189 Accompanies Reversal of Peripheral Neuropathy and Memory Impairment in a Rat Model of Type 2 Diabetes.

Aims: Mitochondrial dysfunction contributes to many forms of peripheral and central nervous system degeneration. Therapies that protect mitochondrial number and function have the potential to impact the progression of conditions such as diabetic neuropathy. We therefore assessed indices of mitochondrial function in dorsal root ganglia (DRG) and brain cortex of the Zucker diabetic fatty (ZDF) rat model of type 2 diabetes and tested the therapeutic impact of a neurogenic compound, NSI-189, on both mitochondrial function and indices of peripheral and central neurological dysfunction. Materials and Methods: ZDF rats were maintained for 16 weeks of untreated diabetes before the start of oral treatment with NSI-189 for an additional 16 weeks. Nerve conduction velocity, sensitivity to tactile and thermal stimuli, and behavioral assays of cognitive function were assessed monthly. AMP-activated protein kinase (AMPK) phosphorylation, mitochondrial protein levels, and respiratory complex activities were assessed in the DRG and brain cortex after 16 weeks of treatment with NSI-189. Results: Treatment with NSI-189 selectively elevated the expression of protein subunits of complexes III and V and activities of respiratory complexes I and IV in the brain cortex, and this was accompanied by amelioration of impaired memory function and plasticity. In the sensory ganglia of ZDF rats, loss of AMPK activity was ameliorated by NSI-189, and this was accompanied by reversal of multiple indices of peripheral neuropathy. Conclusions: Efficacy of NSI-189 against dysfunction of the CNS and PNS function in type 2 diabetic rats was accompanied by improvement of mitochondrial function. NSI-189 exhibited actions at different levels of mitochondrial regulation in central and peripheral tissues.

Prevalence and characteristics of gastroesophageal reflux disease in pregnant women.

INTRODUCTION AND AIMS: The prevalence of gastroesophageal reflux disease (GERD) has been reported to be increasing in recent years. However, there have been few reports on the prevalence of GERD during pregnancy in the Asian population. The aim of our study was to evaluate the prevalence and characteristics of GERD in Vietnamese pregnant women. MATERIALS AND METHODS: This cross-sectional study was conducted at the antenatal clinic of the Nhan Dan Gia Dinh Hospital, Ho Chi Minh, Vietnam. Four hundred females, at various stages of pregnancy, were enrolled. GERD was diagnosed if there was troublesome heartburn and/or acid regurgitation, at least once a week, during the current pregnancy. RESULTS: The overall prevalence of GERD in pregnancy was 38.5% (154/400). The prevalence of GERD in the third trimester was significantly higher than that in the second trimester (46.8% vs. 30.7%, P=0.008) and tended to be higher than its prevalence in the first trimester (46.8% vs. 35.4%, P=0.051). In the pregnant women with GERD, the frequency of regurgitation was significantly higher than that of heartburn (92.9% vs. 30.5%, P<0.001). Those typical symptoms were more prevalent in the daytime, compared with nighttime. CONCLUSION: Our study showed that GERD was prevalent during pregnancy in Vietnam. In the pregnant women with GERD, regurgitation was much more common than heartburn, and those typical reflux symptoms occurred more frequently in the daytime, compared with nighttime.

Maternal and fetal characteristics for predicting risk of Cesarean section following induction of labor: pooled analysis of PROBAAT trials.

OBJECTIVE: Induction of labor (IOL) is one of the most widely used obstetric interventions. However, one-fifth of IOLs result in Cesarean section (CS). We aimed to assess maternal and fetal characteristics that influence the likelihood of CS following IOL, according to the indication for CS. METHODS: This was a secondary analysis of pooled data from four randomized controlled trials, including women undergoing IOL at term who had a singleton pregnancy and an unfavorable cervix, intact membranes and the fetus in cephalic presentation. The main outcomes of this analysis were CS for failure to progress (FTP) and CS for suspected fetal compromise (SFC). Restricted cubic splines were used to determine whether continuous maternal and fetal characteristics had a non-linear relationship with outcome. Optimal cut-offs for those characteristics with a non-linear pattern were determined based on the maximum area under the receiver-operating-characteristics curve. Adjusted odds ratios (aOR) were computed, using multivariable logistic regression analysis, for the associations between optimally categorized characteristics and outcome. RESULTS: Of a total of 2990 women undergoing IOL, 313 (10.5%) had CS for FTP and 227 (7.6%) had CS for SFC. The risk of CS for FTP was increased in women aged 31-35 years compared with younger women (aOR, 1.51 (95% CI, 1.15-1.99)), in nulliparous compared with parous women (aOR, 8.07 (95% CI, 5.34-12.18)) and in Sub-Saharan African compared with Caucasian women (aOR, 2.09 (95% CI, 1.33-3.28)). Higher body mass index (BMI) increased incrementally the risk of CS for FTP (aOR, 1.06 (95% CI, 1.04-1.08)). High birth-weight percentile was also associated with an increased risk of CS due to FTP (aOR, 2.66 (95% CI, 1.74-4.07) for birth weight between the 80.0th and 89.9th percentiles and aOR, 4.08 (95% CI, 2.75-6.05) for birth weight ≥ 90th percentile, as compared with birth weight between the 20.0th and 49.9th percentiles). For CS due to SFC, higher maternal age (aOR, 1.09 (95% CI, 1.05-1.12)) and BMI (aOR, 1.05 (95% CI, 1.03-1.08)) were associated with an incremental increase in risk. The risk of CS for SFC was increased in nulliparous compared with parous women (aOR, 5.91 (95% CI, 3.76-9.28)) and in South Asian compared with Caucasian women (aOR, 2.50 (95% CI, 1.23-5.10)). Birth weight < 10.0th percentile increased significantly the risk of CS due to SFC (aOR, 1.93 (95% CI, 1.22-3.05)), as compared with birth weight between the 20.0th and 49.9th percentiles. Bishop score did not demonstrate a significant association with the risk of CS for FTP or for SFC. CONCLUSIONS: In women undergoing IOL, maternal age, BMI, parity, ethnicity and birth-weight percentile are predictors of CS due to FTP and of CS due to SFC, but the direction and magnitude of the associations differ according to the indication for CS. These characteristics should be considered in combination with the Bishop score to stratify the risk of CS for different indications in women undergoing IOL. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Bacterial Cytological Profiling (BCP) as a Rapid and Accurate Antimicrobial Susceptibility Testing Method for Staphylococcus aureus.

Successful treatment of bacterial infections requires the timely administration of appropriate antimicrobial therapy. The failure to initiate the correct therapy in a timely fashion results in poor clinical outcomes, longer hospital stays, and higher medical costs. Current approaches to antibiotic susceptibility testing of cultured pathogens have key limitations ranging from long run times to dependence on prior knowledge of genetic mechanisms of resistance. We have developed a rapid antimicrobial susceptibility assay for Staphylococcus aureus based on bacterial cytological profiling (BCP), which uses quantitative fluorescence microscopy to measure antibiotic induced changes in cellular architecture. BCP discriminated between methicillin-susceptible (MSSA) and -resistant (MRSA) clinical isolates of S. aureus (n = 71) within 1-2 h with 100% accuracy. Similarly, BCP correctly distinguished daptomycin susceptible (DS) from daptomycin non-susceptible (DNS) S. aureus strains (n = 20) within 30 min. Among MRSA isolates, BCP further identified two classes of strains that differ in their susceptibility to specific combinations of beta-lactam antibiotics. BCP provides a rapid and flexible alternative to gene-based susceptibility testing methods for S. aureus, and should be readily adaptable to different antibiotics and bacterial species as new mechanisms of resistance or multidrug-resistant pathogens evolve and appear in mainstream clinical practice.

Ultrasound study of FeCr2S4 in high magnetic fields.

We report on ultrasound studies of FeCr2S4 in static and pulsed magnetic fields exhibiting an orbital-order transition at 9 K. A longitudinal acoustic mode exhibits distinct features in the phase space of temperature and magnetic field due to magnetic and structural transformations. Pulsed-field measurements show significant differences in the sound velocity below and above the orbital-ordering transition as well as the spin-reorientation transition at 60 K. Our results indicate a reduction of the magnetocrystalline anisotropy on entering the orbitally ordered phase.

FeCr2S4 in magnetic fields: possible evidence for a multiferroic ground state.

We report on neutron diffraction, thermal expansion, magnetostriction, dielectric, and specific heat measurements on polycrystalline FeCr2S4 in external magnetic fields. The ferrimagnetic ordering temperatures TC ≈ 170 K and the transition at TOO ≈ 10 K, which has been associated with orbital ordering, are only weakly shifted in magnetic fields up to 9 T. The cubic lattice parameter is found to decrease when entering the state below TOO. The magnetic moments of the Cr- and Fe-ions are reduced from the spin-only values throughout the magnetically ordered regime, but approach the spin-only values for fields >5.5 T. Thermal expansion in magnetic fields and magnetostriction experiments indicate a contraction of the sample below about 60 K. Below TOO this contraction is followed by a moderate expansion of the sample for fields larger than ~4.5 T. The transition at TOO is accompanied by an anomaly in the dielectric constant. The dielectric constant depends on both the strength and orientation of the external magnetic field with respect to the applied electric field for T < TOO. A linear correlation of the magnetic-field-induced change of the dielectric constant and the magnetic-field dependent magnetization is observed. This behaviour is consistent with the existence of a ferroelectric polarization and a multiferroic ground state below 10 K.

Impaired urine concentration and absence of tissue ACE: involvement of medullary transport proteins.

ACE.2 mice lack all tissue angiotensin-converting enzyme (ACE) but have 33% of normal plasma ACE activity. They exhibit the urine-concentrating defect and hyperkalemia present in mice that lack all ACE, but in contrast to the complete knockout, ACE.2 mice have normal medullary histology and creatinine clearance. To explore the urine-concentrating defect in ACE.2 mice, renal medullary transport proteins were analyzed using Western blot analysis. In the inner medulla, UT-A1, ClC-K1, and aquaporin-1 (AQP1) were significantly reduced to 28 +/- 5, 6 +/- 6, and 39 +/- 5% of the level in wild-type mice, respectively, whereas AQP2 and UT-B were unchanged. In the outer medulla, Na(+)-K(+)-2Cl(-) cotransporter (NKCC2/BSC1) and AQP1 were significantly reduced to 56 +/- 11 and 29 +/- 6%, respectively, whereas Na(+)-K(+)-ATPase, UT-A2, UT-B, and AQP2 were unchanged, and renal outer medullary potassium channel was significantly increased to 711 +/- 187% of the level in wild-type mice. The abnormal expression of these transporters was similar in ACE.2 mice backcrossed onto a C57BL/6 or a Swiss background and was not rescued by ANG II infusion. We conclude that the urine-concentrating defect in ACE.2 mice is associated with, and may result from, downregulation of some or all of these key urea, salt, and water transport proteins.

Signaling through CD40 enhances cytotoxic T lymphocyte generation by CD8+ T cells from mice bearing large tumors.

Recent studies have demonstrated the importance of CD40/CD154 (CD40L) interactions for the generation of cell-mediated antitumor immune responses. Here we show that signaling via CD40 (through the use of the activating anti-CD40 mAb, IC10) can actually promote the in vitro generation of CTL activity by CD8+ splenic T cells from mice bearing a large MOPC-315 tumor. Anti-CD40 mAb had to be added at the initiation of the stimulation cultures of tumor-bearing splenic cells in order to realize fully its potentiating activity for cytotoxic T lymphocyte (CTL) generation, suggesting that signaling through CD40 is important at the inductive stage of antitumor cytotoxicity. Moreover, anti-CD40 mAb was found to enhance the expression of the B7-2 (CD86) and, to a lesser extent, the B7-1 (CD80) costimulatory molecules on B220+ cells (i.e., B cells), and B7-2 and, to a lesser extent, B7-1 molecules played an important role in the potentiating effect of anti-CD40 mAb for CTL generation by tumor-bearer splenic cells. Furthermore, B220+ cells were found to be essential for the potentiating effect of anti-CD40 mAb, as depletion of B220+ cells at the inductive stage completely abrogated the ability of anti-CD40 mAb to enhance CTL generation. Thus, signaling through CD40 enhances CTL generation by CD8+ T cells from tumor-bearing mice by a mechanism that involves the up-regulation of B7-2 and, to a lesser extent, B7-1 expression on B220+ cells.

Sec61p serves multiple roles in secretory precursor binding and translocation into the endoplasmic reticulum membrane.

The evolutionarily conserved Sec61 protein complex mediates the translocation of secretory proteins into the endoplasmic reticulum. To investigate the role of Sec61p, which is the main subunit of this complex, we generated recessive, cold-sensitive alleles of sec61 that encode stably expressed proteins with strong defects in translocation. The stage at which posttranslational translocation was blocked was probed by chemical crosslinking of radiolabeled secretory precursors added to membranes isolated from wild-type and mutant strains. Two classes of sec61 mutants were distinguished. The first class of mutants was defective in preprotein docking onto a receptor site of the translocon that included Sec61p itself. The second class of mutants allowed docking of precursors onto the translocon but was defective in the ATP-dependent release of precursors from this site that in wild-type membranes leads to pore insertion and full translocation. Only mutants of the second class were partially suppressed by overexpression of SEC63, which encodes a subunit of the Sec61 holoenzyme complex responsible for positioning Kar2p (yeast BiP) at the translocation channel. These mutants thus define two early stages of translocation that require SEC61 function before precursor protein transfer across the endoplasmic reticulum membrane.

Lack of control of renin release by adrenergic nervous system in the aglomerular toadfish.

Aglomerular toadfish, Opsanus tau, release renin in response to hemorrhage or vasodilator drugs, presumably by stimulating a renal arterial baroreceptor. We aimed to determine whether the adrenergic nervous system and prostaglandins play a role in the control of renin release in unanesthetized toadfish kept in 50% seawater. Isoproterenol (1 microgram/kg) increased plasma renin activity (PRA) fourfold and decreased blood pressure (BP); both effects were abolished by a concomitant infusion of propranolol. Propranolol itself slightly decreased the basal level of heart rate and BP, but not that of PRA. Norepinephrine (1 microgram/kg) increased BP, but did not change PRA. Repeated injection of 6-hydroxydopamine did not alter resting levels of either PRA or BP. Monoamine-specific nerve fluorescence activity could not be demonstrated in association with arterioles of kidneys from intact toadfish or from those treated with monoamine oxidase inhibitor and norepinephrine (5 mg/kg). Furthermore, treatment of toadfish with indomethacin (10 or 20 mg/kg) prevented neither the increase in PRA nor the reduction in BP after a massive hemorrhage. These results indicate that renin release in toadfish primarily occurs in response to a reduction in renal arterial pressure, whereas it appears unlikely that the adrenergic nervous system or prostaglandins have a significant role in the control of renin release.