Antibodies, which are produced by B-lineage cells, consist of immunoglobulin heavy (IgH) and light (IgL) chains that have amino-terminal variable regions and carboxy-terminal constant regions. In response to antigens, B cells undergo two types of genomic alterations to increase antibody diversity. Affinity for antigen can be increased by introduction of point mutations into IgH and IgL variable regions by somatic hypermutation. In addition, antibody effector functions can be altered by changing the expressed IgH constant region exons through IgH class switch recombination (CSR). Somatic hypermutation and CSR both require the B-cell-specific activation-induced cytidine deaminase protein (AID), which initiates these reactions through its single-stranded (ss)DNA-specific cytidine deaminase activity. In biochemical assays, replication protein A (RPA), a ssDNA-binding protein, associates with phosphorylated AID from activated B cells and enhances AID activity on transcribed double-stranded (ds)DNA containing somatic hypermutation or CSR target sequences. This AID-RPA association, which requires phosphorylation, may provide a mechanism for allowing AID to access dsDNA targets in activated B cells. Here we show that AID from B cells is phosphorylated on a consensus protein kinase A (PKA) site and that PKA is the physiological AID kinase. Thus, AID from non-lymphoid cells can be functionally phosphorylated by recombinant PKA to allow interaction with RPA and promote deamination of transcribed dsDNA substrates. Moreover, mutation of the major PKA phosphorylation site of AID preserves ssDNA deamination activity, but markedly reduces RPA-dependent dsDNA deamination activity and severely impairs the ability of AID to effect CSR in vivo. We conclude that PKA has a critical role in post-translational regulation of AID activity in B cells.

Evidence-based management has improved long-term survival in patients with heart failure (HF). However, an unintended consequence of increased longevity is that patients with HF are exposed to a greater symptom burden over time. In addition to classic symptoms such as dyspnea and edema, patients with HF frequently suffer additional symptoms such as pain, depression, gastrointestinal distress, and fatigue. In addition to obvious effects on quality of life, untreated symptoms increase clinical events including emergency department visits, hospitalizations, and long-term mortality in a dose-dependent fashion. Symptom management in patients with HF consists of two key components: comprehensive symptom assessment and sufficient knowledge of available approaches to alleviate the symptoms. Successful treatment addresses not just the physical but also the emotional, social, and spiritual aspects of suffering. Despite a lack of formal experience during cardiovascular training, symptom management in HF can be learned and implemented effectively by cardiology providers. Co-management with palliative medicine specialists can add significant value across the spectrum and throughout the course of HF.

Context HIV infection has become a manageable chronic disease. There are few studies of pain and symptoms in the current treatment era. Objectives The primary objective was to determine the prevalence of and risk factors for pain and physical and psychological symptoms in a population of ambulatory HIV patients. Methods We performed a cross-sectional study using the Brief Pain Inventory and the Memorial Symptom Assessment Scale. Results We evaluated 156 individuals with a median age of 47.5 years (range 21–71), median time since HIV diagnosis of 11 years (range <1–25), and median CD4+ cell count of 502 cells/mm3 (interquartile range [IQR] 308–683). The majority (125, 80.6%) had an undetectable viral load. Seventy-six (48.7%) reported pain, of whom 39 (51.3%) had moderate to severe pain, and 43 (57.3%) had pain that caused moderate to severe interference with their lives. The median number of symptoms was eight (IQR 5–14.5) of 32 queried. In multivariable analyses, patients with psychiatric illness were 39.8% more likely to have pain (P<0.001). Psychiatric illness was associated with 0.7 and 1.2 point higher MSAS subscale scores, and intravenous (IV) drug use was associated with 0.4 and 0.5 higher subscale scores (out of four). Conclusion Pain and other physical and psychological symptoms were common among ambulatory HIV patients. Pain and symptoms were strongly associated with psychiatric illness and IV drug use. Future investigation should evaluate interventions that include psychiatric and substance abuse components for HIV patients with pain.

Background: Women comprise approximately one-third of the advanced heart failure population but may receive fewer advanced heart failure therapies including left ventricular assist devices (LVADs). During the early pulsatile-flow device era, women had higher post-LVAD mortality and increased complications. However, knowledge about these differences in the continuous-flow device era is limited. Therefore, we sought to explore temporal trends in LVAD utilization and post-LVAD mortality by sex. Methods and Results: Patients with LVAD implantation from 2004 to 2016 were identified using the Nationwide Inpatient Sample. Trends in LVAD utilization and post-LVAD inpatient mortality were compared by sex and device era. Although LVADs are being increasingly utilized for patients with advanced systolic heart failure, women continue to represent a smaller proportion of LVAD recipients—25.8% in 2004 to 21.9% in 2016 ( P for trend, 0.91). Women had increased inpatient mortality after LVAD implantation compared with men in the pulsatile-flow era (46.9% versus 31.1%, P <0.0001) but not in the continuous-flow era (13.3% versus 12.1%, P =0.27; P for interaction=0.0002). Inpatient mortality decreased for both sexes over time after LVAD, with a sharp fall in 2008 to 2009. Female sex was independently associated with increased post-LVAD inpatient mortality beyond adjustment for demographics and risk factors during the pulsatile-flow era (odds ratio, 2.13; 95% CI, 1.45–3.10; P <0.0001) but not during the continuous-flow era (1.18; 0.93–1.48; P =0.16). Conclusions: Although utilization of LVAD therapy increased over time for both sexes, LVAD implantation remains stably lower in women, which may suggest a potential underutilization of this potentially life-saving therapy. Prospective studies are needed to confirm these findings.