Enterococcus faecalis Endocarditis of All Four Native Valves: A Case Report.

Enterococcus faecalis is commonly implicated in Infective Endocarditis (IE), resulting in remarkable morbidity and mortality. We present an unusual case documenting the clinical course and outcome of an elderly female patient who developed quadruple valve endocarditis due to Enterococcus faecalis infection. She presented with altered mental status, resulting in hospitalization, and was found to have bacteremia complicated by endocarditis, epidural abscess, discitis, and splenic infarction. Urinalysis was consistent with bacterial infection two days before being admitted to the hospital. Unfortunately, despite aggressive therapeutic regimens, the patient died.  This is one of the few documented endocarditis cases involving all heart valves. It reviews the importance of maintaining a high index of clinical suspicion for assessing IE, with a low threshold for performing a transesophageal echocardiogram as a diagnostic tool.

Treatment of pain in length-dependent peripheral neuropathy with the use of spinal cord stimulation: a systematic review.

BACKGROUND: Chronic intractable pain from peripheral neuropathy is a debilitating condition that might not respond to conventional medical management and pharmacotherapy. The primary objective of this systematic review was to assess change (or reduction) in pain intensity in patients with length-dependent peripheral neuropathy after spinal cord stimulation (SCS) therapy. METHODS: This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. The primary outcome was change (or reduction) in pain intensity after 12 months of SCS therapy compared with baseline in participants with length-dependent peripheral neuropathy. Secondary outcomes included change in pain intensity after 6 months and change in opioid consumption after 12 months. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) guidelines were used to appraise the quality of evidence. RESULTS: Nineteen studies consisting of 376 participants who underwent SCS implantation met the inclusion criteria. Qualitative synthesis revealed that all eligible studies reported a significant improvement in pain intensity after 12 months of SCS therapy as compared with baseline. Mean differences with 95% confidence intervals were calculated for 4 studies, all of which achieved the minimal clinically important difference for change in pain intensity at 12 months. The GRADE quality of evidence for this outcome was appraised as very low quality. CONCLUSION: This systematic review highlights that SCS could lead to significant improvement in pain intensity for length-dependent peripheral neuropathy, although future well-powered randomized controlled trials are warranted to increase the certainty of evidence in this finding. STUDY REGISTRATION: PROSPERO (https://www.crd.york.ac.uk/PROSPERO/) ID: CRD42022377572.

Neuromodulation for Peripheral Nerve Regeneration: Systematic Review of Mechanisms and In Vivo Highlights.

While denervation can occur with aging, peripheral nerve injuries are debilitating and often leads to a loss of function and neuropathic pain. Although injured peripheral nerves can regenerate and reinnervate their targets, this process is slow and directionless. There is some evidence supporting the use of neuromodulation to enhance the regeneration of peripheral nerves. This systematic review reported on the underlying mechanisms that allow neuromodulation to aid peripheral nerve regeneration and highlighted important in vivo studies that demonstrate its efficacy. Studies were identified from PubMed (inception through September 2022) and the results were synthesized qualitatively. Included studies were required to contain content related to peripheral nerve regeneration and some form of neuromodulation. Studies reporting in vivo highlights were subject to a risk of bias assessment using the Cochrane Risk of Bias tool. The results of 52 studies indicate that neuromodulation enhances natural peripheral nerve regeneration processes, but still requires other interventions (e.g., conduits) to control the direction of reinnervation. Additional human studies are warranted to verify the applicability of animal studies and to determine how neuromodulation can be optimized for the greatest functional restoration.

Microbiological and Physiological Effects of Pain.

Pain is an important innate defense mechanism that can dramatically alter a person's quality of life. Understanding the microbiological and physiological effects of pain may be important in the pursuit of novel pain interventions. The three descriptors of pain recognized by the International Association for the Study of Pain are nociceptive, neuropathic, and nociplastic pain. Our review examined the current understanding of all three pain types, focusing on the key molecules involved in the manifestation of each type as well as physiological effects. Additionally, we compared the differences in painful and painless neuropathies and discussed the neuroimmune interaction involved in the manifestation of pain.

Peripheral Nerve Stimulation for Low Back Pain: A Systematic Review.

PURPOSE OF REVIEW: Low back pain (LBP) is a prevalent condition that is associated with diminished physical function, poor mental health outcomes, and reduced quality of life. Peripheral nerve stimulation (PNS) is an emerging modality that has been utilized to treat LBP. The primary objective of this systematic review is to appraise the level of evidence on the efficacy of PNS for treatment of LBP. RECENT FINDINGS: Twenty-nine articles were included in this systematic review, consisting of 828 total participants utilizing PNS as the primary modality for LBP and 173 participants using PNS as salvage or adjunctive therapy for LBP after SCS placement. Different modalities of PNS therapy were reported across studies, including conventional PNS systems stimulating the lumbar medial branch nerves, peripheral nerve field stimulation (PNFS), and restorative neuromuscular stimulation of the multifidus muscles. All studies consistently reported positive modest to moderate improvement in pain intensity with PNS therapy when comparing baseline pain intensity to each study's respective primary follow-up period. There was a very low GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) quality of evidence supporting this finding. Inconsistency was present in some comparative studies that demonstrated no difference between PNS therapy versus control cohorts (sham or SCS therapy alone), which therefore highlighted the potential for placebo effect. This systematic review highlights that PNS, PNFS, and neuromuscular stimulation may provide modest to moderate pain relief in patients with LBP, although evidence is currently limited due to risk of bias, clinical and methodological heterogeneity, and inconsistency in data.

Saturated fatty acids dampen the immunogenicity of cancer by suppressing STING.

Oncogenes destabilize STING in epithelial cell-derived cancer cells, such as head and neck squamous cell carcinomas (HNSCCs), to promote immune escape. Despite the abundance of tumor-infiltrating myeloid cells, HNSCC presents notable resistance to STING stimulation. Here, we show how saturated fatty acids in the microenvironment dampen tumor response to STING stimulation. Using single-cell analysis, we found that obesity creates an IFN-I-deprived tumor microenvironment with a massive expansion of suppressive myeloid cell clusters and contraction of effector T cells. Saturated fatty acids, but not unsaturated fatty acids, potently inhibit the STING-IFN-I pathway in HNSCC cells. Myeloid cells from obese mice show dampened responses to STING stimulation and are more suppressive of T cell activation. In agreement, obese hosts exhibited increased tumor burden and lower responsiveness to STING agonist. As a mechanism, saturated fatty acids induce the expression of NLRC3, depletion of which results in a T cell inflamed tumor microenvironment and IFN-I-dependent tumor control.

Cervical Spinal Cord Stimulation for the Treatment of Headache Disorders: A Systematic Review.

OBJECTIVES: Chronic headache remains a major cause of disability and pain worldwide. Although the literature has extensively described pharmacologic options for headache treatment and prophylaxis, there remains a paucity of data on the efficacy of neuromodulation interventions for treatment of headache unresponsive to conventional pharmacologic therapy. The primary aim of this review was to appraise the literature for the efficacy of cervical spinal cord stimulation (cSCS) in treating any intractable chronic headache, including migraine headaches (with or without aura), cluster headache, tension headache, and other types of headaches. MATERIALS AND METHODS: In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines, we performed a systematic review by identifying studies in PubMed, Embase (Scopus), Web of Science, and Cochrane Central Register of Controlled Trials that assessed cSCS to treat chronic headache. Data were synthesized qualitatively, with primary outcomes of headache intensity and frequency. The secondary outcome was adverse effects. RESULTS: In total, 16 studies comprising 107 patients met the inclusion criteria. Findings were presented based on type of headache, which included migraine headache with or without aura, cluster headache, trigeminal neuropathy, occipital neuralgia, posttraumatic headache, cervicogenic headache, short-lasting unilateral neuralgiform headache with autonomic symptoms, and poststroke facial pain. Per the Grading of Recommendations, Assessment, Development and Evaluations criteria, there was very low-quality evidence that cSCS is associated with a decrease in migraine headache frequency, migraine headache intensity, and trigeminal neuropathy intensity. Placement for cSCS leads ranged from C1 to C4. CONCLUSIONS: Our review suggests promising data from observational studies that cSCS may be helpful in decreasing frequency and intensity of chronic intractable headache. Future well-powered, randomized controlled trials are needed.

Efficacy of Neuromodulation Interventions for the Treatment of Sexual Dysfunction: A Systematic Review.

OBJECTIVES: The primary aim of this review was to analyze the literature for the efficacy of neuromodulation interventions in treating both male and female sexual dysfunction. MATERIALS AND METHODS: Studies were identified from PubMed, Scopus, PsychINFO, CINAHL, and Cochrane. Results were synthesized qualitatively without pooling owing to the heterogeneous nature of outcome assessments. RESULTS: Overall findings from studies generally supported that neuromodulation interventions were associated with improvement in sexual function. Specific domains that improved in male patients included erectile function, desire, and satisfaction, whereas desire, arousal, orgasm, lubrication, quality of "sex life," intercourse capability, and dyspareunia improved in female patients. Male ejaculation, orgasm, and intercourse capability were the only domains that continued to decline after the use of neuromodulation interventions, although this was only reported in one study. CONCLUSION: Our review suggests that there may be promise and potential utility of neuromodulation in improving sexual dysfunction; however, further research is needed.

Peripheral Nerve Stimulation in Painful Conditions of the Upper Extremity-An Overview.

Our objective is to present a brief history of the evolution of peripheral nerve stimulation, the current understanding of peripheral nerve stimulation mechanisms in chronic pain, peripheral nerve stimulation applications in upper extremity chronic pain conditions, and complications of peripheral nerve stimulation. The evolution of peripheral nerve stimulation from the early ages to the current status has been facilitated by discoveries in neurobehavioral mechanisms of pain, advances in technology and percutaneous lead development, and the availability of high-quality portable ultrasound units. Peripheral nerve stimulation application in managing upper extremity pain of amputated limbs, post-stroke shoulder pain, complex regional pain syndrome (CRPS), and median, ulnar, and radial neuropathies are discussed. Finally, we describe complications of peripheral nerve stimulation. The availability of ultrasound-guided peripheral nerve stimulation techniques and superior peripheral nerve stimulation technology have opened up new and minimally invasive treatment options for chronic intractable neuropathic pain of the upper extremity. Additionally, the ability to place peripheral nerve stimulation leads percutaneously without open peripheral nerve surgery expands the pool of implanting physicians, while simultaneously decreasing the risks and complications that are associated with open surgery.

Implantable Peripheral Nerve Stimulation for Peripheral Neuropathic Pain: A Systematic Review of Prospective Studies.

Peripheral nerve stimulation (PNS) has been utilized for over 50 years with accumulating evidence of efficacy in a variety of chronic pain conditions. The level and strength of evidence supporting the use of PNS for peripheral neuropathic pain remains unclear. The purpose of this review is to synthesize data from prospective studies on the efficacy of PNS for neuropathic pain as it pertains to pain intensity, neurological deficits/neuropathy (e.g., weakness, sensory deficits, gait/balance), and other secondary outcomes (quality of life, satisfaction, emotional functioning, and adverse events). In compliance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines, this review identified articles from MEDLINE(R), EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus. Overall, per the Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria, pooled results demonstrate very low quality or low quality of evidence supporting modest to substantial improvement in pain and neurological function after PNS implantation for treatment of peripheral neuropathic pain. PNS for phantom limb pain was the only indication that had moderate level evidence. Future prospective and well-powered studies are warranted to assess the efficacy of PNS for peripheral neuropathic pain.

Effects of Different Titanium Surfaces Created by 3D Printing Methods, Particle Sizes, and Acid Etching on Protein Adsorption and Cell Adhesion, Proliferation, and Differentiation.

The surfaces of 3D printed titanium prostheses have major impacts on the clinical performance of the prostheses. To investigate the surface effects of the products generated by 3D printed titanium on osseointegration, six surface types of titanium discs produced by the direct metal laser sintering (DMLS) and electron beam melting (EBM) methods, with two sizes of titanium particles and post-printing acid etching, were used to examine the surface topography and to explore the protein adsorption, pro-inflammatory cytokine gene expressions, and MC3T3-E1 cell adhesion, proliferation, and differentiation. The EBM-printed disc showed a stripy and smooth surface without evidence of the particles used, while the DMLS surface contained many particles. After acid etching, small particles on the DMLS surface were removed, whereas the large particles were left. Moreover, distinct proteins with low molecular weights were attached to the 3D printed titanium discs but not to the pre-printing titanium particles. The small titanium particles stimulated the highest TNF-α and IL-6 gene expressions at 24 h. The alizarin red content and osteocalcin gene expression at day 21 were the highest in the groups of acid-etched discs printed by DMLS with the small particles and by EBM. Therefore, the acid-treated surfaces without particles favor osteogenic differentiation. The surface design of 3D printed titanium prostheses should be based on their clinical applications.

Neuromodulation Therapy for Chemotherapy-Induced Peripheral Neuropathy: A Systematic Review.

Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating and painful condition in patients who have received chemotherapy. The role of neuromodulation therapy in treating pain and improving neurological function in CIPN remains unclear and warrants evidence appraisal. In compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we performed a systematic review to assess change in pain intensity and neurological function after implementation of any neuromodulation intervention for CIPN. Neuromodulation interventions consisted of dorsal column spinal cord stimulation (SCS), dorsal root ganglion stimulation (DRG-S), or peripheral nerve stimulation (PNS). In total, 15 studies utilized SCS (16 participants), 7 studies utilized DRG-S (7 participants), and 1 study utilized PNS (50 participants). Per the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) criteria, there was very low-quality GRADE evidence supporting that dorsal column SCS, DRG-S, and PNS are associated with a reduction in pain severity from CIPN. Results on changes in neurological function remained equivocal due to mixed study findings on thermal sensory thresholds and touch sensation or discrimination. Future prospective, well-powered, and comparative studies assessing neuromodulation for CIPN are warranted.

The Aspergillus nidulans bimC4 mutation provides an excellent tool for identification of kinesin-14 inhibitors.

Centrosome amplification is a hallmark of many types of cancer cells, and clustering of multiple centrosomes is critical for cancer cell survival and proliferation. Human kinesin-14 HSET/KFIC1 is essential for centrosome clustering, and its inhibition leads to the specific killing of cancer cells with extra centrosomes. Since kinesin-14 motor domains are conserved evolutionarily, we conceived a strategy of obtaining kinesin-14 inhibitors using Aspergillus nidulans, based on the previous result that loss of the kinesin-14 KlpA rescues the non-viability of the bimC4 kinesin-5 mutant at 42 °C. However, it was unclear whether alteration of BimC or any other non-KlpA protein would be a major factor reversing the lethality of the bimC4 mutant. Here we performed a genome-wide screen for bimC4 suppressors and obtained fifteen suppressor strains. None of the suppressor mutations maps to bimC. The vast majority of them contain mutations in the klpA gene, most of which are missense mutations affecting the C-terminal motor domain. Our study confirms that the bimC4 mutant is suitable for a cell-based screen for chemical inhibitors of kinesin-14. Since the selection is based on enhanced growth rather than diminished growth, cytotoxic compounds can be excluded.