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Comparisons of histopathological features and microbiological findings between decedents with respiratory symptoms due to SARS-CoV-2 infection or other causes, in settings with high prevalence of HIV and Mycobacterium tuberculosis (MTB) infections have not been reported. Deaths associated with a positive ante-mortem SARS-CoV-2 PCR test and/or respiratory disease symptoms at Chris Hani Baragwanath Academic Hospital in Soweto, South Africa from 15th April to 2nd November 2020, during the first wave of the South African COVID-19 epidemic, were investigated. Deceased adult patients had post-mortem minimally-invasive tissue sampling (MITS) performed to investigate for SARS-CoV-2 infection and molecular detection of putative pathogens on blood and lung samples, and histopathology examination of lung, liver and heart tissue. During the study period MITS were done in patients displaying symptoms of respiratory disease including 75 COVID-19-related deaths (COVID+) and 42 non-COVID-19-related deaths (COVID-). The prevalence of HIV-infection was lower in COVID+ (27%) than in the COVID- (64%), MTB detection was also less common among COVID+ (3% vs 13%). Lung histopathology findings showed differences between COVID+ and COVID- in the severity of the morphological appearance of Type-II pneumocytes, alveolar injury and repair initiated by SARS-CoV-2 infection. In the liver necrotising granulomatous inflammation was more common among COVID+. No differences were found in heart analyses. The prevalence of bacterial co-infections was higher in COVID+. Most indicators of respiratory distress syndrome were undifferentiated between COVID+ and COVID- except for Type-II pneumocytes. HIV or MTB infection does not appear in these data to have a meaningful correspondence with COVID-related deaths.

Health care providers in the United States are facing challenges in selecting appropriate medication for patients with acute and chronic pain in the midst of the current opioid crisis and COVID-19 pandemic. When compared with conventional opioids, the partial [micro]-opioid receptor agonist buprenorphine has unique pharmacologic properties that may be more desirable for pain management. The formulations of buprenorphine approved by the US Food and Drug Administration for pain management include intravenous injection, transdermal patch, and buccal film. A comparison of efficacy and safety data from studies of buprenorphine and conventional opioids suggests that buprenorphine may be a better-tolerated treatment option for many patients that provides similar or superior analgesia. Our benefit-risk assessment in this narrative review suggests that health care providers should consider that buprenorphine may be an appropriate alternative for pain management over other opioids. Keywords: buprenorphine, buprenorphine buccal film, analgesia, pain, opioids

Egyptian fruit bats (Rousettus aegyptiacus) were inoculated subcutaneously (n = 22) with Marburg virus (MARV). No deaths, overt signs of morbidity, or gross lesions was identified, but microscopic pathological changes were seen in the liver of infected bats. The virus was detected in 15 different tissues and plasma but only sporadically in mucosal swab samples, urine, and fecal samples. Neither seroconversion nor viremia could be demonstrated in any of the in-contact susceptible bats (n = 14) up to 42 days after exposure to infected bats. In bats rechallenged (n = 4) on day 48 after infection, there was no viremia, and the virus could not be isolated from any of the tissues tested. This study confirmed that infection profiles are consistent with MARV replication in a reservoir host but failed to demonstrate MARV transmission through direct physical contact or indirectly via air. Bats develop strong protective immunity after infection with MARV.

Naldemedine, an oral, peripherally acting μ-opioid receptor antagonist approved for the treatment of opioid-induced constipation (OIC), is renally excreted. This subgroup analysis integrated data from 3 Phase 3 trials (COMPOSE-1, COMPOSE-2, COMPOSE-3) to evaluate the safety and efficacy of naldemedine in patients with renal impairment (RI). Patients age 18-80 years with chronic non-cancer pain (CNCP) and OIC received oral naldemedine 0.2 mg or placebo once daily. RI subgroups consisted of patients with normal function (baseline glomerular filtration rate ≥90 mL/min/1.73 m ), mild (≥60 to <90 mL/min/1.73 m ), and moderate (≥30 to <60 mL/min/1.73 m ) RI. Safety assessments based on ≤12 weeks of treatment from all 3 studies included incidence of treatment-emergent adverse events (TEAEs). Efficacy was based on the proportion of responders in COMPOSE-1 and COMPOSE-2 only, defined as ≥3 spontaneous bowel movements (SBMs)/week and a ≥1-SBM/week increase from baseline for ≥9 of 12 weeks and ≥3 of the last 4 weeks. In total, 2328 patients were included in this analysis. The incidence of TEAEs was similar in the naldemedine and placebo groups (overall, 47.1% vs 45.6%; normal, 44.6% vs 43.6%; mild RI, 49.0% vs 44.7%; moderate RI, 46.6% vs 55.9%). GI-related TEAEs occurred more frequently in the naldemedine group versus placebo (overall, 21.8% vs 13.8%; normal, 21.6% vs 12.5%; mild RI, 22.6% vs 14.7%; moderate RI, 18.0% vs 14.2%). A significantly greater proportion of patients in the naldemedine 0.2 mg group were responders versus the placebo group (overall, 50.1% vs 34.1%, <0.0001; normal, 52.0% vs 39.3%; mild RI, 48.3% vs 30.3%; moderate RI, 52.5% vs 31.7%). This integrated analysis confirmed that OIC treatment with naldemedine 0.2 mg was generally well tolerated and effective in patients with CNCP and mild or moderate RI. Safety and efficacy results were consistent with the overall population. COMPOSE-1: NCT01965158; COMPOSE-2: NCT01993940; COMPOSE-3: NCT01965652.

Introduction: Opioid-induced constipation (OIC), a common side effect of opioid utilization in treating chronic non-cancer pain, is caused by the action of opioids on peripheral p-opioid receptors in the enteric nervous system. Naldemedine (NAL), a peripherally acting p-opioid receptor antagonist (PAMORA), demonstrated consistent efficacy and safety in the treatment of OIC from two phase 3, randomised, placebo-controlled, double-blind clinical trials [NCT01965158 (COMPOSE-1) and NCT01993940 (COMPOSE-2)]. In both studies there were significant improvements in the frequency of Spontaneous Bowel Movements (SBMs) and in the OIC symptoms of incomplete evacuation and straining. The effect of NAL in treating the symptoms of OIC in laxative inadequate responders (LIR) has not been reported. Methods: A post-hoc analysis from the pooled two phase 3, randomized, placebo-controlled, doubleblind clinical trials (COMPOSE-1; COMPOSE-2) was performed in the LIR and Non-LIR subgroup. LIR was defined as subjects who were on laxative therapy prior to entering the study and those who stopped its use within 30 days prior to screening, and who signed the informed consent which required the subject to have self-reported OIC (ie, incomplete bowel movement, hard stools, straining, or false alarms). Non-LIR was defined as those subjects who did not receive laxatives or only received rescue laxatives at or after screening. NAL effect on SBM frequency, complete SBMs (CSBM), and SBMs without straining was evaluated. Treatment-emergent adverse events (TEAEs) were defined as those that were reported after randomization and were assessed as well. Results: There was statistically significant increase in SBM frequency (Fig 1), CSBMs (Fig 2), and SBM without straining for both LIR and non-LIR groups as compared to placebo. TEAEs were comparable between the NAL and PBO in both LIR and non-LIR groups. The most common TEAEs were gastrointestinal-related. Conclusion: These data demonstrate that NAL improved the key symptoms of OIC: frequency, incomplete evacuation, and straining, in those subjects who have been previously treated with a laxative. These results suggest that NAL is a useful treatment option in the management of OIC in subjects with chronic non-cancer pain.

Despite approximately 2.6 million stillbirths occurring annually, there is a paucity of systematic biological investigation and consequently knowledge on the causes of these deaths in low- and middle-income countries (LMICs). We investigated the utility of minimally invasive tissue sampling (MITS), placental examination, and clinical history, in attributing the causes of stillbirth in a South African LMIC setting. This prospective, observational pilot study undertook sampling of brain, lung, and liver tissue using core biopsy needles, blood and cerebrospinal fluid collection, and placental examination. Testing included microbial culture and/or molecular testing and tissue histological examination. The cause of death was determined for each case by an international panel of medical specialists and categorized using the World Health Organization's International Classification of Diseases, Tenth Revision application to perinatal deaths. A cause of stillbirth was identifiable for 117 of 129 (90.7%) stillbirths, including an underlying maternal cause in 63.4% (n = 83) and an immediate fetal cause in 79.1% (n = 102) of cases. The leading underlying causes of stillbirth were maternal hypertensive disorders (16.3%), placental separation and hemorrhage (14.0%), and chorioamnionitis (10.9%). The leading immediate causes of fetal death were antepartum hypoxia (35.7%) and fetal infection (37.2%), including due to Escherichia coli (16.3%), Enterococcus species (3.9%), and group B Streptococcus (3.1%). In this pilot, proof-of-concept study, focused investigation of stillbirth provided granular detail on the causes thereof in an LMIC setting, including provisionally highlighting the largely underrecognized role of fetal sepsis as a dominant cause.

Misuse, abuse and diversion of prescription opioid analgesics represent a global public health concern. The development of abuse-deterrent formulations (ADFs) of prescription opioid analgesics is an important step toward reducing abuse and diversion of these medications, as well as potentially limiting medical consequences when misused or administered in error. ADFs aim to hinder extraction of the active ingredient, prevent administration through alternative routes and/or make abuse of the manipulated product less attractive, less rewarding or aversive. However, opioid ADFs may still be abused via the intended route of administration by increasing the dose and/or dosing frequency. The science of abuse deterrence and the regulatory landscape are still relatively new and evolving. This paper reviews the current status of opioid ADFs, with particular focus on different approaches that can be used to deter abuse, regulatory considerations and implications for clinical management.

Objective: Opioid-induced constipation is among the most common side effects associated with opioid use in patients with chronic non-cancer pain, and it can have a significant negative impact on health-related quality of life (QOL). This analysis evaluated the effect of naldemedine 0.2 mg on patient-reported outcomes in three phase 3 clinical studies. Methods: COMPOSE-1 and COMPOSE-2 were identical randomized, double-blind, placebocontrolled, parallel-group studies of 12 weeks' duration, allowing data to be integrated (n=1095). COMPOSE-3 was similar in design, but of 52 weeks' duration (n=1241). Patients were adults with chronic non-cancer pain who had been treated with opioid analgesics for [greater than or equal to]3 months and experiencing opioid-induced constipation. Patient-reported outcomes included Patient Assessment of Constipation Symptoms (PAC-SYM; 12 questions assessed on a 5-point Likert scale), PAC-QOL (28 questions assessed on a 5-point Likert scale), and Subject Global Satisfaction (measured on a 7-point Likert scale). The proportion of patients achieving a [greater than or equal to]1.5 improvement in PAC-SYM and PAC-QOL was calculated. The correlation between change in PAC-SYM and PAC-QOL scores and frequency of bowel movements was also explored. Results: The proportion of PAC-SYM and PAC-QOL responders was significantly higher for naldemedine than for placebo at all assessed time points in COMPOSE-1/COMPOSE-2 (p<0.005 for both) and COMPOSE-3 (p<0.005 and p<0.0001, respectively). There was a statistically significant correlation between improvement in PAC-SYM/PAC-QOL and frequency of bowel movements at all time points (p[less than or equal to]0.0002). The majority of patients treated with naldemedine reported markedly or moderately improved satisfaction with constipation and abdominal symptoms on the Subject Global Satisfaction questionnaire. Discussion: Naldemedine treatment was associated with a rapid and sustained clinically relevant improvement in patient-reported outcomes, indicating improvement in opioid-induced constipation-related symptoms and QOL. ClinicalTrials.gov Registration: NCT01965158, NCT01993940, NCT01965652. Keywords: gastrointestinal tract, minimal clinically important difference, mu opioid receptor, patient satisfaction, quality of life

The safety and tolerability of naldemedine was also assessed (Clintrials.gov Identifiers NCT01993940 and NCT01965158). Results: A total of 628 subjects were determined to be LIRs (naldemedine = 317, placebo = 311) and 446 were non-LIRs (naldemedine = 221, placebo = 226) from both studies. There was a significantly greater proportion of res-ponders (defined as [greater than or equal to]9/12 weeks and 3/4 weeks achieving an increase from baseline of [greater than or equal to]3 spontaneous bowel movements [SBMs]/week and [greater than or equal to]1 SBM/week) with naldemedine than placebo in both LIR (46.4% vs 30.2%, respectively, P < 0.0001) and non-LIR subjects (54.3% vs 38.9%, respectively, P= 0.0009). Treatment-emergent adverse events were comparable between naldemedine and placebo, with the most common being gastrointestinal related. Conclusion: Naldemedine resulted in consistent response in the treatment of OIC, independent of previous laxative utilization.