Detection and significance of drug- resistant HIV-1 minor populations

The human immunodeficiency virus (HIV) is the cause of the HIV/AIDS pandemic affecting millions of people around the world. Treatment with antiretroviral drugs, if used properly, leads to a dramatic decrease in virus production in the patient and prevents the onset of AIDS. However, treatment is not always successful, mainly due to the extraordinary ability of the virus to change and become resistant to the antiretroviral drugs. The general aim of this thesis was to study the development of HIV-1 drug resistance, specifically the detection and significance of small populations of drug-resistant virus in infected individuals that can go undetected by the standard resistance tests used in the clinics today. In study I, we developed and evaluated an assay called selective real-time PCR (SPCR), which can detect and display the proportions of different populations of drug-resistant virus carrying the clinically relevant M184I/V mutations in the HIV-1 reverse transcriptase enzyme. These mutations confer high-level resistance to one of the most commonly used drugs today, lamivudine (3TC). The SPCR assay was then applied to several different clinical cohorts in the subsequent papers. We found SPCR to be a well-functioning, sensitive and reliable method to study the kinetics of antiretroviral resistance development in HIV-1, which was able to detect resistance mutations not seen by conventional genotyping assays. In study II, we evaluated the presence of M184I/V-containing minor viral populations and their potential role in treatment failure in didanosine (ddI)-treated patients experienced with multiple nucleoside reverse transcriptase inhibitors. We found that the survival advantage of virus strains having the M184I/V mutations were limited during ddI treatment, suggesting that the presence of these mutations should not preclude the use of ddI in nucleoside-experienced patients. In study III, we investigated to which extent unique drug resistance patterns appear in cerebrospinal fluid as compared to blood in patients who had failed 3TC-containing therapy. We found differences in drug resistance patterns in both minor and major populations, which were likely to be related to differences in the selective pressure of antiretroviral drugs within the two compartments rather than unique evolutionary pathways. Minor populations were not seen to play a major role in resistance development in cerebrospinal fluid in the patients we tested. In study IV, we studied to which extent selection of M184I/V mutations occurs in treatment-naïve patients during the first months after initiation of antiretroviral therapy containing two, three or four drugs. We found the selection of drug-resistant variants to be rare in the three- and four-drug cohorts, but common in the two-drug cohort, suggesting that current treatment regimens initiated in treatment-naïve patients should be sufficient to stop resistance development during the first phase of viral decay, as long as the patients are adherent. The clinical significance of minority populations in the development of resistance to antiretroviral drugs is an important topic to be defined. SPCR and similar assays will provide valuable tools to further expand the current knowledge in this field

Risk factors, health outcomes, healthcare services utilization, and direct medical costs of patients with long COVID

Objectives: Data on the economic burden of long COVID are scarce. We aimed to examine the prevalence and medical costs of treating long COVID. Methods: We conducted this historical cohort study using data from patients with COVID-19 among members of a large health provider in Israel. Cases were defined according to physician diagnosis (definite long COVID) or suggestive symptoms given ≥ 4 weeks from infection (probable cases). Healthcare resource utilization and direct healthcare costs (HCCs) in the period before infection and afterward were compared across study groups. Results: Between March 2020, and March 2021, a total of 180,759 COVID-19 patients (mean [SD] age = 32.9 years [19.0 years]; 89,665 [49.6%] females) were identified. Overall, 14,088 (7.8%) individuals developed long COVID (mean [SD] age = 40.0 years [19.0 years]; 52.4% females). Among them, 1477(10.5%) were definite long COVID and 12,611(89.5%) were defined as probable long COVID. Long COVID was associated with age (adjusted odds ratio [AOR] = 1.058 per year, 95% CI: 1.053-1.063), female sex (AOR = 1.138; 95% CI: 1.098-1.180), smoking (AOR = 1.532; 95% CI: 1.358-1.727), and symptomatic acute phase (AOR = 1.178; 95% CI: 1.133-1.224), primarily muscle pain and cough. Hypertension was an important risk factor for long COVID among younger adults. Compared with patients with non-long COVID, definite and probable cases were associated with AORs of 2.47 (2.22-2.75) and 1.76 (1.68-1.84) for post-COVID hospitalization, respectively. Although among patients with non-long COVID HCCs decreased from $1400 during 4 months before the infection to$1021 and among patients with long COVID, HCCs increased from $2435 to$2810. Conclusion: Long COVID is associated with a substantial increase in the utilization of healthcare services and direct medical costs. Our findings underline the need for timely planning and allocating resources for patient-centered care for patients with long COVID as well as for its secondary prevention in high-risk patients

3D Visualization of Autonomous Systems

Drönare är ett växande fenomen i dagens samhälle och deras användningsområdenhar snabbt ökat de senaste åren. För att underlätta utvecklingen av drönarteknologi kansimuleringar tillämpas då de möjliggör testning i en kontrollerad och riskfri miljö. I dettaprojekt visualiseras simuleringar av drönare i ett försök att skapa värde för denna utveckling. Visualiseringen skedde med hjälp av Unreal Engine 5. Under projektets gång studerades arbetsmetoderna som nyttjades och hur en systemanatomi kan bidra till utvecklingen iett småskaligt mjukvaruprojekt. Största värdet som producerades för kunden var kommunikationsmodulen. Kommunikationen uppnåddes med hjälp av två JSON-filer som visualiseringen respektive simuleringen skrev till för att kommunicera med varandra. Värdeti denna modul ligger i att kunden sökte en modulär lösning för att kommunicera mellanen 3D-visualisering och en simulering. En erfarenhet som uppmärksammades angåendearbetsmetoderna är vikten av en fungerande gruppdynamik. Bidragande faktorer till detvar agila arbetsmetoder, goda kommunikationsvägar och en väl planerad användning avGit. Systemanatomier upplevdes ge begränsat värde till projektet

3D Visualization of Autonomous Systems

Drönare är ett växande fenomen i dagens samhälle och deras användningsområdenhar snabbt ökat de senaste åren. För att underlätta utvecklingen av drönarteknologi kansimuleringar tillämpas då de möjliggör testning i en kontrollerad och riskfri miljö. I dettaprojekt visualiseras simuleringar av drönare i ett försök att skapa värde för denna utveckling. Visualiseringen skedde med hjälp av Unreal Engine 5. Under projektets gång studerades arbetsmetoderna som nyttjades och hur en systemanatomi kan bidra till utvecklingen iett småskaligt mjukvaruprojekt. Största värdet som producerades för kunden var kommunikationsmodulen. Kommunikationen uppnåddes med hjälp av två JSON-filer som visualiseringen respektive simuleringen skrev till för att kommunicera med varandra. Värdeti denna modul ligger i att kunden sökte en modulär lösning för att kommunicera mellanen 3D-visualisering och en simulering. En erfarenhet som uppmärksammades angåendearbetsmetoderna är vikten av en fungerande gruppdynamik. Bidragande faktorer till detvar agila arbetsmetoder, goda kommunikationsvägar och en väl planerad användning avGit. Systemanatomier upplevdes ge begränsat värde till projektet