Key principles to accelerate progress in noncommunicable disease care and treatment: Discussion Paper

Recognizing the need for greater attention worldwide to noncommunicable diseases (NCDs) such as cardiovascular disease and diabetes, implementers are increasingly putting NCD programs in place. This effort is yielding practice-based experiences and evidence that may not be systematically documented and shared, reflected in a limited body of peer-reviewed and gray literature and few platforms for knowledge exchange. To draw on such knowledge that is grounded in experience, we gathered information through reviews of literature, local needs assessments, technical dialogues at the national and local levels, and structured global stakeholder engagement events to yield four principles that reflect the current state of knowledge on developing and implementing community-based services for health promotion and disease management: (1) Support and empower people living with chronic disease to provide better self-care and advocate for improved services. (2) Invest in integrating NCDs into existing development platforms but do not underestimate true costs and effort. (3) Engage a broad range of front-line health workers to champion care. (4) Build coalitions to leverage the strengths of both the public sector’s and private sector’s capacity and leadership. If applied consistently by funders and implementers, these principles have the potential to accelerate progress in reaching low-resourced communities with NCD care and treatment services. At the same time, if implementers commit to proactively, transparently, and collaboratively sharing experience-based learning, the NCD movement will not only pick up speed and be well supported by evidence but will also benefit from programmatic, financial, and political synergies at the global, national, and local levels

Rapid Rebound of a Preexisting CXCR4-tropic Human Immunodeficiency Virus Variant After Allogeneic Transplantation With CCR5 Δ32 Homozygous Stem Cells

Allogeneic stem cell transplantation (alloSCT) of homozygous CCR5 δ32 stem cells once resulted in the cure of human immunodeficiency virus (HIV) infection. We have recently reported a viral breakthrough in a similar setting. Here, we demonstrate that the rapid rebound after alloSCT was related to a highly replicative CXCR4-tropic HIV variant, which could already be detected before alloSCT

Prevention of herpes simplex virus induced stromal keratitis by a glycoprotein B-specific monoclonal antibody.

The increasing incidence of acyclovir (ACV) and multidrug-resistant strains in patients with corneal HSV-1 infections leading to Herpetic Stromal Keratitis (HSK) is a major health problem in industrialized countries and often results in blindness. To overcome this obstacle, we have previously developed an HSV-gB-specific monoclonal antibody (mAb 2c) that proved to be highly protective in immunodeficient NOD/SCID-mice towards genital infections. In the present study, we examined the effectivity of mAb 2c in preventing the immunopathological disease HSK in the HSK BALB/c mouse model. Therefore, mice were inoculated with HSV-1 strain KOS on the scarified cornea to induce HSK and subsequently either systemically or topically treated with mAb 2c. Systemic treatment was performed by intravenous administration of mAb 2c 24 h prior to infection (pre-exposure prophylaxis) or 24, 40, and 56 hours after infection (post-exposure immunotherapy). Topical treatment was performed by periodical inoculations (5 times per day) of antibody-containing eye drops as control, starting at 24 h post infection. Systemic antibody treatment markedly reduced viral loads at the site of infection and completely protected mice from developing HSK. The administration of the antiviral antibody prior or post infection was equally effective. Topical treatment had no improving effect on the severity of HSK. In conclusion, our data demonstrate that mAb 2c proved to be an excellent drug for the treatment of corneal HSV-infections and for prevention of HSK and blindness. Moreover, the humanized counterpart (mAb hu2c) was equally effective in protecting mice from HSV-induced HSK when compared to the parental mouse antibody. These results warrant the future development of this antibody as a novel approach for the treatment of corneal HSV-infections in humans

HEV-associated neuralgic amyotrophy: a multicentric case series

Background: Neuralgic amyotrophy (NA) has been described as a possible extrahepatic manifestation of hepatitis E virus (HEV) infection. Usually, HEV-associated NA occurs bilaterally. The clinical characteristics determining the course of HEV-associated NA have still not been defined. Methods: In this retrospective multicentric case series, 16 patients with HEV-associated NA were studied and compared to 176 HEV patients without NA in terms of their age, sex, and ALT levels. Results: Neither gender distribution (75% vs. 67% male) nor age (47 vs. 48 years median) differed significantly between the NA patients and controls. Eight NA patients (50%) presented with bilateral involvement — seven of these had right-side dominance and one had left-side dominance. Thirteen cases (81%) were hospitalized. Eight of these patients stayed in hospital for five to seven days, and five patients stayed for up to two weeks. The time from the onset of NA to the HEV diagnosis, as well as the diagnostic and therapeutic proceedings, showed a large variability. In total, 13 (81%) patients received treatment: 1/13 (8%) received intravenous immunoglobulins, 8/13 (62%) received glucocorticoids, 3/13 (23%) received ribavirin, and 6/13 (46%) received pregabalin/gabapentin. Patients with ages above the median (47 years) were more likely to be treated (p = 0.001). Conclusion: HEV-associated NA causes a relevant morbidity. In our case series neither the type of treatment nor the time of initiation of therapy had a significant effect on the duration of hospitalization or the course of the disease. The clinical presentation, the common diagnostic and therapeutic procedures, and the patients' characteristics showed large variability, demonstrating the necessity of standardized protocols for this rare but relevant disease

A Therapeutic Antiviral Antibody Inhibits the Anterograde Directed Neuron-to-Cell Spread of Herpes Simplex Virus and Protects against Ocular Disease

Herpes simplex virus (HSV) is a leading cause of blindness and viral encephalitis in the developed world. Upon reactivation from sensory neurons, HSV returns via axonal transport to peripheral tissues where it causes, e.g., severe, potentially blinding ocular diseases. In the present study we investigated whether the HSV-1/2 glycoprotein B-specific antibody mAb 2c or its humanized counterpart mAb hu2c can protect from ocular disease in a mouse model of HSV-1-induced acute retinal necrosis (ARN). In this model the viral spread from the initially infected to the contralateral eye resembles the routes taken in humans upon HSV reactivation. Systemic antibody treatment prior or early after infection effectively protected the mice from the development of ARN. These observations suggest that the antibody potently neutralized the infection and inhibited the viral transmission, since there was almost no virus detectable in the contralateral eyes and trigeminal ganglia of antibody treated mice. Besides of neutralizing free virus or limiting the infection via activating the complement or cellular effector functions, blocking of the anterograde directed neuron-to-cell spread of HSV represents a viable mode of action how mAb 2c protected the mice from ARN. We proved this hypothesis using a microfluidic chamber system. Neurons and epithelial cells were cultured in two separate compartments where the neurons sent axons via connecting microgrooves to the epithelial cells. Neurons were infected with a reporter HSV-1 strain expressing mCherry, and the co-culture was treated with neutralizing antibodies. In contrast to commercial polyclonal human HSV-neutralizing immunoglobulins, mAb 2c effectively blocked the anterograde directed neuron-to-cell transmission of the virus. Our data suggest that the humanized HSV-1/2-gB antibody protects mice from ocular disease by blocking the neuronal spread of HSV. Therefore, mAb hu2c may become a potent novel therapeutic option for severe ocular HSV infections

Role of BK polyomavirus (BKV) and Torque teno virus (TTV) in liver transplant recipients with renal impairment

Purpose. Renal impairment is a common complication after liver transplantation (LT). While BK polyomavirus (BKV) has been linked to renal failure in kidney transplant recipients, Torque teno virus (TTV) is a surrogate marker for immunosuppression that does not have a clear association with any human disease. The impact of BKV and TTV on renal impairment after LT is unknown. Methodology. In this retrospective study, urine and serum samples from 136 liver transplant recipients were screened for BKV and TTV by quantitative PCR. In addition, serum was screened for BKV-specific antibodies and the VP1 typing region was sequenced for BKV genotyping. All parameters were correlated with clinical data. Results/Key findings. BK viruria was detected up to 21 years after transplantation in 16.9% of cases. BK viraemia was detected in 8.7% of patients with BK viruria up to 4 years after LT. BKV-specific antibodies were detected in 93.6% of all LT recipients and correlated with BKV viral load in urine. There was no correlation between renal impairment and the detection of BK DNA in urine (OR 0.983). TTV DNA was detected in 84.6% of serum samples and in 66.6% of urine samples. The TTV viral load in serum correlated with the BKV viral load but had no impact on renal impairment. Conclusion. Our data indicate that the detection of BKV and TTV is not a risk factor for renal impairment after LT. A correlation of TTV and BKV viral load seems to be an indicator for the immune status of the host

Proliferative response of CD4⁺ and CD8⁺ lymphocytes after mAb 2c application.

<p>Lymphocytes derived from spleens or DLNs (R = ipsilateral, L = contralateral) of HSV-1 KOS infected mice receiving prophylactical or postexposure treatment (therapy) with mAb 2c were stimulated either with UV‑inactivated HSV-1 or Concavalin A for four days. Proliferation of CD4⁺ and CD8⁺ lymphocytes was determined by flow cytometry. Differences between the groups were statistically significant as calculated by a nonparametric ANOVA one way test (*<i>P</i> < 0.05; **<i>P</i> < 0.01). Error bars represent the SEM.</p

Effective prevention of corneal HSV-1 KOS infection in mice by systemic mAb 2c administration.

<p>Ocular disease scores of infected mice for blepharitis, epithelial defects and corneal opacity (stromal keratitis) are shown as an average score of ten mice per group over a period of 14 days <b>(A)</b>. The clinical disease scores taken on day 14 after infection are shown as dot plot <b>(B)</b>. Every dot represents a single mouse. Differences between the groups were statistically significant by a nonparametric ANOVA one way test (**<i>P</i> < 0.01; ***<i>P</i> < 0.001). Error bars represent the SEM.</p

Potent reduction of the severity of HSV-mediated corneal damage by mAb 2c.

<p>Groups of ten mice were either topically or systemically treated with mAb 2c. Pictures representative for topically PBS-treated mice <b>(A)</b> or systemically treated mice <b>(B)</b> were taken at day 14 post infection. Pathological changes of the cornea are shown as representative corneal sections from each group. Hematoxylin-eosin staining. Magnification: 120x. Scale bars: 100 μm.</p