The iconic restaurant still conjures up fond memories of the food and the cruising.

Add spaghetti to chili and people call you crazy. Add spaghetti and Middle Eastern spices and you're a genius (at least in Cincinnati).

The highly coveted pulp of the native fruit is a fall staple in Indiana

The iconic restaurant still conjures up fond memories of the food and the cruising.

Add spaghetti to chili and people call you crazy. Add spaghetti and Middle Eastern spices and you're a genius (at least in Cincinnati).

Purpose: To evaluate ¹¹C-choline PET/CT detection performance for biochemically recurrent prostate cancer (PCa) in a large non-European cohort in the context of emerging evidence for PSMA PET in this setting, and to map patterns of PCa recurrence. Methods: We retrospectively analyzed ¹¹C-choline PET/CT scans from 287 patients who were enrolled onto an imaging protocol based on rising prostate-specific antigen (PSA) levels (mean:3.43 ng/mL, median:0.94 ng/mL, range:0.15–89.91) and suspected recurrent PCa. A total of 187 patients had undergone primary radical prostatectomy (RP; 79/187 had secondary radiotherapy), 30 had undergone primary radiotherapy (RT), and 70 had persistent PSA elevation after receiving initial treatment (69 post-RP, 1 post-RT). The level of suspicion for recurrence on ¹¹C-choline PET/CT was scored (0:negative, 1:equivocal, 2:positive) by two readers. The correlation between ¹¹C-choline PET/CT positivity and initial treatment, Gleason score, NCCN stage, PSA level, PSA doubling time, PSA velocity, and time between initial treatment and PET imaging was evaluated. Prostate Cancer Molecular Imaging Standardized Evaluation (PROMISE) criteria were used to map ¹¹C-choline recurrence patterns. Results: Considering scores 1 and 2 as positives, consensus between the two readers deemed 66% of the ¹¹C-choline PET/CT scans as positive. When sorted by PSA level, 45% of patients with PSA<0.5 ng/mL, 56% of patients with PSA 0.5–0.99 ng/mL, 70% of patients with PSA 1.0–1.99 ng/mL, and 90% of patients with PSA ≥2.0 ng/mL scored either 1 or 2 on ¹¹C-choline PET/CT scans. When considering scores of 2 only, ¹¹C-choline PET/CT positivity was 54% (28%, 46%, 62%, and 81%, respectively, for patients with PSA <0.5 ng/mL, 0.5–0.99 ng/mL, 1.0–1.99 ng/mL, and ≥2.0 ng/mL). In multivariate analysis, only the PSA level was significantly associated with scan positivity. Pattern analysis showed that pelvic lymph nodes were the most common site of recurrence, and 28% of patients had ¹¹C-choline-positive suspected recurrences outside the initial treatment field. Conclusion: ¹¹C-choline PET/CT can detect PCa recurrence even among patients with low PSA levels when interpretation accounts for the clinical context, providing a certain pre-test probability. Until PSMA agents are fully approved for PCa, choline PET/CT may provide clinical utility.

Introduction: Neuroendocrine differentiation is associated with treatment failure and poor outcome in metastatic castration-resistant prostate cancer (mCRPC). We investigated the effect of circulating neuroendocrine biomarkers on the efficacy of PSMA-targeted radioligand therapy (RLT). Methods: Neuroendocrine biomarker profiles (progastrin-releasing peptide, neuron-specific enolase, and chromogranin-A) were analyzed in 50 patients commencing ¹⁷⁷Lu-PSMA-617 RLT. The primary endpoint was PSA response in relation to baseline neuroendocrine marker profiles. Additional endpoints included progression-free survival. Tumor uptake on post-therapeutic scans, a known predictive marker for response, was used as control-variable. Results: Neuroendocrine biomarker profiles were abnormal in the majority of patients. Neuroendocrine biomarker levels did not predict treatment failure or early progression (P ≥ 0.13). By contrast, intense PSMA-ligand uptake in metastases predicted both treatment response (P = 0.0030) and reduced risk of early progression (P = 0.0111). Conclusion: Neuroendocrine marker profiles do not predict adverse outcome of RLT. By contrast, high ligand uptake was confirmed to be crucial for achieving tumor-response.

OBJECTIVE

Many patients with hyperglycemic crises present with combined features of diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS). The implications of concomitant acidosis and hyperosmolality are not well known. We investigated hospital outcomes in patients with isolated or combined hyperglycemic crises.

This policy brief traces the successes and failures of the 1986 Immigration Reform and Control Act, which represented the first and most comprehensive legislation to take on the issue of illegal immigration to the United States. The brief makes the case that IRCA's major flaws were rooted in statutory design more than regulatory challenges and implementation by the administrative agencies.

Dopaminergic neurons innervate extensive areas of the brain and release dopamine (DA) onto a wide range of target neurons. However, DA release is also precisely regulated. In Drosophila melanogaster brain explant preparations, DA is released specifically onto α3/α'3 compartments of mushroom body (MB) neurons that have been coincidentally activated by cholinergic and glutamatergic inputs. The mechanism for this precise release has been unclear. Here we found that coincidentally activated MB neurons generate carbon monoxide (CO), which functions as a retrograde signal evoking local DA release from presynaptic terminals. CO production depends on activity of heme oxygenase in postsynaptic MB neurons, and CO-evoked DA release requires Ca²⁺ efflux through ryanodine receptors in DA terminals. CO is only produced in MB areas receiving coincident activation, and removal of CO using scavengers blocks DA release. We propose that DA neurons use two distinct modes of transmission to produce global and local DA signaling.

SIGNIFICANCE STATEMENT Dopamine (DA) is needed for various higher brain functions, including memory formation. However, DA neurons form extensive synaptic connections, while memory formation requires highly specific and localized DA release. Here we identify a mechanism through which DA release from presynaptic terminals is controlled by postsynaptic activity. Postsynaptic neurons activated by cholinergic and glutamatergic inputs generate carbon monoxide, which acts as a retrograde messenger inducing presynaptic DA release. Released DA is required for memory-associated plasticity. Our work identifies a novel mechanism that restricts DA release to the specific postsynaptic sites that require DA during memory formation.

Information on infant safety after exposure to maternal antiretroviral regimens during pregnancy in international clinical trials is lacking. As antiretroviral drugs are released to populations in resource-limited settings through clinical trials, it becomes critical to collect pediatric outcome data.

The study demonstrates the feasibility of reporting infant outcomes following adult antiretroviral trials in developing countries, provides HIV-free infant survival and prospective growth data in association with maternal parameters, and details morbidity, mortality, and genetic defects following maternal antiretroviral exposure. (Read the full article)

There is evidence from both developed and developing countries that antiretroviral treatment significantly reduces mortality in HIV-infected children. However, in sub-Saharan Africa, numerous health system, financial, and human resource obstacles make delivering quality pediatric HIV care a challenge.

We describe the experience of the Baylor International Pediatrics AIDS Initiative in Malawi, Lesotho, and Swaziland. Despite challenges delivering pediatric treatment in these countries, mortality and clinical outcomes approaching those from developed countries are feasible. (Read the full article)

Trigger scores and early warning systems provide an objective measure of a patient’s condition, allowing earlier recognition of severe illness and adaptation of care. Such scores are established in adult and pediatric populations but remain unevaluated and rarely used in neonates.

This newly designed Neonatal Trigger Score provides an objective adjunct to multidisciplinary clinical assessment in detecting unwell neonates. It is more sensitive and specific than previously validated pediatric early warning system scores. (Read the full article)

Pharmacologic treatment with sapropterin dihydrochloride (6R-tetrahydrobiopterin; BH4) has been an effective option for some phenylketonuria patients since its approval by the US Food and Drug Administration in 2007 and the European Medicines Agency in 2008.

This retrospective multicenter study revealed the long-term effects of sapropterin on metabolic control, dietary tolerance, and the outcome of BH4-responsive phenylketonuria patients harboring specific phenotypes and genotypes. It also confirmed that the minor adverse events disappeared by lowering the dose. (Read the full article)

Childhood interstitial lung diseases occur in a variety of clinical contexts and are associated with high morbidity and mortality. Advances in the understanding of disease pathogenesis and use of standardized terminology have facilitated increased case ascertainment.

This study demonstrates that cases of newly described forms of childhood interstitial lung diseases likely occur at all children’s hospitals. With advances in genetic testing and recognition of imaging patterns, a significant portion of cases are identifiable with noninvasive evaluations. (Read the full article)

Asthma is a clinical condition treated mostly at primary care community clinics. Epidemics of asthma exacerbation occur annually with return to school after summer vacation and have been reported in many countries, including Israel.

In 82 234 asthmatic children, unscheduled primary care physician visits and drug prescriptions for asthma exacerbations peaked in September after a summer trough, with a lesser peak in late autumn and fluctuations through the winter months. (Read the full article)

In HIV-infected children, decisions to start antiretroviral therapy must weigh immunologic benefits against potential risks. Current guidelines recommend using CD4 percentage and age when deciding to start treatment. Population-level effects of these factors on immunologic recovery are unknown.

Starting antiretroviral therapy at higher CD4 percentages and younger ages maximizes potential for immunologic recovery. However, not all benefits are sustained, and viral failure may occur. Our results help clinicians better weigh immunologic benefits against viral failure risks. (Read the full article)

An underground stall in Seoul's Yongsan district holds one of the biggest classic video game malls you'll ever see. Take a tour through our photos.

In 1985, as a relatively new editor at Computer Design magazine, I was asked to go forth and cover a new business called CAE (computer-aided engineering). I knew nothing about it, but I had been writing about design for test, so there seemed to be somewhat of a connection. Little did I know that “CAE” would turn into “EDA” and that I’d write about it for the next 30 years, for Computer Design, EE Times, Cadence, and a few others.

Now that I’m about to retire, I’m looking back over those 30 years. What a ride it has been! By the numbers I covered 31 Design Automation Conferences (DACs), hundreds of new products, dozens of acquisitions and startups, dozens of lawsuits, and some blind alleys that didn’t work out (like “silicon compilation”). Chip design went from gate arrays and PLDs with a few thousand gates to processors and SoCs with billions of transistors.

In 1985 there were three big CAE vendors – Daisy Systems, Mentor Graphics, and Valid Logic. All sold bundled packages that included workstations and CAE software; in fact, Daisy and Valid designed and manufactured their own workstations. In the early 1980s a workstation with schematic capture and gate-level logic simulation might have set you back $120,000. In 1985 OrCAD, now part of Cadence, came out with a $500 schematic capture package running on IBM PCs.

Cadence and Synopsys emerged in the late 1980s, and by the 1990s the EDA industry was pretty much a software-only business (apart from specialized machines like simulation accelerators). Since the early 1990s the “big three” EDA vendors have been Cadence, Synopsys, and Mentor, giving the industry stability but allowing for competition and innovation.

Here, in my view, are some of the highlights that occurred during the past 30 years of EDA.

EDA is a Highlight

The biggest highlight in EDA is the existence of a commercial EDA industry! Marching hand in hand with the fabless semiconductor revolution, commercial EDA made it possible for hundreds of companies to design semiconductors, as opposed to a small handful that could afford large internal CAD operations and fabs. With hundreds of semiconductor companies as opposed to a half-dozen, there’s a lot more creativity, and you get the level of sophistication and intelligence that you see in your smartphone, video camera, tablet, gaming console, and car today.

CAE + CAD = EDA. This is not just a terminology issue. By the mid-1980s it became clear that front-end design (CAE) and physical design (CAD) belonged together. The big CAE vendors got involved in IC and PCB CAD, and presented increasingly integrated solutions. People got tired of writing “CAE/CAD” and “EDA” was born.

The move from gate-level design to RTL. This move happened around 1990, and in my view this is EDA’s primary technology success story during the past 30 years. Moving up in abstraction made the design and verification of much larger chips possible. Going from gate-level schematics to a hardware description language (HDL) revolutionized logic design and verification. Which would you rather do – draw all the gates that form an adder, or write a few lines of code and let a synthesis tool find an adder in your chosen technology?

Two developments made this shift in design possible. One was the emergence of commercial RTL synthesis (or “logic synthesis”) tools from Synopsys and other companies, which happened around 1990. Another was the availability of Verilog, developed by Gateway Design Automation and purchased by Cadence in 1989, as a standard RTL HDL. Although most EDA vendors at the time were pushing VHDL, designers wanted Verilog and that’s what most still use (with SystemVerilog coming on strong in the verification space).

IC functional verification underwent huge changes in the late 1990s and early 2000s, largely due to new technology developed by Verisity, which was acquired by Cadence in 2005. Before Verisity, verification engineers were writing and running directed tests in an ad-hoc manner. Verisity introduced or improved technologies such as pseudo-random test generation, coverage metrics, reusable verification IP, and semi-automated verification planning. The Verisity “e” language became a widely used hardware verification language (HVL).

The biggest way that EDA has expanded its focus has been through semiconductor IP. Today Synopsys and Cadence are leading providers in this area. Thanks to the availability of design and verification IP, many SoC designs today reuse as much as 80% of previous content. This makes it much, much faster to design the remaining portion. While IP began with fairly simple elements, today commercially available IP can include whole subsystems along with the software that runs on them. With IP, EDA vendors are providing not only design tools but design content.

Finally, the EDA industry has done an amazing job of keeping up with SoC complexity and with advanced process nodes. Thanks to intense and early collaboration between foundries, IP, and EDA providers, tools and IP have been ready for process nodes going down to 10nm.

Where Does ESL Fit?

In some ways, electronic system level (ESL) design is both a lowlight and a highlight. It’s a lowlight because people have been talking about it for 30 years and the acceptance and adoption have come very slowly. ESL is a highlight because it’s finally starting to happen, and its impact on design and verification flows could be dramatic. Still, ESL is vaguely defined and can be used to describe almost anything that happens at a higher abstraction level than RTL.

High-level synthesis (HLS) is an ESL technology that is seeing increasing use in production environments. Current HLS tools are not restricted to datapaths, and they produce RTL code that gives better quality of results than hand-written RTL. Another ESL methodology that’s catching on is virtual prototyping, which lets software developers write software pre-silicon using SystemC models. Both HLS and virtual prototyping are made possible by the standardization of SystemC and transaction-level modeling (TLM). However, it’s still not easy to use the same SystemC code for HLS and virtual prototyping.

And Now, Some Lowlights

Every new industry has some twists and turns, and EDA is no exception. For example, the EDA industry in the 1980s and 1990s sparked a lot of lawsuits. At EE Times my colleagues and I wrote a number of articles about EDA legal disputes, mostly about intellectual property, trade secrets, or patent issues. Over the past decade, fortunately, there have been far fewer EDA lawsuits than we had before the turn of the century.

Another issue that was troublesome in the 1980s and 1990s was so-called “standards wars.” These would occur as EDA vendors picked one side or the other in a standards dispute. For example, power intent formats were a point of conflict in the early 2000s, but the Common Power Format (CPF) and the Unified Power Format (UPF) are on the road to convergence today with the IEEE 1801 effort. As mentioned previously, Verilog and VHDL were competing for adoption in the early 1990s. For the most part, Verilog won, showing that the designer community makes the final decision about which standards will be used.

How on earth did there get to be something like 30 DFM (design for manufacturability) companies 10-12 years ago? To my knowledge, none of these companies are around today. A few were acquired, but most simply faded away. A lot of investors lost money. Today, VCs and angel investors are funding very few EDA or IP startups. There are fewer EDA startups than there used to be, and that’s too bad, because that’s where a lot of the innovation comes from.

Here’s another current lowlight -- not enough bright engineering or computer science students are joining EDA companies. They’re going to Google, Apple, Facebook, and the like. EDA is perceived as a mature industry that is still technically very difficult. We need to bring some excitement back into EDA.

Where Is EDA Headed?

Now we come to what you might call “headlights” and look at what’s coming. My list includes:

• System Design Enablement. This term has been coined by Cadence to describe a focus on whole systems or end products including chips, packages, boards, embedded software, and mechanical components. There are far more systems companies than semiconductor companies, leaving a large untapped market that’s looking for solutions.
• New frontiers for EDA. At a 2015 Design Automation Conference speech, analyst Gary Smith suggested that EDA can move into markets such as embedded software, mechanical CAD, biomedical, optics, and more.
• Vertical markets. EDA has until now been “horizontal,” providing the same solution for all market segments. Going forward, markets like consumer, automotive, and industrial will have differing needs and will need optimized tools and IP.
• Internet of Things. This is a current buzzword, but the impact on EDA remains uncertain. Many IoT devices will be heavily analog, use mature process nodes, and be dirt cheap. Lip-Bu Tan, Cadence CEO, recently pointed out that the silicon percentage of IoT revenue will be small and that a lot of the profits will be on the service side.

Moving On

For the past six years I’ve been writing the Industry Insights blog at Cadence.com. All things change, and with this post comes a farewell – I am retiring in late June and will be pursuing a variety of interests other than EDA. I’ll be watching, though, to see what happens next in this small but vital industry. Thanks for reading!

Richard Goering

Bernadette Jordan, member of parliament for South Shore,St. Margarets, on behalf of Canada’s Minister of Natural Resources, the Honourable Amarjeet Sohi, has announced a $374,830 investment to help homeowners bring their home energy use to the net-zero level.

The Spanish government is exploring ways to persuade investors to finance a 100 billion-euro ($116 billion) transformation of its energy system as it tries to move beyond past policy mistakes that led to widespread losses and lawsuits.

In a new photography book, the home computer revolution of the 1970s, 1980s and 1990s is told through nostalgic industrial-design images

Title: How Long Does a Retrobulbar Block Last?
Category: Procedures and Tests
Created: 4/24/2020 12:00:00 AM
Last Editorial Review: 4/24/2020 12:00:00 AM

ABSTRACT

Packaging of genomic RNA (gRNA) by retroviruses is essential for infectivity, yet the subcellular site of the initial interaction between the Gag polyprotein and gRNA remains poorly defined. Because retroviral particles are released from the plasma membrane, it was previously thought that Gag proteins initially bound to gRNA in the cytoplasm or at the plasma membrane. However, the Gag protein of the avian retrovirus Rous sarcoma virus (RSV) undergoes active nuclear trafficking, which is required for efficient gRNA encapsidation (L. Z. Scheifele, R. A. Garbitt, J. D. Rhoads, and L. J. Parent, Proc Natl Acad Sci U S A 99:3944–3949, 2002, https://doi.org/10.1073/pnas.062652199; R. Garbitt-Hirst, S. P. Kenney, and L. J. Parent, J Virol 83:6790–6797, 2009, https://doi.org/10.1128/JVI.00101-09). These results raise the intriguing possibility that the primary contact between Gag and gRNA might occur in the nucleus. To examine this possibility, we created a RSV proviral construct that includes 24 tandem repeats of MS2 RNA stem-loops, making it possible to track RSV viral RNA (vRNA) in live cells in which a fluorophore-conjugated MS2 coat protein is coexpressed. Using confocal microscopy, we observed that both wild-type Gag and a nuclear export mutant (Gag.L219A) colocalized with vRNA in the nucleus. In live-cell time-lapse images, the wild-type Gag protein trafficked together with vRNA as a single ribonucleoprotein (RNP) complex in the nucleoplasm near the nuclear periphery, appearing to traverse the nuclear envelope into the cytoplasm. Furthermore, biophysical imaging methods suggest that Gag and the unspliced vRNA physically interact in the nucleus. Taken together, these data suggest that RSV Gag binds unspliced vRNA to export it from the nucleus, possibly for packaging into virions as the viral genome.

IMPORTANCE Retroviruses cause severe diseases in animals and humans, including cancer and acquired immunodeficiency syndromes. To propagate infection, retroviruses assemble new virus particles that contain viral proteins and unspliced vRNA to use as gRNA. Despite the critical requirement for gRNA packaging, the molecular mechanisms governing the identification and selection of gRNA by the Gag protein remain poorly understood. In this report, we demonstrate that the Rous sarcoma virus (RSV) Gag protein colocalizes with unspliced vRNA in the nucleus in the interchromatin space. Using live-cell confocal imaging, RSV Gag and unspliced vRNA were observed to move together from inside the nucleus across the nuclear envelope, suggesting that the Gag-gRNA complex initially forms in the nucleus and undergoes nuclear export into the cytoplasm as a viral ribonucleoprotein (vRNP) complex.

The IR Biotyper is a new automated typing system based on Fourier-transform infrared (FT-IR) spectroscopy that gives results within 4 h. We aimed (i) to use the IR Biotyper to retrospectively analyze an outbreak of extended-spectrum beta-lactamase-producing Klebsiella pneumoniae (ESBL-KP) in a neonatal intensive care unit and to compare results to BOX-PCR and whole-genome sequencing (WGS) results as the gold standard and (ii) to assess how the cutoff values used to define clusters affect the discriminatory power of the IR Biotyper. The sample consisted of 18 isolates from 14 patients. Specimens were analyzed in the IR Biotyper using the default analysis settings, and spectra were analyzed using OPUS 7.5 software. The software contains a feature that automatically proposes a cutoff value to define clusters; the cutoff value defines up to which distance the spectra are considered to be in the same cluster. Based on FT-IR, the outbreak represented 1 dominant clone, 1 secondary clone, and several unrelated clones. FT-IR results, using the cutoff value generated by the accompanying software after 4 replicates, were concordant with WGS for all but 1 isolate. BOX-PCR was underdiscriminatory compared to the other two methods. Using the cutoff value generated after 12 replicates, the results of FT-IR and WGS were completely concordant. The IR Biotyper can achieve the same typeability and discriminatory power as genome-based methods. However, to attain this high performance requires either previous, strain-dependent knowledge about the optimal technical parameters to be used or validation by a second method.

Retrospective lineage tracing harnesses naturally occurring mutations in cells to elucidate single cell development. Common single-cell phylogenetic fate mapping methods have utilized highly mutable microsatellite loci found within the human genome. Such methods were limited by the introduction of in vitro noise through polymerase slippage inherent in DNA amplification, which we characterized to be approximately 10–100x higher than the in vivo replication mutation rate. Here, we present RETrace, a method for simultaneously capturing both microsatellites and methylation-informative cytosines to characterize both lineage and cell type, respectively, from the same single cell. An important unique feature of RETrace was the introduction of linear amplification of microsatellites in order to reduce in vitro amplification noise. We further coupled microsatellite capture with single-cell reduced representation bisulfite sequencing (scRRBS), to measure the CpG methylation status on the same cell for cell type inference. When compared to existing retrospective lineage tracing methods, RETrace achieved higher accuracy (88% triplet accuracy from an ex vivo HCT116 tree) at a higher cell division resolution (lowering the required number of cell division difference between single cells by approximately 100 divisions). Simultaneously, RETrace demonstrated the ability to capture on average 150,000 unique CpGs per single cell in order to accurately determine cell type. We further formulated additional developments that would allow high-resolution mapping on microsatellite-stable cells or tissues with RETrace. Overall, we present RETrace as a foundation for multi-omics lineage mapping and cell typing of single cells.

In Arabidopsis, LTR retrotransposons are activated by mutations in the chromatin gene DECREASE in DNA METHYLATION 1 (DDM1), giving rise to 21- to 22-nt epigenetically activated siRNA (easiRNA) that depend on RNA DEPENDENT RNA POLYMERASE 6 (RDR6). We purified virus-like particles (VLPs) from ddm1 and ddm1rdr6 mutants in which genomic RNA is reverse transcribed into complementary DNA. High-throughput short-read and long-read sequencing of VLP DNA (VLP DNA-seq) revealed a comprehensive catalog of active LTR retrotransposons without the need for mapping transposition, as well as independent of genomic copy number. Linear replication intermediates of the functionally intact COPIA element EVADE revealed multiple central polypurine tracts (cPPTs), a feature shared with HIV in which cPPTs promote nuclear localization. For one member of the ATCOPIA52 subfamily (SISYPHUS), cPPT intermediates were not observed, but abundant circular DNA indicated transposon "suicide" by auto-integration within the VLP. easiRNA targeted EVADE genomic RNA, polysome association of GYPSY (ATHILA) subgenomic RNA, and transcription via histone H3 lysine-9 dimethylation. VLP DNA-seq provides a comprehensive landscape of LTR retrotransposons and their control at transcriptional, post-transcriptional, and reverse transcriptional levels.

We investigated whether cycloheximide (CHX) would induce amnesia for the stress-induced impairment of extinction retrieval. First, a single restraint stress session was demonstrated to impair extinction retrieval, but not fear conditioning. A second experiment showed that when CHX was administered immediately after restraint, rats exhibited significant extinction retrieval at test (i.e., retrograde amnesia for the stress). In a third experiment, the stress session impaired various amounts of extinction durations, suggesting that the stress inhibited extinction retrieval rather than enhancing the original fear learning. These results suggest memories for acute stress are susceptible to disruption, which could have clinical implications.

ABSTRACTIntroduction:Multimonth dispensing (MMD) of antiretroviral therapy (ART) is a differentiated model of care that can help overcome health system challenges and reduce the burden of HIV care on clients. Although 3-month dispensing has been the standard of care, interest has increased in extending refill intervals to 6 months. We explored client and provider experiences with MMD in Malawi as part of a cluster randomized trial evaluating 3- versus 6-month ART dispensing.Methods:Semi-structured in-depth interviews were conducted with 17 ART providers and 62 stable, adult clients with HIV on ART. Clients and providers were evenly divided by arm and were eligible for an interview if they had been participating in the study for 1 year (clients) or 6 months (providers). Questions focused on perceived challenges and benefits of the 3- or 6-month amount of ART dispensing. Interviews were transcribed, and data were coded and analyzed using constant comparison.Results:Both clients and providers reported that the larger medication supply had benefits. Clients reported decreased costs due to less frequent travel to the clinic and increased time for income-generating activities. Clients in the 6-month dispensing arm reported a greater sense of personal freedom and normalcy. Providers felt that the 6-month dispensing interval reduced their workload. They also expressed concerned about clients' challenges with ART storage at home, but clients reported no storage problems. Although providers mentioned the potential risk of clients sharing the larger medication supply with family or friends, clients emphasized the value of ART and reported only rare, short-term sharing, mostly with their spouses. Providers mentioned clients' lack of motivation to seek care for illnesses that might occur between refill appointments.Conclusions:The 6-month ART dispensing arm was particularly beneficial to clients for decreased costs, increased time for income generation, and a greater sense of normalcy. Providers' concerns about storage, sharing, and return visits to the facility did not emerge in client interviews. Further data are needed on the feasibility of implementing a large-scale program with 6-month dispensing.

Background:

Incentive payments for chronic diseases in British Columbia were intended to support primary care physicians in providing more comprehensive care, but research shows that not all physicians bill incentives and not all eligible patients have them billed on their behalf. We investigated patient and physician characteristics associated with billing incentives for chronic diseases in BC.

Background:

Peripregnancy emergency department use may be common, but data specific to health care systems like that in Canada are lacking. As prior research was limited to livebirths, omitting pregnancies ending in miscarriage or induced abortion, the current study quantified and characterized emergency department use among women in Ontario with a recognized pregnancy.

Background:

Female physicians have been shown to receive fewer awards from medical societies than their male colleagues. We examined the sex distribution of recipients of Canadian residency association awards.

Treating malaria in HIV-coinfected individuals should consider potential drug-drug interactions. Artemether-lumefantrine is the most widely recommended treatment for uncomplicated malaria globally. Lumefantrine is metabolized by CYP3A4, an enzyme that commonly used antiretrovirals often induce or inhibit. A population pharmacokinetic meta-analysis was conducted using individual participant data from 10 studies with 6,100 lumefantrine concentrations from 793 nonpregnant adult participants (41% HIV-malaria-coinfected, 36% malaria-infected, 20% HIV-infected, and 3% healthy volunteers). Lumefantrine exposure increased 3.4-fold with coadministration of lopinavir-ritonavir-based antiretroviral therapy (ART), while it decreased by 47% with efavirenz-based ART and by 59% in the patients with rifampin-based antituberculosis treatment. Nevirapine- or dolutegravir-based ART and malaria or HIV infection were not associated with significant effects. Monte Carlo simulations showed that those on concomitant efavirenz or rifampin have 49% and 80% probability of day 7 concentrations <200 ng/ml, respectively, a threshold associated with an increased risk of treatment failure. The risk of achieving subtherapeutic concentrations increases with larger body weight. An extended 5-day and 6-day artemether-lumefantrine regimen is predicted to overcome these drug-drug interactions with efavirenz and rifampin, respectively.

Etravirine (ETR) is a nonnucleoside reverse transcriptase inhibitor (NNRTI) used in treatment-experienced individuals. Genotypic resistance test-interpretation systems can predict ETR resistance; however, genotype-based algorithms are derived primarily from HIV-1 subtype B and may not accurately predict resistance in non-B subtypes. The frequency of ETR resistance among recombinant subtype C HIV-1 and the accuracy of genotypic interpretation systems were investigated. HIV-1_LAI containing full-length RT from HIV-1 subtype C-positive individuals experiencing virologic failure (>10,000 copies/ml and >1 NNRTI resistance-associated mutation) were phenotyped for ETR susceptibility. Fold change (FC) was calculated against a composite 50% effective concentration (EC₅₀) from treatment-naive individuals and three classifications were assigned: (i) <2.9-FC, susceptible; (ii) ≥2.9- to 10-FC, partially resistant; and (iii) >10-FC, fully resistant. The Stanford HIVdb-v8.4 was used for genotype predictions merging the susceptible/potential low-level and low-level/intermediate groups for 3 x 3 comparison. Fifty-four of a hundred samples had reduced ETR susceptibility (≥2.9-FC). The FC correlated with HIVdb-v8.4 (Spearman’s rho = 0.62; P < 0.0001); however, 44% of samples were partially (1 resistance classification difference) and 4% completely discordant (2 resistance classification differences). Of the 34 samples with an FC of >10, 26 were HIVdb-v8.4 classified as low-intermediate resistant. Mutations L100I, Y181C, or M230L were present in 27/34 (79%) of samples with an FC of >10 but only in 2/46 (4%) of samples with an FC of <2.9. No other mutations were associated with ETR resistance. Viruses containing the mutation K65R were associated with reduced ETR susceptibility, but 65R reversions did not increase ETR susceptibility. Therefore, genotypic interpretation systems were found to misclassify ETR susceptibility in HIV-1 subtype C samples. Modifications to genotypic algorithms are needed to improve the prediction of ETR resistance for the HIV-1 subtype C.

Although they are usually not considered to be diabetes complications, musculoskeletal disorders (MSKDs) are common in individuals with type 1 or type 2 diabetes and can strongly interfere with daily diabetes care, especially in people using diabetes technologies. The authors of this retrospective study in a population of 140 patients with type 1 diabetes report the distribution of subtypes of MSKDs and speculate about the mechanisms involved. The authors emphasize the need for multidisciplinary care involving not only the diabetes care team but also orthopedic surgeons. This report should lead to large, prospective studies to increase knowledge about these under-studied complications.

In a new photography book, the home computer revolution of the 1970s, 1980s and 1990s is told through nostalgic industrial-design images

Don't analyse them too closely, they didn't have HD in the 1970s.

After finding common ground, Jen and Judy split up to spend time with new friends who could end up being something more.

Multi-function retro calculator watches.

Attorney General Eric Holder announced Tuesday that the Justice Department would formally support a proposal under consideration by the U.S. Sentencing Commission to allow certain individuals serving time in federal prison for nonviolent drug offenses to be eligible for reduced sentences.

Attorney General Eric Holder today released the following statement regarding the U.S. Sentencing Commission vote approving retroactivity of sentence reductions for drug offenses