3D electronic implants in subretinal space: Long-term follow-up in rodents.

Clinical results with photovoltaic subretinal prosthesis (PRIMA) demonstrated restoration of sight via electrical stimulation of the interneurons in degenerated retina, with resolution matching the 100 µm pixel size. Since scaling the pixels below 75 µm in the current bipolar planar geometry will significantly limit the penetration depth of the electric field and increase stimulation threshold, we explore the possibility of using smaller pixels based on a novel 3-dimensional honeycomb-shaped design. We assessed the long-term biocompatibility and stability of these arrays in rats by investigating the anatomical integration of the retina with flat and 3D implants and response to electrical stimulation over lifetime - up to 32-36 weeks post-implantation in aged rats. With both flat and 3D implants, signals elicited in the visual cortex decreased after the day of implantation by more than 3-fold, and gradually recovered over the next 12-16 weeks. With 25 µm high honeycomb walls, the majority of bipolar cells migrate into the wells, while amacrine and ganglion cells remain above the cavities, which is essential for selective network-mediated stimulation of the retina. Retinal thickness and full-field stimulation threshold with 40 µm-wide honeycomb pixels were comparable to those with planar devices - 0.05 mW/mm2 with 10 ms pulses. However, fewer cells from the inner nuclear layer migrated into the 20 µm-wide wells, and stimulation threshold increased over 12-16 weeks, before stabilizing at about 0.08 mW/mm2. Such threshold is still significantly lower than 1.8 mW/mm2 with a previous design of flat bipolar pixels, confirming the promise of the 3D honeycomb-based approach to high resolution subretinal prosthesis.

Guillain Barre syndrome mimicking brain death.

A 49-year-old female patient presented at the hospital with a history of herpetic blisters, frequent episodes of vomiting and loose stools, bilateral upper and lower limb weakness, and diminishing sensorium. She was diagnosed with hyponatraemia and respiratory failure and later became unconscious with absent brainstem reflexes. The patient was initially treated for herpetic encephalitis, a chronic obstructive pulmonary disease with acute exacerbation, hyponatraemia and neuroparalytic snake bite. Further evaluation, however, identified the uncommon Guillain Barre syndrome presentation with overlap of Bickerstaff brainstem encephalitis. This is an uncommon disorder characterised by the involvement of higher mental functions, fixed dilated pupils, absent brainstem reflexes and quadriplegia that resembles a neuroparalytic snake bite and brain death. After receiving intravenous immunoglobulins for treatment, the patient completely recovered.

Bothersome Hot Flashes Following Neoadjuvant Androgen Deprivation Therapy and Stereotactic Body Radiotherapy for Localized Prostate Cancer.

BACKGROUND: Androgen deprivation therapy (ADT) improves local cancer control in unfavorable localized prostate cancer treated with radiotherapy. ADT is known to cause hormonally related symptoms that resolve with testosterone recovery. Hot flashes are particularly burdensome. This study sought to evaluate the timeline of hot flashes following short-course ADT and stereotactic body radiotherapy (SBRT) as well as its relationship with testosterone recovery. METHODS: Institutional IRB approval was obtained for this retrospective review of prospectively collected data (IRB#: 2009-510). ADT was initiated three months prior to the start of SBRT. Hot flashes were self-reported via question 13a of the Expanded Prostate Index Composite (EPIC)-26 prior to ADT initiation, the first day of robotic SBRT, and at each follow-up (one, three, six, nine, 12, 18, 24, and 36 months). The responses were grouped into three relevant categories (no problem, very small-small problem, and moderate-big problem). Scores were transformed to a 0-100 scale with higher scores reflecting less bother. Testosterone levels were measured at each follow-up. RESULTS: From 2007 to 2010, 122 localized prostate cancer patients (nine low-, 64 intermediate-, and 49 high-risk according to the D'Amico classification) at a median age of 72 years (range 54.5-88.3) were treated with short course ADT (three to six months) and SBRT (35-36.25 Gy) at Georgetown University Hospital. Thirty-two percent were Black and 27% were obese. Seventy-seven percent of patients received three months of ADT. At baseline, 2% of men experienced hot flashes that were a "moderate to big problem" and that proportion peaked at the start of SBRT (45%) before returning to baseline (2%) nine months post-SBRT with a cumulative incidence of 52.4%. The median baseline EPIC-26 hot flash score of 94 declined to 50 at the start of SBRT but this returned to baseline (92) by six months post SBRT. These changes were both statistically and clinically significant (MID = 9.5083, p<0.01). Testosterone recovery (> 230 ng/dL) occurred in approximately 70% of patients by 12 months post SBRT. Resolution of hot flashes correlated with testosterone recovery. CONCLUSION: Bothersome hot flashes occur in greater than 50% of men treated with neoadjuvant ADT. Resolution of hot flashes occurs in the majority of patients within one year after treatment. Reassurance of the temporary nature of hot flashes may assist in reducing patient anxiety. Measuring testosterone levels at follow-up visits may allow for anticipatory counseling that may limit the associated bother.

Impact of neoadjuvant relugolix on patient-reported sexual function and bother.

Introduction: Sexual function following local treatment for prostate cancer is an important quality of life concern. Relugolix is a novel oral GnRH receptor antagonist used in combination with radiation therapy in the treatment of unfavorable prostate cancer. It has been shown to achieve rapid and profound testosterone suppression. As a result, these very low testosterone levels may impact both sexual functioning and perceptions. This prospective study sought to assess neoadjuvant relugolix-induced sexual dysfunction prior to stereotactic body radiation therapy (SBRT). Methods: Between March 2021 and September 2023, 87 patients with localized prostate cancer were treated with neoadjuvant relugolix followed by SBRT per an institutional protocol. Sexual function and bother were assessed via the sexual domain of the validated Expanded Prostate Index Composite (EPIC-26) survey. Responses were collected for each patient at pre-treatment baseline and after several months of relugolix. A Utilization of Sexual Medications/Devices questionnaire was administered at the same time points to assess erectile aid usage. Results: The median age was 72 years and 43% of patients were non-white. The median baseline Sexual Health Inventory for Men (SHIM) score was 13 and 41.7% of patients utilized sexual aids prior to relugolix. Patients initiated relugolix at a median of 4.5 months (2-14 months) prior to SBRT. 95% and 87% of patients achieved effective castration (≤ 50 ng/dL) and profound castration (< 20 ng/dl) at SBRT initiation, respectively. Ability to have an erection, ability to reach orgasm, quality of erections, frequency of erections, and overall sexual function significantly declined following relugolix. There was a non- significant increase in sexual bother. Discussion: In concordance with known side effects of androgen deprivation therapy (ADT), neoadjuvant relugolix was associated with a significant decline in self-reported sexual function. However, patients indicated only a minimal and non-significant increase in bother. Future investigations should compare outcomes while on relugolix directly to GnRH agonist-induced sexual dysfunction.

Enhancing Prosthetic Vision by Upgrade of a Subretinal Photovoltaic Implant in situ.

In patients with atrophic age-related macular degeneration, subretinal photovoltaic implant (PRIMA) provided visual acuity up to 20/440, matching its 100µm pixels size. Next-generation implants with smaller pixels should significantly improve the acuity. This study in rats evaluates removal of a subretinal implant, replacement with a newer device, and the resulting grating acuity in-vivo. Six weeks after the initial implantation with planar and 3-dimensional devices, the retina was re-detached, and the devices were successfully removed. Histology demonstrated a preserved inner nuclear layer. Re-implantation of new devices into the same location demonstrated retinal re-attachment to a new implant. New devices with 22µm pixels increased the grating acuity from the 100µm capability of PRIMA implants to 28µm, reaching the limit of natural resolution in rats. Reimplanted devices exhibited the same stimulation threshold as for the first implantation of the same implants in a control group. This study demonstrates the feasibility of safely upgrading the subretinal photovoltaic implants to improve prosthetic visual acuity.

Potential of DPD ((S)-4,5-dihydroxy-2,3-pentanedione) Analogs in Microparticulate Formulation as Vaccine Adjuvants.

The molecule (S)-4,5-dihydroxy-2,3-pentanedione (DPD) is produced by many different species of bacteria and is involved in bacterial communication. DPD is the precursor of signal molecule autoinducer-2 (AI-2) and has high potential to be used as a vaccine adjuvant. Vaccine adjuvants are compounds that enhance the stability and immunogenicity of vaccine antigens, modulate efficacy, and increase the immune response to a particular antigen. Previously, the microparticulate form of (S)-DPD was found to have an adjuvant effect with the gonorrhea vaccine. In this study, we evaluated the immunogenicity and adjuvanticity of several synthetic analogs of the (S)-DPD molecule, including ent-DPD((R)-4,5-dihydroxy-2,3-pentanedione), n-butyl-DPD ((S)-1,2-dihydroxy-3,4-octanedione), isobutyl-DPD ((S)-1,2-dihydroxy-6-methyl-3,4-heptanedione), n-hexyl-DPD ((S)-1,2-dihydroxy-3,4-decanedione), and phenyl-DPD ((S)-3,4-dihydroxy-1-phenyl-1,2-butanedione), in microparticulate formulations. The microparticulate formulations of all analogs of (S)-DPD were found to be noncytotoxic toward dendritic cells. Among these analogs, ent-DPD, n-butyl-DPD, and isobutyl-DPD were found to be immunogenic toward antigens and showed adjuvant efficacy with microparticulate gonorrhea vaccines. It was observed that n-hexyl-DPD and phenyl-DPD did not show any adjuvant effect. This study shows that synthetic analogs of (S)-DPD molecules are capable of eliciting adjuvant effects with vaccines. A future in vivo evaluation will further confirm that these analogs are promising vaccine adjuvants.

Three-dimensional electro-neural interfaces electroplated on subretinal prostheses.

Objective.Retinal prosthetics offer partial restoration of sight to patients blinded by retinal degenerative diseases through electrical stimulation of the remaining neurons. Decreasing the pixel size enables increasing prosthetic visual acuity, as demonstrated in animal models of retinal degeneration. However, scaling down the size of planar pixels is limited by the reduced penetration depth of the electric field in tissue. We investigated 3-dimensional (3d) structures on top of photovoltaic arrays for enhanced penetration of the electric field, permitting higher resolution implants.Approach.3D COMSOL models of subretinal photovoltaic arrays were developed to accurately quantify the electrodynamics during stimulation and verified through comparison to flat photovoltaic arrays. Models were applied to optimize the design of 3D electrode structures (pillars and honeycombs). Return electrodes on honeycomb walls vertically align the electric field with bipolar cells for optimal stimulation. Pillars elevate the active electrode, thus improving proximity to target neurons. The optimized 3D structures were electroplated onto existing flat subretinal prostheses.Main results.Simulations demonstrate that despite exposed conductive sidewalls, charge mostly flows via high-capacitance sputtered iridium oxide films topping the 3D structures. The 24µm height of honeycomb structures was optimized for integration with the inner nuclear layer cells in the rat retina, whilst 35µm tall pillars were optimized for penetrating the debris layer in human patients. Implantation of released 3D arrays demonstrates mechanical robustness, with histology demonstrating successful integration of 3D structures with the rat retinain-vivo.Significance. Electroplated 3D honeycomb structures produce vertically oriented electric fields, providing low stimulation thresholds, high spatial resolution, and high contrast for pixel sizes down to 20µm. Pillar electrodes offer an alternative for extending past the debris layer. Electroplating of 3D structures is compatible with the fabrication process of flat photovoltaic arrays, enabling much more efficient retinal stimulation.

Early biochemical outcomes following neoadjuvant/adjuvant relugolix with stereotactic body radiation therapy for intermediate to high risk prostate cancer.

Introduction: Injectable GnRH receptor agonists have been shown to improve cancer control when combined with radiotherapy. Prostate SBRT offers an abbreviated treatment course with comparable efficacy to conventionally fractionated radiotherapy. Relugolix is a new oral GnRH receptor antagonist which achieves rapid, sustained testosterone suppression. This prospective study sought to evaluate early testosterone suppression and PSA response following relugolix and SBRT for intermediate to high prostate cancer. Methods: Relugolix was initiated at least 2 months prior to SBRT. Interventions to improve adherence were not utilized. PSA and total testosterone levels were obtained prior to and 1-4 months post SBRT. Profound castration was defined as serum testosterone ≤ 20 ng/dL. Early PSA nadir was defined as the lowest PSA value within 4 months of completion of SBRT. Per prior trials, we examined the percentage of patients who achieved PSA level of ≤ 0.5 ng/mL and ≤ 0.2 ng/mL during the first 4 months post SBRT. Results: Between July 2021 and January 2023, 52 men were treated at Georgetown with relugolix (4-6 months) and SBRT (36.25-40 Gy in 5 fractions) per an institutional protocol (IRB 12-1775). Median age was 71 years. 26.9% of patients were African American and 28.8% were obese (BMI ≥30 kg/m2). The median pretreatment PSA was 9.1 ng/ml. 67% of patients were ≥ Grade Group 3. 44 patients were intermediate- and 8 were high-risk. Patients initiated relugolix at a median of 3.6 months prior to SBRT with a median duration of 6.2 total months. 92.3% of patients achieved profound castration during relugolix treatment. Poor drug adherence was observed in 2 patients. A third patient chose to discontinue relugolix due to side effects. By post-SBRT month 4, 87.2% and 74.4% of patients achieved PSA levels ≤ 0.5 ng/ml and ≤ 0.2 ng/ml, respectively. Discussion: Relugolix combined with SBRT allows for high rates of profound castration with low early PSA nadirs. We observed a 96% testosterone suppresion rate without the utilization of scheduled cues/reminders. This finding supports the notion that patients with localized prostate cancer can consistently and successfully follow an oral ADT protocol without daily reminders. Given relugolix's potential benefits over injectable GnRH receptor agonists, its usage may be preferred in specific patient populations (fear of needles, prior cardiovascular events). Future studies should focus on boundaries to adherence in specific underserved populations.

Three-dimensional electro-neural interfaces electroplated on subretinal prostheses.

Objective: High-resolution retinal prosthetics offer partial restoration of sight to patients blinded by retinal degenerative diseases through electrical stimulation of the remaining neurons. Decreasing the pixel size enables an increase in prosthetic visual acuity, as demonstrated in animal models of retinal degeneration. However, scaling down the size of planar pixels is limited by the reduced penetration depth of the electric field in tissue. We investigate 3-dimensional structures on top of the photovoltaic arrays for enhanced penetration of electric field to permit higher-resolution implants. Approach: We developed 3D COMSOL models of subretinal photovoltaic arrays that accurately quantify the device electrodynamics during stimulation and verified it experimentally through comparison with the standard (flat) photovoltaic arrays. The models were then applied to optimise the design of 3D electrode structures (pillars and honeycombs) to efficiently stimulate the inner retinal neurons. The return electrodes elevated on top of the honeycomb walls surrounding each pixel orient the electric field inside the cavities vertically, aligning it with bipolar cells for optimal stimulation. Alternatively, pillars elevate the active electrode into the inner nuclear layer, improving proximity to the target neurons. Modelling results informed a microfabrication process of electroplating the 3D electrode structures on top of the existing flat subretinal prosthesis. Main results: Simulations demonstrate that despite the conductive sidewalls of the 3D electrodes being exposed to electrolyte, most of the charge flows via the high-capacitance sputtered Iridium Oxide film that caps the top of the 3D structures. The 24 µm height of the electroplated honeycomb structures was optimised for integration with the inner nuclear layer cells in rat retina, while 35 µm height of the pillars was optimized for penetrating the debris layer in human patients. Release from the wafer and implantation of the 3D arrays demonstrated that they are mechanically robust to withstand the associated forces. Histology demonstrated successful integration of the 3D structures with the rat retina in-vivo. Significance: Electroplated 3D honeycomb structures produce a vertically oriented electric field that offers low stimulation threshold, high spatial resolution and high contrast for the retinal implants with pixel sizes down to 20µm in width. Pillar electrodes offer an alternative configuration for extending the stimulation past the debris layers. Electroplating of the 3D structures is compatible with the fabrication process of the flat photovoltaic arrays, thereby enabling much more efficient stimulation than in their original flat configuration.

Testosterone as a Biomarker for Quality of Life (QOL) Following Androgen Deprivation Therapy (ADT) and Stereotactic Body Radiotherapy (SBRT).

BACKGROUND: Androgen deprivation therapy (ADT) causes fatigue and sexual dysfunction. The time to testosterone recovery depends on patient and treatment-specific characteristics. The kinetics of testosterone recovery in men treated with neoadjuvant ADT and stereotactic body radiotherapy (SBRT) is not well established. This study seeks to characterize testosterone recovery and evaluate its relationship with the improvement in patient-reported hormonal and sexual function. METHODS: Institutional review board (IRB) approval was obtained for retrospective review of prospectively collected data. All patients with localized prostate cancer treated with short-course ADT (3-6 months of Leuprolide) and robotic SBRT (35-36.25 Gy in five fractions) at a single institution were included in this analysis. Testosterone levels were measured at the start of radiation, every 3 months for the first year, and every 6 months thereafter. Total testosterone recovery was defined as a serum level of >230 ng/dL. Sexual and hormonal function was recorded using the Expanded Prostate Index Composite (EPIC)-26 prior to ADT initiation, the first day of SBRT, and at each follow-up. The EPIC-26 subdomain scores were transformed to a 0-100 scale with higher scores reflecting less bother. RESULTS: Between January 2009 and May 2018, 122 men with a median age of 72 years (range: 55-89 years) received ADT followed by SBRT. Thirty-two percent (N=39) were black and 27% [N=39 were obese (BMI > 30)]. The median pre-SBRT testosterone level was 15 ng/dL (range: 3-89 ng/dL). Around 77% (N=94) of patients received 3 months of ADT. The median pre-ADT EPIC-26 Hormone and Sexual Domain Scores were 94 and 41, respectively. At 12 months, 71% (N=87) of patients recovered to a eugonadal state with a mean recovery time of 4 months post-SBRT. Hormonal and sexual subdomain scores declined significantly following ADT but recovered to within the minimally important difference (MID) for sexual and hormonal domain scores by 12 months post-SBRT. CONCLUSIONS: Testosterone recovery following short-course ADT with leuprolide and SBRT occurs rapidly in the majority of patients within one year after treatment. Quality of life domain improvements followed the testosterone recovery trend closely. Testosterone testing at follow-up appointments would allow for anticipatory counseling that may limit the bother associated with temporary quality of life decrements.

3D electronic implants in subretinal space: long-term follow-up in rodents.

Photovoltaic subretinal prosthesis (PRIMA) enables restoration of sight via electrical stimulation of the interneurons in degenerated retina, with resolution limited by the 100 µm pixel size. Since decreasing the pixel size below 75 µm in the current bipolar geometry is impossible, we explore the possibility of using smaller pixels based on a novel 3-dimensional honeycomb-shaped design. We assessed the long-term biocompatibility and stability of these arrays in rats by investigating the anatomical integration of the retina with flat and 3D implants and response to electrical stimulation over lifetime - up to 9 months post-implantation in aged rats. With both flat and 3D implants, VEP amplitude decreased after the day of implantation by more than 3-fold, and gradually recovered over about 3 months. With 25 µm high honeycomb walls, the majority of bipolar cells migrate into the wells, while amacrine and ganglion cells remain above the cavities, which is essential for selective network-mediated stimulation of the second-order neurons. Retinal thickness and full-field stimulation threshold with 40 µm-wide honeycomb pixels were comparable to those with planar devices - 0.05 mW/mm2 with 10ms pulses. However, fewer cells from the inner nuclear layer migrated into the 20 µm-wide wells, and stimulation threshold increased over 5 months, before stabilizing at about 0.08 mW/mm2. Such threshold is significantly lower than 1.8 mW/mm2 with a previous design of flat bipolar pixels, confirming the promise of the 3D honeycomb-based approach to high resolution subretinal prosthesis.

Evaluating the Release of Different Commercial Orally Modified Niacin Formulations In Vitro.

OBJECTIVES: To evaluate the release profile of different modified-release oral formulations of niacin, such as immediate-release (IR) powder and tablets, timed-release (TR) caplets, extended-release (ER) capsules, and controlled-release (CR) tablets, to assure their defined release pattern and correlate this release with their matrix polymers. SIGNIFICANCE: Niacin is used to manage hyperlipidemia by reducing cutaneous flushing and hepatotoxicity adverse events. The release profiles of different types of modified-release dosage forms depend on the types of coating materials (polymers) used in the matrix formation. Although different types of niacin formulations exist, none of the niacin dissolution profiles have been evaluated and compared in the literature. METHODS: Four commercial orally modified-release niacin brands were collected from a local CVS pharmacy retail store, in Miami, FL, USA. The in vitro release study was conducted in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) conditions. RESULTS: The results of the release patterns of four niacin-modified dosage forms (IR, ER, TR, and CR) were aligned with their release definitions. However, the CR dosage form did not follow an ideal release pattern. CONCLUSIONS: The release rate of niacin in vitro was pH dependent, which was confirmed by the similarity factor (f2) results. All the f2 comparison values were below 50 in both the SIF and SGF media, while all the comparisons were below the f2 values for all brands in the SIF media.

The Autoinducer N-Octanoyl-L-Homoserine Lactone (C8-HSL) as a Potential Adjuvant in Vaccine Formulations.

Autoinducers AI-1 and AI-2 play an important role in bacterial quorum sensing (QS), a form of chemical communication between bacteria. The autoinducer N-octanoyl-L-Homoserinehomoserine lactone (C8-HSL) serves as a major inter- and intraspecies communicator or 'signal', mainly for Gram-negative bacteria. C8-HSL is proposed to have immunogenic properties. The aim of this project is to evaluate C8-HSL as a potential vaccine adjuvant. For this purpose, a microparticulate formulation was developed. The C8-HSL microparticles (MPs) were formulated by a water/oil/water (W/O/W) double-emulsion solvent evaporation method using PLGA (poly (lactic-co-glycolic acid)) polymer. We tested C8-HSL MPs with two spray-dried bovine serum albumin (BSA)-encapsulated bacterial antigens: colonization factor antigen I (CFA/I) from Escherichia coli (E. coli.) and the inactive protective antigen (PA) from Bacillus anthracis (B. anthracis). We formulated and tested C8-HSL MP to determine its immunogenicity potential and its ability to serve as an adjuvant with particulate vaccine formulations. An in vitro immunogenicity assessment was performed using Griess's assay, which indirectly measures the nitric oxide radical (NOˑ) released by dendritic cells (DCs). The C8-HSL MP adjuvant was compared with FDA-approved adjuvants to determine its immunogenicity potential. C8-HSL MP was combined with particulate vaccines for measles, Zika and the marketed influenza vaccine. The cytotoxicity study showed that MPs were non-cytotoxic toward DCs. Griess's assay showed a comparable release of NOˑ from DCs when exposed to CFA and PA bacterial antigens. Nitric oxide radical (NOˑ) release was significantly higher when C8-HSL MPs were combined with particulate vaccines for measles and Zika. C8-HSL MPs showed immunostimulatory potential when combined with the influenza vaccine. The results showed that C8-HSL MPs were as immunogenic as FDA-approved adjuvants such as alum, MF59, and CpG. This proof-of-concept study showed that C8-HSL MP displayed adjuvant potential when combined with several particulate vaccines, indicating that C8-HSL MPs can increase the immunogenicity of both bacterial and viral vaccines.

Bothersome Hematospermia Following Stereotactic Body Radiation Therapy for Prostate Cancer.

BACKGROUND: Hematospermia following prostate radiation therapy is a benign and often self-limiting side effect. However, it may be bothersome to some men and their partners with a negative impact on sexual quality of life (QOL). This study sought to evaluate the incidence, duration, and resolution of hematospermia in patients following stereotactic body radiation therapy (SBRT) for prostate cancer. METHODS: 227 patients treated with SBRT from 2013 to 2019 at Georgetown University Hospital for localized prostate carcinoma with a minimum follow up of two years were included in this retrospective review of data that was prospectively collected. Patients who were greater than 70 years old and/or received hormonal therapy were excluded. Hematospermia was defined as bright red blood in the ejaculate. Time points for data collection included initial consultation, pre-treatment, 1-, 3-, 6-, 9-, 12-, 18-, 24-month. All patients were treated with the CyberKnife Radiosurgical System (Accuray). Data on hematospermia including duration, resolution and recurrence was collected. Utilization of 5-alpha reductase inhibitors was documented at each visit. RESULTS: 227 patients (45 low-, 177 intermediate-, and 5 high-risk according to the D'Amico classification) at a median age of 65 years (range 47-70) received SBRT for their localized prostate cancer. The 2-year cumulative incidence of hematospermia was 5.6%(14 patients). For these patients, all but one patient (93%) saw resolution of their hematospermia by two years post-SBRT. The median time for hematospermia was 9 months post-treatment. Of the 14 patients who reported hematospermia, 70% were managed with 5-alpha reductase inhibitors. Hematospermia was transient in most patients with 70% of the men reporting resolution by the next follow-up visit. CONCLUSION: The incidence of bothersome hematospermia following SBRT was low. Hematospermia, as noted by other studies, often self-resolves. 5-alpha reductase inhibitors may lead to quicker resolution of bothersome hematospermia.

Potential Applications of Microparticulate-Based Bacterial Outer Membrane Vesicles (OMVs) Vaccine Platform for Sexually Transmitted Diseases (STDs): Gonorrhea, Chlamydia, and Syphilis.

Sexually transmitted diseases (STDs) are a major global health issue. Approximately 250 million new cases of STDs occur each year globally. Currently, only three STDs (human papillomavirus (HPV), hepatitis A, and hepatitis B) are preventable by vaccines. Vaccines for other STDs, including gonorrhea, chlamydia, and syphilis, await successful development. Currently, all of these STDs are treated with antibiotics. However, the efficacy of antibiotics is facing growing challenge due to the emergence of bacterial resistance. Therefore, alternative therapeutic approaches, including the development of vaccines against these STDs, should be explored to tackle this important global public health issue. Mass vaccination could be more efficient in reducing the spread of these highly contagious diseases. Bacterial outer membrane vesicle (OMV) is a potential antigen used to prevent STDs. OMVs are released spontaneously during growth by many Gram-negative bacteria. They present a wide range of surface antigens in native conformation that possess interesting properties such as immunogenicity, adjuvant potential, and the ability to be taken up by immune cells, all of which make them an attractive target for application as vaccines against pathogenic bacteria. The major challenge associated with the use of OMVs is its fragile structure and stability. However, a particulate form of the vaccine could be a suitable delivery system that can protect the antigen from degradation by a harsh acidic or enzymatic environment. The particulate form of the vaccine can also act as an adjuvant by itself. This review will highlight some practical methods for formulating microparticulate OMV-based vaccines for STDs.

A Review on Current COVID-19 Vaccines and Evaluation of Particulate Vaccine Delivery Systems.

First detected in Wuhan, China, a highly contagious coronavirus, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), also known as COVID-19, spread globally in December of 2019. As of 19 September 2021, approximately 4.5 million people have died globally, and 215 million active cases have been reported. To date, six vaccines have been developed and approved for human use. However, current production and supply capabilities are unable to meet global demands to immunize the entire world population. Only a few countries have been able to successfully vaccinate many of their residents. Therefore, an alternative vaccine that can be prepared in an easy and cost-effective manner is urgently needed. A vaccine that could be prepared in this manner, as well as can be preserved and transported at room temperature, would be of great benefit to public health. It is possible to develop such an alternative vaccine by using nano- or microparticle platforms. These platforms address most of the existing vaccine limitations as they are stable at room temperature, are inexpensive to produce and distribute, can be administered orally, and do not require cold chain storage for transportation or preservation. Particulate vaccines can be administered as either oral solutions or in sublingual or buccal film dosage forms. Besides improved patient compliance, the major advantage of oral, sublingual, and buccal routes of administration is that they can elicit mucosal immunity. Mucosal immunity, along with systemic immunity, can be a strong defense against SARS-CoV-2 as the virus enters the system through inhalation or saliva. This review discusses the possibility to produce a particulate COVID vaccine by using nano- or microparticles as platforms for oral administration or in sublingual or buccal film dosage forms in order to accelerate global vaccination.

Bleeding Risk Following Stereotactic Body Radiation Therapy for Localized Prostate Cancer in Men on Baseline Anticoagulant or Antiplatelet Therapy.

PURPOSE: Patients on anticoagulant/antiplatelet medications are at a high risk of bleeding following external beam radiation therapy for localized prostate cancer. SBRT may reduce the bleeding risk by decreasing the volume of bladder/rectum receiving high doses. This retrospective study sought to evaluate the rates of hematuria and hematochezia following SBRT in these patients. METHODS: Localized prostate cancer patients treated with SBRT from 2007 to 2017 on at least one anticoagulant/antiplatelet at baseline were included. The minimum follow-up was 3 years with a median follow-up of 72 months. Patients who had a rectal spacer placed prior to SBRT were excluded. Radiotherapy was delivered in 5 fractions to a dose of 35 Gy or 36.25 Gy utilizing the CyberKnife system. Hematuria and hematochezia were prospectively assessed before and after treatment using the Expanded Prostate Cancer Index Composite (EPIC-26). Toxicities were scored using the CTCAE v4. Cystoscopy and colonoscopy findings were retrospectively reviewed. RESULTS: Forty-four men with a median age of 72 years with a history of taking at least one anticoagulant and/or antiplatelet medication received SBRT. Warfarin (46%), clopidogrel (34%) and rivaroxaban (9%) were the most common medications. Overall, 18.2% experienced hematuria with a median time of 10.5 months post-SBRT. Altogether, 38.6% experienced hematochezia with a median time of 6 months post-SBRT. ≥ Grade 2 hematuria and hematochezia occurred in 4.6% and 2.5%, respectively. One patient required bladder neck fulguration and one patient underwent rectal cauterization for multiple non-confluent telangiectasia. There were no grade 4 or 5 toxicities. Cystoscopy revealed bladder cancer (40%) and benign prostatic bleeding (40%) as the most common hematuria etiology. Colonoscopy demonstrated hemorrhoids (54.5%) and radiation proctitis (9.1%) as the main causes of hematochezia. There was no significant change from the mean baseline EPIC-26 hematuria and hematochezia scores at any point during follow up. CONCLUSION: In patients with baseline anticoagulant usage, moderate dose prostate SBRT was well tolerated without rectal spacing. High grade bleeding toxicities were uncommon and resolved with time. Baseline anticoagulation usage should not be considered a contraindication to prostate SBRT.

Moderate Intensity Treadmill Exercise Increases Survival of Newborn Hippocampal Neurons and Improves Neurobehavioral Outcomes after Traumatic Brain Injury.

Physician-prescribed rest after traumatic brain injury (TBI) is both commonplace and an increasingly scrutinized approach to TBI treatment. Although this practice remains a standard of patient care for TBI, research of patient outcomes reveals little to no benefit of prescribed rest after TBI, and in some cases prolonged rest has been shown to interfere with patient well-being. In direct contrast to the clinical advice regarding physical activity after TBI, animal models of brain injury consistently indicate that exercise is neuroprotective and promotes recovery. Here, we assessed the effect of low and moderate intensity treadmill exercise on functional outcome and hippocampal neural proliferation after brain injury. Using the controlled cortical impact (CCI) mouse model of TBI, we show that 10 days of moderate intensity treadmill exercise initiated after CCI reduces anxiety-like behavior, improves hippocampus-dependent spatial memory, and promotes hippocampal proliferation and newborn neuronal survival. Pathophysiological measures including lesion volume and axon degeneration were not altered by exercise. Taken together, these data reveal that carefully titrated physical activity may be a safe and effective approach to promoting recovery after brain injury.

Urinary Morbidity in Men Treated With Stereotactic Body Radiation Therapy (SBRT) for Localized Prostate Cancer Following Transurethral Resection of the Prostate (TURP).

Background: Clinical data suggest that stereotactic body radiation therapy (SBRT) provides similar clinical outcomes as other radiation modalities for prostate cancer. However, data reporting on the safety of SBRT after TURP is limited. Herein, we report our experience using SBRT to deliver hypofractionated radiotherapy in patients with a history of TURP including physician-reported toxicities and patient-reported quality of life. Methods: Forty-seven patients treated with SBRT from 2007 to 2016 at Georgetown University Hospital for localized prostate carcinoma with a history of prior TURP were included in this retrospective analysis. Treatment was delivered using the CyberKnife® (Accuray Incorporated, Sunnyvale, CA) with doses of 35 Gy or 36.25 Gy in 5 fractions without prostatic urethral sparing. Toxicities were recorded and scored using the CTCAE v.4. Cystoscopy findings were retrospectively reviewed. Urinary quality of life data was assessed using the International Prostate Symptom Scoring (IPSS) and Expanded Prostate Cancer Index Composite 26 (EPIC-26). A Wilcoxon signed-rank sum test was used to determine if there was a statistically significant increase or decrease in IPSS or EPIC scores between timepoints. Minimally important differences were calculated by obtaining half the standard deviation at time of start of treatment. Results: Forty-seven patients at a median age of 72 years (range 63-84) received SBRT. The mean follow-up was 4.7 years (range 2-10 years). Late Grade 2 and grade 3 urinary toxicity occurred in 23 (48.9%) and 3 (6.4%) men, respectively. There were no Grade 4 or 5 toxicities. Approximately 51% of patients experienced hematuria following treatment. Mean time to hematuria was 10.5 months. Twenty-five cystoscopies were performed during follow-up and the most common finding was hyperemia, varices of the bladder neck/TURP defect, and/or necrotic tissue in the TURP defect. Baseline urinary QOL composite scores were low, but they did not clinically significantly decline in the first 2 years following treatment. Conclusions: In patients with prior TURP, prostate SBRT was well-tolerated. GU toxicity rates were comparable to similar patients treated with conventionally fractionated radiation therapy. Urinary quality of life was poor at baseline, but did not worsen clinically over time. Stricter dosimetric criteria could potentially improve the rate of high-grade late toxicity, but may increase the risk of peri-urethral recurrence.