Immune compromise in HIV-1/HTLV-1 coinfection with paradoxical resolution of CD4 lymphocytosis during antiretroviral therapy: a case report

Human immunodeficiency virus type-1 (HIV-1) and human T lymphotropic virus type-1 (HTLV-1) infections have complex effects on adaptive immunity, with specific tropism for, but contrasting effects on, CD4 T lymphocytes: depletion with HIV-1, proliferation with HTLV-1. Impaired T lymphocyte function occurs early in HIV-1 infection but opportunistic infections (OIs) rarely occur in the absence of CD4 lymphopenia. In the unusual case where a HIV-1 infected individual with a high CD4 count presents with recurrent OIs, a clinician is faced with the possibility of a second underlying comorbidity. We present a case of pseudo-adult T cell leukemia/lymphoma (ATLL) in HIV-1/HTLV-1 coinfection where the individual fulfilled Shimoyama criteria for chronic ATLL and had pulmonary Mycobacterium kansasii, despite a high CD4 lymphocyte count. However, there was no evidence of clonal T-cell proliferation by T-cell receptor gene rearrangement studies nor of monoclonal HTLV-1 integration by high-throughput sequencing. Mutually beneficial interplay between HIV-1 and HTLV-1, maintaining high level HIV-1 and HTLV-1 viremia and proliferation of poorly functional CD4 cells despite chronicity of infection is a postulated mechanism. Despite good microbiological response to antimycobacterial therapy, the patient remained systemically unwell with refractory anemia. Subsequent initiation of combined antiretroviral therapy led to paradoxical resolution of CD4 T lymphocytosis as well as HIV-1 viral suppression and decreased HTLV-1 proviral load. This is proposed to be the result of attenuation of immune activation post-HIV virological control. This case illustrates the importance of screening for HTLV-1 in HIV-1 patients with appropriate clinical presentation and epidemiological risk factors and explores mechanisms for the complex interactions on HIV-1/HTLV-1 adaptive immunity

International Olympic Committee Consensus Statement: Molecular Basis of Connective Tissue and Muscle Injuries in Sport

Tendon and ligament injures cause significant loss of performance in sport and decreased functional capacity in the workplace. Many of these injures remain difficult to treat, and many individuals have long-term pain and discomfort. Animal studies of growth factor and cell-based therapies have shown promising results, but these treatments also can be misused to enhance athletic performance. The International Olympic Committee (IOC) now has high-level scientific advisors who can advise the IOC as to the use and abuse of these technologies

T cell receptor Vβ staining identifies the malignant clone in adult T cell leukemia and reveals killing of leukemia cells by autologous CD8+ T cells

There is growing evidence that CD8+ cytotoxic T lymphocyte (CTL) responses can contribute to long-term remission of many malignancies. The etiological agent of adult T-cell leukemia/lymphoma (ATL), human T lymphotropic virus type-1 (HTLV-1), contains highly immunogenic CTL epitopes, but ATL patients typically have low frequencies of cytokine-producing HTLV-1-specific CD8+ cells in the circulation. It remains unclear whether patients with ATL possess CTLs that can kill the malignant HTLV-1 infected clone. Here we used flow cytometric staining of TCRVβ and cell adhesion molecule-1 (CADM1) to identify monoclonal populations of HTLV-1-infected T cells in the peripheral blood of patients with ATL. Thus, we quantified the rate of CD8+-mediated killing of the putative malignant clone in ex vivo blood samples. We observed that CD8+ cells from ATL patients were unable to lyse autologous ATL clones when tested directly ex vivo. However, short in vitro culture restored the ability of CD8+ cells to kill ex vivo ATL clones in some donors. The capacity of CD8+ cells to lyse HTLV-1 infected cells which expressed the viral sense strand gene products was significantly enhanced after in vitro culture, and donors with an ATL clone that expressed the HTLV-1 Tax gene were most likely to make a detectable lytic CD8+ response to the ATL cells. We conclude that some patients with ATL possess functional tumour-specific CTLs which could be exploited to contribute to control of the disease

Internal fixation implants for intracapsular hip fractures in older adults: Review

Background Hip fractures are a major healthcare problem, presenting a huge challenge and burden to patients, healthcare systems and society. The increased proportion of older adults in the world population means that the absolute number of hip fractures is rising rapidly across the globe. The majority of hip fractures are treated surgically. This review evaluates evidence for types of internal fixation implants used in joint‐preserving surgery for intracapsular hip fractures. Objectives To determine the relative effects (benefits and harms) of different implants for the internal fixation of intracapsular hip fractures in older adults. Search methods We searched CENTRAL, MEDLINE, Embase, Web of Science, Cochrane Database of Systematic Reviews, Epistemonikos, Proquest Dissertations and Theses, and National Technical Information Service in July 2020. We also searched clinical trials databases, conference proceedings, reference lists of retrieved articles and conducted backward‐citation searches. Selection criteria We included randomised controlled trials (RCTs) and quasi‐RCTs comparing implants used for internal fixation of fragility intracapsular proximal femoral fractures in older adults. Types of implants were smooth pins (these include pins with fold‐out hooks), screws, or fixed angle plates. We excluded studies in which all or most fractures were caused by specific pathologies other than osteoporosis or were the result of a high energy trauma. Data collection and analysis Two review authors independently assessed studies for inclusion. One review author extracted data and assessed risk of bias which was checked by a second review author. We collected data for seven outcomes: activities of daily living (ADL), delirium, functional status, health‐related quality of life (HRQoL), mobility, mortality (reported within four months of surgery as early mortality, and at 12 months since surgery), and unplanned return to theatre for treating a complication resulting directly or indirectly from the primary procedure (such as deep infection or non‐union). We assessed the certainty of the evidence for these outcomes using GRADE. Main results We included 38 studies (32 RCTs, six quasi‐RCTs) with 8585 participants with 8590 intracapsular fractures. The mean ages of participants in the studies ranged from 60 to 84 years; 73% were women, and 38% of fractures were undisplaced. We report here the findings of the four main comparisons, which were between different categories of implants. We downgraded the certainty of the outcomes for imprecision (when data were available from insufficient numbers of participants or the confidence interval (CI) was wide), study limitations (e.g. high or unclear risks of bias), and inconsistency (when we noted substantial levels of statistical heterogeneity). Smooth pins versus fixed angle plate (four studies, 1313 participants) We found very low‐certainty evidence of little or no difference between the two implant types in independent mobility with no more than one walking stick (1 study, 112 participants), early mortality (1 study, 383 participants), mortality at 12 months (2 studies, 661 participants), and unplanned return to theatre (3 studies, 736 participants). No studies reported on ADL, delirium, functional status, or HRQoL. Screws versus fixed angle plates (11 studies, 2471 participants) We found low‐certainty evidence of no clinically important differences between the two implant types in functional status using WOMAC (MD ‐3.18, 95% CI ‐6.35 to ‐0.01; 2 studies, 498 participants; range of scores from 0 to 96, lower values indicate better function), and HRQoL using EQ‐5D (MD 0.03, 95% CI 0.00 to 0.06; 2 studies, 521 participants; range ‐0.654 (worst), 0 (dead), 1 (best)). We also found low‐certainty evidence showing little or no difference between the two implant types in mortality at 12 months (RR 1.04, 95% CI 0.83 to 1.31; 7 studies, 1690 participants), and unplanned return to theatre (RR 1.10, 95% CI 0.95 to 1.26; 11 studies, 2321 participants). We found very low‐certainty evidence of little or no difference between the two implant types in independent mobility (1 study, 70 participants), and early mortality (3 studies, 467 participants). No studies reported on ADL or delirium. Screws versus smooth pins (seven studies, 1119 participants) We found low‐certainty evidence of no or little difference between the two implant types in mortality at 12 months (RR 1.07, 95% CI 0.85 to 1.35; 6 studies, 1005 participants; low‐certainty evidence). We found very low‐certainty evidence of little or no difference between the two implant types in early mortality (3 studies, 584 participants) and unplanned return to theatre (5 studies, 862 participants). No studies reported on ADL, delirium, functional status, HRQoL, or mobility. Screws or smooth pins versus fixed angle plates (15 studies, 3784 participants) In this comparison, we combined data from the first two comparison groups. We found low‐certainty evidence of no or little difference between the two groups of implants in mortality at 12 months (RR 1.04, 95% CI.083 to 1.31; 7 studies, 1690 participants) and unplanned return to theatre (RR 1.02, 95% CI 0.88 to 1.18; 14 studies, 3057 participants). We found very low‐certainty evidence of little or no difference between the two groups of implants in independent mobility (2 studies, 182 participants), and early mortality (4 studies, 850 participants). We found no additional evidence to support the findings for functional status or HRQoL as reported in 'Screws versus fixed angle plates'. No studies reported ADL or delirium. Authors' conclusions There is low‐certainty evidence that there may be little or no difference between screws and fixed angle plates in functional status, HRQoL, mortality at 12 months, or unplanned return to theatre; and between screws and pins in mortality at 12 months. The limited and very low‐certainty evidence for the outcomes for which data were available for the smooth pins versus fixed angle plates comparison, as well as the other outcomes for which data were available for the screws and fixed angle plates, and screws and pins comparisons means we have very little confidence in the estimates of effect for these outcomes. Additional RCTs would increase the certainty of the evidence. We encourage such studies to report outcomes consistent with the core outcome set for hip fracture, including long‐term quality of life indicators such as ADL and mobility

Molecular dynamics simulations reveal membrane lipid interactions of the full-length lymphocyte specific kinase Lck

The membrane-bound lymphocyte-specific protein-tyrosine kinase (Lck) triggers T cell antigen receptor signalling to initiate adaptive immune responses. Despite many structure–function studies, the mode of action of Lck and the potential role of plasma membrane lipids in regulating Lck’s activity remains elusive. Advances in molecular dynamics simulations of membrane proteins in complex lipid bilayers have opened a new perspective in gathering such information. Here, we have modelled the full-length Lck open and closed conformations using data available from different crystalographic studies and simulated its interaction with the inner leaflet of the T cell plasma membrane. In both conformations, we found that the unstructured unique domain and the structured domains including the kinase interacted with the membrane with a preference for PIP lipids. Interestingly, our simulations suggest that the Lck-SH2 domain interacts with lipids differently in the open and closed Lck conformations, demonstrating that lipid interaction can potentially regulate Lck’s conformation and in turn modulate T cell signalling. Additionally, the Lck-SH2 and kinase domain residues that significantly contacted PIP lipids are found to be conserved among the Src family of kinases, thereby potentially representing similar PIP interactions within the family

Evolution of retrovirus-infected premalignant T-cell clones prior to Adult T-cell leukemia/lymphoma diagnosis

Adult T cell leukemia/lymphoma (ATL) is an aggressive hematological malignancy caused by Human T-cell leukemia virus type-1 (HTLV-1). ATL is preceded by decades of chronic HTLV-1 infection, and the tumors carry both somatic mutations and proviral DNA integrated into the tumor genome. In order to gain insight into the oncogenic process, we used targeted sequencing to track the evolution of the malignant clone in six individuals, 2-10 years before the diagnosis of ATL. Clones of premalignant HTLV-1-infected cells bearing known driver mutations were detected in the blood up to 10 years before individuals developed acute and lymphoma subtype ATL. Six months before diagnosis, the total number and variant allele fraction of mutations increased in the blood. Peripheral blood mononuclear cells from premalignant cases (1 year pre-diagnosis) had significantly higher mutational burden in genes frequently mutated in ATL than did high risk, age-matched HTLV-1-carriers who remained ATL-free after a median of 10 years of follow up. These data show that HTLV-1-infected T cell clones carrying key oncogenic driver mutations can be detected in cases of ATL years before the onset of symptoms. Early detection of such mutations may enable earlier and more effective intervention to prevent the development of ATL

Surgical interventions for treating extracapsular hip fractures in older adults: a network meta‐analysis: Review

Background Hip fractures are a major healthcare problem, presenting a challenge and burden to individuals and healthcare systems. The number of hip fractures globally is rising. The majority of extracapsular hip fractures are treated surgically. Objectives To assess the relative effects (benefits and harms) of all surgical treatments used in the management of extracapsular hip fractures in older adults, using a network meta‐analysis of randomised trials, and to generate a hierarchy of interventions according to their outcomes. Search methods We searched CENTRAL, MEDLINE, Embase, Web of Science and five other databases in July 2020. Selection criteria We included randomised controlled trials (RCTs) and quasi‐RCTs comparing different treatments for fragility extracapsular hip fractures in older adults. We included internal and external fixation, arthroplasties and non‐operative treatment. We excluded studies of hip fractures with specific pathologies other than osteoporosis or resulting from high‐energy trauma. Data collection and analysis Two review authors independently assessed studies for inclusion. One review author completed data extraction which was checked by a second review author. We collected data for three outcomes at different time points: mortality and health‐related quality of life (HRQoL) ‐ both reported within 4 months, at 12 months and after 24 months of surgery, and unplanned return to theatre (at end of study follow‐up). We performed a network meta‐analysis (NMA) with Stata software, using frequentist methods, and calculated the differences between treatments using risk ratios (RRs) and standardised mean differences (SMDs) and their corresponding 95% confidence intervals (CIs). We also performed direct comparisons using the same codes. Main results We included 184 studies (160 RCTs and 24 quasi‐RCTs) with 26,073 participants with 26,086 extracapsular hip fractures in the review. The mean age in most studies ranged from 60 to 93 years, and 69% were women. After discussion with clinical experts, we selected nine nodes that represented the best balance between clinical plausibility and efficiency of the networks: fixed angle plate (dynamic and static), cephalomedullary nail (short and long), condylocephalic nail, external fixation, hemiarthroplasty, total hip arthroplasty (THA) and non‐operative treatment. Seventy‐three studies (with 11,126 participants) with data for at least two of these treatments contributed to the NMA. We selected the dynamic fixed angle plate as a reference treatment against which other treatments were compared. This was a common treatment in the networks, providing a clinically appropriate comparison. We downgraded the certainty of the evidence for serious and very serious risks of bias, and because some of the estimates included the possibility of transitivity owing to the proportion of stable and unstable fractures between treatment comparisons. We also downgraded if we noted evidence of inconsistency in direct or indirect estimates from which the network estimate was derived. Most estimates included the possibility of benefits and harms, and we downgraded the evidence for these treatments for imprecision. Overall, 20.2% of participants who received the reference treatment had died by 12 months after surgery. We noted no evidence of any differences in mortality at this time point between the treatments compared. Effect estimates of all treatments included plausible benefits as well as harms. Short cephalomedullary nails had the narrowest confidence interval (CI), with 7 fewer deaths (26 fewer to 15 more) per 1000 participants, compared to the reference treatment (risk ratio (RR) 0.97, 95% CI 0.87 to 1.07). THA had the widest CI, with 62 fewer deaths (177 fewer to 610 more) per 1000 participants, compared to the reference treatment (RR 0.69, 95% CI 0.12 to 4.03). The certainty of the evidence for all treatments was low to very low. Although we ranked the treatments, this ranking should be interpreted cautiously because of the imprecision in all the network estimates for these treatments. Overall, 4.3% of participants who received the reference treatment had unplanned return to theatre. Compared to this treatment, we found very low‐certainty evidence that 58 more participants (14 to 137 more) per 1000 participants returned to theatre if they were treated with a static fixed angle plate (RR 2.48, 95% CI 1.36 to 4.50), and 91 more participants (37 to 182 more) per 1000 participants returned to theatre if treated with a condylocephalic nail (RR 3.33, 95% CI 1.95 to 5.68). We also found that these treatments were ranked as having the highest probability of unplanned return to theatre. In the remaining treatments, we noted no evidence of any differences in unplanned return to theatre, with effect estimates including benefits as well as harms. The certainty of the evidence for these other treatments ranged from low to very low. We did not use GRADE to assess the certainty of the evidence for early mortality, but our findings were similar to those for 12‐month mortality, with no evidence of any differences in treatments when compared to dynamic fixed angle plate. Very few studies reported HRQoL and we were unable to build networks from these studies and perform network meta‐analysis. Authors' conclusions Across the networks, we found that there was considerable variability in the ranking of each treatment such that there was no one outstanding, or subset of outstanding, superior treatments. However, static implants such as condylocephalic nails and static fixed angle plates did yield a higher risk of unplanned return to theatre. We had insufficient evidence to determine the effects of any treatments on HRQoL, and this review includes data for only two outcomes. More detailed pairwise comparisons of some of the included treatments are reported in other Cochrane Reviews in this series. Short cephalomedullary nails versus dynamic fixed angle plates contributed the most evidence to each network, and our findings indicate that there may be no difference between these treatments. These data included people with both stable and unstable extracapsular fractures. At this time, there are too few studies to draw any conclusions regarding the benefits or harms of arthroplasty or external fixation for extracapsular fracture in older adults. Future research could focus on the benefits and harms of arthroplasty interventions compared with internal fixation using a dynamic implant