A Repurposing Programme Evaluating Transdermal Oestradiol Patches for the Treatment of Prostate Cancer Within the PATCH and STAMPEDE Trials: Current Results and Adapting Trial Design.

AIMS: Androgen deprivation therapy (ADT), usually achieved with luteinising hormone releasing hormone analogues (LHRHa), is central to prostate cancer management. LHRHa reduce both testosterone and oestrogen and are associated with significant long-term toxicity. Previous use of oral oestrogens as ADT was curtailed because of cardiovascular toxicity. Transdermal oestrogen (tE2) patches are a potential alternative ADT, supressing testosterone without the associated oestrogen-depletion toxicities (osteoporosis, hot flushes, metabolic abnormalities) and avoiding cardiovascular toxicity, and we here describe their evaluation in men with prostate cancer. MATERIALS AND METHODS: The PATCH (NCT00303784) adaptive trials programme (incorporating recruitment through the STAMPEDE [NCT00268476] platform) is evaluating the safety and efficacy of tE2 patches as ADT for men with prostate cancer. An initial randomised (LHRHa versus tE2) phase II study (n = 251) with cardiovascular toxicity as the primary outcome measure has expanded into a phase III evaluation. Those with locally advanced (M0) or metastatic (M1) prostate cancer are eligible. To reflect changes in both management and prognosis, the PATCH programme is now evaluating these cohorts separately. RESULTS: Recruitment is complete, with 1362 and 1128 in the M0 and M1 cohorts, respectively. Rates of androgen suppression with tE2 were equivalent to LHRHa, with improved metabolic parameters, quality of life and bone health indices (mean absolute change in lumbar spine bone mineral density of -3.0% for LHRHa and +7.9% for tE2 with an estimated difference between arms of 9.3% (95% confidence interval 5.3-13.4). Importantly, rates of cardiovascular events were not significantly different between the two arms and the time to first cardiovascular event did not differ between treatment groups (hazard ratio 1.11, 95% confidence interval 0.80-1.53; P = 0.54). Oncological outcomes are awaited. FUTURE: Efficacy results for the M0 cohort (primary outcome measure metastases-free survival) are expected in the final quarter of 2023. For M1 patients (primary outcome measure - overall survival), analysis using restricted mean survival time is being explored. Allied translational work on longitudinal samples is underway.

Appreciating the links between heart failure and depression.

Depression and heart failure frequently occur together, symptoms overlap and the prognosis is worsened. Both conditions share biopsychosocial risk factors and are accompanied by behavioural/lifestyle, neurohormonal, inflammatory and autonomic changes that are implicated aetiologically. Depression has been conceptualized as a decompensated response to allostatic overload, wherein adaptive psychological, behavioural and physiological responses to chronic and/or severe stress, become unsustainable. Heart failure can similarly be viewed as a decompensated response to circulatory overload, wherein adaptive functional (neurohormonal effects on circulation, inotropic effects on heart) and structural (myocardial remodelling) changes, become unsustainable. It has been argued that the disengaged state of depression can initially be protective, limiting an individual's exposure to external challenges, such that full recovery is often possible. In contrast, heart failure, once past a tipping-point, can progress relentlessly. Here, we consider the bidirectional interactions between depression and heart failure. Targeted treatment of depression in the context of heart failure may improve quality of life, yet overall benefits on mortality remain elusive. However, effective treatment of heart failure typically enhances function and improves key psychological and behavioural determinants of low mood. Prospectively, research that examines the mechanistic associations between depression and heart failure offers fresh opportunity to optimize personalized management in the advent of newer interventions for both conditions.

Stability and Cooling of the C_{7}

We have studied the stability of the smallest long-lived all carbon molecular dianion (C_{7}^{2-}) in new time domains and with a single ion at a time using a cryogenic electrostatic ion-beam storage ring. We observe spontaneous electron emission from internally excited dianions on millisecond timescales and monitor the survival of single colder C_{7}^{2-} molecules on much longer timescales. We find that their intrinsic lifetime exceeds several minutes-6 orders of magnitude longer than established from earlier experiments on C_{7}^{2-}. This is consistent with our calculations of vertical electron detachment energies predicting one inherently stable isomer and one isomer which is stable or effectively stable behind a large Coulomb barrier for C_{7}^{2-}→C_{7}^{-}+e^{-} separation.

Impact of direct-acting antiviral treatment of hepatitis C on the quality of life of adults in Ukraine.

BACKGROUND: Direct-acting antivirals (DAAs) are highly effective in achieving sustained virologic response among those with chronic hepatitis C virus (HCV) infection. Quality of life (QOL) benefits for an HCV-infected population with high numbers of people who inject drugs and people living with HIV (PLHIV) in Eastern Europe have not been explored. We estimated such benefits for Ukraine. METHODS: Using data from a demonstration study of 12-week DAA conducted in Kyiv, we compared self-reported QOL as captured with the MOS-SF20 at study entry and 12 weeks after treatment completion (week 24). We calculated domain scores for health perception, physical, role and social functioning, mental health and pain to at entry and week 24, stratified by HIV status. RESULTS: Among the 857 patients included in the final analysis, health perception was the domain that showed the largest change, with an improvement of 85.7% between entry and week 24. The improvement was larger among those who were HIV negative (104.4%) than among those living with HIV (69.9%). Other domains that showed significant and meaningful improvements were physical functioning, which improved from 80.5 (95% CI 78.9-82.1) at study entry to 89.4 (88.1-90.7) at 24 weeks, role functioning (64.5 [62.3-66.8] to 86.5 [84.9-88.2]), social functioning (74.2 [72.1-76.2] to 84.8 [83.2-86.5]) and bodily pain (70.1 [68.2-72.0] to 89.8 [88.5-91.1]). Across all domains, QOL improvements among PLHIV were more modest than among HIV-negative participants. CONCLUSION: QOL improved substantially across all domains between study entry and week 24. Changes over the study period were smaller among PLHIV.

Mogamulizumab efficacy is underscored by its associated rash that mimics cutaneous T-cell lymphoma: a retrospective single-centre case series.

BACKGROUND: Mogamulizumab is a humanized antibody against chemokine receptor type 4. It was recently approved by the US Food and Drug Administration for relapsed or refractory mycosis fungoides (MF) and Sézary syndrome (SS). The most commonly reported adverse event in the phase III licensing trial was drug eruption (28%), now termed mogamulizumab-associated rash (MAR). Clinical recommendations about MAR and its treatment differ between the current package insert and postapproval insights reported from two single-centre studies that focused on its characterization, but less so on outcomes and clinicopathological differentiation from cutaneous T-cell lymphoma (CTCL). OBJECTIVES: To describe our experience in the diagnosis of MAR and treatment of patients with CTCL with mogamulizumab. METHODS: This is a single-centre retrospective case series study. RESULTS: We found a higher incidence of MAR in patients with CTCL (17 of 24, 68%) than previously reported. MAR development is associated with complete (11 of 17) or partial (four of 17) responses, with an overall response rate of 88%, compared with 29% (two of seven) in patients without MAR. Diagnosis of MAR may be obscured by its ability to mimic key CTCL features both clinically and histologically, but an absence of T-cell-receptor clonality and relatively decreased CD4 : CD8 ratio compared with baseline lesions strongly favour MAR over recurrent disease. CONCLUSIONS: MAR has the potential to create a significant management problem for patients on mogamulizumab. Misidentification of MAR as recurrent CTCL may detrimentally result in the premature discontinuation of mogamulizumab in patients whose disease is historically hard to treat. Thorough clinicopathological investigation of new lesions during treatment with mogamulizumab is required to inform ideal treatment decisions and achieve better outcomes.

Mycosis fungoides-derived exosomes promote cell motility and are enriched with microRNA-155 and microRNA-1246, and their plasma-cell-free expression may serve as a potential biomarker for disease burden.

BACKGROUND: Literature regarding exosomes as mediators in intercellular communication to promote progression in mycosis fungoides (MF) is lacking. OBJECTIVES: To characterize MF-derived exosomes and their involvement in the disease. METHODS: Exosomes were isolated by ultracentrifugation from cutaneous T-cell lymphoma (CTCL) cell lines, and from plasma of patients with MF and controls (healthy individuals). Exosomes were confirmed by electron microscopy, NanoSight and CD81 staining. Cell-line exosomes were profiled for microRNA array. Exosomal microRNA (exomiRNA) expression and uptake, and plasma-cell-free microRNA (cfmiRNA) were analysed by reverse-transcriptase quantitative polymerase chain reaction. Exosome uptake was monitored by fluorescent labelling and CD81 immunostaining. Migration was analysed by transwell migration assay. RESULTS: MyLa- and MJ-derived exosomes had a distinctive microRNA signature with abundant microRNA (miR)-155 and miR-1246. Both microRNAs were delivered into target cells, but only exomiR-155 was tested, demonstrating a migratory effect on target cells. Plasma levels of cfmiR-1246 were significantly highest in combined plaque/tumour MF, followed by patch MF, and were lowest in controls (plaque/tumour > patch > healthy), while cfmiR-155 was upregulated only in plaque/tumour MF vs. controls. Specifically, exomiR-1246 (and not exomiR-155) was higher in plasma of plaque/tumour MF than in healthy controls. Plasma exosomes from MF but not from controls increased cell migration. CONCLUSIONS: Our findings show that MF-derived exosomes promote cell motility and are enriched with miR-155, a well-known microRNA in MF, and miR-1246, not previously reported in MF. Based on their plasma expression we suggest that they may serve as potential biomarkers for tumour burden.

Total extra peritoneal inguinal hernia repair: a single-surgeon preliminary findings report.

INTRODUCTION: Inguinal hernia repair is one of the most frequent operations in general surgery. Various techniques have been used to repair inguinal hernias since the first reconstructive technique described by Bassini in 1887. In 1989 Lichtenstein reported a new technique: tension free inguinal hernia repair. Laparoscopic inguinal hernia repair was introduced in the early 1990s, and soon also became popular. Literature has shown the benefits of laparoscopy (in comparison with open repair) to be mostly related to the more minimally invasive nature of the surgery, having lower wound infection rates, faster recovery, and less postoperative pain. AIM: To evaluate our totally extraperitoneal (TEP) inguinal hernia repair initial results and compare them to literature data. MATERIALS AND METHODS: In a prospective review and analysis, we examined 61 cases of hernia repair via laparoscopy (specifically TEP), performed by a single surgeon, between April 2019 and December 2019 at the Kaspela University Hospital in Plovdiv. The centre's Institutional Review Board approved the study with no specific consents required due to the retrospective, minimal risk nature of the study. The routine informed consent required by the National Insurance Fund has been considered sufficient for the study objectives.The surgical outcome measures included operating time (hours/minutes), conversion, peritoneal injury, surgical emphysema; and the clinical outcome measures included postoperative seroma, post-operative infection, and post-operative chronic groin pain. RESULTS: Inguinal pain on discharge was characterized as mild by 56 (96.55%) patients and moderate by 2 (3.44%), there were no patients describing the pain as severe. The most frequently reported postoperative complications were annoyance and discomfort (10.34%), swelling (6.9%), seroma (3.44), hematoma (1.72%), paresthesia 1.72% (1); however, only those with seromas required special treatment. CONCLUSIONS: Limitations of the present study include the relatively small number of patients, all cases were operated on by a single surgeon and short postoperative follow-up period, but we are sharing our initial six months results. These results demonstrate that laparoscopic TEP inguinal hernia repair without mesh fixation is a reliable technique, which can reduce postoperative morbidity when applied by experienced surgeons.

Spontaneous Electron Emission from Hot Silver Dimer Anions: Breakdown of the Born-Oppenheimer Approximation.

We report the first experimental evidence of spontaneous electron emission from a homonuclear dimer anion through direct measurements of Ag_{2}^{-}→Ag_{2}+e^{-} decays on milliseconds and seconds timescales. This observation is very surprising as there is no avoided crossing between adiabatic energy curves to mediate such a process. The process is weak, yet dominates the decay signal after 100 ms when ensembles of internally hot Ag_{2}^{-} ions are stored in the cryogenic ion-beam storage ring, DESIREE, for 10 s. The electron emission process is associated with an instantaneous, very large reduction of the vibrational energy of the dimer system. This represents a dramatic deviation from a Born-Oppenheimer description of dimer dynamics.

Managing multidrug-resistant tuberculosis in South Africa: a budget impact analysis.

SETTING: In South Africa prior to 2016, the standard treatment regimen for multidrug- and rifampicin-resistant tuberculosis (MDR/RR-TB) was 24 months long and required daily injectable aminoglycoside (IA) treatment during the first 6 months. Recent evidence supports the replacement of IA with well-tolerated oral bedaquiline (BDQ) and a shortened 9-12 month regimen.DESIGN: Using a Markov model, we analyzed the 5-year budgetary impact and cost per successful treatment outcome of four regimens: 1) IA long-course, 2) oral long-course, 3) IA short-course, and 4) oral short-course. We used the South African MDR/RR-TB case register (2013-2015) to assess treatment outcomes for the then-standard IA long-course. Data on the improvement in outcomes for BDQ-based regimens were based on the literature. Costs were estimated from the provider perspective using costs incurred to provide decentralized treatment for MDR-TB at a Johannesburg hospital.RESULTS: Based on our analysis, by 2023, the cost/successful outcome for the four regimens was respectively 1) US$7374, 2) US$7860, 3) US$5149, and 4) US$4922. The annual total cost of each regimen was US$37 million, US$43 million, US$26 million, and US$28 million.CONCLUSION: Despite the high cost of BDQ, a BDQ-based shortened regimen for the treatment of MDR/RR-TB will result in improved treatment outcomes and cost savings for South Africa.

Comparison of preoperative versus postoperative transversus abdominis plane and rectus sheath block in patients undergoing minimally invasive colorectal surgery.

AIM: Ultrasound-guided transversus abdominis plane and rectus sheath block (TAPRSB) decreases pain scores and narcotic use postoperatively after colorectal surgery (CRS). It is unclear if the effectiveness of TAPRSB varies according to whether it is performed preoperatively or postoperatively. Our aim was to investigate this. METHOD: We compared patients who underwent preoperative TAPRSB or postoperative TAPRSB during minimally invasive CRS. Primary end-points were pain scores and oral morphine milligram equivalent (MME) use postoperatively. Secondary end-points included perioperative factors affecting pain scores and postoperative MME. Summary statistics and univariate analysis by nonparametric tests were utilized. The mixed-effect model was applied to model the repeatedly measured pain score. RESULTS: From April 2015 until May 2018 168 patients received TAPRSB before (115) or after (53) minimally invasive CRS. The cohort included 79 (47.0%) women, and had an average age of 59.11 (±12.32) years and mean body mass index of 28.32 (±5.82) kg/m2 . Indication for surgery was cancer in 66 (39.3%), polyp in 43 (25.6%) and diverticulitis in 43 (25.6%). Right colectomy was performed in 61 (36.3%), low anterior resection in 46 (27.4%) and sigmoid colectomy in 40 (23.8%) patients. The demographics of the groups were similar. Postoperative TAPRSB was only associated with lower pain scores at 12 h postoperatively. As secondary outcomes, average pain scores and MME were lower in patients who were older, had right colectomy or intracorporeal anastomosis. CONCLUSIONS: Postoperative TAPRSB resulted in lower pain scores than preoperative TAPRSB 12 h after minimally invasive CRS, but otherwise no differences were seen in pain scores or MME use.

Can routine inpatient mortality data improve HIV mortality estimates? Inpatient mortality at an urban hospital in South Africa.

BACKGROUND: South Africa (SA) has one of the world's largest HIV treatment programmes, to which a dramatic increase in life expectancy has been attributed. However, there continue to be concerns regarding the reporting of HIV-related mortality in SA, which varies by source. As accurate HIV mortality estimates are key to measuring the success of the national programme as well as identifying areas for improvement, we propose a complementary approach to monitoring changes in HIV-related mortality using routine inpatient records to examine trends in causes of death and HIV status over time. OBJECTIVES: To investigate the feasibility of this approach by calculating mortality due to natural causes in the medical ward of a hospital during 2010 by HIV status. METHODS: We conducted a cross-sectional study of inpatient mortality at a regional hospital in Johannesburg, SA, analysing all deaths due to natural causes among adult medical ward inpatients. Cause of death was recorded from the mortuary register. HIV status was ascertained directly from the mortuary register or from laboratory tests specific for HIV diagnosis or monitoring. RESULTS: Of 1 167 inpatients who died, the majority were HIV-positive (58%). HIV positivity among males (55%) was slightly lower than that among females (61%), and HIV-positive patients were younger (median 40 years) than those who were HIV-negative (56 years) and of unknown HIV status (68 years). 'Infections and parasites' was the most common cause of natural death (29%). On average, HIV-positive patients were admitted for slightly longer (mean 10.5 days) than HIV-negative patients (9.6 days) and those of unknown HIV status (8.9 days), yet HIV-positive inpatient deaths accounted for the majority (62%) of the total bed days. CONCLUSIONS: Even with widespread access to antiretroviral therapy, the majority of inpatient natural deaths at a large public sector hospital in 2010 were of HIV-positive patients and were probably related to HIV. In view of the importance of accurate data on causes of death, both for the HIV programme and to track other diseases, large-scale expansion of this approach over a longer period should be considered.

Improved simplified clinical algorithm for identifying patients eligible for immediate initiation of antiretroviral therapy for HIV (SLATE II): protocol for a randomized evaluation.

BACKGROUND: The World Health Organization recommends rapid (≤ 7 days) or same-day initiation of antiretroviral treatment (ART) for HIV-positive patients. South Africa adopted this recommendation in 2017, but multiple clinic visits, long waiting times, and delays for laboratory tests remain common. Streamlined approaches to same-day initiation that allow the majority of patients to start ART immediately, while ensuring that patients who do require additional services receive them, are needed to achieve national and international treatment program goals. METHODS/DESIGN: The SLATE II (Simplified Algorithm for Treatment Eligibility) study is an individually randomized evaluation of a clinical algorithm to reliably determine a patient's eligibility for immediate ART initiation without waiting for laboratory results or additional clinic visits. It differs from the earlier SLATE I study in management of patients with symptoms of tuberculosis (under SLATE II these patients may be started on ART immediately) and other criteria for immediate initiation. SLATE II will randomize (1:1) 600 adult, HIV-positive patients who present for HIV testing or care and are not yet on ART in South Africa. Patients randomized to the standard arm will receive standard-of-care ART initiation from clinic staff. Patients randomized to the intervention arm will be administered a symptom report, medical history, brief physical exam, and readiness assessment. Symptomatic patients will also have a tuberculosis (TB) module with lipoarabinomannan antigen of mycobacteria test. Patients who have satisfactory results for all four components will be dispensed antiretrovirals (ARVs) immediately, at the same clinic visit. Patients who have any negative results will be referred for further investigation, care, counseling, tests, or other services prior to being dispensed ARVs. Follow-up will be by passive medical record review. The primary outcomes will be ART initiation in  ≤ 7 days and retention in care 8 months after study enrollment. DISCUSSION: SLATE II improves upon the SLATE I study by reducing the number of reasons for delaying ART initiation and allowing more patients with TB symptoms to start ART on the day of diagnosis. If successful, SLATE II will provide a simple and streamlined approach that can readily be adopted in other settings without investment in additional technology. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03315013 . Registered on 19 October 2017.

Early Targeting of L-Selectin on Leukocytes Promotes Recovery after Spinal Cord Injury, Implicating Novel Mechanisms of Pathogenesis.

L-selectin, a lectin-like receptor on all leukocyte classes, functions in adhesive and signaling roles in the recruitment of myeloid cells from the blood to sites of inflammation. Here, we consider L-selectin as a determinant of neurological recovery in a murine model of spinal cord injury (SCI). Spinal cord-injured, L-selectin knock-out (KO) mice (male) showed improved long-term recovery with greater white matter sparing relative to wild-type (WT) mice and reduced oxidative stress in the injured cord at 72 h post-SCI. There was a partial and transient reduction in accumulation of neutrophils in the injured spinal cords of KOs at 24 h post-injury. To complement these findings with KO mice, we sought a pharmacologic means for lowering L-selectin levels. We found that diclofenac, a nonsteroidal anti-inflammatory drug (NSAID), induced the shedding of L-selectin from the cell surface of myeloid subsets, specifically neutrophils and non-classical monocytes, in the blood and the injured spinal cord. Diclofenac administration to injured WT mice enhanced neurological recovery to a level comparable to that of KOs but did not improve recovery in KOs. While diclofenac treatment had no effect on myeloid cell accumulation, there was a reduction in oxidative stress at 72 h post-SCI. These findings implicate L-selectin in secondary pathogenesis beyond a role in leukocyte recruitment and raise the possibility of repurposing diclofenac for the treatment of SCI.

Erratum: Rotationally Cold OH

This corrects the article DOI: 10.1103/PhysRevLett.119.073001.

The costs and outcomes of paediatric tuberculosis treatment at primary healthcare clinics in Johannesburg, South Africa.

BACKGROUND: Little up-to-date information is available about the costs of providing drug-susceptible tuberculosis (DS-TB) treatment to paediatric patients in South Africa (SA), nor have actual costs incurred at clinics been compared with costs expected from guidelines. OBJECTIVES: To estimate actual and guideline treatment costs by means of a retrospective cohort analysis. METHODS: We report patient characteristics, outcomes and treatment costs from a retrospective cohort of paediatric and adolescent (<18 years) DS-TB patients registered for treatment from 1 April 2011 to 31 March 2013 at three primary healthcare clinics in Johannesburg, SA. Actual treatment costs in 2015 SA rands and US dollars were estimated from the provider perspective using a standard bottom-up microcosting approach and compared with an estimate of guideline costs. RESULTS: We enrolled 88 DS-TB patients (median age 4 years (interquartile range 1.0 - 9.5), 44.3% female, 22.7% HIV co-infected, 92.0% pulmonary TB). Treatment success was high (89.8%; 13.6% cured, 76.1% completed treatment), and the mean (standard deviation (SD)) cost per patient with treatment success was ZAR1 820/USD143 (ZAR593/USD46), comprising fixed costs (44.0%), outpatient visits (30.7%), medication (19.3%) and laboratory investigations (6.0%). This was 17% more than the mean (SD) cost estimated by applying treatment guidelines (ZAR1 553/USD122 (ZAR1 620/USD127)), with differences due mainly to higher laboratory costs and more outpatient visits taking place than were recommended in national guidelines. CONCLUSIONS: These results are the first reported estimates of paediatric DS-TB treatment costs in SA and show the potential cost savings of closer adherence to national treatment guidelines. The findings were robust in sensitivity analyses and are lower than previous cost estimates in adults.

Dianion diagnostics in DESIREE: High-sensitivity detection of Cn2- from a sputter ion source.

A sputter ion source with a solid graphite target has been used to produce dianions with a focus on carbon cluster dianions, Cn2-, with n = 7-24. Singly and doubly charged anions from the source were accelerated together to kinetic energies of 10 keV per atomic unit of charge and injected into one of the cryogenic (13 K) ion-beam storage rings of the Double ElectroStatic Ion Ring Experiment facility at Stockholm University. Spontaneous decay of internally hot Cn2- dianions injected into the ring yielded Cn- anions with kinetic energies of 20 keV, which were counted with a microchannel plate detector. Mass spectra produced by scanning the magnetic field of a 90° analyzing magnet on the ion injection line reflect the production of internally hot C72- - C242- dianions with lifetimes in the range of tens of microseconds to milliseconds. In spite of the high sensitivity of this method, no conclusive evidence of C62- was found while there was a clear C72- signal with the expected isotopic distribution. This is consistent with earlier experimental studies and with theoretical predictions. An upper limit is deduced for a C62- signal that is two orders-of-magnitude smaller than that for C72-. In addition, CnO2- and CnCu2- dianions were detected.

Autologous stem-cell transplantation after second-line brentuximab vedotin in relapsed or refractory Hodgkin lymphoma.

Background: We previously demonstrated that brentuximab vedotin (BV) used as second-line therapy in patients with Hodgkin lymphoma is a tolerable and effective bridge to autologous hematopoietic cell transplantation (AHCT). Here, we report the post-AHCT outcomes of patients treated with second-line standard/fixed-dose BV and an additional cohort of patients where positron-emission tomography adapted dose-escalation of second-line BV was utilized. Patients and methods: Patients on the dose-escalation cohort received 1.8 mg/kg of BV intravenously every 3 weeks for two cycles. Patients in complete remission (CR) after two cycles received two additional cycles of BV at 1.8 mg/kg, while patients with stable disease or partial response were escalated to 2.4 mg/kg for two cycles. All patients, regardless of treatment cohort, proceeded directly to AHCT or received additional pre-AHCT therapy at the discretion of the treating physician based on remission status after second-line BV. Results: Of the 20 patients enrolled to the BV dose-escalation cohort, 8 patients underwent BV dose-escalation. BV escalation was well-tolerated, but no patients who were escalated converted to CR. Of 56 evaluable patients treated across cohorts, the overall response rate (ORR) to second-line BV was 75% with 43% CR. Twenty-eight (50%) patients proceeded directly to AHCT without post-BV chemotherapy, and a total of 50 patients proceeded to AHCT. Thirteen patients received consolidative post-AHCT therapy with either radiation, BV, or a PD-1 inhibitor. After AHCT, the 2-year progression-free survival (PFS) and overall survival were 67% and 93%, respectively. The 2-year PFS among patients in CR at the time of AHCT (n = 37) was 71% compared with 54% in patients not in CR (p = 0.12). The 2-year PFS in patients who proceeded to AHCT directly after receiving BV alone was 77%. Conclusions: Second-line BV is an effective bridge to AHCT that produces responses of sufficient depth to provide durable remission in conjunction with AHCT (clinicaltrials.gov: NCT01393717).

Can routine inpatient mortality data improve HIV mortality estimates? Inpatient mortality at an urban hospital in South Africa

Background. South Africa (SA) has one of the world's largest HIV treatment programmes, to which a dramatic increase in life expectancy has been attributed. However, there continue to be concerns regarding the reporting of HIV-related mortality in SA, which varies by source. As accurate HIV mortality estimates are key to measuring the success of the national programme as well as identifying areas for improvement, we propose a complementary approach to monitoring changes in HIV-related mortality using routine inpatient records to examine trends in causes of death and HIV status over time.Objectives. To investigate the feasibility of this approach by calculating mortality due to natural causes in the medical ward of a hospital during 2010 by HIV status.Methods. We conducted a cross-sectional study of inpatient mortality at a regional hospital in Johannesburg, SA, analysing all deaths due to natural causes among adult medical ward inpatients. Cause of death was recorded from the mortuary register. HIV status was ascertained directly from the mortuary register or from laboratory tests specific for HIV diagnosis or monitoring.Results. Of 1 167 inpatients who died, the majority were HIV-positive (58%). HIV positivity among males (55%) was slightly lower than that among females (61%), and HIV-positive patients were younger (median 40 years) than those who were HIV-negative (56 years) and of unknown HIV status (68 years). 'Infections and parasites' was the most common cause of natural death (29%). On average, HIV-positive patients were admitted for slightly longer (mean 10.5 days) than HIV-negative patients (9.6 days) and those of unknown HIV status (8.9 days), yet HIV-positive inpatient deaths accounted for the majority (62%) of the total bed days.Conclusions. Even with widespread access to antiretroviral therapy, the majority of inpatient natural deaths at a large public sector hospital in 2010 were of HIV-positive patients and were probably related to HIV. In view of the importance of accurate data on causes of death, both for the HIV programme and to track other diseases, large-scale expansion of this approach over a longer period should be considered

Long-term Stability of a Compounded Suspension of Torsemide (5 mg/mL) for Oral Administration.

BACKGROUND: Torsemide use for congestive heart failure (CHF) has been reported, but prescription frequency is unknown. Commercially available tablet sizes in North America limit dosing precision, indicating a need to evaluate its strength and stability in suspension. OBJECTIVES: To determine the frequency of torsemide prescriptions and to determine a beyond use date (BUD) of a compounded suspension of torsemide for oral administration stored under 2 temperature conditions for 90 days. ANIMALS: No animals used. METHODS: Pharmacy records were retrospectively reviewed for torsemide and furosemide prescriptions from 2008 to 2015 at 2 veterinary referral centers. After preliminary strength testing, compounded torsemide suspension (5 mg/mL) for oral administration was prepared using torsemide tablets suspended in OraPlus:OraSweet 1:1, buffered to a pH of 8.3 and stored at refrigeration (2-8°C) and room temperature (20-25°C) in 2 oz amber plastic bottles. Samples were analyzed by reverse phase high-performance liquid chromatography (RP-HPLC) on days 0, 14, 30, 60, and 90. RESULTS: Prescriptions for torsemide increased from 2008 to 2015. Analysis of the torsemide 5 mg/mL suspension for oral administration at each time point met United States Pharmacopeia (USP) requirements for torsemide content of 90-110% of label claim. The average strength at 90 days decreased to 92 ± 3% at 2-8°C and 95 ± 2% at 20-25°C. Stability testing did not detect unknown impurities. CONCLUSIONS: Increasing torsemide use warrants availability of a validated and stable compounded formulation. Our results support the assignment of a 90-day BUD for torsemide 5 mg/mL suspension for oral administration compounded in OraPlus:Sweet 1:1 buffered to a pH of 8.3.