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Background It has been more than 20 years for a new treatment for Alzheimer’s Disease (AD) to emerge. This treatment has recently been in the form of a monoclonal antibody targeting the end‐products of neuronal death. We are testing the safety of a novel approach using activated stem cells injected directly into the ventricles of the brain. Method After animal testing, we received FDA clearance for a 3 + 3, Phase 1 trial in 9 patients using escalating doses of the test product. The first patient was screened for age less than 80 years, FAST stage 4 or 5, having a Mini Mental Status Exam (MMSE) between 10 and 20, as well as exhibiting brain PET and CSF AD markers. The patient underwent a 3‐step process of liposuction, Ommaya reservoir implantation, and injection following cell selection and expansion based on Wnt expression in the lab (the test product). The patient was admitted to the hospital 43 days after initial lipoaspirate cell expansion and Wnt expression selection, for the injection, and observed overnight. Five ml. of the test product containing 2M cells was injected. Vital signs (VS) and clinical examinations were performed per protocol. CSF analysis, MMSE, amyloid PET and MRI imaging will be performed at regular intervals post‐injection for 1 year. Result There were no adverse events following any of the first 2 steps in the patient’s procedures. The injection process required 3 minutes to perform, without anesthetic. This was well‐tolerated with no immediate or remote headache, nausea, vomiting or change in VS up to 5 weeks post‐injection as of this publication. Conclusion This “first in human” trial of intracerebroventricular injection of Wnt‐expressing, adipose‐derived stem cells appears well‐tolerated and safe for our first injected patient with a minimum of 5 weeks followup. Our intention is to submit parallel Phase 2 trials to the FDA using this Phase 1 safety data, for treatment of patients with AD, MS‐P, Parkinson’s Disease, CTE, and ALS.

Wastewater-based epidemiology can be particularly valuable at university campuses where high-resolution spatial sampling in a well-controlled context could not only provide insight into what affects campus community as well as how those inferences can be extended to a broader city/county context. In the present study, a large-scale wastewater surveillance was successfully implemented on a large university campus enabling early detection of 85% of COVID-19 cases thereby averting potential outbreaks. Wastewater-based surveillance has gained prominence and come to the forefront as a leading indicator of forecasting COVID-19 (coronavirus disease 2019) infection dynamics owing to its cost-effectiveness and its ability to inform early public health interventions. A university campus could especially benefit from wastewater surveillance, as universities are characterized by largely asymptomatic populations and are potential hot spots for transmission that necessitate frequent diagnostic testing. In this study, we employed a large-scale GIS (geographic information systems)-enabled building-level wastewater monitoring system associated with the on-campus residences of 7,614 individuals. Sixty-eight automated wastewater samplers were deployed to monitor 239 campus buildings with a focus on residential buildings. Time-weighted composite samples were collected on a daily basis and analyzed on the same day. Sample processing was streamlined significantly through automation, reducing the turnaround time by 20-fold and exceeding the scale of similar surveillance programs by 10- to 100-fold, thereby overcoming one of the biggest bottlenecks in wastewater surveillance. An automated wastewater notification system was developed to alert residents to a positive wastewater sample associated with their residence and to encourage uptake of campus-provided asymptomatic testing at no charge. This system, integrated with the rest of the “Return to Learn” program at the University of California (UC) San Diego-led to the early diagnosis of nearly 85% of all COVID-19 cases on campus. COVID-19 testing rates increased by 1.9 to 13× following wastewater notifications. Our study shows the potential for a robust, efficient wastewater surveillance system to greatly reduce infection risk as college campuses and other high-risk environments reopen. IMPORTANCE Wastewater-based epidemiology can be particularly valuable at university campuses where high-resolution spatial sampling in a well-controlled context could not only provide insight into what affects campus community as well as how those inferences can be extended to a broader city/county context. In the present study, a large-scale wastewater surveillance was successfully implemented on a large university campus enabling early detection of 85% of COVID-19 cases thereby averting potential outbreaks. The highly automated sample processing to reporting system enabled dramatic reduction in the turnaround time to 5 h (sample to result time) for 96 samples. Furthermore, miniaturization of the sample processing pipeline brought down the processing cost significantly ($13/sample). Taken together, these results show that such a system could greatly ameliorate long-term surveillance on such communities as they look to reopen. Author Video : An author video summary of this article is available.

Background There is very little reported human experience with cell therapy for AD. We test the safety of using Wnt‐activated adipose tissue‐derived stem cells (ADSCs) injected directly into the ventricles of the brain to address multifactorial etiologies. Method Two million and 5 million expanded, Wnt‐expressing, ADSCs were tested in the first 5 patients (\"low‐dose and medium‐dose\") of a Phase 1 FDA clinical trial using escalating doses. Participants had age <80 years, FAST stages 4 and 5, and cognitive, amyloid PET centiloid scores, and CSF analyses consistent with AD. The participants underwent: 1) lipoaspiration and cell preparation, 2) Ommaya reservoir implantation, and 3) infusion of a single dose of the test product via Ommaya reservoir. The primary endpoint was safety. Secondary endpoints included normalization of phosphorylated tau (p ‐Tau), and amyloid beta, and improvement in cognitive testing scores. Result Adverse events (AEs) from pre‐injection surgical procedures included mild bruising and discomfort. Test product injection showed no AEs (range: 23‐55 weeks) including headache or nausea (Figure 1). At 12 weeks post‐injection, CSF phosphorylated tau (p ‐Tau) improved in 80% of the participants from a median of 60.2 pg/ml (range: 46.9 ‐ 76.1) to a normal median of 36.8 (range 15.0 – 66.6), amyloid PET scan centiloid scores decreased in 60% of participants from a pre‐injection median of 137.2 (range: 55.33 – 155.47) to a median of 100.53 (range: 55.58 – 168.1, Figure 3). ADAS‐cog scores improved in 80% of participants by week 12 from a pre‐injection median of 53 (range: 40 – 69) to a median of 38 (range: 20 – 69, Figure 4), MMSE scores improved in 60% of participants by week 12 from a pre‐injection median of 16 (range: 14 – 19) to a median of 18 (range: 12 – 20). Conclusion This \"first‐in‐human\" trial of intracerebroventricular injection of expanded autologous, Wnt‐expressing, adipose tissue‐derived stem cells proved well‐tolerated and safe for the low‐dose and medium dose cohorts. Secondary endpoints showed promising improvements.

There is very little reported human experience with cell therapy for AD. We test the safety of using Wnt-activated adipose tissue-derived stem cells (ADSCs) injected directly into the ventricles of the brain to address multifactorial etiologies. Two million and 5 million expanded, Wnt-expressing, ADSCs were tested in the first 5 patients (\"low-dose and medium-dose\") of a Phase 1 FDA clinical trial using escalating doses. Participants had age <80 years, FAST stages 4 and 5, and cognitive, amyloid PET centiloid scores, and CSF analyses consistent with AD. The participants underwent: 1) lipoaspiration and cell preparation, 2) Ommaya reservoir implantation, and 3) infusion of a single dose of the test product via Ommaya reservoir. The primary endpoint was safety. Secondary endpoints included normalization of phosphorylated tau (p -Tau), and amyloid beta, and improvement in cognitive testing scores. Adverse events (AEs) from pre-injection surgical procedures included mild bruising and discomfort. Test product injection showed no AEs (range: 23-55 weeks) including headache or nausea (Figure 1). At 12 weeks post-injection, CSF phosphorylated tau (p -Tau) improved in 80% of the participants from a median of 60.2 pg/ml (range: 46.9 - 76.1) to a normal median of 36.8 (range 15.0 - 66.6), amyloid PET scan centiloid scores decreased in 60% of participants from a pre-injection median of 137.2 (range: 55.33 - 155.47) to a median of 100.53 (range: 55.58 - 168.1, Figure 3). ADAS-cog scores improved in 80% of participants by week 12 from a pre-injection median of 53 (range: 40 - 69) to a median of 38 (range: 20 - 69, Figure 4), MMSE scores improved in 60% of participants by week 12 from a pre-injection median of 16 (range: 14 - 19) to a median of 18 (range: 12 - 20). This \"first-in-human\" trial of intracerebroventricular injection of expanded autologous, Wnt-expressing, adipose tissue-derived stem cells proved well-tolerated and safe for the low-dose and medium dose cohorts. Secondary endpoints showed promising improvements.

The microbiome, particularly the composition and diversity of microbial communities within various tissues, influences cancer development, progression and therapy response across various malignancies.1–5 Understanding specific microbial signatures associated with cancers, termed the oncobiome, is crucial for advancing diagnostic and therapeutic strategies.

The urogenital microbiome is an understudied yet important human microbiome niche. Research has been stimulated by the relatively recent discovery that urine is not sterile; urinary tract microbes have been linked to health problems, including urinary infections, incontinence, and cancer. Replicability is a well-established challenge in microbiome research with a variety of contributing factors at all stages, from sample collection to code execution. Here, we focus on voided urine sample storage conditions for urogenital microbiome analysis. Using urine samples collected from 10 adult females, we investigated the microbiome preservation efficacy of AssayAssure Genelock (Genelock), compared with no preservative, under different temperature conditions. We varied temperature over 48 h in order to examine the impact of conditions samples may experience with home voided urine collection and shipping to a central biorepository. The following common lab and shipping conditions were investigated: −20°C, ambient temperature, 4°C, freeze-thaw cycle, and heat cycle. At 48 h, all samples were stored at −80°C until processing. After generating 16S rRNA gene amplicon sequencing data using the highly sensitive KatharoSeq protocol, we observed individual variation in both alpha and beta diversity metrics below interhuman differences, corroborating reports of individual microbiome variability in other specimen types. While there was no significant difference in beta diversity when comparing Genelock versus no preservative, we did observe a higher concordance with Genelock samples shipped at colder temperatures (–20°C and 4°C) when compared with the samples shipped at −20°C without preservative. Our results indicate that Genelock does not introduce a significant amount of microbial bias when used on a range of temperatures and is most effective at colder temperatures. IMPORTANCE The urogenital microbiome is an understudied yet important human microbiome niche. Research has been stimulated by the relatively recent discovery that urine is not sterile; urinary tract microbes have been linked to health problems, including urinary infections, incontinence, and cancer. The quality of life and economic impact of UTIs and urgency incontinence alone are enormous, with$3.5 billion and $ 82.6 billion, respectively, spent in the United States. annually. Given the low biomass of urine, novelty of the field, and limited reproducibility evidence, it is critical to study urine sample storage conditions to optimize scientific rigor. Efficient and reliable preservation methods inform methods for home self-sample collection and shipping, increasing the potential use in larger-scale studies. Here, we examined both buffer and temperature variation effects on 16S rRNA gene amplicon sequencing results from urogenital samples, providing data on the consequences of common storage methods on urogenital microbiome results.

An analysis of fecal microbiome data from individuals in the United States, United Kingdom, and Mexico shows that associations with dietary components vary both by country and by level of resolution (i.e., genus and strain). Our work sheds light on why there may be conflicting reports regarding microbial associations with diet, disease, and health.

Wastewater-based surveillance has gained prominence and come to the forefront as a leading indicator of forecasting COVID-19 (coronavirus disease 2019) infection dynamics owing to its cost-effectiveness and its ability to inform early public health interventions. A university campus could especially benefit from wastewater surveillance, as universities are characterized by largely asymptomatic populations and are potential hot spots for transmission that necessitate frequent diagnostic testing. In this study, we employed a large-scale GIS (geographic information systems)-enabled building-level wastewater monitoring system associated with the on-campus residences of 7,614 individuals. Sixty-eight automated wastewater samplers were deployed to monitor 239 campus buildings with a focus on residential buildings. Time-weighted composite samples were collected on a daily basis and analyzed on the same day. Sample processing was streamlined significantly through automation, reducing the turnaround time by 20-fold and exceeding the scale of similar surveillance programs by 10- to 100-fold, thereby overcoming one of the biggest bottlenecks in wastewater surveillance. An automated wastewater notification system was developed to alert residents to a positive wastewater sample associated with their residence and to encourage uptake of campus-provided asymptomatic testing at no charge. This system, integrated with the rest of the “Return to Learn” program at the University of California (UC) San Diego-led to the early diagnosis of nearly 85% of all COVID-19 cases on campus. COVID-19 testing rates increased by 1.9 to 13× following wastewater notifications. Our study shows the potential for a robust, efficient wastewater surveillance system to greatly reduce infection risk as college campuses and other high-risk environments reopen. IMPORTANCE Wastewater-based epidemiology can be particularly valuable at university campuses where high-resolution spatial sampling in a well-controlled context could not only provide insight into what affects campus community as well as how those inferences can be extended to a broader city/county context. In the present study, a large-scale wastewater surveillance was successfully implemented on a large university campus enabling early detection of 85% of COVID-19 cases thereby averting potential outbreaks. The highly automated sample processing to reporting system enabled dramatic reduction in the turnaround time to 5 h (sample to result time) for 96 samples. Furthermore, miniaturization of the sample processing pipeline brought down the processing cost significantly ($13/sample). Taken together, these results show that such a system could greatly ameliorate long-term surveillance on such communities as they look to reopen. Author Video: An author video summary of this article is available.

We have chosen to test the safety of human intracerebroventricular (ICV) brain injections of autologous non-genetically-modified adipose-derived stromal vascular fraction (ADSVF). In this IRB-approved trial, 24 patients received ICV ADSVF via an implanted reservoir between 5/22/14 and 5/22/17. Seven others were injected via their ventriculo-peritoneal shunts. Ten patients had Alzheimer’s disease (AD), 6 had amyotrophic lateral sclerosis (ALS), 6 had progressive multiple sclerosis (MS-P), 6 had Parkinson’s “Plus” (PD+), 1 had spinal cord injury, 1 had traumatic brain injury, and 1 had stroke. Median age was 74 (range 41–83). Injections were planned every 2–3 months. Thirty-one patients had 113 injections. Patients received SVF injection volumes of 3.5–20 cc (median:4 cc) containing 4.05 × 105 to 6.2 × 107 cells/cc, which contained an average of 8% hematopoietic and 7.5% adipose stem cells. Follow-up ranged from 0 to 36 months (median: 9.2 months). MRIs post injection(s) were unchanged, except for one AD patient whose hippocampal volume increased from < 5th percentile to 48th percentile (NeuroQuant® volumetric MRI). Of the 10 AD patients, 8 were stable or improved in tests of cognition. Two showed improvement in P-tau and ß-amyloid levels. Of the 6 MS-P patients all are stable or improved. Four of 6 ALS patients died of disease progression. Twelve of 111 injections (11%) led to 1-4 days of transient meningismus, and mild temperature elevation, which resolved with acetaminophen and/or dexamethasone. Two (1.8% of injections) required hospitalization for these symptoms. One patient (0.9% of injections) had his reservoir removed and later replaced for presumed infection. In this Phase 1 safety trial, ADSVF was safely injected into the human brain ventricular system in patients with no other treatment options. Secondary endpoints of clinical improvement or stability were particularly promising in the AD and MS-P groups. These results will be submitted for a Phase 2 FDA-approved trial.

INTRODUCTION Primary glioblastoma (GBM) is associated with poor survival. Adjunctive therapeutic vaccines may improve survival. METHODS Key eligibility criteria were: (1) primary GBM, (2) age < 70 years, (3) successful GBM cell culture, (4) successful monocyte collection by leukapheresis, and (5) KPS > 70. IL-4 and GM-CSF were used to generate dendritic cells (DC) from monocytes. DC were incubated with autologous tumor antigens (ATA) from the lysate of cultured autologous GBM cells to produce each patient-specific DC-ATA vaccine. Each dose was admixed with GM-CSF at the time of subcutaneous injections at weeks 1, 2, 3, 8, 12, 16, 20 and 24. RESULTS Tumor collection took place during 08/2018 to 01/2020. Intent-to-treat enrollment took place during 10/2018 to 03/2020. 80 GBM tumors were collected; cell line success rate was 71/73 (97%); sufficient monocytes were collected for 63/65 (97%). 42 men and 18 women enrolled, just prior to starting standard concurrent radiation therapy (RT) and temozolomide (TMZ), with intent-to-treat after recovery from RT/TMZ. Median age was 59 years (range 27 to 70). Average KPS was 83.2. MGMT methylation was documented in 22%; IDH mutation in 12%. As of this update 53 patients had started treatment and received 309 doses. Injections have been well-tolerated and no patient has discontinued treatment because of treatment-emergent adverse events. Within two weeks of starting injections, 12/16 patients (75%) had an increase in markers associated with Th1/NK, Th2/immunoglobulins, and Th2 hypersensitivity (eotaxins, IgE and IL17F); 9/15 (60%) had a decrease in tumor markers, growth factors, and angiogenesis factors by week-8. Survival analysis as of 12/31/19 (n = 50, median follow up 6.4 months) showed projected 6-, 12-, and 15- month overall survival rates of 94%, 76%, and 76% respectively, with 8 patients in follow up between 12 and 15 months. CONCLUSION This patient-specific DC-ATA approach is feasible, well-tolerated, associated with changes in serologic markers, and early survival rates are encouraging.