Infant Mortality Screening and Prevention Initiatives in Nepal.

Infant mortality is one of the leading public health crises in Nepal. While Nepal has made significant advances in mitigating under-five mortality, much work is still needed to be done regarding the healthcare of infants. The Nepalese government has identified this as a problem and has introduced a series of interventions to improve the health outcomes of infants. The aim of this review is to identify the goals, interventions, and effectiveness of major infant mortality prevention programs around the country. A comprehensive literature search was performed using PubMed and Google Scholar. The literature search revealed six programs that Nepal has utilized to combat infant mortality. The Community Based Management of Childhood Illness (CB-IMCI) program utilizes specially trained community workers to help identify and treat children with common childhood illnesses. The National Neonatal Health Strategy (NNHS) links families to the community and then to the broader healthcare system, with success found in its referral system. The Safe Delivery Incentives Program (SDIP) has found success with monetizing safe delivery practices, and shown an increase in safe deliveries with skilled healthcare workers present. Free Newborn Care (FNC) services were aimed at treating sick newborns for free, but ongoing concerns for program sustainability have led to further revision. The Every Newborn Action Plan (ENAP) is another plan aimed at preventing newborn deaths through improving health system administration and finances, but with limited efficacy data, it is hard to determine its success due to the lack of objective benchmark markers and data collected. Finally, the Birth Preparedness Package (BPP) is a highly efficacious program that encourages communities to plan for pregnancies by planning for delay barriers. Nepal has made significant strides in reducing infant mortality; however, much work still needs to be done. From 1990 to 2020, Nepal has reduced the under-five mortality rate from 138.8 deaths per 1,000 live births to 28.2 deaths per 1,000 live births.

Impact of Time to Surgery for Patients Using Workers' Compensation Insurance Undergoing Minimally Invasive Transforaminal Lumbar Interbody Fusion: A Preliminary Analysis of Clinical Outcomes.

OBJECTIVE: To conduct a preliminary analysis on the impact of time to surgery (TTS) and duration of symptoms (DOS) on clinical outcomes in workers' compensation patients undergoing minimally invasive transforaminal lumbar interbody fusion (MIS TLIF). METHODS: Patients using workers' compensation insurance undergoing primary, single-level MIS TLIF were identified. Patient-reported outcome measures (PROMs) were administered at preoperative/6-week/12-week/6-month postoperative time points and included visual analog scale (VAS) back/VAS leg/Oswestry Disability Index/12-Item Short-Form Physical Composite Score/12-Item Short-Form Mental Composite Score. Patients were grouped by TTS: <90 days, 90-179 days, and ≥180 days. Demographics were compared by χ2; perioperative characteristics, mean PROMs, and postoperative improvement (ΔPROM) were compared using 1-way analysis of variance. Minimum clinically important difference (MCID) achievement rates were compared using simple logistic regression. A secondary analysis was performed by grouping patients by DOS: <180 days, 180-364 days, and ≥365 days. Mean PROMs, ΔPROMs, and MCID achievement were similarly compared between DOS groups using 1-way analysis of variance and logistic regression. RESULTS: A total of 193 patients were included. Prevalence of herniated nucleus pulposus and initial appointment type were significantly associated with TTS (P < 0.042, all). No significant differences in mean PROMs or ΔPROMs were observed among TTS groups. MCID achievement was significantly lower for VAS back at 6 months in the longest TTS group. Mean PROMs were significantly different based on DOS for VAS leg at 6 weeks only. MCID achievement was significantly lower for the longest DOS group for VAS leg at 6 months only. ΔPROMs did not significantly differ among DOS groups. CONCLUSIONS: Neither TTS nor DOS was significantly associated with MIS TLIF outcomes. Workers' compensation patients may achieve similar clinical improvement even with longer symptom burden and substantial delays in operative treatment.

Influence of Preoperative 12-Item Short Form Mental Composite Score on Clinical Outcomes in an Isthmic Spondylolisthesis Population Undergoing Minimally Invasive Transforaminal Lumbar Interbody Fusion.

OBJECTIVE: To determine preoperative 12-Item Short Form Health Survey (SF-12) Mental Component Summary (MCS) influence on minimally important clinical difference (MCID) and patient-reported outcome measures in patients with isthmic spondylolisthesis receiving minimally invasive transforaminal lumbar interbody fusion. METHODS: Patients with isthmic spondylolisthesis undergoing primary, single-level minimally invasive transforaminal lumbar interbody fusion at L5-S1 were retrospectively identified and divided into preoperative SF-12 MCS <50 and SF-12 MCS ≥50 groups. Visual analog scale (VAS) back/leg, Oswestry Disability Index (ODI), SF-12 Physical Composite Score (PCS), and Patient-Reported Outcome Measurement Information System physical function (PROMIS-PF) were assessed. Improvements from preoperative score were analyzed via paired samples t test. Patient-reported outcome measures and MCID attainment between groups were evaluated using linear regression and χ2, respectively. RESULTS: SF-12 MCS <50 and SF-12 MCS ≥50 groups included 35 and 26 patients, respectively. SF-12 MCS < 50 group had inferior scores for all VAS back time points except 6 weeks, all VAS leg time points except 6 weeks/1 year, all ODI time points, SF-12 PCS at 6 months/2 years, and PROMIS-PF at preoperative/6 months (all P ≤ 0.049). SF-12 MCS <50 group improved for VAS back/leg to 1 year, ODI and SF-12 PCS from 12 weeks to 1 year, and PROMIS-PF at 1 year only (all P ≤ 0.047). SF-12 MCS ≥50 group improved for VAS back from 12 weeks to 1 year, SF-12 PCS 6 months to 2 years, and VAS leg, ODI, and PROMIS-PF 12 weeks to 2 years (all P ≤ 0.018). MCID attainment differed for ODI at 6 weeks and PROMIS-PF at 12 weeks only (both P ≤ 0.035). CONCLUSIONS: Patients with SF-12 MCS <50 demonstrated fewer long-term improvements from preoperative to 2 years and inferior patient-reported outcome measures at most time points for pain and disability following minimally invasive transforaminal lumbar interbody fusion. MCID attainment largely did not differ by preoperative mental functioning.

Adeno-Associated Virus (AAV) Capsid Stability and Liposome Remodeling During Endo/Lysosomal pH Trafficking.

Adeno-associated viruses (AAVs) are small, non-pathogenic ssDNA viruses being used as therapeutic gene delivery vectors for the treatment of a variety of monogenic diseases. An obstacle to successful gene delivery is inefficient capsid trafficking through the endo/lysosomal pathway. This study aimed to characterize the AAV capsid stability and dynamics associated with this process for a select number of AAV serotypes, AAV1, AAV2, AAV5, and AAV8, at pHs representative of the early and late endosome, and the lysosome (6.0, 5.5, and 4.0, respectively). All AAV serotypes displayed thermal melt temperatures that varied with pH. The stability of AAV1, AAV2, and AAV8 increased in response to acidic conditions and then decreased at pH 4.0. In contrast, AAV5 demonstrated a consistent decrease in thermostability in response to acidification. Negative-stain EM visualization of liposomes in the presence of capsids at pH 5.5 or when heat shocked showed induced remodeling consistent with the externalization of the PLA2 domain of VP1u. These observations provide clues to the AAV capsid dynamics that facilitate successful infection. Finally, transduction assays revealed a pH and temperature dependence with low acidity and temperatures > 4 °C as detrimental factors.

Thermal Stability as a Determinant of AAV Serotype Identity.

Currently, there are over 150 ongoing clinical trials utilizing adeno-associated viruses (AAVs) to target various genetic diseases, including hemophilia (AAV2 and AAV8), congenital heart failure (AAV1 and AAV6), cystic fibrosis (AAV2), rheumatoid arthritis (AAV2), and Batten disease (AAVrh.10). Prior to patient administration, AAV vectors must have their serotype, concentration, purity, and stability confirmed. Here, we report the application of differential scanning fluorimetry (DSF) as a good manufacturing practice (GMP) capable of determining the melting temperature (Tm) for AAV serotype identification. This is a simple, rapid, cost effective, and robust method utilizing small amounts of purified AAV capsids (∼25 µL of ∼1011 particles). AAV1-9 and AAVrh.10 exhibit specific Tms in buffer formulations commonly used in clinical trials. Notably, AAV2 and AAV3, which are the least stable, have varied Tms, whereas AAV5, the most stable, has a narrow Tm range in the different buffers, respectively. Vector stability was dictated by VP3 only, specifically, the ratio of basic/acidic amino acids, and was independent of VP1 and VP2 content or the genome packaged. Furthermore, stability of recombinant AAVs differing by a single basic or acidic amino acid residue are distinguishable. Hence, AAV DSF profiles can serve as a robust method for serotype identification of clinical vectors.