-
Journal of Assisted Reproduction and... Apr 2024Unpredictable genetic modifications and chromosomal aberrations following CRISPR/Cas9 administration hamper the efficacy of germline editing. Repair events triggered by...
PURPOSE
Unpredictable genetic modifications and chromosomal aberrations following CRISPR/Cas9 administration hamper the efficacy of germline editing. Repair events triggered by double-strand DNA breaks (DSBs) besides non-homologous end joining and repair template-driven homology-directed repair have been insufficiently investigated in mouse. In this work, we are the first to investigate the precise repair mechanisms triggered by parental-specific DSB induction in mouse for paternal mutational correction in the context of an infertility-related mutation.
METHODS
We aimed to correct a paternal 22-nucleotide deletion in Plcz1, associated with lack of fertilisation in vitro, by administrating CRISPR/Cas9 components during intracytoplasmic injection of Plcz1-null sperm in wild-type oocytes combined with assisted oocyte activation. Through targeted next-generation sequencing, 77 injected embryos and 26 blastomeres from seven injected embryos were investigated. In addition, low-pass whole genome sequencing was successfully performed on 17 injected embryo samples.
RESULTS
Repair mechanisms induced by two different CRISPR/Cas9 guide RNA (gRNA) designs were investigated. In 13.73% (7/51; gRNA 1) and 19.05% (4/21; gRNA 2) of the targeted embryos, only the wild-type allele was observed, of which the majority (85.71%; 6/7) showed integrity of the targeted chromosome. Remarkably, for both designs, only in one of these embryos (1/7; gRNA 1 and 1/4; gRNA2) could repair template use be detected. This suggests that alternative repair events have occurred. Next, various genetic events within the same embryo were detected after single-cell analysis of four embryos.
CONCLUSION
Our results suggest the occurrence of mosaicism and complex repair events after CRISPR/Cas9 DSB induction where chromosomal integrity is predominantly contained.
PubMed: 38557805
DOI: 10.1007/s10815-024-03095-9 -
Wearable Technologies 2024Low-back pain is a common occupational hazard for industrial workers. Several studies show the advantages of using rigid and soft back-support passive exoskeletons and...
Low-back pain is a common occupational hazard for industrial workers. Several studies show the advantages of using rigid and soft back-support passive exoskeletons and exosuits (exos) to reduce the low-back loading and risk of injury. However, benefits of using these exos have been shown to be task-specific. Therefore, in this study, we developed a benchmarking approach to assess exos for an industrial workplace at Hankamp Gears B.V. We assessed two rigid (Laevo Flex, Paexo back) and two soft (Auxivo Liftsuit 1.0, and Darwing Hakobelude) exos for tasks resembling the workplace. We measured the assistive moment provided by each exo and their respective influence on muscle activity as well as the user's perception of comfort and exertion. Ten participants performed four lifting tasks ( hold, , , and ), while their electromyography and subjective measures were collected. The two rigid exos provided the largest assistance during the tasks. Reductions in erector spinae activity were seen to be task-specific, with larger reductions for the two rigid exos. Overall, Laevo Flex offered a good balance between assistive moments, reductions in muscle activity, as well as user comfort and reductions in perceived exertion. Thus, we recommend benchmarking exos for intended use in the industrial workplace. This will hopefully result in a better adoption of the back-support exoskeletons in the workplace and help reduce low-back pain.
PubMed: 38510984
DOI: 10.1017/wtc.2024.2 -
Cureus Feb 2024Patients with Parkinson's disease (PD) exhibit both a severe neuromuscular disorder and low bone quality at presentation. These issues are made worse by inactivity and a...
Patients with Parkinson's disease (PD) exhibit both a severe neuromuscular disorder and low bone quality at presentation. These issues are made worse by inactivity and a chairbound state. Each and every pathologic and degenerative process that affects the naturally aging spine also affects these individuals. Stooped posture is a symptom of a disease and can easily cause spinal degeneration. PD is associated with many physical abnormalities that cause a unique and specific need for rehabilitation. Patients' experiences highlight the challenges doctors face in diagnosis, treatment, and rehabilitation. This case report details the rehabilitation of a 67-year-old patient with PD who underwent spinal fixation for spinal stenosis and presented with complaints of weakness in both lower limbs. An advanced rehabilitation program was devised, primarily emphasizing strength training to enhance overall functionality. Pre- and post-intervention assessments were conducted, encompassing range of motion (ROM), manual muscle testing (MMT), Oswestry Disability Index, Functional Independence Measure, Lower Limb Functional Scale, and Berg Balance Scale, all of which demonstrated noteworthy improvements in joints ROM, strength, functional independence, balance, and lower limb function. This case report underscores the significance of rehabilitation programs in such cases, highlighting their important role in enhancing overall functioning.
PubMed: 38496068
DOI: 10.7759/cureus.54149 -
Neuroscience and Biobehavioral Reviews May 2024Within addiction science, incubation of craving is an operational label used to describe time-dependent increases in drug seeking during periods of drug deprivation. The... (Review)
Review
Within addiction science, incubation of craving is an operational label used to describe time-dependent increases in drug seeking during periods of drug deprivation. The purpose of this systematic review was to describe the preclinical literature on incubation of craving and the clinical literature on craving measured over extended periods of abstinence to document this translational homology and factors impacting correspondence. Across the 44 preclinical studies that met inclusion criteria, 31 reported evidence of greater lever pressing, nose pokes, spout licks, or time spent in drug-paired compartments (i.e., drug seeking) relative to neutral compartments after longer periods of abstinence relative to shorter periods of abstinence, labelled as "incubation of craving." In contrast, no clinical studies (n = 20) identified an increase in opioid craving during longer abstinence periods. The lack of clinical evidence for increases in craving in clinical populations weakens the translational utility of operationalizing the time-dependent increase in drug-seeking behavior observed in preclinical models as models of incubation of "craving".
Topics: Animals; Humans; Analgesics, Opioid; Craving; Inpatients; Outpatients; Behavior, Animal; Cues; Drug-Seeking Behavior; Self Administration
PubMed: 38492446
DOI: 10.1016/j.neubiorev.2024.105618 -
Journal of Medicinal Chemistry Mar 2024Dengue is a global public health threat, with about half of the world's population at risk of contracting this mosquito-borne viral disease. Climate change,...
Dengue is a global public health threat, with about half of the world's population at risk of contracting this mosquito-borne viral disease. Climate change, urbanization, and global travel accelerate the spread of dengue virus (DENV) to new areas, including southern parts of Europe and the US. Currently, no dengue-specific small-molecule antiviral for prophylaxis or treatment is available. Here, we report the discovery of as a potent, pan-serotype DENV inhibitor (EC's ranging from 0.057 to 11 nM against the four DENV serotypes). The observed oral bioavailability of across preclinical species, its low clearance in human hepatocytes, the absence of major in vitro pharmacology safety alerts, and a dose-proportional increase in efficacy against DENV-2 infection in mice were all supportive of its selection as a development candidate against dengue. is being progressed in clinical studies for the prevention or treatment of dengue.
Topics: Mice; Humans; Animals; Dengue Virus; Serogroup; Dengue; Hydrocarbons, Halogenated; Indoles
PubMed: 38482827
DOI: 10.1021/acs.jmedchem.3c02336 -
Sensors (Basel, Switzerland) Feb 2024Walking speed is a significant aspect of evacuation efficiency, and this speed varies during fire emergencies due to individual physical abilities. However, in...
Walking speed is a significant aspect of evacuation efficiency, and this speed varies during fire emergencies due to individual physical abilities. However, in evacuations, it is not always possible to keep an upright posture, hence atypical postures, such as stoop walking or crawling, may be required for survival. In this study, a novel 3D passive vision-aided inertial system (3D PVINS) for indoor positioning was used to track the movement of 20 volunteers during an evacuation in a low visibility environment. Participants' walking speeds using trunk flexion, trunk-knee flexion, and upright postures were measured. The investigations were carried out under emergency and non-emergency scenarios in vertical and horizontal directions, respectively. Results show that different moving directions led to a roughly 43.90% speed reduction, while posture accounted for over 17%. Gender, one of the key categories in evacuation models, accounted for less than 10% of the differences in speed. The speeds of participants under emergency scenarios when compared to non-emergency scenarios was also found to increase by 53.92-60% when moving in the horizontal direction, and by about 48.28-50% when moving in the vertical direction and descending downstairs. Our results also support the social force theory of the warming-up period, as well as the effect of panic on the facilitating occupants' moving speed.
Topics: Humans; Walking; Posture; Standing Position; Walking Speed; Fires
PubMed: 38474914
DOI: 10.3390/s24051378 -
Scientific Reports Mar 2024The validity of observational methods in ergonomics is still challenging research. Criterion validity in terms of concurrent validity is the most commonly studied.... (Observational Study)
Observational Study
The validity of observational methods in ergonomics is still challenging research. Criterion validity in terms of concurrent validity is the most commonly studied. However, studies comparing observational methods with biomechanical values are rare. Thus, the aim of this study is to compare the Ovako Working Posture Analysing System (OWAS) and the Rapid Entire Body Assessment (REBA) with in vivo load measurements at hip, spine, and knee during stoop and squat lifting of 14 participants. The results reveal that OWAS and REBA action levels (AL) can distinguish between different in vivo load measurements during manual lifting. However, the results also reveal that the same OWAS- and REBA-AL do not necessarily provide equal mean values of in vivo load measurements. For example, resultant contact force in the vertebral body replacement for squat lifting ranged from 57% body weight (%BW) in OWAS-AL1 to 138%BW in OWAS-AL3 compared to 46%BW in REBA-AL0 and 173%BW in REBA-AL3. Furthermore, the results suggest that the performed squat lifting techniques had a higher risk for work-related musculoskeletal disorders than the performed stoop lifting techniques.
Topics: Humans; Biomechanical Phenomena; Knee; Knee Joint; Musculoskeletal Diseases; Risk Assessment; Spine
PubMed: 38472286
DOI: 10.1038/s41598-024-56580-7 -
Journal of Neurosurgery. Case Lessons Mar 2024Ankylosing spondylitis (AS) is an autoimmune spondylarthritis often associated with rigid kyphoscoliosis. The authors describe a surgical approach that employs...
BACKGROUND
Ankylosing spondylitis (AS) is an autoimmune spondylarthritis often associated with rigid kyphoscoliosis. The authors describe a surgical approach that employs multilevel three-column osteotomies for the restoration of normal global alignment.
OBSERVATIONS
A 48-year-old male with a past medical history of AS presented to the clinic with a stooped-over posture: his chin-brow vertical angle (CBVA) was 58.0°; T1 slope (T1S), 97.8°; thoracic kyphosis (TK; T1-12), 94.2°; proximal TK (T1-5), 50.8°; distal TK (T5-12), 43.5°; and sagittal vertical axis (SVA), 22.6 cm. A two-stage procedure was planned. During stage 1, instrumentation was placed from C5 to T10, followed by a T3 vertebral column resection. During stage 2, bilateral pedicle screws were placed from T11 to the pelvis. An L3 pedicle subtraction osteotomy (PSO) was completed and was followed by a T7 PSO. Postoperatively, the patient had significant postural improvement: CBVA was 29.3°; T1S, 57.8°; TK, 77.3°; proximal TK, 33.5°; distal TK, 43.8°; and SVA, 15 cm. At 6 years postoperatively, the patient continued to do well and was without evidence of construct breakdown.
LESSONS
The authors propose that multilevel three-column osteotomies, if optimally located, successfully correct spinal malalignment associated with AS.
PubMed: 38467052
DOI: 10.3171/CASE23708 -
The British Journal of Surgery Mar 2024Surgery in selected patients with locally advanced pancreatic cancer after induction chemotherapy may have drawbacks related to surgical risks and breaks or delays in...
Impact of a non-therapeutic laparotomy in patients with locally advanced pancreatic cancer treated with induction (m)FOLFIRINOX: Trans-Atlantic Pancreatic Surgery (TAPS) Consortium study.
BACKGROUND
Surgery in selected patients with locally advanced pancreatic cancer after induction chemotherapy may have drawbacks related to surgical risks and breaks or delays in oncological treatment, in particular when curative intent resection is not possible (that is non-therapeutic laparotomy). The aim of this study was to assess the incidence and oncological impact of a non-therapeutic laparotomy in patients with locally advanced pancreatic cancer treated with induction (m)FOLFIRINOX chemotherapy.
METHODS
This was a retrospective international multicentre study including patients diagnosed with pathology-proven locally advanced pancreatic cancer treated with at least one cycle of (m)FOLFIRINOX (2012-2019). Patients undergoing a non-therapeutic laparotomy (group A) were compared with those not undergoing surgery (group B) and those undergoing resection (group C).
RESULTS
Overall, 663 patients with locally advanced pancreatic cancer were included (67 patients (10.1%) in group A, 425 patients (64.1%) in group B, and 171 patients (25.8%) in group C). A non-therapeutic laparotomy occurred in 28.2% of all explorations (67 of 238), with occult metastases in 30 patients (30 of 67, 44.8%) and a 90-day mortality rate of 3.0% (2 of 67). Administration of palliative therapy (65.9% versus 73.1%; P = 0.307) and median overall survival (20.4 [95% c.i. 15.9 to 27.3] versus 20.2 [95% c.i. 19.1 to 22.7] months; P = 0.752) did not differ between group A and group B respectively. The median overall survival in group C was 36.1 (95% c.i. 30.5 to 41.2) months. The 5-year overall survival rates were 11.4%, 8.7%, and 24.7% in group A, group B, and group C, respectively. Compared with group B, non-therapeutic laparotomy (group A) was not associated with reduced overall survival (HR = 0.88 [95% c.i. 0.61 to 1.27]).
CONCLUSION
More than a quarter of surgically explored patients with locally advanced pancreatic cancer after induction (m)FOLFIRINOX did not undergo a resection. Such non-therapeutic laparotomy does not appear to substantially impact oncological outcomes.
Topics: Humans; Antineoplastic Combined Chemotherapy Protocols; Pancreatic Neoplasms; Laparotomy; Retrospective Studies; Fluorouracil; Leucovorin; Neoadjuvant Therapy; Irinotecan; Oxaliplatin
PubMed: 38456678
DOI: 10.1093/bjs/znae033 -
Nature Communications Mar 2024The presence of a companion can reduce fear, but the neural mechanisms underlying this social buffering of fear are incompletely known. We studied social buffering of...
The presence of a companion can reduce fear, but the neural mechanisms underlying this social buffering of fear are incompletely known. We studied social buffering of fear in male and female, and its encoding in the amygdala of male, auditory fear-conditioned rats. Pharmacological, opto,- and/or chemogenetic interventions showed that oxytocin signaling from hypothalamus-to-central amygdala projections underlied fear reduction acutely with a companion and social buffering retention 24 h later without a companion. Single-unit recordings with optetrodes in the central amygdala revealed fear-encoding neurons (showing increased conditioned stimulus-responses after fear conditioning) inhibited by social buffering and blue light-stimulated oxytocinergic hypothalamic projections. Other central amygdala neurons showed baseline activity enhanced by blue light and companion exposure, with increased conditioned stimulus responses that persisted without the companion. Social buffering of fear thus switches the conditioned stimulus from encoding "fear" to "safety" by oxytocin-mediated recruitment of a distinct group of central amygdala "buffer neurons".
Topics: Rats; Male; Female; Animals; Conditioning, Psychological; Oxytocin; Central Amygdaloid Nucleus; Rats, Wistar; Fear; Neurons
PubMed: 38453902
DOI: 10.1038/s41467-024-45626-z