An international, open-label, randomised trial comparing a two-step approach versus the standard three-step approach of the WHO analgesic ladder in patients with cancer.

BACKGROUND: Worldwide, cancer pain management follows the World Health Organization (WHO) three-step analgesic ladder. Using weak opioids (e.g. codeine) at step 2 is debatable with low-dose strong opioids being potentially better, particularly in low- and middle-income countries where weak opioids are expensive. We wanted to assess the efficiency, safety and cost of omitting step 2 of the WHO ladder. PATIENTS AND METHODS: We carried out an international, open-label, randomised (1 : 1) parallel group trial. Eligible patients had cancer, pain ≥4/10 on a 0-10 numerical rating scale, required at least step 1 (paracetamol) of the WHO ladder and were randomised to the control arm (weak opioid, step 2 of the WHO ladder) or the experimental arm (strong opioid, step 3). Primary outcome was time to stable pain control (3 consecutive days with pain ≤3). Secondary outcomes included distress, opioid-related side-effects and costs. The primary outcome analysis was by intention to treat and the follow-up was for 20 days. RESULTS: One hundred and fifty-three patients were randomised (76 control, 77 experimental). There was no statistically significant difference in time to stable pain control between the arms, P = 0.667 (log-rank test). The adjusted hazard ratio for the control arm was 1.03 (95% confidence interval 0.72-1.49). In the control arm, 38 patients (53%) needed to change to a strong opioid due to ineffective analgesia. The median time to change was day 6 (interquartile range 4-11). Compared to the control arm, patients in the experimental arm had less nausea (P = 0.009) and costs were less. CONCLUSION: This trial provides some evidence that the two-step approach is an alternative option for cancer pain management.

Efficacy and safety of a quadruple ultra-low-dose treatment for hypertension (QUARTET USA): Rationale and design for a randomized controlled trial.

BACKGROUND: Over half of patients with elevated blood pressure require multi-drug treatment to achieve blood pressure control. However, multi-drug treatment may lead to lower adherence and more adverse drug effects compared with monotherapy. OBJECTIVE: The Quadruple Ultra-low-dose Treatment for Hypertension (QUARTET) USA trial was designed to evaluate whether initiating treatment with ultra-low-dose quadruple-combination therapy will lower office blood pressure more effectively, and with fewer side effects, compared with initiating standard dose monotherapy in treatment naive patients with SBP < 180 and DBP < 110 mm Hg and patients on monotherapy with SBP < 160 and DBP < 100 mm Hg. METHODS/DESIGN: QUARTET USA was a prospective, randomized, double-blind trial (ClinicalTrials.gov NCT03640312) conducted in federally qualified health centers in a large city in the US. Patients were randomly assigned (1:1) to either ultra-low-dose quadruple combination therapy or standard dose monotherapy. The primary outcome was mean change from baseline in office systolic blood pressure at 12-weeks, adjusted for baseline values. Secondary outcomes included measures of blood pressure change and variability, medication adherence, and health related quality of life. Safety outcomes included occurrence of serious adverse events, relevant adverse drug effects, and electrolyte abnormalities. A process evaluation aimed to understand provider experiences of implementation and participant experiences around side effects, adherence, and trust with clinical care. DISCUSSION: QUARTET USA was designed to evaluate whether a novel approach to blood pressure control would lower office blood pressure more effectively, and with fewer side effects, compared with standard dose monotherapy. QUARTET USA was conducted within a network of federally qualified healthcare centers with the aim of generating information on the safety and efficacy of ultra-low-dose quadruple-combination therapy in diverse groups that experience a high burden of hypertension.

Caudal paramedian approach to cryptorchidectomy in 29 small ruminants (2011-2019).

OBJECTIVE: To describe a caudal paramedian approach to cryptorchidectomy in small ruminants. STUDY DESIGN: Retrospective case series. ANIMALS: Sheep (n = 20) and goats (n = 9) with cryptorchidism. METHODS: Medical records from January 2011 to July 2019 of small ruminants that underwent caudal paramedian cryptorchidectomy at our institution were retrospectively reviewed. Data from animal signalment, operative and postoperative complications, and client satisfaction were evaluated. RESULTS: Twenty sheep and nine goats underwent caudal paramedian cryptorchidectomy during the study period. The median age of rams was 2 months, and the median age of bucks was 3 months; median weights for rams and bucks were 20.5 kg (range, 14.5-41.3) and 28.1 kg (range, 12.9-82), respectively. Cryptorchidism was bilateral in 27.6% (8/29) of cases and unilateral in 72.4% (21/29). Among unilateral cases, 85.7% (18/21) were right sided and 14.3% (3/21) were left sided. Twenty-four of 29 (82.8%) cases were performed under sedation. One operative complication occurred in a 4-year-old 82 kg buck (rate, 3.4% [95% CI: 0.1%-17.2%]). Postoperatively, there were two minor and one major complications (rates, 6.9% [95% CI: 0.8%-22.1%] and 3.4% [95% CI: 0.1%-17.2%], respectively). Long-term follow-up (range, 8-117 months) reports described owner satisfaction and all animals doing well at the time of follow-up telephone call. CONCLUSION: Caudal paramedian approach to cryptorchidectomy was safely performed in small ruminants less than 4 months old. CLINICAL SIGNIFICANCE: Ease of surgical technique, minimal operative and postoperative complications, and owner satisfaction make this a suitable method for cryptorchidectomy.

Acute Kidney Injury in Cirrhosis: Baseline Serum Creatinine Predicts Patient Outcomes.

OBJECTIVES: The International Ascites Club (IAC) recently defined Stage 1 acute kidney injury (AKI) for cirrhosis as an acute increase in serum creatinine (SCr) by ≥0.3 mg/dl or by ≥50% in <48 h from a stable value within 3 months. The baseline SCr may influence AKI risk and patient outcomes. The objective of this study is to determine in cirrhosis whether the baseline SCr has any effect on the in-hospital AKI course and patient survival. METHODS: North American Consortium for the Study of End-Stage Liver Disease is a consortium of tertiary-care hepatology centers prospectively enroling non-elective cirrhotic inpatients. Patients with different baseline SCr levels (≤0.5, 0.51-1.0, 1.01-1.5, >1.5 mg/dl) were evaluated for the development of AKI, and compared for AKI outcomes and 30-day survival. RESULTS: 653 hospitalized cirrhotics (56.7±10years, 64% men, 30% with infection) were included. The incidence of AKI was 47% of enrolled patients. Patients with higher baseline SCr were more likely to develop AKI, with significantly higher delta and peak SCr (P<0.001) than the other groups, more likely to have a progressive AKI course (P<0.0001), associated with a significantly reduced 30-day survival (P<0.0001). Multivariate logistic regression showed that the delta SCr during an AKI episode to be the strongest factor impacting AKI outcomes and survival (P<0.001), with a delta SCr of 0.70 mg/dl having a 68% sensitivity and 80% specificity for predicting 30-day mortality. CONCLUSIONS: Admitted cirrhotic patients with higher baseline SCr are at higher risk for in-hospital development of AKI, and more likely to have AKI progression with reduced survival. Therefore, such patients should be closely monitored and treated promptly for their AKI.

Hepatitis C virus in Mexican Americans: a population-based study reveals relatively high prevalence and negative association with diabetes.

This study aimed to estimate the prevalence and risk factors for hepatitis C virus (HCV) infection in Mexican Americans living in South Texas. We tested plasma for the presence of HCV antibody from the Cameron County Hispanic Cohort (CCHC), a randomized, population-based cohort in an economically disadvantaged Mexican American community on the United States/Mexico border with high rates of chronic disease. A weighted prevalence of HCV antibody of 2·3% [n = 1131, 95% confidence interval (CI) 1·2-3·4] was found. Participants with diabetes had low rates of HCV antibody (0·4%, 95% CI 0·0-0·9) and logistic regression revealed a statistically significant negative association between HCV and diabetes (OR 0·20, 95% CI 0·05-0·77) after adjusting for sociodemographic and clinical factors. This conflicts with reported positive associations of diabetes and HCV infection. No classic risk factors were identified, but important differences between genders emerged in analysis. This population-based study of HCV in Mexican Americans suggests that national studies do not adequately describe the epidemiology of HCV in this border community and that unique risk factors may be involved.

Cancer treatment-related neuropathic pain: proof of concept study with menthol--a TRPM8 agonist.

PURPOSE: Effective treatment of neuropathic pain without unacceptable side effects is challenging. Cancer sufferers increasingly live with long-term treatment-related neuropathic pain, resulting from chemotherapy-induced peripheral neuropathy (CIPN) or surgical scars. This proof-of-concept study aimed to determine whether preclinical evidence for TRPM8 ion channels in sensory neurons as a novel analgesic target could be translated to clinical benefit in patients with neuropathic pain, using the TRPM8 activator menthol. PATIENTS AND METHODS: Patients with problematic treatment-related neuropathic pain underwent a baseline assessment using validated questionnaires, psychophysical testing, and objective functional measures. The painful area was treated with topical 1 % menthol cream twice daily. Assessments were repeated at 4-6 weeks. The primary outcome was the change in Brief Pain Inventory total scores at 4-6 weeks. Secondary outcomes included changes in function, mood and skin sensation. RESULTS: Fifty-one patients (female/male, 32/19) were recruited with a median age of 61 (ranging from 20 to 89). The commonest aetiology was CIPN (35/51), followed by scar pain (10/51). Thirty-eight were evaluable on the primary outcome. Eighty-two per cent (31/38) had an improvement in total Brief Pain Inventory scores (median, 47 (interquartile range, 30 to 64) to 34 (6 to 59), P < 0.001). Improvements in mood (P = 0.0004), catastrophising (P = 0.001), walking ability (P = 0.008) and sensation (P < 0.01) were also observed. CONCLUSION: This proof-of-concept study indicates that topical menthol has potential as a novel analgesic therapy for cancer treatment-related neuropathic pain. Improvements in patient-rated measures are supported by changes in objective measures of physical function and sensation. Further systematic evaluation of efficacy is required.

The prevalence of cardiovascular risk factors in obese children.

Childhood Obesity poses a public health problem in Ireland. Complications associated include metabolic disease and cardiovascular disease risk. Our aim was to determine the prevalence of cardiovascular risk factors in a cohort of obese Irish children. Assessments were performed on obese children attending weight management clinic. Pedometers and self report physical activity questionnaires were administered to each participant to determine physical activity levels. Fifty-nine children (21 prepubertal and 38 pubertal/post-pubertal) were metabolically profiled. Mean ± SD of z scores for BMI, Waist Circumference and Body Fat % were +3.29 ± 0.48, +3.98 ± 0.73 and +2.75 ± 0.50 respectively. 43% (n = 9) prepubertal and 68% (n = 26) pubertal/postpubertal children had at least one other cardiovascular risk factor in addition to obesity. Increased moderate-vigorous physical activity levels correlated with reduced incidence of cardiovascular risk factors. There is a significant prevalence of cardiovascular risk factors among obese pre-pubertal children and pubertal/post-pubertal adolescents attending an Irish obesity clinic.

MELD exceptions for portopulmonary hypertension: current policy and future implementation.

Since 2006, waitlist candidates with portopulmonary hypertension (POPH) have been eligible for standardized Model for End-Stage Liver Disease (MELD) exception points. However, there are no data evaluating the current POPH exception policy and its implementation. We used Organ Procurement and Transplantation Network (OPTN) data to compare outcomes of patients with approved POPH MELD exceptions from 2006 to 2012 to all nonexception waitlist candidates during this period. Since 2006, 155 waitlist candidates had approved POPH MELD exceptions, with only 73 (47.1%) meeting the formal OPTN exception criteria. Furthermore, over one-third of those with approved POPH exceptions either did not fulfill hemodynamic criteria consistent with POPH or had missing data, with 80% of such patients receiving a transplant based on receiving exception points. In multivariable multistate survival models, waitlist candidates with POPH MELD exceptions had an increased risk of death compared to nonexception waitlist candidates, regardless of whether they did (hazard ratio [HR]: 2.46, 95% confidence interval [CI]: 1.73-3.52; n = 100) or did not (HR: 1.60, 95% CI: 1.04-2.47; n = 55) have hemodynamic criteria consistent with POPH. These data highlight the need for OPTN/UNOS to reconsider not only the policy for POPH MELD exceptions, but also the process by which such points are awarded.

Pain related to cancer treatments and diagnostic procedures: a no man's land?

BACKGROUND: While guidelines are available for the management of cancer-related pain, little attention is given to the assessment and treatment of pain caused by treatments and diagnostic procedures in cancer patients. METHODS: We evaluated the literature on pain related to cancer treatment and diagnostic procedures within a critical analysis. RESULTS: The data available are sparse, suggesting that little attention has been directed at this important aspect of oncology. This points to potentially suboptimal patient management. CONCLUSIONS: Appropriate studies are necessary in order to understand the incidence and appropriate management of pain, both during and/or after oncological treatments and diagnostic procedures. At the same time, Health Care Professionals should have heightened awareness of the causes and treatment of pain with the aim of anticipating and managing pain most appropriately for each individual patient. This is clearly an important component of holistic patient care before, during, and after oncological treatment.

Phase I/II trial of formoterol fumarate combined with megestrol acetate in cachectic patients with advanced malignancy.

PURPOSE: The aim of this study was to test the safety, tolerability and efficacy of a novel combination of an anabolic ß2-agonist and an appetite stimulant in patients with cancer cachexia. METHODS: Thirteen patients (M/F 5:8) with advanced malignancy and involuntary weight loss received oral formoterol (80 µg/day) and megestrol acetate (480 mg/day) for up to 8 weeks. Quadriceps size (MRI), quadriceps and hand-grip strength, lower limb extensor power, physical activity and quality of life were measured at baseline and at 8 weeks. Response criteria were specified pre-trial, with a major response defined as an increase in muscle size ≥ 4 % or function ≥ 10 %. RESULTS: Six patients withdrew before 8 weeks, reflecting the frail, comorbid population. In contrast, six out of seven (86 %) patients completing the course achieved a major response for muscle size and/or function. In the six responders, mean quadriceps volume increased significantly (left 0.99 vs. 1.05 L, p=0.012; right 1.02 vs. 1.06 L, p=0.004). There was a trend towards an increase in quadriceps and handgrip strength (p>0.05). The lack of appetite symptom score declined markedly (76.2 vs. 23.8; p=0.005), indicating improvement. Adverse reactions were few, the commonest being tremor (eight reports), peripheral oedema (three), tachycardia (two) and dyspepsia (two). CONCLUSIONS: In this frail cohort with advanced cancer cachexia, an 8-week course of megestrol and formoterol in combination was safe and well tolerated. Muscle mass and/or function were improved to a clinically significant extent in most patients completing the course. This combination regimen warrants further investigation in larger, randomized trials.

Plasma-activated liquid as a potential decontaminant in healthcare: assessment of antibacterial activity and use with cleaning cloths.

BACKGROUND: Cold air plasma (CAP) can generate plasma-activated liquids (PALs) with high concentrations of reactive oxygen (ROS) and nitrogen species (RNS), e.g., nitrites, with antimicrobial properties. AIM: We investigated the concentrations of ROS and RNS in saline PAL. We assessed planktonic bacterial inactivation by PAL and the decontamination of contaminated cleaning cloths. METHODS: Phosphate-buffered saline (PBS) was treated with an air-driven CAP jet for 90 or 300 s to generate PAL. The ROS and RNS were measured using quantitative fluorescent (2,7-dichlorofluorescin diacetate) and colourimetric (Greiss) assays. Isolates of MRSA and Escherichia coli were incubated in PAL overnight and inactivation measured through colony forming unit (cfu) assays. Sections of cleaning cloths were incubated with MRSA and E. coli, and treated with PAL for 1 h. Bacterial inactivation was measured through resazurin reduction assays. RESULTS: Nitrites increased from 0.1 µM in untreated PBS to 49.1 µM and to 94.0 µM in 90- and 300-s CAP-treated PAL, respectively. ROS increased from 30 µM in untreated PBS to 75 µM and to 103 µM in 90- and 300-s CAP-treated PAL, respectively. 90-s PAL reduced MRSA and E. coli viability (P<0.05) and 300-s PAL resulted in more than a 7-log reduction of both. One-hour treatment of contaminated cleaning cloths in PAL resulted in a 55% and 73% reduction in viable MRSA and E. coli, respectively (P<0.05). CONCLUSION: Inactivation of planktonic bacteria correlated with ROS and RNS concentrations. PAL reduced bacteria contaminated cleaning cloths. PAL has potential as a hospital disinfectant, including cleaning cloths.

Using dynamic biomaterials to study the temporal role of bioactive peptides during osteogenesis.

The extracellular matrix is a highly dynamic environment, and the precise temporal presentation of biochemical signals is critical for regulating cell behavior during development, healing, and disease progression. To mimic this behavior, we developed a modular DNA-based hydrogel platform to enable independent and reversible control over the immobilization of multiple biomolecules during in vitro cell culture. We combined reversible DNA handles with a norbornene-modified hyaluronic acid hydrogel to orthogonally add and remove multiple biomolecule-DNA conjugates at user-defined timepoints. We demonstrated that the persistent presentation of the cell adhesion peptide RGD was required to maintain cell spreading on hyaluronic acid hydrogels. Further, we discovered the delayed presentation of osteogenic growth peptide (OGP) increased alkaline phosphatase activity compared to other temporal variations. This finding is critically important when considering the design of OGP delivery approaches for bone repair. More broadly, this platform provides a unique approach to tease apart the temporal role of multiple biomolecules during development, regeneration, and disease progression.

Process Evaluation of a Double-Blind Randomized Controlled Trial to Assess the Efficacy and Safety of a Quadruple Ultra-Low-Dose Treatment for Hypertension Within a Federally Qualified Health Center Network (QUARTET USA).

BACKGROUND: This convergent parallel-design mixed-methods process evaluation of the QUARTET USA (Quadruple Ultra-Low-Dose Treatment for Hypertension USA) clinical trial (NCT03640312) explores patient and health care professional perceptions about the use of low-dose quadruple therapy (LDQT) as a novel strategy for hypertension management. METHODS AND RESULTS: A survey of all 62 patients enrolled in the QUARTET USA trial was conducted. A subsample of 13 patients and 11 health care professionals, recruited via purposive sampling, took part in semistructured interviews. At enrollment, 68% of participants (mean [SD] age, 51.7 [11.5] years; 56% self-identified as Hispanic: Mexican ethnicity, 16% as Hispanic: other ethnicity, 16% as Black race, 8% as White race, and 1.6% as South Asian race) reported that their current health depended on blood pressure medications, and 48% were concerned about blood pressure medications. At trial completion, 80% were satisfied with LDQT, 96% were certain the benefits of taking LDQT outweighed the disadvantages, and 96% reported that LDQT was convenient to take. Both patients and health care professionals found LDQT acceptable because it reduced patients' perceived pill burden and facilitated medication adherence. Health care professionals stated that a perceived limitation of LDQT was the inability to titrate doses. Steps to facilitate LDQT implementation include introducing stepped-care combinations and treatment protocols, inclusion in clinical practice guidelines, and eliminating patient cost barriers. CONCLUSIONS: LDQT was an acceptable strategy for hypertension treatment among patients and health care professionals involved in the QUARTET USA clinical trial. Although LDQT was generally perceived as beneficial for maintaining patients' blood pressure control and facilitating adherence, some clinicians perceived limitations in titration inflexibility, adverse effects, and costs. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03640312.

Efficacy and safety of a four-drug, quarter-dose treatment for hypertension: the QUARTET USA randomized trial.

New approaches are needed to lower blood pressure (BP) given persistently low control rates. QUARTET USA sought to evaluate the effect of four-drug, quarter-dose BP lowering combination in patients with hypertension. QUARTET USA was a randomized (1:1), double-blinded trial conducted in federally qualified health centers among adults with hypertension. Participants received either a quadpill of candesartan 2 mg, amlodipine 1.25 mg, indapamide 0.625 mg, and bisoprolol 2.5 mg or candesartan 8 mg for 12 weeks. If BP was >130/>80 mm Hg at 6 weeks in either arm, then participants received open label add-on amlodipine 5 mg. The primary outcome was mean change in systolic blood pressure (SBP) at 12 weeks, controlling for baseline BP. Secondary outcomes included mean change in diastolic blood pressure (DBP), and safety included serious adverse events, relevant adverse drug effects, and electrolyte abnormalities. Among 62 participants randomized between August 2019-May 2022 (n = 32 intervention, n = 30 control), mean (SD) age was 52 (11.5) years, 45% were female, 73% identified as Hispanic, and 18% identified as Black. Baseline mean (SD) SBP was 138.1 (11.2) mmHg, and baseline mean (SD) DBP was 84.3 (10.5) mmHg. In a modified intention-to-treat analysis, there was no significant difference in SBP (-4.8 mm Hg [95% CI: -10.8, 1.3, p = 0.123] and a -4.9 mmHg (95% CI: -8.6, -1.3, p = 0.009) greater mean DBP change in the intervention arm compared with the control arm at 12 weeks. Adverse events did not differ significantly between arms. The quadpill had a similar SBP and greater DBP lowering effect compared with candesartan 8 mg. Trial registration number: NCT03640312.

Persisting role of healthcare settings in hepatitis C transmission in Pakistan: cause for concern.

Transmission of hepatitis C (HCV) in Pakistan is a continuing public health problem; 15 years ago it was linked to the practice of reusing therapeutic instruments in healthcare settings. We sought to examine current risk factors for HCV transmission in a hospital population in Karachi, Pakistan. We enrolled 300 laboratory-confirmed HCV-positive participants and 300 laboratory confirmed HCV-negative participants from clinics at Indus Hospital. Independent and significant risk factors for both men and women were: receiving o12 injections in the past year, blood transfusions, having had dental work performed, and delivery in hospital or transfusion for women. Interestingly, being of Mohajir origin or born in Sindh province were protective.Encouragingly, a strong protective effect was observed for those that reported bringing their own needle for injections (59%). The widespread reuse of therapeutic needles in healthcare settings in Karachi remains a major driver of the HCV epidemic.

Neuropathic pain in cancer.

Cancer-related neuropathic pain is common; it can be disease related or related to the acute or chronic effects of cancer treatment. For example, chemotherapy-induced peripheral neuropathy occurs in 90% of patients receiving neurotoxic chemotherapy. Cancer treatments have become more effective; patients are living longer with cancer and there are more cancer survivors. However, side-effects (particularly neuropathy) have become more problematic. The key to management of cancer-related neuropathy is a considered assessment, remembering not to miss the opportunity of reversing the cause of the pain with appropriate oncological management. An increasing range of oncological therapies are available, including radiotherapy, chemotherapy, hormonal therapy, or one of the evolving approaches (e.g. immune therapies). Patients are often elderly and with comorbidities; therefore, all treatment decisions have to be made carefully and reviewed appropriately. Cancer pain is often of mixed aetiology or, if purely neuropathic, may be one of several pains experienced by a patient. For these reasons, opioids are used more frequently in patients with cancer-related neuropathic pain. Standard guidelines for the use of anticonvulsants (e.g. pregabalin and gabapentin), antidepressants (e.g. duloxetine and tricyclics), and topical treatments (e.g. capsaicin and lidocaine) may be applicable, but there is a lack of good-quality clinical trials in cancer-related neuropathic pain. Choice is dictated not just by age, drug interactions, and comorbidities, but also by the coexistence of many symptoms in patients with cancer. Treating more than one symptom with a particular neuropathic pain agent can avoid polypharmacy.

Anti-neutrophil cytoplasmic antibody associated vasculitis of the brain and oral cavity: a case report.

We report a patient with a novel presentation of anti-neutrophil cytoplasmic antibody positive (ANCA+) vasculitis of the brain and oral mucosa. ANCA+ vasculitis of the brain is usually associated with pachymeningitis and hypophysitis, and there are no cases reported with simultaneous brain and oral mucosal involvement. A 35-year-old African Zambian man presented with headache and bleeding swollen gingiva. He was myeloperoxidase (MPO) antibody positive with cytoplasmic staining. His MRI showed stable small callosal, periventricular and subcortical white matter non-enhancing lesions, without change over 15 months-compatible with vasculitis. His gingival biopsy was consistent with vasculitis. His headache and oral lesions responded to oral corticosteroids and intravenous immunoglobulin which have induced clinical remission. Our patient expands the clinical syndrome of ANCA+ MPO+ C-type vasculitis of the central nervous system with headaches complicating cerebral vasculitis and oral mucosal involvement.