Stress-Induced Proteasome Sub-Cellular Translocation in Cardiomyocytes Causes Altered Intracellular Calcium Handling and Arrhythmias.

The ubiquitin-proteasome system (UPS) is an essential mechanism responsible for the selective degradation of substrate proteins via their conjugation with ubiquitin. Since cardiomyocytes have very limited self-renewal capacity, as they are prone to protein damage due to constant mechanical and metabolic stress, the UPS has a key role in cardiac physiology and pathophysiology. While altered proteasomal activity contributes to a variety of cardiac pathologies, such as heart failure and ischemia/reperfusion injury (IRI), the environmental cues affecting its activity are still unknown, and they are the focus of this work. Following a recent study by Ciechanover's group showing that amino acid (AA) starvation in cultured cancer cell lines modulates proteasome intracellular localization and activity, we tested two hypotheses in human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs, CMs): (i) AA starvation causes proteasome translocation in CMs, similarly to the observation in cultured cancer cell lines; (ii) manipulation of subcellular proteasomal compartmentalization is associated with electrophysiological abnormalities in the form of arrhythmias, mediated via altered intracellular Ca2+ handling. The major findings are: (i) starving CMs to AAs results in proteasome translocation from the nucleus to the cytoplasm, while supplementation with the aromatic amino acids tyrosine (Y), tryptophan (W) and phenylalanine (F) (YWF) inhibits the proteasome recruitment; (ii) AA-deficient treatments cause arrhythmias; (iii) the arrhythmias observed upon nuclear proteasome sequestration(-AA+YWF) are blocked by KB-R7943, an inhibitor of the reverse mode of the sodium-calcium exchanger NCX; (iv) the retrograde perfusion of isolated rat hearts with AA starvation media is associated with arrhythmias. Collectively, our novel findings describe a newly identified mechanism linking the UPS to arrhythmia generation in CMs and whole hearts.

Unleashing Natural IL18 Activity Using an Anti-IL18BP Blocker Induces Potent Immune Stimulation and Antitumor Effects.

Recombinant cytokines have limited anticancer efficacy mostly due to a narrow therapeutic window and systemic adverse effects. IL18 is an inflammasome-induced proinflammatory cytokine, which enhances T- and NK-cell activity and stimulates IFNγ production. The activity of IL18 is naturally blocked by a high-affinity endogenous binding protein (IL18BP). IL18BP is induced in the tumor microenvironment (TME) in response to IFNγ upregulation in a negative feedback mechanism. In this study, we found that IL18 is upregulated in the TME compared with the periphery across multiple human tumors and most of it is bound to IL18BP. Bound IL18 levels were largely above the amount required for T-cell activation in vitro, implying that releasing IL18 in the TME could lead to potent T-cell activation. To restore the activity of endogenous IL18, we generated COM503, a high-affinity anti-IL18BP that blocks the IL18BP:IL18 interaction and displaces precomplexed IL18, thereby enhancing T- and NK-cell activation. In vivo, administration of a surrogate anti-IL18BP, either alone or in combination with anti-PD-L1, resulted in significant tumor growth inhibition and increased survival across multiple mouse tumor models. Moreover, the anti-IL18BP induced pronounced TME-localized immune modulation including an increase in polyfunctional nonexhausted T- and NK-cell numbers and activation. In contrast, no increase in inflammatory cytokines and lymphocyte numbers or activation state was observed in serum and spleen. Taken together, blocking IL18BP using an Ab is a promising approach to harness cytokine biology for the treatment of cancer.

The effect of subsequent pregnancy and childbirth on stress urinary incontinence recurrence following midurethral sling procedure: a meta-analysis.

OBJECTIVE: This study aimed to assess the risk of stress urinary incontinence recurrence and reoperation after a midurethral sling procedure in women with subsequent childbirth and to assess the effect of delivery mode on this risk. DATA SOURCES: An electronic database search was performed using MEDLINE with the OvidSP interface and PubMed, Embase, Web of Science, and the Cochrane Library up to September 20, 2023. STUDY ELIGIBILITY CRITERIA: This study included experimental and nonexperimental studies, composed of randomized controlled and observational (case-control, cohort, and cross-sectional) studies assessing the risk factors for stress urinary incontinence recurrence and reoperation after childbirth in women who had previously undergone a midurethral sling procedure for stress urinary incontinence. METHODS: Analysis was performed using RevMan (version 5.3; Cochrane Collaboration, Oxford, United Kingdom). Quantitative synthesis was used if the included studies were sufficient in numbers and homogeneity. The overall certainty of the evidence was assessed using criteria recommended by the Grading of Recommendations Assessment, Development, and Evaluation Working Group. RESULTS: A total of 2001 studies were identified, of which 6 were eligible for analysis, composed of 381 patients who had at least 1 childbirth after a midurethral sling procedure (study group) and 860 patients who underwent a midurethral sling without having a subsequent childbirth (control group). All included studies were observational, the patients' mean age at the time of the midurethral sling procedure ranged from 34 to 36 years, and the mean time from midurethral sling procedure to delivery ranged from 21 to 31 months. No difference in stress urinary incontinence recurrence (relative risk, 0.1.02; 95% confidence interval, 0.78-1.33) or reoperation (relative risk, 1.37; 95% confidence interval, 0.87-2.17) was found between the study and control groups. The average follow-up time among the included studies of this comparison was 9.8 years (range, 2-18). Furthermore, the mode of delivery (vaginal vs cesarean) did not seem to affect the risk of stress urinary incontinence recurrence. CONCLUSION: Subsequent pregnancy and childbirth did not increase the risk of stress urinary incontinence recurrence or reoperation after a midurethral sling procedure.

Pain and anxiety management with virtual reality for office hysteroscopy: systemic review and meta-analysis.

PURPOSE: Office hysteroscopy (OH) is a commonly performed procedure, although it might be associated with some degree of pain and anxiety. Our aim was to determine the effects of virtual reality on pain and anxiety levels felt by patients undergoing OH. METHODS: MEDLINE, Embase, Google Scholar, Cochrane Library, clinicaltrials.gov, ProQuest, Grey literature, and manual searching of references within studies found in the initial search were systematically searched using the terms 'Virtual Reality' and 'Hysteroscopy' without time or language limitations. The review considered all studies assessing the impact of virtual reality (VR) over OH outcomes, and prospective randomized trials were included in the meta-analysis. Retrospective and case - control studies were excluded from the meta-analysis. RESULTS: We identified 17 studies, of which four randomized controlled studies were included in the meta-analysis (327 participants, 168 in the VR group and 159 in the control group). On a 0-10 scale, pain sensation and maximal pain sensation during the operation were not statistically different between study and control groups (relative risk (RR) = -0.64, 95% C.I (-1.57)0.29) and (RR = -0.93, 95% C.I (-3.33) - 1.47), respectively. Anxiety measurement was statistically lower in the study group (RR = -1.73, 95% C.I (-2.79) - ( -0.67)). CONCLUSIONS: The available data suggest that VR techniques do not decrease the pain sensation during OH however, they do contribute to a reduction in the anxiety levels experienced by patients. PROSPERO registration number CRD42023432819.

When Do Women with Second Trimester Pregnancy Loss Need Repeated Doses of Misoprostol? Insights from a Teaching Hospital.

BACKGROUND: Cases of second trimester pregnancy loss can be treated either pharmacologically or by surgical evacuation. Misoprostol, an E1-prostaglandin analog, is used to facilitate the evacuation of the uterus. OBJECTIVES: To determine the risk factors associated with patients who were treated with five or more repeated doses of misoprostol. METHODS: We conducted a retrospective study of patients treated with vaginal misoprostol at our institution between December 2016 and October 2021 for second trimester pregnancy loss. RESULTS: In total, 114 patients were eligible for analysis; 83 were treated with < 5 doses and 31 with ≥ 5. We recorded each case in which repeated doses were administered, irrespective of predetermined conditions such as gravidity, parity, maternal age, or gestational age. Moreover, cases of five or more misoprostol dosing were not associated with an increased complications rate, except for the increased duration of hospitalization (3.1 vs. 2.2 days, P-value < 0.01). CONCLUSIONS: Repeated dosing could not be predicted before treatment among those treated with vaginally administered misoprostol for second trimester pregnancy loss. However, low complication rates of repeated dosing may reassure both physicians and patients regarding safety, efficacy, and future fertility.

Does vaginal cleansing with iodine decreases infection rate in office hysteroscopy?

PURPOSE: To determine whether preoperative vaginal cleansing with iodine-based solution prior to hysteroscopy, reduces postoperative infection rate compared to no vaginal cleansing. METHODS: A retrospective study at a single tertiary, university affiliated hospital of all individuals who have had an office hysteroscopy. Study group consisted of patients who have had preoperative vaginal cleansing with iodine-based solution and were compared to those who have not. Any procedural related complaints at the 30 days following the hysteroscopy were recorded. RESULTS: A total of 505 were available for analysis, 183 in the study group and 322 in the control group. The most common indications for operation were infertility evaluation (33.9% vs. 28.6%) and retained products of conception (33.3% vs. 29.2%), and most common procedures were diagnostic only (49.7% vs. 42.5%) followed by adhesiolysis (12% vs. 14.3%). No statistical differences were noted with regards to postoperative infections, as only one case of pelvic inflammatory disease was noted, in the iodine cleansing group (0.19% for postoperative infection). CONCLUSION: Our comparative study may suggest that the use of preoperative iodine solution prior to office hysteroscopy does not decrease the postoperative infection rate up to 30 days, thus can be avoided.

Cesarean scar niche, fertility and uterine rupture during labor - A retrospective study.

OBJECTIVES: To determine how does a uterine niche diagnosed prior to conception, affects future fertility and obstetrical outcomes, in a group of patients with secondary infertility undergoing fertility treatments. STUDY DESIGN: A retrospective case-control study was performed, recruiting patients after cesarean delivery, before fertility treatment. Using stored ultrasound photos and video loops, we determined niche's sonographic parameters during the preconception period and retrieved the fertility and obstetrical outcomes thereafter. RESULTS: 104 patients met the inclusion criteria, and 86 were available for analysis. 56 (65%) had uterine niches larger than 2 mm in depth, and 30 (34%) had a uterine scar of 2 mm or less. Demographic characteristics were not different between groups. No statistically significant differences were observed regarding rates of implantation and clinical pregnancy between the groups. There were four cases of cesarean scar rupture during failed trial of labor (TOLAC), all of which were in the group with larger than 2 mm niche (33% of all TOLAC cases in the respected group). CONCLUSIONS: While it appears that pre-conception presence of uterine niches larger than 2 mm in depth does not adversely affect future fertility, these niches might serve as a risk factor for future uterine rupture during TOLAC.

The Value of Preoperative Multichannel Urodynamic Testing for Detecting Occult Stress Urinary Incontinence in Women Undergoing Prolapse Repair Surgery.

BACKGROUND: Diagnosing occult stress urinary incontinence (OSUI) prior to surgical intervention for pelvic organ prolapse (POP) repair may allow for adding an anti-incontinence procedure and thus prevent postoperative SUI. OBJECTIVES: To compare preoperative detection rates for OSUI by either a multichannel urodynamic investigation or by a plain pelvic examination. METHODS: We retrospectively evaluated the medical charts of all women who underwent urodynamic investigation prior to surgical repair of advanced POP at our institution between 1 January 2006 and 31 December 2012. RESULTS: In total, 720 women underwent surgical POP repair during the study period, of whom 54 (7.5%) were diagnosed with OSUI preoperatively. Of these patients, 54 (100%) were detected by multichannel urodynamic investigation while only 27 (50%) were detected by a plain pelvic examination (P = 0.001). Bladder fullness during the pelvic examination was associated with higher detection rates for OSUI (P = 0.001). Women with OSUI who underwent concomitant tension-free vaginal tape and POP repair procedures did not develop de novo SUI or obstructive voiding symptoms (OVS) postoperatively. CONCLUSIONS: Preoperative multichannel urodynamic investigation has significantly higher detection rates for OSUI than a plain pelvic examination. Utilizing this modality resulted in no cases of de novo SUI or OVS postoperatively.

Maternal and Neonatal Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Immunoglobulin G Levels After the Pfizer-BioNTech Booster Dose for Coronavirus Disease 2019 (COVID-19) Vaccination During the Second Trimester of Pregnancy.

OBJECTIVE: To evaluate maternal and neonatal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunoglobulin G (IgG) antibody levels at birth after a third (booster) dose of the Pfizer-BioNTech messenger RNA (Pfizer) coronavirus disease 2019 (COVID-19) vaccine during the second trimester of pregnancy, and compare them with those in women who received two vaccine doses during the second trimester. METHODS: We conducted a prospective cohort study of women admitted to the delivery ward at a single center who received the third Pfizer COVID-19 vaccine dose (booster group) at 17-30 weeks of pregnancy and who did not have previous SARS-CoV-2 infection. Maternal and neonatal antibody levels were measured on admission for delivery and in the umbilical cord blood after birth. Antibody levels for the booster group were compared with those in a historical control group of pregnant women who received their second vaccine dose (two-dose group) within the same gestational age window. RESULTS: Between October 2021 and February 2022, antibody levels were measured in 121 women and 109 neonates at a mean±SD of 15.3±3.9 weeks after booster vaccination. Neonatal titers measured two times higher than maternal titers, with inverse correlation between maternal and neonatal titers at birth and time interval from third vaccination. The two-dose group included 121 women and 107 neonates, with antibody levels measured at a mean±SD of 14.6±2.6 weeks after the second dose. Median [interquartile range] maternal antibody titers were higher in the booster group (4,485 [2,569-9,702] AU/mL) compared with the two-dose group (1,122 [735-1,872] AU/mL) (P<.001). Furthermore, neonatal antibody titers were higher in the booster group (8,773 [5,143-18,830] AU/mL) compared with the two-dose group (3,280 [2,087-5,754] AU/mL) (P<.001). CONCLUSION: Maternal and neonatal SARS-CoV-2 IgG antibody titers after second-trimester maternal Pfizer COVID-19 vaccination were significantly higher after the booster dose compared with the two-dose vaccination series. Although there is uncertainty as to whether antibody levels correlate with protection, these data support the importance of booster vaccination during pregnancy to restore maternal and neonatal protection against COVID-19.

Third trimester messenger RNA COVID-19 booster vaccination upsurge maternal and neonatal SARS-CoV-2 immunoglobulin G antibody levels at birth.

OBJECTIVE: BNT162b2 messenger RNA (mRNA) COVID-19 vaccine administered during pregnancy was found to produce a strong maternal immunoglobulin (IgG) response which crosses the placenta to the newborn. Our aim was to evaluate maternal and neonatal SARS-CoV-2 IgG antibody levels at birth, following a COVID-19 booster vaccine during the third trimester. STUDY DESIGN: A prospective cohort study including women admitted to delivery ward at least 7 days after their BNT162b2 (Pfizer/BioNTech) booster vaccination without a prior clinical COVID-19 infection. SARS-CoV-2 IgG antibodies levels were measured in maternal blood upon admission to delivery and in the umbilical blood within 30 min following delivery. The correlation between antibody titers, feto-maternal characteristics, maternal side effects following vaccination, and time interval from vaccination to delivery were analyzed. RESULTS: Between September to November 2021, high antibody levels were measured in all 102 women and 93 neonatal blood samples, at a mean ± standard deviation duration of 7.0 ± 2.9 weeks after the third vaccine. We found positive correlation between maternal and neonatal antibodies (r = 0.73, 95% confidence interval [CI] 0.61 to 0.81, p < 0.001), with neonatal titers approximately 1.4 times higher compared to maternal titers. In the multivariable analysis maternal antibody levels dropped by -7.2% (95% CI -12.0 to -2.3%, p = 0.005) for each week that passed since the receipt of the third vaccine dose. In contrary, systemic side effects after the third vaccine were associated with higher maternal antibody levels of 52.0% (95% CI 4.7 to 120.8%, p = 0.028). Also, for each 1 unit increase in maternal body mass index, maternal antibody levels increased by 3.6% (95% CI 0.4 to 6.9%, p = 0.025). CONCLUSIONS: BNT162b2 mRNA COVID-19 booster dose during the third trimester of pregnancy was associated with strong maternal and neonatal responses as reflected by maternal and neonatal SARS-CoV-2 IgG antibody levels measured at birth. These findings support the administration of the COVID-19 booster to pregnant women to restore maternal and neonatal protection during the ongoing pandemic.

Changes in the obstetrical emergency department profile during the COVID-19 pandemic.

BACKGROUND: The COVID-19 outbreak caused persons to be reluctant to seek medical care due to fear of contracting the infection. OBJECTIVES: To evaluate the effect of the COVID-19 pandemic on admission rates to the delivery room and the feto-maternal unit, and to assess the effect on the nature of presenting obstetrical complaints to the emergency department. STUDY DESIGN: A retrospective cohort study in one medical center. The population was women > 20 weeks pregnant who presented to the obstetrical emergency department with self-complaints during 29 days at the peak of the pandemic outbreak, and a matched group during the exact period in the previous year. We compared between the groups: clinical, obstetrical, and demographic data, including age, area of residence, gravidity, parity, previous cesarean deliveries, high-risk pregnancy follow-up, the last 30 days admissions to the obstetrical emergency department, gestational age, chief complaints, cervical dilatation, cervical effacement, admissions to the delivery room or feto-maternal unit, time from admissions to the delivery room to birth, if applicable, and acute obstetrical complications diagnosed at the emergency department. RESULTS: During the pandemic outbreak, 398 women met study inclusion criteria, compared to 544 women in the matched period of the previous year. During the COVID-19 period, women visited the obstetrical emergency department at a more advanced mean gestational age (37.6 ± 3.7 vs. 36.7 ± 4.6, p = .001). Higher proportions of women in the COVID-19 cohort presented in active labor, defined by cervical dilation of at least 5 cm on admission to the labor ward [37 (9.3%) vs 28 (5.1%), p = .013)] and with premature rupture of membranes [82 (20.6%) vs 60 (11.0%), p < .001)], and consequently with more admissions to the delivery room [198 (49.7%) vs 189 (34.7%), p < .001)]. We also recorded a significant increase in urgent obstetrical events in the emergency department during the recorded COVID-19 pandemic [23 (5.8%) vs 12 (2.2%)), p = .004]. However, the rates of neonatal and maternal morbidity did not change. During the outbreak the proportion of visits during the night was higher than during the matched period of the previous year: [138 (34.7%) vs 145 (26.6%)), p = .008]. In a multivariate logistic regression, the higher rates of admission to the delivery room during active labor and of urgent events during the pandemic outbreak compared to the matched period in the previous year remained statistically significant. CONCLUSIONS: The pandemic outbreak of COVID-19 caused a behavioral change among women who presented to the obstetrical emergency department. This was characterized by delayed arrival to the obstetrical emergency department and the delivery room, which led to a significant increase in urgent and acute interventions. The change in behavior did not affect the rates of maternal and neonatal morbidity.

Maternal and Neonatal SARS-CoV-2 Immunoglobulin G Antibody Levels at Delivery After Receipt of the BNT162b2 Messenger RNA COVID-19 Vaccine During the Second Trimester of Pregnancy.

IMPORTANCE: BNT162b2 messenger RNA (mRNA) COVID-19 vaccination in the third trimester was found to be associated with a strong maternal humoral IgG response that crossed the placenta and approached maternal titers in the newborn. OBJECTIVE: To evaluate maternal and neonatal SARS-CoV-2 immunoglobulin G (IgG) antibody levels at birth after mRNA COVID-19 vaccination during the second trimester of pregnancy. DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort study, conducted at a single medical center in Haifa, Israel, from May to July 2021, included women with a singleton pregnancy over 24 weeks of gestation at least 7 days after receipt of their second COVID-19 vaccine dose who were not known to be previously infected with COVID-19. EXPOSURES: BNT162b2 (Pfizer/BioNTech) vaccination. MAIN OUTCOMES AND MEASURES: The primary outcomes were SARS-CoV-2 IgG antibody titers measured in the parturient at admission and in the umbilical cord blood within 30 minutes after delivery. Secondary outcomes were the correlation between antibody titers, feto-maternal characteristics, maternal adverse effects after vaccination, and time interval from vaccination to delivery. RESULTS: Antibody levels were measured for 129 women (mean [SD] age, 31.9 [4.9] years) and 114 neonates, with 100% of the tests having positive results. The mean (SD) gestational age at administration of the second vaccine dose was 24.9 (3.3) weeks. Neonatal IgG titers were 2.6 times higher than maternal titers (median [range], 3315.7 [350.1-17 643.5] AU/mL vs 1185.2 [146.6-32 415.1] AU/mL). A positive correlation was demonstrated between maternal and neonatal antibodies (r = 0.92; 95% CI, 0.89-0.94). Multivariable analysis revealed that for each week that passed since receipt of the second vaccine dose, maternal and neonatal antibody levels changed by -10.9% (95% CI, -17.2% to -4.2%; P = .002) and -11.7% (95% CI, -19.0 to -3.8%; P = .005), respectively. For each 1-year increase in the mother's age, maternal and neonatal antibody levels changed by -3.1% (95% CI, -5.3% to -0.9%; P = .007) and -2.7% (95% CI, -5.2% to -0.1%; P = .04), respectively. CONCLUSIONS AND RELEVANCE: In this cohort study, receipt of the BNT162b2 mRNA COVID-19 vaccine during the second trimester of pregnancy was associated with maternal and neonatal humoral responses, as reflected in maternal and neonatal SARS-CoV-2 IgG antibody levels measured after delivery. These findings support COVID-19 vaccination of pregnant individuals during the second trimester to achieve maternal protection and newborn safety during the pandemic.

Group B Streptococcus real-time PCR may potentially reduce intrapartum maternal antibiotic treatment.

BACKGROUND: Protocols for preventing early-onset group B streptococcal (GBS) neonatal infection may result in unnecessary antibiotics administration. Real-time polymerase chain reaction (PCR) can provide a result within 30-60 min and has been found to be specific and sensitive for defining intrapartum GBS status. OBJECTIVE: To evaluate whether implementation of GBS fast real-time PCR to all women who require GBS prophylaxis may reduce the use of maternal prophylactic antibiotics. METHODS: This prospective cohort study included women admitted to a single delivery ward who required prophylactic antibiotics either due to a positive antepartum GBS culture screening performed at 35-37 weeks or due to an unknown GBS status with an intrapartum risk factor. All the women were tested by a double vaginal swab (real-time PCR and culture) as soon as it became apparent, they required antibiotic prophylaxis and prior to its administration. RESULTS: Between May 2019 and August 2020, 303 women met eligibility criteria and were enrolled, but four were excluded from the analysis due to failed culture or PCR tests. Of 299 women included in the study, 208 (69.5%) and 180 (60.2%) women, showed no evidence of GBS on intrapartum culture or PCR, respectively. Of 89 GBS antepartum carriers, 43 (48.3%) and 32 (35.9%) had negative intrapartum culture and PCR results, respectively. Of the 210 women with risk factors, 165 (78.5%) were culture negative and 148 (70.4%) had a negative PCR. Using intrapartum culture as the gold standard, intrapartum GBS real-time PCR was found to have a sensitivity of 97.8% (95% confidence interval [CI] 92.3, 99.7) and a specificity of 85.6% (95% CI 80.1, 90.1). CONCLUSIONS: Compared with antepartum universal culture screening or intrapartum risk-factor assessment, the need for maternal antibiotic treatment may be substantially reduced by implementation of intrapartum GBS real-time PCR, without compromising the sensitivity of GBS detection.

Enhanced Recovery after Surgery is Feasible and Beneficial and Should Be the Standard in Major Gynecological Surgeries.

BACKGROUND: Enhanced recovery after surgery (ERAS) protocols are evidence-based protocols designed to standardize medical care, improve outcomes, and lower healthcare costs. OBJECTIVES: To evaluate the implementation of the ERAS protocol and the effect on recovery during the hospitalization period after gynecological laparotomy surgeries. METHODS: We compared demographic and clinical data of consecutive patients at a single institute who underwent open gynecological surgeries before (August 2017 to December 2018) and after (January 2019 to March 2020) the implementation of the ERAS protocol. Eighty women were included in each group. RESULTS: The clinical and demographic characteristics were similar among the women operated before and after implementation of the ERAS protocol. Following implementation of the protocol, decreases were observed in post-surgical hospitalization (from 4.89 ± 2.56 to 4.09 ± 1.65 days, P = 0.01), in patients reporting nausea symptoms (from 18 (22.5%) to 7 (8.8%), P = 0.017), and in the use of postoperative opioids (from 77 (96.3%) to 47 (58.8%), P < 0.001). No significant changes were identified between the two periods regarding vomiting, 30-day re-hospitalization, and postoperative minor and major complications. CONCLUSIONS: Implementation of the ERAS protocol is feasible and was found to result in less postoperative opioid use, a faster return to normal feeding, and a shorter postoperative hospital stay. Implementation of the protocol implementation was not associated with an increased rate of complications or with re-admissions.

Structural and functional brain-wide alterations in A350V Iqsec2 mutant mice displaying autistic-like behavior.

IQSEC2 is an X-linked gene that is associated with autism spectrum disorder (ASD), intellectual disability, and epilepsy. IQSEC2 is a postsynaptic density protein, localized on excitatory synapses as part of the NMDA receptor complex and is suggested to play a role in AMPA receptor trafficking and mediation of long-term depression. Here, we present brain-wide structural volumetric and functional connectivity characterization in a novel mouse model with a missense mutation in the IQ domain of IQSEC2 (A350V). Using high-resolution structural and functional MRI, we show that animals with the A350V mutation display increased whole-brain volume which was further found to be specific to the cerebral cortex and hippocampus. Moreover, using a data-driven approach we identify putative alterations in structure-function relations of the frontal, auditory, and visual networks in A350V mice. Examination of these alterations revealed an increase in functional connectivity between the anterior cingulate cortex and the dorsomedial striatum. We also show that corticostriatal functional connectivity is correlated with individual variability in social behavior only in A350V mice, as assessed using the three-chamber social preference test. Our results at the systems-level bridge the impact of previously reported changes in AMPA receptor trafficking to network-level disruption and impaired social behavior. Further, the A350V mouse model recapitulates similarly reported brain-wide changes in other ASD mouse models, with substantially different cellular-level pathologies that nonetheless result in similar brain-wide alterations, suggesting that novel therapeutic approaches in ASD that result in systems-level rescue will be relevant to IQSEC2 mutations.

Experimental mitigation of the effects of the limited size aperture or misalignment by singular-value-decomposition-based beam orthogonalization in a free-space optical link using Laguerre-Gaussian modes.

Limited-size receiver (Rx) apertures and transmitter-Rx (Tx-Rx) misalignments could induce power loss and modal crosstalk in a mode-multiplexed free-space link. We experimentally demonstrate the mitigation of these impairments in a 400 Gbit/s four-data-channel free-space optical link. To mitigate the above degradations, our approach of singular-value-decomposition-based (SVD-based) beam orthogonalization includes (1) measuring the transmission matrix H for the link given a limited-size aperture or misalignment; (2) performing SVD on the transmission matrix to find the U, Σ, and V complex matrices; (3) transmitting each data channel on a beam that is a combination of Laguerre-Gaussian modes with complex weights according to the V matrix; and (4) applying the U matrix to the channel demultiplexer at the Rx. Compared with the case of transmitting each channel on a beam using a single mode, our experimental results when transmitting multi-mode beams show that (a) with a limited-size aperture, the power loss and crosstalk could be reduced by ∼8 and ∼23dB, respectively; and (b) with misalignment, the power loss and crosstalk could be reduced by ∼15 and ∼40dB, respectively.

"Hiding" a low-intensity 50 Gbit/s QPSK free-space OAM beam using an orthogonal coaxial high-intensity 50 Gbit/s QPSK beam.

In this paper, we experimentally demonstrate an approach that "hides" a low-intensity 50 Gbit/s quadrature-phase-keying (QPSK) free-space optical beam when it coaxially propagates on the same wavelength with an orthogonal high-intensity 50 Gbit/s QPSK optical beam. Our approach is to coaxially transmit the strong and weak beams carrying different orthogonal spatial modes within a modal basis set, e.g., orbital angular momentum (OAM) modes. Although the weak beam has much lower power than that of the strong beam, and the beams are in the same frequency band and on the same polarization, the two beams can still be effectively demultiplexed with little inherent crosstalk at the intended receiver due to their spatial orthogonality. However, an eavesdropper may not readily identify the weak beam when simply analyzing the spatial intensity profile. The correlation coefficient between the intensity profiles of the strong beam and the combined strong and weak beams is measured to characterize the potential for "hiding" a weak beam when measuring intensity profiles. Such a correlation coefficient is demonstrated to be higher than 0.997 when the power difference between the strong fundamental Gaussian beam and the weak OAM beam is ∼8,∼10, and ∼10dB for the weak OAM -1,-2, and -3 beams, respectively. Moreover, a 50 Gbit/s QPSK data link having its Q factor above the 7% forward error correction limit is realized when the power of the weak OAM -3 beam is 30 dB lower than that of the strong fundamental Gaussian beam.

Brain-wide structural and functional disruption in mice with oligodendrocyte-specific Nf1 deletion is rescued by inhibition of nitric oxide synthase.

Neurofibromin gene (NF1) mutation causes neurofibromatosis type 1 (NF1), a disorder in which brain white matter deficits identified by neuroimaging are common, yet of unknown cellular etiology. In mice, Nf1 loss in adult oligodendrocytes causes myelin decompaction and increases oligodendrocyte nitric oxide (NO) levels. Nitric oxide synthase (NOS) inhibitors rescue this pathology. Whether oligodendrocyte pathology is sufficient to affect brain-wide structure and account for NF1 imaging findings is unknown. Here we show that Nf1 gene inactivation in adult oligodendrocytes (Plp-Nf1fl/+ mice) results in a motor coordination deficit. Magnetic resonance imaging in awake mice showed that fractional anisotropy is reduced in Plp-Nf1fl/+ corpus callosum and that interhemispheric functional connectivity in the motor cortex is also reduced, consistent with disrupted myelin integrity. Furthermore, NOS-specific inhibition rescued both measures. These results suggest that oligodendrocyte defects account for aspects of brain dysfunction in NF1 that can be identified by neuroimaging and ameliorated by NOS inhibition.

Demonstrating the use of OAM modes to facilitate the networking functions of carrying channel header information and orthogonal channel coding.

We experimentally demonstrate the use of orbital angular momentum (OAM) modes as a degree of freedom to facilitate the networking functions of carrying header information and orthogonal channel coding. First, for carrying channel header information, we transmit a 10 Gb/s on-off keying (OOK) data channel as a Gaussian beam and add to it a 10 Mb/s OOK header carried by an OAM beam with the mode order ℓ=3. We recover the header and use it to drive a switch and select the output port. Secondly, for orthogonal channel coding, we configure transmitters to generate orthogonal spatial codes (orthogonal spatial beam profiles of OAM modes), each carrying an independent data stream. We measure the correlation between the OAM codes and demonstrate their use in a multiple access system carrying two 10 Gb/s OOK data channels. At the end of this Letter, we combine the concepts of using OAM modes for carrying channel header information and orthogonal channel coding in one experiment. We transmit a 10 Gb/s OOK data channel as a Gaussian beam and add to it two 10 Mb/s OOK header waveforms carried by different OAM codes. In the routing node, we recover one of the headers to drive the switch.

Quantum Entanglement in Deep Learning Architectures.

Modern deep learning has enabled unprecedented achievements in various domains. Nonetheless, employment of machine learning for wave function representations is focused on more traditional architectures such as restricted Boltzmann machines (RBMs) and fully connected neural networks. In this Letter, we establish that contemporary deep learning architectures, in the form of deep convolutional and recurrent networks, can efficiently represent highly entangled quantum systems. By constructing tensor network equivalents of these architectures, we identify an inherent reuse of information in the network operation as a key trait which distinguishes them from standard tensor network-based representations, and which enhances their entanglement capacity. Our results show that such architectures can support volume-law entanglement scaling, polynomially more efficiently than presently employed RBMs. Thus, beyond a quantification of the entanglement capacity of leading deep learning architectures, our analysis formally motivates a shift of trending neural-network-based wave function representations closer to the state-of-the-art in machine learning.