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Clinical characteristics and histopathology of COVID-19 related deaths in South African adults
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.
Journal Article
Lack of Marburg Virus Transmission From Experimentally Infected to Susceptible In-Contact Egyptian Fruit Bats
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.
Journal Article
Naldemedine Is Effective in the Treatment of Opioid-Induced Constipation in Chronic Non-Cancer Pain in Subjects With or Without Inadequate Response to Laxatives
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.
Journal Article
An Observational Pilot Study Evaluating the Utility of Minimally Invasive Tissue Sampling to Determine the Cause of Stillbirths in South African Women
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.
Journal Article
Abuse-deterrent formulations of prescription opioid analgesics in the management of chronic noncancer pain
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.
Journal Article
A Renal Impairment Subgroup Analysis of the Safety and Efficacy of Naldemedine for the Treatment of Opioid-Induced Constipation in Patients with Chronic Non-Cancer Pain Receiving Opioid Therapy
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.
Journal Article
Naldemedine is effective in the treatment of opioid-induced constipation in patients with chronic non-cancer pain who had a poor response to laxatives
Background:
Two studies demonstrated the efficacy and safety of naldemedine in adult patients with chronic non-cancer pain and opioid-induced constipation (OIC). However, no studies have compared the efficacy of peripherally acting µ-opioid receptor antagonists in patients with adequate and inadequate responses to prior OIC therapy with laxatives. This post hoc analysis of integrated data from the two previous studies compared the efficacy of naldemedine in patients who were unsuccessfully treated with laxatives [poor laxative responders (PLRs)] with those who either did not receive laxatives >30 days prior to screening or those who only received rescue laxative at or after screening (non-PLRs).
Methods:
Patients with OIC were randomized to once-daily treatment with naldemedine 0.2 mg or placebo. The primary efficacy endpoint was the proportion of responders [⩾3 spontaneous bowel movements (SBMs)/week and an increase from baseline of ⩾1 SBM/week for ⩾9 weeks of the 12-week treatment period and ⩾3 weeks of the final 4 weeks of the 12-week treatment period]. Additional endpoints included change in SBM frequency, change in frequency of SBMs without straining, proportion of complete SBM (CSBM) responders, change in CSBM frequency, and time to first SBM. Treatment-emergent adverse events (TEAEs) were assessed.
Results:
The analysis included 538 (317 PLRs, 221 non-PLRs) and 537 (311 PLRs, 226 non-PLRs) patients in the naldemedine and placebo arms, respectively. There were significantly more responders in the naldemedine PLR (46.4%; p < 0.0001) and non-PLR (54.3%; p = 0.0009) subgroups versus the placebo groups (30.2% and 38.9%, respectively). In both the PLR and non-PLR subgroups, naldemedine treatment was superior to placebo on all additional endpoints. Overall incidence of TEAEs in the PLR subgroups treated with naldemedine or placebo was similar.
Conclusion:
This integrated analysis further supports the efficacy and tolerability of naldemedine in the treatment of OIC and demonstrates a consistent effect in both PLR and non-PLR subgroups.
[ClinicalTrials.gov identifier: NCT01965158 and NCT01993940]
Journal Article
Surgically cured hypoglycemia secondary to pleural solitary fibrous tumour: case report and update review on the Doege-Potter syndrome
The association of paraneoplastic hypoglycemia [Doege-Potter syndrome] and finger clubbing [Pierre-Marie-Bamberg syndrome] with pleural solitary fibrous tumour is rare. We present a previously unpublished but typical example of this rare occurrence together with a detailed updated literature review of previously published cases of pleural SFT discussing the histopathology of SFT; pathophysiology of the hypoglycemia and finger clubbing; treatment and outcome of pleural SFT. The patient, a 57-year-old African male was admitted at our hospital with recurrent episodes of hypoglycemia. He was found to have digital clubbing and decreased breath sounds in the right lower chest but no other significant clinical findings. His insulin level measured during an episode of hypoglycemia was undetectable. Chest radiograph and CT-scan revealed a lobulated mass in the right chest which was diagnosed to be SFT on histology. Surgical excision of the mass resulted in cure of the hypoglycemic episodes and rapid regression of the clubbing. Less than 65 cases of pleural SFT manifesting with hypoglycemia with or without finger-clubbing have been published in the English literature. The mean diameter of these tumours manifesting with hypoglycemia is 20 cm, 54% being benign while 42% were malignant. They predominantly present in the 6th-8th decade, average age of 64 years and a slight male preponderance at 58%. Complete surgical resection remains the most important predictor of clinical outcome in terms of recurrence and metastases, while providing instant cure for the hypoglycemia and rapid resolution of the finger clubbing.
Journal Article
Mapping of prospectivity and estimation of number of undiscovered prospects for lode gold, southwestern Ashanti Belt, Ghana
In the southwestern part of the Ashanti Belt, the results of fractal and Fry analyses of the spatial pattern of 51 known mines/prospects of (mostly lode) gold deposits and the results of analysis of their spatial associations with faults and fault intersections suggest different predominant structural controls on lode gold mineralisation at local and district scales. Intersections of NNE- and NW-trending faults were likely predominantly involved in local-scale structural controls on lode gold mineralisation, whilst NNE-trending faults were likely predominantly involved in district-scale structural controls on lode gold mineralisation. The results of the spatial analyses facilitate the conceptualisation and selection of spatial evidence layers for lode gold prospectivity mapping in the study area. The applications of the derived map of lode gold prospectivity and a map of radial density of spatially coherent lode gold mines/prospects results in a one-level prediction of 37 undiscovered lode gold prospects. The applications of quantified radial density fractal dimensions of the spatial pattern of spatially coherent lode gold mines/prospects result in an estimate of 40 undiscovered lode gold prospects. The study concludes finally that analysis of the spatial pattern of discovered mineral deposits is the key to a strong link between mineral prospectivity mapping and assessment of undiscovered mineral deposits.
Journal Article