Using value of information methods to determine the optimal sample size for effectiveness trials of alcohol interventions for HIV-infected patients in East Africa.

BACKGROUND: Unhealthy alcohol consumption exacerbates the HIV epidemic in East Africa. Potential benefits of new trials that test the effectiveness of alcohol interventions could not be evaluated by traditional sampling methods. Given the competition for health care resources in East Africa, this study aims to determine the optimal sample size given the opportunity cost of potentially re-allocating trial funds towards cost-effective alcohol treatments. METHODS: We used value of information methods to determine the optimal sample size by maximizing the expected net benefit of sampling for a hypothetical 2-arm intervention vs. control randomized trial, across ranges of policymaker's willingness-to-pay for the health benefit of an intervention. Probability distributions describing the relative likelihood of alternative trial results were imputed based on prior studies. In the base case, policymaker's willingness-to-pay was based on a simultaneously resource-constrained priority (routine HIV virological testing). Sensitivity analysis was performed for various willingness-to-pay thresholds and intervention durations. RESULTS: A new effectiveness trial accounting for the benefit of more precise decision-making on alcohol intervention implementation would benefit East Africa $67,000 with the optimal sample size of 100 persons per arm under the base case willingness-to-pay threshold and intervention duration of 20 years. At both a conservative willingness-to-pay of 1 x GDP/capita and a high willingness-to-pay of 3 x GDP/capita for an additional health gain added by an alcohol intervention, a new trial was not recommended due to limited decision uncertainty. When intervention duration was 10 or 5 years, there was no return on investment across suggested willingness-to-pay thresholds. CONCLUSIONS: Value of information methods could be used as an alternative approach to assist the efficient design of alcohol trials. If reducing unhealthy alcohol use is a long-term goal for HIV programs in East Africa, additional new trials with optimal sample sizes ranging from 100 to 250 persons per arm could save the opportunity cost of implementing less cost-effective alcohol strategies in HIV prevention. Otherwise, conducting a new trial is not recommended.

Targeting an alcohol intervention cost-effectively to persons living with HIV/AIDS in East Africa.

BACKGROUND: In the current report, we ask if targeting a cognitive behavioral therapy (CBT)-based intervention aimed at reducing hazardous alcohol consumption to HIV-infected persons in East Africa would have a favorable value at costs that are feasible for scale-up. METHODS: Using a computer simulation to inform HIV prevention decisions in East Africa, we compared 4 different strategies for targeting a CBT intervention-(i) all HIV-infected persons attending clinic; (ii) only those patients in the pre-antiretroviral therapy (ART) stages of care; (iii) only those patients receiving ART; and (iv) only those patients with detectable viral loads (VLs) regardless of disease stage. We define targeting as screening for hazardous alcohol consumption (e.g., using the Alcohol Use Disorders Identification Test and offering the CBT intervention to those who screen positive). We compared these targeting strategies to a null strategy (no intervention) or a hypothetical scenario where an alcohol intervention was delivered to all adults regardless of HIV status. RESULTS: An intervention targeted to HIV-infected patients could prevent 18,000 new infections, add 46,000 quality-adjusted life years (QALYs), and yield an incremental cost-effectiveness ratio of $600/QALY compared to the null scenario. Narrowing the prioritized population to only HIV-infected patients in pre-ART phases of care results in 15,000 infections averted, the addition of 21,000 QALYs and would be cost-saving, while prioritizing based on an unsuppressed HIV-1 VL test results in 8,300 new infections averted, adds 6,000 additional QALYs, and would be cost-saving as well. CONCLUSIONS: Our results suggest that targeting a cognitive-based treatment aimed at reducing hazardous alcohol consumption to subgroups of HIV-infected patients provides favorable value in comparison with other beneficial strategies for HIV prevention and control in this region. It may even be cost-saving under certain circumstances.

Impact and Cost-Effectiveness of Hypothetical Strategies to Enhance Retention in Care within HIV Treatment Programs in East Africa.

OBJECTIVES: Attrition from care among HIV infected patients can lead to poor clinical outcomes. Our objective was to evaluate hypothetical interventions seeking to improve retention-in-care (RIC) for HIV-infected patients in East Africa, asking whether they could offer favorable value compared to earlier ART initiation. METHODS: We used a micro-simulation model to analyze two RIC focused strategies within an East African HIV treatment program--"risk reduction," defined as intervention(s) that decrease the risk of attrition from care; and "outreach," defined as interventions that find patients and relink them with care. We compared this to earlier ART treatment as a measure of the potential health benefits forgone (e.g., opportunity cost). RESULTS: Reducing attrition by 40% at an average cost of $10 per person remains a less efficient use of resources compared to ensuring full access to ART (cost- effectiveness ratio $1300 vs $3700) for ART eligible patients. An outreach intervention had limited clinical benefit in our simulation. If intervention costs are <$10 per person, however, an intervention able to achieve a 40% (or greater) reduction in attrition may be a cost-effective next implementation option following implementation of earlier ART treatment. CONCLUSIONS: Our results suggest that programs should consider retention focused programs once they have already achieved high degrees of ART coverage among eligible patients. It is important that decision makers understand the epidemiology and associated outcomes of those patients who are classified as lost to follow up in their systems prior to implementation in order to achieve the highest value.

Impact of interventions targeting unhealthy alcohol use in Kenya on HIV transmission and AIDS-related deaths.

BACKGROUND: HIV remains a major cause of preventable morbidity and mortality in Kenya. The effects of behaviors that accompany unhealthy alcohol consumption are a pervasive risk factor for HIV transmission and progression. Our objective was to estimate the portion of HIV infections attributable to unhealthy alcohol use and to evaluate the impact of hypothetical interventions directed at unhealthy alcohol use on HIV infections and deaths. METHODS: We estimated outcomes over a time horizon of 20 years using a computer simulation of the Kenyan population. This computer simulation integrates a compartmental model of HIV transmission with a mechanistic model of HIV progression that was previously validated in sub-Saharan Africa. Integration of the transmission and progression models allows simultaneous consideration of alcohol's effects on HIV transmission and progression (e.g., lowering antiretroviral adherence may increase transmission risk by elevating viral load, and may simultaneously increase progression by increasing the likelihood of AIDS). The simulation considers important aspects of heterogeneous sexual mixing patterns, including assortativeness of partners by age and activity level, age-discordant relationships, and high activity subgroups. Outcomes included number of new HIV infections, number of AIDS deaths, and infectivity (number of new infections per infected person per year). RESULTS: Our model estimated that the effects of behaviors accompanying unhealthy alcohol consumption are responsible for 13.0% of new HIV infections in Kenya. An alcohol intervention with effectiveness similar to that observed in a published randomized controlled trial of a cognitive-behavioral therapy-based intervention in Kenya (45% reduction in unhealthy alcohol consumption) could prevent nearly half of these infections, reducing their number by 69,858 and reducing AIDS deaths by 17,824 over 20 years. Estimates were sensitive to assumptions with respect to the magnitude of alcohol's underlying effects on condom use, antiretroviral therapy adherence, and sexually transmitted infection prevalence. CONCLUSIONS: A substantial number of new HIV infections in Kenya are attributable to unhealthy alcohol use. An alcohol intervention with the effectiveness observed in a published randomized controlled trial has the potential to reduce infections over 20 years by nearly 5% and avert nearly 18,000 deaths related to HIV.

Impact of rapid blood culture identification PCR panel on optimal antibiotic use in methicillin-susceptible Staphylococcus aureus bacteremia.

Rapid identification of methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia may optimize antibiotic use and clinical outcomes. The study objective was to assess the impact of the BioFire® blood culture identification (BCID) polymerase chain reaction (PCR) panel on antibiotic use and clinical outcomes in patients with MSSA bacteremia. This was a retrospective chart review of adult inpatients with MSSA bacteremia during the pre-PCR (June 2018-December 2019) and post-PCR (June 2020-December 2021) implementation periods. The primary endpoint was the difference between the pre-PCR and post-PCR groups in time to optimal MSSA antibiotic therapy (oxacillin or cefazolin). Secondary endpoints included duration of anti-MRSA antibiotic use, in-hospital mortality, hospital and ICU lengths of stay, duration of bacteremia, and 30-day MSSA-related and all-cause readmissions. Two hundred patients were included in the study (100 per group). Median time to optimal therapy was reduced by 19.9 hours in the post-PCR group (49 vs 29.1 hours, respectively, P < 0.001). PCR implementation was associated with significant reductions in the initiation of empiric anti-MRSA antibiotic therapy (98% vs 84%, P = 0.001), duration of empiric anti-MRSA antibiotic use (44.2 vs 20.9 hours, P < 0.001), and duration of bacteremia (68.6 vs 47.3 hours, P = 0.015). No significant differences in length of stay, in-hospital mortality, or 30-day MSSA-related or all-cause readmissions were observed. In patients with MSSA bacteremia, BCID PCR panel implementation decreased time to optimal MSSA antibiotic therapy, duration of bacteremia, and duration of empiric anti-MRSA antibiotic therapy. IMPORTANCE: In this retrospective study of 200 patients with methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia, the implementation of the BioFire® blood culture identification polymerase chain reaction (PCR) panel was associated with a decreased time to optimal MSSA antibiotic therapy and shorter durations of empiric anti-MRSA antibiotic therapy and bacteremia. The findings demonstrate the significant role of rapid PCR testing and routine stewardship review in optimizing antimicrobial therapy and management of MSSA bacteremia.

Impact of BioFire® Blood Culture Identification (BCID) panels on antibiotic management of bacteremia due to select organisms.

The purpose of this study was to assess changes in time to optimal therapy (TTOT) for bacteremia due to select organisms after implementation of the BioFire® FilmArray® blood culture identification panels at two community teaching hospitals. TTOT (days) was similar in Pre-BCID compared to BCID1 and BCID2 [(2.48 vs. 2.65, p=0.10); (2.48 vs. 2.37, p=0.27)]. There were no significant differences in time to effective antimicrobial therapy between groups. However, there were significantly more therapy changes and appropriate carbapenem use within 24 hours of the Gram stain result for gram-negative organisms in the BCID2 arm compared to the Pre-BCID arm. Additionally, a significant reduction in the duration of vancomycin for gram-positive organisms was noted in the BCID2 arm compared to the Pre-BCID arm. These findings suggest that the incorporation of the BCID2 panel resulted in changes in prescribing practices, leading to more appropriate antimicrobial utilization in a subset of patients.

Growth patterns in pubertal HIV-infected adolescents and their correlation with cytokines, IGF-1, IGFBP-1, and IGFBP-3.

OBJECTIVE: This study aims to describe the final adult height (FAH) and pubertal growth patterns in human immunodeficiency virus (HIV)-infected adolescents and to compare these to an age-matched population of seroreverting HIV-exposed, uninfected (HEU) adolescents. It further aims to evaluate the interplay of proinflammatory cytokines with insulin-like growth factor 1 (IGF-1), insulin-like growth factor binding protein 3 (IGFBP-3), and IGFBP-1 during the pubertal growth spurt. METHODS: HIV-infected (n=34) and HEU (n=12) adolescents who had achieved FAH were evaluated. Auxologic data, viral load, CD4+ T-lymphocyte (CD4) count, and the use of highly active antiretroviral therapy were obtained via a retrospective chart review. Serum interleukin (IL)-1α, IL-6, tumor necrosis factor (TNF)-α, IGFBP-1, IGFBP-3, and IGF-1 were assessed. RESULTS: The mean FAH standard deviation score for the HIV-infected group was -0.78 (±1.1) compared to 0.05 (±0.78) for the HEU (p=0.034). There was a positive correlation between CD4 count and FAH (p=0.019). The mean age and magnitude of peak growth velocity (GV) was within normal limits. IL-1α, IL-6, TNF-α, IGFBP-3, and IGF-1 were not significantly correlated with HIV RNA or height. IGFBP-1 was detectable in 100% of poorly controlled HIV-infected patients and 25% of the HEU cohort (p=0.0003). CONCLUSIONS: The FAH of HIV-infected patients was significantly shorter than that of HEU patients, and it positively correlated with CD4 count. Our cohort demonstrated normal timing and magnitude of peak GV during puberty.

Diagnosis of GATA2 Deficiency in a Young Woman with Hemophagocytic Lymphohistiocytosis Triggered by Acute Systemic Cytomegalovirus Infection.

BACKGROUND Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disease characterized by an intense immunologic response that results in multiorgan dysfunction. It typically manifests as a result of a familial genetic immunodeficiency disorder or secondary to a trigger such as an infection, malignancy, or autoimmune disease. The major factors involved in the development of the disease are an individual's genetic propensity to develop HLH, such as rare associated mutations, or inflammatory processes that trigger the immune system to go haywire. CASE REPORT Before the COVID-19 pandemic, a 22-year-old woman with a history of congenital absence of the right kidney, right-sided hearing loss, and leukopenia presented with a 3-week history of generalized malaise, fever, chest pain, cough, and shortness of breath. She developed an acute systemic cytomegalovirus infection further complicated by HLH. Based on her history and clinical course, an underlying primary immunodeficiency was suspected. An immunodeficiency gene panel revealed a monoallelic mutation in GATA2, a gene that encodes zinc-transcription factors responsible for the regulation of hematopoiesis. CONCLUSIONS GATA2 deficiency encompasses a large variety of mutations in the GATA2 gene and leads to disorders associated with hematologic and immunologic manifestations of monocytopenia and B-, and natural killer-cell deficiency. Over time, affected individuals are at high risk of developing life-threatening infections and serious hematologic complications, such as myelodysplastic syndromes and/or leukemias. We aimed to illustrate the importance of identifying an underlying genetic disorder associated with secondary HLH to help guide acute and long-term management.

Analysis of the Effect of the Size and Grade of Soft Tissue Sarcoma on Rates of Unplanned Resection, Metastatic Disease, Mortality, and Morbid Re-Resection Over 20 Years.

Soft tissue sarcomas are rare malignancies that are often presumed to be benign and are resected without the typical preoperative workup, such as imaging or biopsy. These unplanned resections occur in approximately 30% of all cases and frequently require further morbid treatments, resulting in worse oncologic outcomes. A retrospective review was performed of all patients who presented to a tertiary sarcoma center with a diagnosis of sarcoma between 1996 and 2017. In-depth chart reviews were performed for the 2600 patients who were identified, with 836 having a primary diagnosis of soft tissue sarcoma in an upper or lower extremity. Data collected included histologic features, grade, size, resection status, demographic features, referral information, metastatic disease, morbid procedures, and mortality rate. Patients were divided into 2 groups based on whether the tumor size was greater or less than 5 cm. This classification was in keeping with the guideline of referring patients to a tertiary sarcoma center for workup for tumors "larger than a golf ball." The difference in the rate of unplanned resection for tumors measuring less than 5 cm (41.6%) and those measuring 5 cm or greater (18.8%) was statistically significant (P<.001), with smaller tumors more likely to undergo unplanned resection, in keeping with the success of the "golf ball rule." The rate of metastatic disease for unplanned resection for tumors measuring 5 cm or greater (50.7%) was significantly greater than that for tumors measuring less than 5 cm (19.7%) (P<.001). The authors found a great deal of morbidity associated with unplanned resection, regardless of tumor size. Before resection is planned, delineation is required beyond tumor size. [Orthopedics. 2021;44(3):166-171.].

'What I Wish My Surgeon Knew': A Novel Approach to Promote Empathic Curiosity in Surgery.

OBJECTIVE: Physician empathy is associated with a variety of superior patient and physician outcomes. Teaching physicians to practice empathic curiosity is challenging however, and relatively few efficient and effective methods have been proposed toward this end. The goal of this study was to evaluate the impact and feasibility of a novel approach to foster empathic curiosity during surgical training. DESIGN: We used an exploratory qualitative approach for our study. Postoperative patients at a single hospital were invited to participate in brief semistructured interviews to better understand their unmet needs. The interview began with the question, "What do you wish your surgeon knew about you?" We audio recorded and transcribed each patient interview. We then iteratively read the transcripts, applied an inductive approach to coding, and used qualitative content analysis to identify themes. SETTING: Veterans Affairs Ann Arbor Healthcare System, an academic-affiliated tertiary care facility. PARTICIPANTS: Patients who underwent general surgery procedures (n = 23) between July and August 2017. RESULTS: Of those who provided demographic information (n = 21), all were male and 95% were white with a mean age of 63.9 (34-77) years. Of these, 33% (n = 7) of patients experienced a postoperative complication. Patients described 3 broad categories of unmet need in the perioperative setting including: (i) being treated holistically and with dignity; (ii) using clear communication and delineating provider roles; and (iii) setting specific and realistic expectations. CONCLUSIONS: Promoting the use of empathically curious questions, such as "What do you wish your surgeon knew about you?" may help surgical trainees to identify unmet needs that are crucial for optimizing surgical care.

Predominance of Spinal Metastases Involving the Posterior Vertebral Body.

BACKGROUND: Spinal metastases pose significant morbidity. For many histologies, the spine is a frequent site for bone metastases. This predilection is not fully understood, and there are conflicting reports regarding the distribution within the vertebral body itself. Knowing this distribution will give clues as to the underlying biologic reason for this increased incidence in the spine and lead to a better understanding of tumor dispersion and growth. METHODS: We retrospectively examined magnetic resonance imaging scans of patients undergoing radiation to the spine from 2015 to 2017 for spinal metastases. The anatomical distribution of lesions was categorized. Lesions were sorted along the sagittal plane into 5 groups: anterior only, anterior + middle, middle only, posterior + middle, and posterior only. Lesions that covered all groups were discarded. χ2 and post-hoc analyses were used for statistical analyses. RESULTS: Three hundred metastatic lesions were examined in 89 patients; 203 lesions were used for analysis. Sixty-five percent of all lesions were found in posterior only and posterior + middle aspects of the vertebral body (P < 0.0001). This localization was significant regardless of histology: lung (67%, P < 0.0001), kidney (66%, P < 0.0001), sarcoma (67%, P < 0.0001), prostate (63%, P = 0.01), and breast (63%, P = 0.01). This was consistent across thoracic (n = 96) and lumbar (n = 63) regions (72% and 64%, respectively, P < 0.0001). CONCLUSIONS: Metastatic lesions of the thoracolumbar spine have a greater propensity to localize to the posterior aspect of the vertebral body. These data support the hypothesis that there may be differences within the vertebral body leading to differential tumor dispersion and growth.

Economic evaluation of mobile phone text message interventions to improve adherence to HIV therapy in Kenya.

BACKGROUND: A surge in mobile phone availability has fueled low cost short messaging service (SMS) adherence interventions. Multiple systematic reviews have concluded that some SMS-based interventions are effective at improving antiretroviral therapy (ART) adherence, and they are hypothesized to improve retention in care. The objective of this study was to evaluate the cost-effectiveness of SMS-based adherence interventions and explore the added value of retention benefits. METHODS: We evaluated the cost-effectiveness of weekly SMS interventions compared to standard care among HIV+ individuals initiating ART for the first time in Kenya. We used an individual level micro-simulation model populated with data from two SMS-intervention trials, an East-African HIV+ cohort and published literature. We estimated average quality adjusted life years (QALY) and lifetime HIV-related costs from a healthcare perspective. We explored a wide range of scenarios and assumptions in one-way and multivariate sensitivity analyses. RESULTS: We found that SMS-based adherence interventions were cost-effective by WHO standards, with an incremental cost-effectiveness ratio (ICER) of $1,037/QALY. In the secondary analysis, potential retention benefits improved the cost-effectiveness of SMS intervention (ICER = $864/QALY). In multivariate sensitivity analyses, the interventions remained cost-effective in most analyses, but the ICER was highly sensitive to intervention costs, effectiveness and average cohort CD4 count at ART initiation. SMS interventions remained cost-effective in a test and treat scenario where individuals were assumed to initiate ART upon HIV detection. CONCLUSIONS: Effective SMS interventions would likely increase the efficiency of ART programs by improving HIV treatment outcomes at relatively low costs, and they could facilitate achievement of the UNAIDS goal of 90% viral suppression among those on ART by 2020.

Persistent dilemmas in zoster eye disease.

Herpes zoster ophthalmicus (HZO) is a common, vision and potentially life-threatening disease caused by the reactivation of the varicella-zoster virus (VZV) in the distribution of the first division of cranial nerve V. Although the rate of herpes zoster increases with age, over half of the people with zoster in general, including HZO, are under age 60. In addition, over 90% of people with zoster are immunocompetent, even though the disease is more common and severe in immunocompromised patients. The incidence of zoster is increasing worldwide for unknown reasons. The epidemiology has not yet been impacted by the zoster vaccine (ZV). The lack of a strong recommendation by physicians for this vaccine is a major barrier to its use. An unresolved dilemma regards the optimum timing for this vaccine. In the USA, the current recommendation by the Centers for Disease Control and Prevention (CDC) is for eligible people age 60 and older, despite its greater efficacy in reducing the incidence of disease and Food and Drug Administration (FDA) approval for age 50-59. Although there is a consensus regarding use of acute high-dose oral antiviral treatment to reduce ocular complications, there is limited evidence for prolonged treatment. The rationale for a proposed randomised controlled trial (RCT) of suppressive antiviral treatment to reduce chronic eye disease and postherpetic neuralgia (PHN) includes evidence that zoster is followed by chronic active VZV infection and similarities between HZO and herpes simplex virus (HSV) eye infection, where this treatment is effective and is the standard of care.

Peripheral Sensory Neurons Expressing Melanopsin Respond to Light.

The ability of light to cause pain is paradoxical. The retina detects light but is devoid of nociceptors while the trigeminal sensory ganglia (TG) contain nociceptors but not photoreceptors. Melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs) are thought to mediate light-induced pain but recent evidence raises the possibility of an alternative light responsive pathway independent of the retina and optic nerve. Here, we show that melanopsin is expressed in both human and mouse TG neurons. In mice, they represent 3% of small TG neurons that are preferentially localized in the ophthalmic branch of the trigeminal nerve and are likely nociceptive C fibers and high-threshold mechanoreceptor Aδ fibers based on a strong size-function association. These isolated neurons respond to blue light stimuli with a delayed onset and sustained firing, similar to the melanopsin-dependent intrinsic photosensitivity observed in ipRGCs. Mice with severe bilateral optic nerve crush exhibit no light-induced responses including behavioral light aversion until treated with nitroglycerin, an inducer of migraine in people and migraine-like symptoms in mice. With nitroglycerin, these same mice with optic nerve crush exhibit significant light aversion. Furthermore, this retained light aversion remains dependent on melanopsin-expressing neurons. Our results demonstrate a novel light-responsive neural function independent of the optic nerve that may originate in the peripheral nervous system to provide the first direct mechanism for an alternative light detection pathway that influences motivated behavior.