Intrahost evolution of the HIV-2 capsid correlates with progression to AIDS.

HIV-2 infection will progress to AIDS in most patients without treatment, albeit at approximately half the rate of HIV-1 infection. HIV-2 capsid (p26) amino acid polymorphisms are associated with lower viral loads and enhanced processing of T cell epitopes, which may lead to protective Gag-specific T cell responses common in slower progressors. Lower virus evolutionary rates, and positive selection on conserved residues in HIV-2 env have been associated with slower progression to AIDS. In this study we analysed 369 heterochronous HIV-2 p26 sequences from 12 participants with a median age of 30 years at enrolment. CD4% change over time was used to stratify participants into relative faster and slower progressor groups. We analysed p26 sequence diversity evolution, measured site-specific selection pressures and evolutionary rates, and determined if these evolutionary parameters were associated with progression status. Faster progressors had lower CD4% and faster CD4% decline rates. Median pairwise sequence diversity was higher in faster progressors (5.7x10-3 versus 1.4x10-3 base substitutions per site, P<0.001). p26 evolved under negative selection in both groups (dN/dS=0.12). Median virus evolutionary rates were higher in faster than slower progressors - synonymous rates: 4.6x10-3 vs. 2.3x10-3; and nonsynonymous rates: 6.9x10-4 vs. 2.7x10-4 substitutions/site/year, respectively. Virus evolutionary rates correlated negatively with CD4% change rates (ρ = -0.8, P=0.02), but not CD4% level. The signature amino acid at p26 positions 6, 12 and 119 differed between faster (6A, 12I, 119A) and slower (6G, 12V, 119P) progressors. These amino acid positions clustered near to the TRIM5α/p26 hexamer interface surface. p26 evolutionary rates were associated with progression to AIDS and were mostly driven by synonymous substitutions. Nonsynonymous evolutionary rates were an order of magnitude lower than synonymous rates, with limited amino acid sequence evolution over time within hosts. These results indicate HIV-2 p26 may be an attractive therapeutic target.

Decreased severity of disease during the first global omicron variant covid-19 outbreak in a large hospital in tshwane, south africa.

INTRODUCTION: The coronavirus disease 2019 (COVID-19) first reported in Wuhan, China in December 2019 is a global pandemic that is threatening the health and wellbeing of people worldwide. To date there have been more than 274 million reported cases and 5.3 million deaths. The Omicron variant first documented in the City of Tshwane, Gauteng Province, South Africa on 9 November 2021 led to exponential increases in cases and a sharp rise in hospital admissions. The clinical profile of patients admitted at a large hospital in Tshwane is compared with previous waves. METHODS: 466 hospital COVID-19 admissions since 14 November 2021 were compared to 3962 admissions since 4 May 2020, prior to the Omicron outbreak. Ninety-eight patient records at peak bed occupancy during the outbreak were reviewed for primary indication for admission, clinical severity, oxygen supplementation level, vaccination and prior COVID-19 infection. Provincial and city-wide daily cases and reported deaths, hospital admissions and excess deaths data were sourced from the National Institute for Communicable Diseases, the National Department of Health and the South African Medical Research Council. RESULTS: For the Omicron and previous waves, deaths and ICU admissions were 4.5% vs 21.3% (p<0.00001), and 1% vs 4.3% (p<0.00001) respectively; length of stay was 4.0 days vs 8.8 days; and mean age was 39 years vs 49,8 years. Admissions in the Omicron wave peaked and declined rapidly with peak bed occupancy at 51% of the highest previous peak during the Delta wave. Sixty two (63%) patients in COVID-19 wards had incidental COVID-19 following a positive SARS-CoV-2 PCR test . Only one third (36) had COVID-19 pneumonia, of which 72% had mild to moderate disease. The remaining 28% required high care or ICU admission. Fewer than half (45%) of patients in COVID-19 wards required oxygen supplementation compared to 99.5% in the first wave. The death rate in the face of an exponential increase in cases during the Omicron wave at the city and provincial levels shows a decoupling of cases and deaths compared to previous waves, corroborating the clinical findings of decreased severity of disease seen in patients admitted to the Steve Biko Academic Hospital. CONCLUSION: There was decreased severity of COVID-19 disease in the Omicron-driven fourth wave in the City of Tshwane, its first global epicentre.

A neural network to predict the knee adduction moment in patients with osteoarthritis using anatomical landmarks obtainable from 2D video analysis.

OBJECTIVE: The knee adduction moment (KAM) can inform treatment of medial knee osteoarthritis; however, measuring the KAM requires an expensive gait analysis laboratory. We evaluated the feasibility of predicting the peak KAM during natural and modified walking patterns using the positions of anatomical landmarks that could be identified from video analysis. METHOD: Using inverse dynamics, we calculated the KAM for 86 individuals (64 with knee osteoarthritis, 22 without) walking naturally and with foot progression angle modifications. We trained a neural network to predict the peak KAM using the 3-dimensional positions of 13 anatomical landmarks measured with motion capture (3D neural network). We also trained models to predict the peak KAM using 2-dimensional subsets of the dataset to simulate 2-dimensional video analysis (frontal and sagittal plane neural networks). Model performance was evaluated on a held-out, 8-person test set that included steps from all trials. RESULTS: The 3D neural network predicted the peak KAM for all test steps with r2( Murray et al., 2012) 2 = 0.78. This model predicted individuals' average peak KAM during natural walking with r2( Murray et al., 2012) 2 = 0.86 and classified which 15° foot progression angle modifications reduced the peak KAM with accuracy = 0.85. The frontal plane neural network predicted peak KAM with similar accuracy (r2( Murray et al., 2012) 2 = 0.85) to the 3D neural network, but the sagittal plane neural network did not (r2( Murray et al., 2012) 2 = 0.14). CONCLUSION: Using the positions of anatomical landmarks from motion capture, a neural network accurately predicted the peak KAM during natural and modified walking. This study demonstrates the feasibility of measuring the peak KAM using positions obtainable from 2D video analysis.

Comorbidity in context: Part 2. Ethicolegal considerations around HIV and tuberculosis during the COVID-19 pandemic in South Africa.

The COVID-19 pandemic has brought discussions around the appropriate and fair rationing of scare resources to the forefront. This is of special importance in a country such as South Africa (SA), where scarce resources interface with high levels of need. A large proportion of the SA population has risk factors associated with worse COVID-19 outcomes. Many people are also potentially medically and socially vulnerable secondary to the high levels of infection with HIV and tuberculosis (TB) in the country. This is the second of two articles. The first examined the clinical evidence regarding the inclusion of HIV and TB as comorbidities relevant to intensive care unit (ICU) admission triage criteria. Given the fact that patients with HIV or TB may potentially be excluded from admission to an ICU on the basis of an assumption of lack of clinical suitability for critical care, in this article we explore the ethicolegal implications of limiting ICU access of persons living with HIV or TB. We argue that all allocation and rationing decisions must be in terms of SA law, which prohibits unfair discrimination. In addition, ethical decision-making demands accurate and evidence-based strategies for the fair distribution of limited resources. Rationing decisions and processes should be fair and based on visible and consistent criteria that can be subjected to objective scrutiny, with the ultimate aim of ensuring accountability, equity and fairness.

Comorbidity in context: Part 1. Medical considerations around HIV and tuberculosis during the COVID-19 pandemic in South Africa.

Infectious diseases pandemics have devastating health, social and economic consequences, especially in developing countries such as South Africa. Scarce medical resources must often be rationed effectively to contain the disease outbreak. In the case of COVID-19, even the best-resourced countries will have inadequate intensive care facilities for the large number of patients needing admission and ventilation. The scarcity of medical resources creates the need for national governments to establish admission criteria that are evidence-based and fair. Questions have been raised whether infection with HIV or tuberculosis (TB) may amplify the risk of adverse COVID-19 outcomes and therefore whether these conditions should be factored in when deciding on the rationing of intensive care facilities. In light of these questions, clinical evidence regarding inclusion of these infections as comorbidities relevant to intensive care unit admission triage criteria is investigated in the first of a two-part series of articles. There is currently no evidence to indicate that HIV or TB infection on their own predispose to an increased risk of infection with SARS-CoV-2 or worse outcomes for COVID-19. It is recommended that, as for other medical conditions, validated scoring systems for poor prognostic factors should be applied. A subsequent article examines the ethicolegal implications of limiting intensive care access of persons living with HIV or TB.

Visual impairment and spectacles ownership among upper secondary school students in northwestern China.

PURPOSE: To assess the prevalence of visual impairment and spectacles ownership among academic and vocational upper secondary school students in rural China. METHODS: This cross-sectional study included 5583 students from four academic upper secondary schools (AUSSs) and two vocational upper secondary schools (VUSSs) in Mei and Qianyang counties, Baoji Prefecture, Shaanxi Province. In March and April 2016, students underwent assessment of visual acuity (VA) and completed a questionnaire regarding spectacles use and family characteristics. Students with visual impairment (presenting VA ≤6/12 in the better eye) and students needing spectacles (uncorrected VA ≤6/12 in the better eye, which could be improved to >6/12 with refraction) were identified. RESULTS: Among 5583 students (54% boys, mean age 16.4±1.0 years) in grades 10 and grade 11 attending AUSSs (n=4549) and VUSSs (n=1034), visual impairment was detected in 4026 students. Among the AUSS students, 3425 (75%) needed spectacles; 2551 (75%) had them. Among the VUSS students, 601 (58%) needed spectacles; this proportion was significantly smaller (P=0.004), as was the proportion who had spectacles (n=212, 35%, P<0.001), compared with the AUSS students. Multivariate analysis showed that ownership of spectacles among children who needed them was associated with worse uncorrected VA (P<0.001), male sex (P<0.001), and residence in an urban area (P<0.034). Spectacles ownership was also strongly associated with AUSS education (P<0.001). CONCLUSION: There is a high rate of unmet need in visual care among upper secondary school students. Lack of spectacles ownership among children who needed them was significantly associated with VUSS education.

Comorbidity in context: Part 1. Medical considerations around HIV and tuberculosis during the COVID-19 pandemic in South Africa

Infectious diseases pandemics have devastating health, social and economic consequences, especially in developing countries such as South Africa. Scarce medical resources must often be rationed effectively to contain the disease outbreak. In the case of COVID-19, even the best-resourced countries will have inadequate intensive care facilities for the large number of patients needing admission and ventilation. The scarcity of medical resources creates the need for national governments to establish admission criteria that are evidence-based and fair. Questions have been raised whether infection with HIV or tuberculosis (TB) may amplify the risk of adverse COVID-19 outcomes and therefore whether these conditions should be factored in when deciding on the rationing of intensive care facilities. In light of these questions, clinical evidence regarding inclusion of these infections as comorbidities relevant to intensive care unit admission triage criteria is investigated in the first of a two-part series of articles. There is currently no evidence to indicate that HIV or TB infection on their own predispose to an increased risk of infection with SARS-CoV-2 or worse outcomes for COVID-19. It is recommended that, as for other medical conditions, validated scoring systems for poor prognostic factors should be applied. A subsequent article examines the ethicolegal implications of limiting intensive care access of persons living with HIV or TB

Comorbidity in context: Part 2. Ethicolegal considerations around HIV and tuberculosis during the COVID-19 pandemic in South Africa

The COVID-19 pandemic has brought discussions around the appropriate and fair rationing of scare resources to the forefront. This is of special importance in a country such as South Africa (SA), where scarce resources interface with high levels of need. A large proportion of the SA population has risk factors associated with worse COVID-19 outcomes. Many people are also potentially medically and socially vulnerable secondary to the high levels of infection with HIV and tuberculosis (TB) in the country. This is the second of two articles. The first examined the clinical evidence regarding the inclusion of HIV and TB as comorbidities relevant to intensive care unit (ICU) admission triage criteria. Given the fact that patients with HIV or TB may potentially be excluded from admission to an ICU on the basis of an assumption of lack of clinical suitability for critical care, in this article we explore the ethicolegal implications of limiting ICU access of persons living with HIV or TB. We argue that all allocation and rationing decisions must be in terms of SA law, which prohibits unfair discrimination. In addition, ethical decision-making demands accurate and evidence-based strategies for the fair distribution of limited resources. Rationing decisions and processes should be fair and based on visible and consistent criteria that can be subjected to objective scrutiny, with the ultimate aim of ensuring accountability, equity and fairness

Delayed disease progression in HIV-2: the importance of TRIM5α and the retroviral capsid.

HIV-2 is thought to have entered the human population in the 1930s through cross-species transmission of SIV from sooty mangabeys in West Africa. Unlike HIV-1, HIV-2 has not led to a global pandemic, and recent data suggest that HIV-2 prevalence is declining in some West African states where it was formerly endemic. Although many early isolates of HIV-2 were derived from patients presenting with AIDS-defining illnesses, it was noted that a much larger proportion of HIV-2-infected subjects behaved as long-term non-progressors (LTNP) than their HIV-1-infected counterparts. Many HIV-2-infected adults are asymptomatic, maintaining an undetectable viral load for over a decade. However, despite lower viral loads, HIV-2 progresses to clinical AIDS without therapeutic intervention in most patients. In addition, successful treatment with anti-retroviral therapy (ART) is more challenging than for HIV-1. HIV-2 is significantly more sensitive to restriction by host restriction factor tripartite motif TRIM5α than HIV-1, and this difference in sensitivity is linked to differences in capsid structure. In this review we discuss the determinants of HIV-2 disease progression and focus on the important interactions between TRIM5α and HIV-2 capsid in long-term viral control.

Search for Neutrinoless Double-ß Decay in

The Majorana Collaboration is operating an array of high purity Ge detectors to search for neutrinoless double-ß decay in ^{76}Ge. The Majorana Demonstrator comprises 44.1 kg of Ge detectors (29.7 kg enriched in ^{76}Ge) split between two modules contained in a low background shield at the Sanford Underground Research Facility in Lead, South Dakota. Here we present results from data taken during construction, commissioning, and the start of full operations. We achieve unprecedented energy resolution of 2.5 keV FWHM at Q_{ßß} and a very low background with no observed candidate events in 9.95 kg yr of enriched Ge exposure, resulting in a lower limit on the half-life of 1.9×10^{25} yr (90% C.L.). This result constrains the effective Majorana neutrino mass to below 240-520 meV, depending on the matrix elements used. In our experimental configuration with the lowest background, the background is 4.0_{-2.5}^{+3.1} counts/(FWHM t yr).

The accuracy of digital infrared imaging for breast cancer detection in women undergoing breast biopsy.

BACKGROUND: Mammography has a lower sensitivity for breast cancer detection in younger women and those with dense breasts. Recent improvements in digital infrared breast imaging suggest there may be a role for this technology and we have studied its performance in 100 women prior to breast needle core biopsy (CB). METHODS: All patients were imaged using a digital infrared breast (DIB) scan (Sentinel BreastScan) prior to breast biopsy. Analysis of the infrared scans was performed, blinded to biopsy results, in four different ways: Sentinel screening report, Sentinel artificial intelligence (neural network), expert manual review and NoTouch BreastScan a novel artificial intelligence programme. RESULTS: Of 106 biopsies performed in 100 women, 65 were malignant and 41 were benign. Sensitivity of Sentinel screening (53%) and Sentinel neural network (48%) was low but analysis with NoTouch software (70%) was much closer to expert manual review (78%). Sensitivity (78%) and specificity (75%) using NoTouch BreastScan were higher in women under 50 and the combination of mammography and DIB, with NoTouch interpretation, in this age group resulted in a sensitivity of 89%. CONCLUSION: DIB using NoTouch is an effective adjunctive test for breast cancer detection in women under 70 and appears to be particularly effective in women under 50 where maximal sensitivity (78%) and specificity (75%) were observed. The combined sensitivity of NoTouch BreastScan and mammography in women under 50 was encouraging at 89%, suggesting a potential way forward for a dual imaging approach in this younger age group.

Longitudinal-transverse separations of deep-inelastic structure functions at low Q2 for hydrogen and deuterium.

We report on a study of the longitudinal to transverse cross section ratio, R=sigmaL/sigmaT, at low values of x and Q2, as determined from inclusive inelastic electron-hydrogen and electron-deuterium scattering data from Jefferson Laboratory Hall C spanning the four-momentum transfer range 0.06

Polarization transfer in the 4He(e-->,e'p-->)3H reaction up to Q2=2.6 (GeV/c)2.

We have measured the proton recoil polarization in the 4He(e-->,e(')p-->)4H reaction at Q(2)=0.5, 1.0, 1.6, and 2.6 (GeV/c)(2). The measured ratio of polarization transfer coefficients differs from a fully relativistic calculation, favoring the inclusion of a medium modification of the proton form factors predicted by a quark-meson coupling model. In addition, the measured induced polarizations agree reasonably well with the fully relativistic calculation indicating that the treatment of final-state interactions is under control.

Superior hypogastric plexus block successfully treats severe penile pain after transurethral resection of the prostate.

BACKGROUND AND OBJECTIVES: Superior hypogastric plexus block has been used to treat cancer pain of the pelvis. METHODS: A patient with severe chronic nonmalignant penile pain after transurethral resection of the prostate underwent a single superior hypogastric plexus block with local anesthetic and steroid. The patient was also started on medications that treat neuropathic pain a few hours after the procedure was finished. RESULTS: The superior hypogastric plexus block resulted in complete pain relief immediately after the procedure. The pain relief continued at 1, 2, 4, and 8 months follow up. CONCLUSIONS: In this case of severe penile pain the superior hypogastric plexus block was useful diagnostically and therapeutically.

Therapeutic drugs for neuropathic pain.

Neuropathic pain is common and may be resistant to usual doses of analgesic medications. However, an improved understanding of the pathophysiology of neuropathic pain and a growing number of adjuvant medications that are useful for the treatment of neuropathic pain provide renewed hope for clinicians and their patients. It is useful to classify adjuvant analgesic drugs into two broad categories. Membrane stabilizing agents, which include the anticonvulsants, antiarrhythmics and probably corticosteroids, may act by blocking sodium channels on damaged neural membranes. Medications that enhance dorsal horn inhibition, which include the antidepressants and some anticonvulsants, may augment biogenic amine or GABAergic mechanisms in the dorsal horn of the spinal cord. Current evidence regarding efficacy generally does not support the use of one agent over another and selection of a particular agent may depend in part on the expected side effects or experience with a given drug. For maximum analgesic effect, more than one agent may be necessary and to improve therapy and minimize side effects, medications generally should be started at lower doses and titrated slowly to effect. Although labor-intensive, this strategy may improve compliance and optimize patient care.

Deafferentation pain exacerbated by subarachnoid lidocaine and relieved by subarachnoid morphine. Case report.

BACKGROUND AND OBJECTIVES: Neuropathic pain syndromes are often resistant to traditional pharmacologic treatment. The authors describe a patient with chronic deafferentation pain of the legs associated with peripheral neuropathy that was refractory to multidisciplinary pain clinic management. METHODS: Numerous medications had been tried, including nortriptyline, mexiletine, and oral and parenteral opioids. Spinal cord stimulation was also ineffective, despite a satisfactory pattern of stimulation-induced paresthesias. For diagnostic purposes, differential spinal anesthesia with lidocaine and morphine was performed, with evoked potential monitoring used to evaluate the intensity of spinal anesthetic block. RESULTS: Paradoxically, lidocaine spinal anesthesia exacerbated pain, whereas subarachnoid morphine provided rapid pain relief. Long-term pain control has been maintained with an implanted spinal infusion pump. CONCLUSIONS: Evoked potential data acquired during lidocaine spinal anesthesia and the rapid pain relief provided by subarachnoid morphine suggest that deafferentation pain may involve segmental, opioid-sensitive dorsal horn pain generators. The long-term pain relief afforded the patient demonstrates that subarachnoid opioids may be efficacious for some forms of neuropathic pain.

Dorsal nerve block for management of intraoperative penile erection.

Intraoperative penile erection during general anesthesia can delay or prevent the completion of cystoscopic or penile surgical procedures. The dorsal penile nerve block is offered as a treatment for intraoperative erection. Advantages of this technique include less potential for cardiovascular complications and improved postoperative analgesia.