Project ASPIRE: A feasibility randomized controlled trial of a brief intervention for reducing risk of depression and alcohol-related harms among South African adolescents.

OBJECTIVE: Brief interventions could reduce adolescents' risk of depression and alcohol-related harms, but evidence of their feasibility and acceptability for low-and middle-income countries is lacking. To address this gap, we conducted a feasibility trial of the ASPIRE intervention, a four-session multi-component counselling intervention for South African adolescents. METHOD: We recruited 117 adolescents who met our inclusion criteria. Participants were randomly assigned to the ASPIRE intervention or a comparison condition. Outcomes were assessed at baseline, six-week, and three-month post-randomization time points. Primary outcomes were based on feasibility of study procedures and intervention delivery (assessed on seven predetermined progression criteria). Clinical outcomes (risk of depression and alcohol harms) were secondary. RESULTS: Despite modifications to all study procedures arising from Covid-19 restrictions, five of the seven key progression criteria were fully met, including: feasibility of data collection and outcome measures, counsellor competencies, randomization and blinding, adverse advents, and acceptability of the intervention. The progression criterion for recruitment and intervention retention were not fully met. CONCLUSION: Findings suggest that the ASPIRE intervention was generally feasible to deliver and acceptable to adolescents. However, modifications to the trial design and intervention delivery are needed to optimize the validity of a definitive randomized controlled trial of the ASPIRE intervention.

Risks to healthcare workers following tracheal intubation of patients with COVID-19: a prospective international multicentre cohort study.

Healthcare workers involved in aerosol-generating procedures, such as tracheal intubation, may be at elevated risk of acquiring COVID-19. However, the magnitude of this risk is unknown. We conducted a prospective international multicentre cohort study recruiting healthcare workers participating in tracheal intubation of patients with suspected or confirmed COVID-19. Information on tracheal intubation episodes, personal protective equipment use and subsequent provider health status was collected via self-reporting. The primary endpoint was the incidence of laboratory-confirmed COVID-19 diagnosis or new symptoms requiring self-isolation or hospitalisation after a tracheal intubation episode. Cox regression analysis examined associations between the primary endpoint and healthcare worker characteristics, procedure-related factors and personal protective equipment use. Between 23 March and 2 June 2020, 1718 healthcare workers from 503 hospitals in 17 countries reported 5148 tracheal intubation episodes. The overall incidence of the primary endpoint was 10.7% over a median (IQR [range]) follow-up of 32 (18-48 [0-116]) days. The cumulative incidence within 7, 14 and 21 days of the first tracheal intubation episode was 3.6%, 6.1% and 8.5%, respectively. The risk of the primary endpoint varied by country and was higher in women, but was not associated with other factors. Around 1 in 10 healthcare workers involved in tracheal intubation of patients with suspected or confirmed COVID-19 subsequently reported a COVID-19 outcome. This has human resource implications for institutional capacity to deliver essential healthcare services, and wider societal implications for COVID-19 transmission.

Systematic review and consensus definitions for the Standardised Endpoints in Perioperative Medicine initiative: patient-centred outcomes.

BACKGROUND: Patient-centred outcomes are increasingly used in perioperative clinical trials. The Standardised Endpoints in Perioperative Medicine (StEP) initiative aims to define which measures should be used in future research to facilitate comparison between studies and to enable robust evidence synthesis. METHODS: A systematic review was conducted to create a longlist of patient satisfaction, health-related quality of life, functional status, patient well-being, and life-impact measures for consideration. A three-stage Delphi consensus process involving 89 international experts was then conducted in order to refine this list into a set of recommendations. RESULTS: The literature review yielded six patient-satisfaction measures, seven generic health-related quality-of-life measures, eight patient well-being measures, five functional-status measures, and five life-impact measures for consideration. The Delphi response rates were 92%, 87%, and 100% for Rounds 1, 2, and 3, respectively. Three additional measures were added during the Delphi process as a result of contributions from the StEP group members. Firm recommendations have been made about one health-related quality-of-life measure (EuroQol 5 Dimension, five-level version with visual analogue scale), one functional-status measure (WHO Disability Assessment Schedule version 2.0, 12-question version), and one life-impact measure (days alive and out of hospital at 30 days after surgery). Recommendations with caveats have been made about the Bauer patient-satisfaction measure and two life-impact measures (days alive and out of hospital at 1 yr after surgery, and discharge destination). CONCLUSIONS: Several patient-centred outcome measures have been recommended for use in future perioperative studies. We suggest that every clinical study should consider using at least one patient-centred outcome within a suite of endpoints.

The association between obesity and disability in survivors of joint surgery: analysis of the health and retirement study.

BACKGROUND: Obesity is associated with osteoarthritis and the need for joint surgery. Obese patients who undergo joint surgery may have a higher risk of morbidity compared with normal or overweight patients but less is known about their risk of postoperative disability. The primary objective of our study was to determine the association between obesity and the development of new dependence in activities of daily living within 2 years after joint surgery. METHODS: We obtained data from the Health and Retirement Study, a longitudinal survey of older Americans. We included participants who indicated having joint surgery for arthritis. We defined obesity as a BMI ≥30 kg m-2. Our outcome was a new or increased dependence in one or more activities of daily living after surgery. RESULTS: We analysed data on 2519 respondents who underwent joint surgery for arthritis. Respondents had a median age of 69yr, 65.5% were female, 66.6% had joint replacement surgery and 45.3% were obese. The overall incidence of a new dependence within 2years was 22.1%. Obese respondents had a higher incidence of new dependence compared with non-obese respondents (25.4% vs 19.4%, P<0.001). In adjusted analysis, obese respondents had increased odds of developing dependence [odds ratio 1.35 (95% CI 1.09-1.68), P=0.007]. CONCLUSIONS: Obesity is associated with an increased risk of developing dependence in the 2 years after joint surgery. Our study findings identify a high-risk group that may benefit from targeted interventions and allocation of perioperative resources to optimize recovery and minimize longer-term disability.

Controversies in anaesthesia for noncardiac surgery in older adults.

As the population of the world is rapidly ageing, the amount of surgery being performed in older patients is also increasing. Special attention is required for the anaesthetic and perioperative management of these patients. The clinical and non-clinical issues specific to older surgical patients are reviewed, with a special emphasis on areas of debate related to anaesthesia care in this group. These issues include the role of frailty and disability in preoperative assessment, choice of anaesthesia technique for hip fracture, postoperative delirium, and approaches to shared decision-making before surgical procedures.

Onset transition to cold nuclear matter from lattice QCD with heavy quarks.

Lattice QCD at finite density suffers from a severe sign problem, which has so far prohibited simulations of the cold and dense regime. Here we study the onset of nuclear matter employing a three-dimensional effective theory derived by combined strong coupling and hopping expansions, which is valid for heavy but dynamical quarks and has a mild sign problem only. Its numerical evaluations agree between a standard Metropolis and complex Langevin algorithm, where the latter is free of the sign problem. Our continuum extrapolated data approach a first order phase transition at µ(B) ≈ m(B) as the temperature approaches zero. An excellent description of the data is achieved by an analytic solution in the strong coupling limit.

Addressing the mental health needs of adolescents in South African communities: a protocol for a feasibility randomized controlled trial.

BACKGROUND: Like many low- and middle-income countries, almost half of the proportion of the South African population is under the age of 25. Given the peak age of onset for most mental health problems is in adolescence, it is vital that adolescents have access to mental health counselling. There are several initiatives to increase access to mental health counselling in South Africa, primarily through the integration of counselling for common mental disorders (CMD) into primary health care services, but adolescents (15-18 years of age) generally do not utilize these services. To address this gap, we will undertake a study to explore the feasibility of conducting a trial of the effectiveness of a community-based mental health counselling intervention for adolescents at-risk for a CMD. METHODS: The study is a feasibility trial of the ASPIRE intervention, a four-session blended multi-component counselling intervention adapted for South African adolescents at risk for depression and alcohol use disorders. We will enrol 100 adolescents from community settings and randomly assign them to the ASPIRE intervention or a comparison condition. Feasibility measures, such as rates of recruitment, consent to participate in the trial and retention, will be calculated. Qualitative interviews with participants and counsellors will explore the acceptability of the intervention. The primary outcomes for a subsequent trial would be reductions in symptoms of depression and days of heavy drinking which will be measured at baseline, 6 weeks, and 3 months post-randomization. DISCUSSION: This feasibility trial using a mixed-methods design will allow us to determine whether we can move forward to a larger effectiveness trial of the ASPIRE intervention. TRIAL REGISTRATION: The trial is registered with the Pan African Clinical Trials Registry (PACTR20200352214510). Registered 28 February 2020-retrospectively registered, https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=9795.

'I was trying to get there, but I couldn't': social norms, vulnerability and lived experiences of home delivery in Mashonaland Central Province, Zimbabwe.

Increasing facility-based delivery rates is pivotal to reach Sustainable Development Goals to improve skilled attendance at birth and reduce maternal and neonatal mortality in low- and middle-income countries (LMICs). The translation of global health initiatives into national policy and programmes has increased facility-based deliveries in LMICs, but little is known about the impact of such policies on social norms from the perspective of women who continue to deliver at home. This qualitative study explores the reasons for and experiences of home delivery among women living in rural Zimbabwe. We analysed qualitative data from 30 semi-structured interviews and 5 focus group discussions with women who had delivered at home in the previous 6 months in Mashonaland Central Province. We found evidence of strong community-level social norms in favour of facility-based delivery. However, despite their expressed intention to deliver at a facility, women described how multiple, interacting vulnerabilities resulted in delivery outside of a health facility. While identified as having delivered 'at home', narratives of birth experiences revealed the majority of women in our study delivered 'on the road', en route to the health facility. Strong norms for facility-based delivery created punishments and stigmatization for home delivery, which introduced additional risk to women at the time of delivery and in the postnatal period. These consequences for breaking social norms promoting facility-based delivery for all further increased the vulnerability of women who delivered at home or on the road. Our findings highlight that equitable public health policy and programme designs should include efforts to actively identify, mitigate and evaluate unintended consequences of social change created as a by-product of promoting positive health behaviours among those most vulnerable who are unable to comply.

A Palladium-palladium oxide miniature pH electrode.

A wire-form miniature palladium-palladium oxide electrode has been fabricated for pH measurement. The electrode exhibits a super-Nernstian behavior and gives a mean pH response of 71.4 millivolts per [pH] (standard deviation, 5.2 millivolts). Uncorrected zero current potential values can be used to determine the pH value of the medium to within 0.012 pH. The electrode should find applications in biological, medical, and clinical studies.

Energy scavenging sources for biomedical sensors.

Energy scavenging has increasingly become an interesting option for powering electronic devices because of the almost infinite lifetime and the non-dependence on fuels for energy generation. Moreover, the rise of wireless technologies promises new applications in medical monitoring systems, but these still face limitations due to battery lifetime and size. A trade-off of these two factors has typically governed the size, useful life and capabilities of an autonomous system. Energy generation from sources such as motion, light and temperature gradients has been established as commercially viable alternatives to batteries for human-powered flashlights, solar calculators, radio receivers and thermal-powered wristwatches, among others. Research on energy harvesting from human activities has also addressed the feasibility of powering wearable or implantable systems. Biomedical sensors can take advantage of human-based activities as the energy source for energy scavengers. This review describes the state of the art of energy scavenging technologies for powering sensors and instrumentation of physiological variables. After a short description of the human power and the energy generation limits, the different transduction mechanisms, recent developments and challenges faced are reviewed and discussed.

A point mutation in the glutamate binding site blocks desensitization of AMPA receptors.

Desensitization of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) receptors is thought to shape the synaptic response and act as a neuroprotective mechanism at central synapses, but the molecular mechanism underlying desensitization is poorly understood. We found that replacing the glutamate binding domain S1 of GluR3 (an AMPA receptor) with S1 of GluR6 (a kainate receptor) resulted in a fully active but completely nondesensitizing receptor. Smaller substitutions within S1 identified, besides two additional modulatory regions, a single exchange, L507Y, as is required and sufficient for the block of desensitization. This phenotype was specific for AMPA receptors and required an aromatic residue at this position. L507 lies between two residues (T504 and R509) that form part of the glutamate binding site. The physical proximity of these residues, which are involved in binding and gating, suggests they may form part of the link between these two events.

Posterior intra-vaginal slingplasty for the treatment of vaginal apex prolapse: Medium-term results of 140 operations with a novel procedure.

OBJECTIVES: Urogynecologists are constantly looking for simple, safe and effective ways to cure vaginal apex prolapse. A novel surgical technique, posterior intra-vaginal slingplasty (PIVS), was reported recently to include both a high therapeutic rate and a low complication rate. The present study was aimed at evaluating the preliminary data of a series of PIVS-treated patients. STUDY DESIGN: A total of 140 patients with vaginal apex prolapse underwent the PIVS operation in a daycare setting. Pre-operative demographics, operative details and post-operative follow-up data were prospectively collected for all patients. RESULTS: The PIVS procedure dose requires neither laparotomy nor deep transvaginal dissection as previously required for operative intervention. No intra-operative complications were recorded. The hospitalization period was relatively short. Three patients (2.1%) presented with surgical failure, whereas 137 (97.8%) of the operated patients reported satisfaction with the therapeutic results. One patient had post-operative unilateral gluteal skin infection. She was treated by surgical removal of the infected hemi-tape. Twelve (8.6%) patients had vaginal tape protrusion, of which 11 underwent segmental tape resection at the outpatient clinic. Two patients had spontaneous rejection of the tape while the vaginal apex remained well suspended. One patient suffered from post-operative fever of unknown origin, which was effectively treated with oral antibiotics. CONCLUSIONS: The novel PIVS operation reduces the complication rate and shortens the rehabilitation period previously reported for the types of operation designed in the past to cure vaginal apex prolapse. The current list of results supports the previously reported efficacy, safety and simplicity of this procedure. However, more long-term data are required to be able to draw solid conclusions concerning the superiority of the discussed operative technique.

Pyrrolizidine alkaloids enhance alcohol-induced hepatocytotoxicity in vitro in normal human hepatocytes.

OBJECTIVE: Herbal remedies containing pyrrilidozine alkaloids (PA)s can induce liver damage, including hepato-sinusoidal obstruction syndrome (HSOS) or veno-occlusive liver disease (VOD). Some individuals misusing alcohol consume also teas and/or herbal remedies containing PA. The interaction or additive toxicity of alcohol to PA toxicity needs to be addressed. The objectives of this study are 1) to review the scientific literature on the PA-induced liver toxicity; 2) identify possible mechanism(s) involved in PA-induced hepatocytotoxicity in the presence or absence of ethanol (EtOH) in vitro in normal human hepatocytes (NHH) in primary culture. To respond to the first objective, we systematically search all the literature engines (PubMed, Google Scholar) for liver induced damage due to PAs and summarize the results in an introductory systematic review. ORIGINAL ARTICLE EXPERIMENTAL DESIGN AND METHODS: Cells were exposed to one dose of 100 mmol/L EtOH for 24 hrs and to 2 doses of 100 mmol/L EtOH for consecutive 24 hrs periods, in the presence or absence of PAs (10 mg/mL), or the caspase-3 inhibitor IDN-1965 (50 µmol/L). Cells were analyzed for apoptosis by light microscopy, immuno-histochemistry, measuring cytokeratin-18 fragmentation, and transmission electron microscopy (TEM) (6000 cells/treatment). Cytotoxicity was determined using succinate dehydrogenase (SDH) activity, an enzyme specific to the mitochondria. RESULTS: In NHH cells, a 100 mmol/L dose of Et-OH resulted in 22±2.5 apoptosis (p<0.001 vs. control). Two consecutive doses of 100 mmol/L Et-OH for 24 hrs each caused 36±3.0% apoptosis (p<0.001 vs. control and p<0.05 vs. one dose Et-OH). Pre-treatment with 50 µmol/L caspase inhibitor significantly reduced Et-OH-induced apoptosis [12±1.5% in 100 mmol/L (p<0.05) and 20±4.0% in 2×100 mmol/L (p<0.001)]. In addition, pre-treatment with 50 µmol caspase inhibitor in cells treated with PA + EtOH reduced apoptosis significantly (vs. non-exposed to caspase-inhibitor): Δ -22±3.0 % (p<0.05). HPC significantly decreased apoptosis compared to conditions lacking this supplementation in cells treated with EtOH-exposed cells present ballooning, Mallory bodies, changes in mitochondrial cristae and apoptosis by TEM. Pre-treatment with 50 µmol caspase inhibitor significantly reduced 100 mmol/L EtOH-induced (one dose) in NHH by 14±0.5% (p<0.05) compared to cells not exposed to the caspase-inhibitor. In cells treated concomitantly with PA and EtOH 100 mM Mallory-bodies and apo-necrotic cells have been observed. Pre-treatment with 50 µmol caspase inhibitor reduced the mitochondrial damage. A significant depletion in glutathione (GSH) was observed in Et-OH treated cells after 1 and 2 treatments (p<0.001 vs. control). Treatment with Et-OH enhanced PA-induced GSH-depletion and resulted in a significant increase in PA-induced cytotoxicity (p<0.001 vs. Et-untreated cells). Exposure to EtOH increased the cell culture media levels of the pro-inflammatory cytokine TNF. PA + EtOH-treated cells increased TNF-α levels in media compared to EtOH alone [86±8 vs. 53±5 pg/mL in cells exposed to 100 mmol/L EtOH (p<0.05) and 218±14 vs. 179±8 pg/mL in cells exposed to 2×100 mmol/L EtOH (p<0.05)]. CONCLUSIONS: PA up-regulates EtOH-induced hepatocytotoxicity by inducing the inflammatory cytokines and enhancing the apoptotic effects of ethanol. There is a need for monitoring herbal medicine in order to optimize traditional medicine use and maximize the clinical benefits. Additionally, there is necessary to communicate to physicians the possible negative results of herbal remedies use. Also, the interactions between herbal remedies and drugs of misuse should be communicated to consumers.

Severe hepatocytotoxicity linked to denosumab.

OBJECTIVE: Denosumab (Prolia, Amgen, Thousand Oaks, CA, USA) is a fully human antibody to the receptor activator of nuclear factor-KB ligand (RANKL). We present a case of submassive hepatic necrosis with evidence implicating cytokine induction resulting from an immune reaction to denosumab. CASE REPORT: A 72-year-old lady presented with elevated liver enzymes. One month previously, she received a s/c administration of 60 mg of denosumab. Viral hepatitis A, B and C and human herpes viruses 6-7 were negative as were routine autoimmune serology. Transaminases reached more than 50 x ULN, and gamma-glutamyl-transpeptidase (GGT) increased to more than 30 x ULN. Serum bilirubin reached 13.8 mg/dL. The serum albumin level decreased to 2.8 g/L. Prednisone (40 mg) and ursodeoxycholic acid (900 mg) were administered. The Naranjo Adverse Drug Reaction probability score was 6, consistent with a probable adverse drug reaction. A liver biopsy revealed sub-massive hepatic necrosis consistent with drug-induced liver injury (DILI). During steroid tapering, there was a slow decline in the levels of both the transaminases and the GGT, and a concomitant increase in the serum albumin. A month after stopping prednisone and ursodeoxycholic acid, there was an acute increase in the level of the transaminases and a decrease in the serum albumin. Steroid reintroduction resulted in normalization of the liver enzymes and synthetic capacity. A lymphocyte toxicity assay to denosumab was demonstrated a hypersensitivity reaction to denosumab resulting in 31% toxicity. The control patient showed no toxicity to denosumab. Cytokine levels (pg/mL) were as follows: Interleukin (IL)1 was 1193 (normal-24.5), IL8 357 (20-60), RANKL 224 (60-80), RANTES 215 (15-50), TNF-a 850 (25-50), TGF-b 546 (20-40), VEGF 735 (25-30). Serum RANKL was markedly reduced in the presence of denosumab (16 pg/mL). The elevated markers of apoptosis ccK18(M-30)(68-132) 140 IU and K18 apoptosis+ necrosis (M65) (62-213) 322 U/L implicate necrosis. CONCLUSIONS: We suggest that RANKL inhibition can produce severe hepatic necrosis together with an increase in proinflammatory cytokines.

[A new minimally invasive procedure for the conservative treatment of uterine prolapse--the posterior IVS].

BACKGROUND: The risk of women who undergo surgery for the treatment of pelvic organ prolapse (POP) by the age of 80 is reported to exceed 10%, and is expected to rise with the increase in life expectancy. Most women affected are in their 5th or 6th decade, and the majority will suffer other medical problems. The current medical literature asserts that the vaginal surgical approach for POP operations are followed by less complications and provide a shorter rehabilitation period than the abdominal route. Hysterectomy is widely accepted as part of POP reconstructive surgery whenever the uterus is significantly prolapsed, however, there is no clear evidence to support the role of hysterectomy in improving surgery outcome. We present our experience with a new minimally invasive procedure - the posterior intravaginal slingplasty (IVS) for utero-suspension in the presence of moderate and advanced uterine prolapse. AIM: To evaluate the feasibility, intra- and post-operative complications and short term results of the posterior IVS procedure and uterosuspension for uterine prolapse. METHODS: Reconstructive surgery using the posterior IVS was performed on 18 women with moderate to severe uterine prolapse who chose to preserve their uterus. Patients were then followed 1,6,12 months and 2 years post-operatively to assess any recurrence of pelvic organ prolapse. RESULTS: No major intra- or post-operative complications were reported. Follow-up of one to 13 months showed good results. CONCLUSIONS: Reconstructive POP surgery may not necessitate hysterectomy. The posterior IVS is a novel safe, minimally invasive, simple and effective surgical procedure for the treatment of POP, permitting uterine preservation. A larger number of patients and a longer follow-up period are required for proper evaluation of the actual safety and efficacy of this procedure.

Site of action of proteinases in the activation of steroidogenesis in rat adrenal gland.

We have investigated the effect of the proteinase inhibitors 1,10-phenantroline (OP) and phenylmethylsulfonyl fluoride (PMSF) on steroidogenesis in rat adrenal cortex. Both PMSF and OP inhibited adrenocorticotropin (ACTH)- and 8-Br cAMP-induced stimulation of corticosterone synthesis. On the contrary, arachidonic acid-induced stimulation of corticosterone synthesis was only slightly inhibited by PMSF and unchanged by OP. Intra- and extracellular cAMP levels were determined by radioimmunoassay. While PMSF did not affect neither the intra- nor the extracellular cAMP levels, OP decreased the intra- and extracellular levels of unstimulated as well as ACTH-stimulated cells. The site of action of the proteinase inhibitors was also studied by recombination of mitochondria with the different subcellular fractions in vitro. Addition of PMSF abolished the stimulation achieved by in vitro activation of cytosol by cAMP and PKA. On the other hand, OP completely inhibited the activation of mitochondria. Our results provide evidence for the involvement of proteinases in ACTH-induced stimulation of steroidogenesis in adrenal cortex both prior to the release of arachidonic acid and at the level of cholesterol transport from the outer to the inner mitochondrial membrane.