Unique prenatal manifestations of biallelic NDUFAF5 variants: expansion of phenotype.

OBJECTIVE: Mitochondrial complex-I deficiency, nuclear type 16, is a rare autosomal recessive disorder caused by biallelic pathogenic variants in NDUFAF5 (C20orf7) (OMIM 618238). The aim of this study was to describe a severe early prenatal manifestation of this disorder, which was previously considered to occur only postnatally. METHODS: This was a multicenter retrospective case series including five fetuses from three non-related families, which shared common sonographic abnormalities, including brain cysts, corpus callosal malformations, non-immune hydrops fetalis and growth restriction. Genetic evaluation included chromosomal microarray analysis and exome sequencing. Two fetuses from the same family were also available for pathology examination, including electron microscopy. RESULTS: Chromosomal microarray analysis revealed no chromosomal abnormality in any of the tested cases. Trio exome sequencing demonstrated that three affected fetuses from three unrelated families were compound heterozygous or homozygous for likely pathogenic variants in NDUFAF5. No other causative variants were detected. The association between NDUFAF5 variants and fetal malformations was further confirmed by segregation analysis. Histological evaluation of fetal tissues and electron microscopy of the skeletal muscle, liver, proximal tubules and heart demonstrated changes that resembled postmortem findings in patients with mitochondrial depletion disorders as well as previously undescribed findings. CONCLUSIONS: Mitochondrial complex-I deficiency and specifically biallelic mutations in NDUFAF5 have a role in abnormal fetal development, presenting with severe congenital malformations. Mitochondrial complex-I disorders should be considered in the differential diagnosis of corpus callosal malformations and brain cysts, especially when associated with extracranial abnormalities, such as fetal growth restriction and non-immune hydrops fetalis. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

VB-201, an oxidized phospholipid small molecule, inhibits CD14- and Toll-like receptor-2-dependent innate cell activation and constrains atherosclerosis.

Atherosclerosis is an inflammatory disease of the vascular wall. Activated monocytes and dendritic cells (DC) in the intima layer of the vasculature promote atherogenesis. Toll-like receptor (TLR)-2 and TLR-4, which are predominantly expressed on these cells and mediate their activation, are essential for atherosclerosis development. In this study we demonstrate that VB-201, an oxidized phospholipid (Ox-PL) small molecule, inhibits TLR signalling restricted to TLR-2 and TLR-4 in human and mouse monocytes and DC. Mechanistically, we show that VB-201 binds directly to TLR-2 and CD14, the TLR-4 co-receptor, to impair downstream cues and cytokine production. In a rabbit model, oral administration of VB-201 constrained atherosclerosis progression. This effect was not due to reduced cholesterol abundance, as hyperlipidaemia was sustained. We suggest that VB-201 may counter inflammation where TLR-2 and/or CD14 complicity is essential, and is therefore beneficial for the treatment of atherosclerosis.

Mucormycosis in a liver allograft: salvage re-transplantation and targeted immunosuppressive management.

Zygomycetes infection is associated with a high mortality in transplant populations. We describe a child with liver allograft Rhizopus oryzae infection who was salvaged by liver re-transplantation. A 10-year-old child presented with anastomotic bile leak that was repaired. A combined antibiotics and voriconazole regimen was introduced for Escherichia coli and Candida krusei growth in the peritoneal fluid. Despite broad antibiotic and antifungal coverage, the patient continued to have an ongoing infection. A follow-up computed tomography scan 8 weeks later showed 2 liver abscesses infiltrating the stomach and the diaphragm, with splenic infarcts and pericardial effusion. Aspirated samples from the liver abscess and the pericardial fluid revealed R. oryzae. Immunosuppression was discontinued and an antifungal regimen combining amphotericin B, posaconazole, and caspofungin was introduced. After 3 weeks of treatment with control of the systemic signs of infection, a positron emission tomography showed the fluorescence stain limited to the liver. With infection confined to the liver, the child underwent liver re-transplantation, splenectomy, and partial gastrectomy. Immunosuppression was reintroduced with recovery of the immune response observed by the CD4 cells adenosine triphophate release (Cylex(™) ImmuKnow(®) assay) and posaconazole was continued for another year. At 3-year follow-up, the child maintained normal graft function. We conclude that discontinuation of immunosuppression combined with a modern antifungal regimen may allow salvage re-transplantation in patients with liver mucormycosis.

Two cycles of escalated BEACOPP followed by four cycles of ABVD utilizing early-interim PET/CT scan is an effective regimen for advanced high-risk Hodgkin's lymphoma.

BACKGROUND: Escalated combination therapy with bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone (escBEACOPP) regimen is superior to cyclophosphamide, vincristine, procarbazine and prednisone alternating with doxorubicin, bleomycin, vinblastine and dacarbazine (COPP-ABVD) for advanced-stage Hodgkin's lymphoma (HL) patients. However, the original schedule of eight cycles of escBEACOPP was associated with significant toxicity. This study was conducted in an attempt to reduce the toxicity of the original schedule, while attempting to preserve improved initial tumor control. PATIENTS AND METHODS: Forty-five newly diagnosed patients with advanced-stage HL and International Prognostic Score > or = 3 received two initial cycles of escBEACOPP and then were evaluated by positron emission tomography (PET)/computed tomography scan. If a good imaging response was obtained, they were treated by four cycles of ABVD. RESULTS: Following the first two cycles of escBEACOPP, the overall response was 100% and at the end of all therapy, 40 (89%) patients were in complete response (disappearance of all clinical evidence of disease and PET negativity), three (7%) in partial response (PET-positive residual lesions and a size reduction of the majority of large masses by >50%), while two (4%) had progressive disease. After a median follow-up of 48 months, progression-free survival (PFS) and overall survival at 4 years were 78% and 95%, respectively. The 4-year PFS for early PET-negative patients (n = 31) and early PET-positive patients (n = 13) were 87% and 53%, respectively (P = 0.01). CONCLUSIONS: These data indicate that combined escBEACOPP-ABVD may improve the outcome in patients with high-risk advanced HL. The potential benefit of early-interim PET activity as a guide to continuing therapy in these patients merits further study in the future.

Making meaning of cancer: A qualitative analysis of oral-digestive cancer survivors' reflections.

This qualitative study aimed to confirm and extend research on meaning making after cancer. In all, 119 adults aged 41 to 88 years (M = 65.50 years and standard deviation = 9.16 years) were interviewed 12 months after diagnosis of oral-digestive cancers. About half tried to understand why they got cancer (43%) and said that cancer changed their view of life (53%). Most (75%) reported that previous life experiences helped them cope with cancer. Cancer survivors made meanings in the areas of existential, social, and personal domains with both positive and negative content. Practitioners may wish to examine meaning making in these areas for those in distress after cancer.

Prevention of human immunodeficiency virus mother-to-child transmission in Israel.

The objective of the study was to investigate the HIV-mother-to-child transmission (MTCT) rate in Israel. This was a retrospective study of HIV-infected pregnant women, mainly immigrants from Ethiopia, in six Israeli AIDS centres, in 2000-2005. Medical records of mothers and newborns were evaluated for HIV status, treatment and MTCT rates. Three hundred pregnancies of 241 HIV-infected women, resulting in 304 live births, were studied. In 86/241(36%) women, HIV diagnosis was made during the current pregnancy or shortly after labour. Thirty others were diagnosed during previous pregnancies. Highly active antiretroviral therapy (HAART) was prescribed in 76% of pregnancies. The mean viral load before labour was 23,000 +/- 100,000 copies/mL with a mean CD4 of 406 +/- 223 (range 4-1277) cells/mm(3). Caesarian sections were preformed in 175/300 pregnancies (103/175 with viral load <1000 copies/mL). During labour, azidothymidine (AZT) was given to 80% and nevirapine to 8% of the women. Eighty-eight percent of the neonates received AZT for six weeks. The overall HIV-MTCT rate was 3.6%. MTCT correlated significantly with delayed HIV diagnosis, low CD4, lack of HAART during pregnancy and lack of perinatal treatment. HIV treatment of mothers and their newborns throughout pregnancy, labour and perinatal period are crucial for effective prevention of MTCT, emphasizing the need for early HIV screening, diagnosis and treatment.

Global connectivity of the fronto-parietal cognitive control network is related to depression symptoms in the general population.

We all vary in our mental health, even among people not meeting diagnostic criteria for mental illness. Understanding this individual variability may reveal factors driving the risk for mental illness, as well as factors driving subclinical problems that still adversely affect quality of life. To better understand the large-scale brain network mechanisms underlying this variability, we examined the relationship between mental health symptoms and resting-state functional connectivity patterns in cognitive control systems. One such system is the fronto-parietal cognitive control network (FPN). Changes in FPN connectivity may impact mental health by disrupting the ability to regulate symptoms in a goal-directed manner. Here we test the hypothesis that FPN dysconnectivity relates to mental health symptoms even among individuals who do not meet formal diagnostic criteria but may exhibit meaningful symptom variation. We found that depression symptoms severity negatively correlated with between-network global connectivity (BGC) of the FPN. This suggests that decreased connectivity between the FPN and the rest of the brain is related to increased depression symptoms in the general population. These findings complement previous clinical studies to support the hypothesis that global FPN connectivity contributes to the regulation of mental health symptoms across both health and disease.

Patient experience with discharge instructions in postdischarge recovery: a qualitative study.

OBJECTIVES: We examined the role of discharge instructions in postoperative recovery for patients undergoing colorectal surgery and report themes related to patient perceptions of discharge instructions and postdischarge experience. DESIGN: Semistructured interviews were conducted as part of a formative evaluation of a Project Re-Engineered Discharge intervention adapted for surgical patients. SETTING: Michael E. DeBakey VA Medical Center, a tertiary referral centre in Houston, Texas. PARTICIPANTS: Twelve patients undergoing elective colorectal surgery. Interviews were conducted at the two-week postoperative appointment. RESULTS: Participants demonstrated understanding of the content in the discharge instructions. During the interviews, participants reported several positive roles for discharge instructions in their postdischarge care: a sense of security, a reminder of inhospital education, a living document and a source of empowerment. Despite these positive associations, participants reported that the instructions provided insufficient information to promote access to care that effectively addressed acute issues following discharge. Participants noted difficulty reaching providers after discharge, which resulted in the adoption of workarounds to overcome system barriers. CONCLUSIONS: Despite concerted efforts to provide patient-centred instructions, the discharge instructions did not provide enough context to effectively guide postdischarge interactions with the healthcare system. Insufficient information on how to access and communicate with the most appropriate personnel in the healthcare system is an important barrier to patients receiving high-quality postdischarge care. Tools and strategies from team training programmes, such as team strategies and tools to enhance performance and patient safety, could be adapted to include patients and provide them with structured methods for communicating with healthcare providers post discharge.

Cognitive task information is transferred between brain regions via resting-state network topology.

Resting-state network connectivity has been associated with a variety of cognitive abilities, yet it remains unclear how these connectivity properties might contribute to the neurocognitive computations underlying these abilities. We developed a new approach-information transfer mapping-to test the hypothesis that resting-state functional network topology describes the computational mappings between brain regions that carry cognitive task information. Here, we report that the transfer of diverse, task-rule information in distributed brain regions can be predicted based on estimated activity flow through resting-state network connections. Further, we find that these task-rule information transfers are coordinated by global hub regions within cognitive control networks. Activity flow over resting-state connections thus provides a large-scale network mechanism for cognitive task information transfer and global information coordination in the human brain, demonstrating the cognitive relevance of resting-state network topology.

User-centered design of discharge warnings tool for colorectal surgery patients.

OBJECTIVES: Readmission following colorectal surgery, typically due to surgery-related complications, is common. Patient-centered discharge warnings may guide recognition of early complication signs after colorectal surgery. MATERIALS AND METHODS: User-centered design of a discharge warnings tool consisted of iterative health literacy review and a heuristic evaluation with human factors and clinical experts as well as patient end users to establish content validity and usability. RESULTS: Literacy evaluation of the prototype suggested >12th-grade reading level. Subsequent revisions reduced reading level to 8th grade or below. Contents were formatted during heuristic evaluation into 3 action-oriented zones (green, yellow, and red) with relevant warning lexicons. Usability testing demonstrated comprehension of this 3-level lexicon and recognition of appropriate patient actions to take for each level. DISCUSSION: We developed a discharge warnings tool for colorectal surgery using staged user-centered design. The lexicon of surgical discharge warnings could structure communication among patients, caregivers, and clinicians to improve post-discharge care.

Adaptive response to hypoxia and remote ischaemia pre-conditioning: a new hypoxia-inducible factors era in clinical medicine.

Transient ischaemia leads to tolerance to subsequent protracted ischaemia. This 'ischaemia pre-conditioning' results from the induction of numerous protective genes, involved in cell metabolism, proliferation and survival, in antioxidant capacity, angiogenesis, vascular tone and erythropoiesis. Hypoxia-inducible factors (HIF) play a pivotal role in this transcriptional adaptive response. HIF prolyl hydroxylases (PHDs), serving as oxygen sensors, control HIFα degradation. HIF-mediated ischaemic pre-conditioning can be achieved with the administration of PHD inhibitors, with the attenuation of organ injury under various hypoxic and toxic insults. Clinical trials are currently under way, evaluating PHD inhibitors as inducers of erythropoietin. Once their safety is established, their potential use might be further tested in clinical trials in various forms of acute ischaemic and toxic organ damage. Repeated transient limb ischaemia was also found to attenuate ischaemic injury in remote organs. This 'remote ischaemic pre-conditioning' phenomenon (RIP) has been extensively studied recently in small clinical trials, preceding, or in parallel with an abrupt insult, such as myocardial infarction, cardiac surgery or radiocontrast administration. Initial results are promising, suggesting organ protection. Large-scale multi-centre studies are currently under way, evaluating the protective potential of RIP in cardiac surgery, in the management of myocardial infarction and in organ transplantation. The mechanisms of organ protection provided by RIP are poorly understood, but HIF seemingly play a role as well. Thus, Inhibition of HIF degradation with PHD inhibitors, as well as RIP (in part through HIF), might develop into novel clinical interventions in organ protection in the near future.

Characteristics of candidaemia with Candida-albicans compared with non-albicans Candida species and predictors of mortality.

Candidaemia due to non-albicans Candida species is increasing in frequency. We describe 272 episodes of candidaemia, define parameters associated with Candida albicans and other Candida species, and analyse predictors associated with mortality. Patients with C. albicans (55%) had the highest fatality rate and frequently received immunosuppressive therapy, while patients with Candida parapsilosis (16%) had the lowest fatality and complication rates. Candida tropicalis (16%) was associated with youth, severe neutropenia, acute leukaemia or bone marrow transplantation, Candida glabrata (10%) was associated with old age and chronic disease, and Candida krusei (2%) was associated with prior fluconazole therapy. The overall fatality rate was 36%, and predictors of death by multi-variate analysis were shock, impaired performance status, low serum albumin and congestive heart failure. Isolation of non-albicans Candida species, prior surgery and catheter removal were protective factors. When shock was excluded from analysis, antifungal therapy was shown to be protective. Unlike previous concerns, infection with Candida species other than C. albicans has not been shown to result in an increased fatality rate.

Testosterone treatment and MMPI-2 improvement in transgender men: a prospective controlled study.

OBJECTIVE: Most transgender men desire to receive testosterone treatment in order to masculinize their bodies. In this study, we aimed to investigate the short-term effects of testosterone treatment on psychological functioning in transgender men. This is the 1st controlled prospective follow-up study to examine such effects. METHOD: We examined a sample of transgender men (n = 48) and nontransgender male (n = 53) and female (n = 62) matched controls (mean age = 26.6 years; 74% White). We asked participants to complete the Minnesota Multiphasic Personality Inventory (2nd ed., or MMPI-2; Butcher, Graham, Tellegen, Dahlstrom, & Kaemmer, 2001) to assess psychological functioning at baseline and at the acute posttreatment follow-up (3 months after testosterone initiation). Regression models tested (a) Gender × Time interaction effects comparing divergent mean response profiles across measurements by gender identity; (b) changes in psychological functioning scores for acute postintervention measurements, adjusting for baseline measures, comparing transgender men with their matched nontransgender male and female controls and adjusting for baseline scores; and (c) changes in meeting clinical psychopathological thresholds. RESULTS: Statistically significant changes in MMPI-2 scale scores were found at 3-month follow-up after initiating testosterone treatment relative to baseline for transgender men compared with female controls (female template): reductions in Hypochondria (p < .05), Depression (p < .05), Hysteria (p < .05), and Paranoia (p < .01); and increases in Masculinity-Femininity scores (p < .01). Gender × Time interaction effects were found for Hysteria (p < .05) and Paranoia (p < .01) relative to female controls (female template) and for Hypochondria (p < .05), Depression (p < .01), Hysteria (p < .01), Psychopathic Deviate (p < .05), Paranoia (p < .01), Psychasthenia (p < .01), and Schizophrenia (p < .01) compared with male controls (male template). In addition, the proportion of transgender men presenting with co-occurring psychopathology significantly decreased from baseline compared with 3-month follow-up relative to controls (p < .05). CONCLUSIONS: Findings suggest that testosterone treatment resulted in increased levels of psychological functioning on multiple domains in transgender men relative to nontransgender controls. These findings differed in comparisons of transgender men with female controls using the female template and with male controls using the male template. No iatrogenic effects of testosterone were found. These findings suggest a direct positive effect of 3 months of testosterone treatment on psychological functioning in transgender men.

Genotypic variation of HIV-1 reverse transcriptase and protease: comparative analysis of clade C and clade B.

OBJECTIVE: To compare drug-resistant variants from untreated (naive) and treated patients infected with clade B or C virus. METHODS: Consecutive samples (165) from patients throughout Israel were analyzed. All those in the treated group were failing highly active antiretroviral therapy. RESULTS: There were 87 clade B (14 naive) and 78 clade C (20 naive) [corrected] with significant differences in the prevalence of known drug-resistance mutations between the clades: in naive patients in the protease region M36I 7% and 95% (P < 0.0001), K20R 0% and 27% (P = 0.063), A71V 18% and 0% (P = 0.063), M46I 0% and 13%, and V77I 18% and 0% (P = 0.063), respectively, and in the reverse transcriptase region A98G/S 0% and 20% (P = 0.12), respectively. Most clade C viruses also showed significant differences from clade B consensus sequence at additional protease sites: R41K 100%, H69K/Q 85%, L89M 95% and I93L 80% (P < 0.0001). There were also significant differences (P < 0.03 to < 0.0001) in treated patients in clades B and C: in the protease region L10I 40% and 12%, M36I 26% and 95%, L63P 67% and 40%, A71I 38% and 7%, G73I and V77I 18% and 0%, I84V 16% and 3%, and L90M 40% and 12%, respectively; in the reverse transcriptase M41L 41% and 17%, D67N 41% and12%, K70R 30% and 7%, T215Y 48% and 29%, K219Q 21% and 7%, and A98G/S 3% and 24%, respectively. CONCLUSION: Significantly differences between clade B and C viruses may be associated with development of differing resistance patterns during therapy and may affect drug utility in patients infected with clade C.

Assessment of the coagulation profile in hemato-oncological patients receiving ATG-based conditioning treatment for allogeneic stem cell transplantation.

Antithymocyte globulin (ATG) is increasingly used in pre-allogeneic stem cell transplantation (allo-SCT) conditioning regimens to prevent graft rejection and graft-versus-host disease. However, ATG was also found to be associated with increased incidence of thrombosis during organ transplantation. In the present study, we tested the coagulation status of 21 patients with hematologic malignancies undergoing allo-SCT who received ATG-based (11 patients) or non-ATG-based (10) conditioning treatment. We assessed several thrombophilia markers as well as circulating total and endothelial microparticles (TMP/EMP) and soluble CD40 ligand (CD40L). No significant difference in the mean values of prothrombin time, partial thromboplastin time, fibrinogen, antithrombin, protein C, protein S, thrombin-antithrombin III complex, homocysteine levels, prevalence of genetic thrombophilia markers and levels of EMP, TMP or CD40L was observed between the ATG-treated and ATG-untreated patients, as well as before and after conditioning in each group separately. Platelet counts decreased significantly in ATG-treated patients; however, this decrease was not associated with clinical or laboratory evidence of disseminated intravascular coagulation. No patient developed thromboembolic event or veno-occlusive liver disease. Our results suggest that allo-SCT is not associated with increased hypercoagulability and addition of ATG to conditioning regimen has no significant procoagulant effect.

Engraftment-associated hypophosphatemia--the role of cytokine release and steep leukocyte rise post stem cell transplantation.

Hypophosphatemia associated with bone marrow transplantation has been infrequently reported. The suggested mechanism is phosphate uptake by the replicating cells. Various cytokines are associated with the development of hypophosphatemia. The present study evaluated the interrelationship between cytokine release, the rise in WBC and the development of hypophosphatemia during the engraftment period. Blood samples were obtained from 60 patients undergoing peripheral blood stem cell transplant, on the day of admission and then daily from the day of transplant until discharge. Hypophosphatemia developed in 62% of the patients. The median day of minimal phosphorus level was +8 and it antedated engraftment by 2 days. There was a significant correlation between the day of minimal phosphorus level and the day of maximal WBC and a significant correlation between the fall in phosphorus level and WBC rise. IL-6 and IL-8 showed similar kinetics. Higher IL-6 and IL-8 levels were directly associated with lower phosphorus levels. In conclusion, hypophosphatemia commonly occurs in the post-transplant period. We assume that both a direct effect of cytokine release and an increased consumption by the dividing WBCs contribute to its appearance. As its occurrence usually antedates engraftment it can be used as a forerunner for WBC recovery.

Extramedullary progression despite a good response in the bone marrow in patients treated with thalidomide for multiple myeloma.

We report two patients who were treated with thalidomide for resistant multiple myeloma (MM) and developed extramedullary plasmacytomas despite a good response in the bone marrow. The first patient had progressive disease 18 months post autologous peripheral stem cell transplant. Two and a half months after the initiation of thalidomide therapy extensive new plasmacytomas of the skin and nasal mucosa appeared while the medullary response continued. The second patient was treated with thalidomide for resistant MM. Despite a medullary response he developed neurological signs compatible with cranial nerve involvement and an MRI study was suggestive of a plasmacytoma involving the sellar region. We assume that a change in the expression of some adhesion molecules on the myeloma and/or the stromal cells is responsible for this phenomenon. Treating Physicians should be aware of this phenomenon in MM patients receiving thalidomide.

Acute neutrophilic dermatosis induced by all-trans-retinoic acid treatment for acute promyelocytic leukemia.

All-trans-retinoic acid (ATRA) is considered the recommended induction treatment for acute promyelocytic leukemia (APL). Although the dermatological side effects associated with ATRA treatment are relatively common, acute neutrophilic dermatosis (Sweet's syndrome) has only been rarely reported. We describe such a case who responded to chemotherapy and not to low doses of corticosteroids.