Genetic Variability of SOX10-Related Disorders within an Italian Family: Straddling the Line between Kallmann and Waardenburg Syndrome.

Introduction: Kallmann syndrome (KS) is a genetically heterogeneous developmental disorder that most often manifests hypogonadotropic hypogonadism (HH) and hypo-/anosmia due to early embryonic impairment in the migration of gonadotropin-releasing hormone neurons. SOX10 (SRY-Box 10; MIM*602229), a key transcriptional activator involved in the development of neural crest cells, has been associated with KS and is identified as one of the causative genes of Waardenburg syndrome (WS). Case Presentation: A 28-year-old female patient, who was clinically diagnosed with KS in her childhood, presented with HH and anosmia, mild bilateral sensorineural hearing loss (SNHL), and pigmentation abnormalities. Next-generation sequencing analysis detected a missense heterozygous SOX10 pathogenic variant (NM_006941.4:c.506C>T) in the proposita and in her mother, whose phenotype included exclusively anosmia and hypopigmented skin patches. The same variant has been described by Pingault et al. [Clin Genet. 2015;88(4):352-9] in a patient with apparently isolated bilateral severe SNHL. Conclusion: Our finding substantiates the extreme phenotypic variability of SOX10-related disorders, which range from classical KS and/or WS to contracted endophenotypes that could share a common pathway in the development of neural crest cells and highlights the need for careful evaluation and long-term follow-up of SOX10 patients, with special focus on atypical/additional and/or late-onset phenotypic traits.

Diabetic Foot Osteomyelitis in Patients with and without Peripheral Arterial Disease: Two Different Diseases?

The aim of the current study was to evaluate the outcomes of patients with diabetic foot osteomyelitis (DFO), comparing subjects with and without peripheral arterial disease (PAD). The study is a prospective study including a population of patients affected by a DFO located in the forefoot. All patients were managed by a surgical conservative approach defined by the removal of the infected bone, in association with the antibiotic therapy. Patients were divided into two groups: those with PAD (neuro-ischaemic DFO) and those without (neuropathic DFO). After 1 year of follow-up, the following outcome were evaluated and compared between groups: healing, healing time, minor amputation, major amputation, hospitalization, need for surgical re-intervention. Overall, 166 patients were included, 87(52.4%) of them had neuro-ischaemic DFO and 79 (47.6%) neuropathic DFO. Patients with neuro-ischaemic DFO in comparison to neuropathic DFO were older (72.5 ± 9 vs 64.1 ± 15.5 years, P < .0001), had longer diabetes duration (21.8 ± 5.6 vs 16.4 ± 7.6 years, P < .0001), higher rate of dialysis (13.8 vs 1.3%, P = .001) and ischaemic heart disease (79.3 vs 12.7%, P < .0001). Outcomes for neuro-ischaemic DFO and neuropathic DFO were: healing (96.5 vs 97.5%, P = .7), healing time (7.8 ± 6.2 vs 5.7 ± 3.7 weeks, P = .01), minor amputation (16.1 vs 3.8%, P = .006), major amputation (0 vs 0%, ns), hospitalization (90.8 vs 51.9%, P < .0001), surgical re-intervention (14.9 vs 8.8%, P = .004) respectively. In addition, PAD resulted in an independent predictor of minor amputation, hospitalization, and surgical re-intervention. DFO in patients with PAD was characterized by longer healing time, more cases of minor amputation, hospitalization, and surgical re-intervention. PAD independently predicted the risk of minor amputation, hospitalization, and surgical re-intervention, while it was not associated with the healing rate.

Nanomedicine in the Treatment of Diabetes.

Nanomedicine could improve the treatment of diabetes by exploiting various therapeutic mechanisms through the use of suitable nanoformulations. For example, glucose-sensitive nanoparticles can release insulin in response to high glucose levels, mimicking the physiological release of insulin. Oral nanoformulations for insulin uptake via the gut represent a long-sought alternative to subcutaneous injections, which cause pain, discomfort, and possible local infection. Nanoparticles containing oligonucleotides can be used in gene therapy and cell therapy to stimulate insulin production in ß-cells or ß-like cells and modulate the responses of T1DM-associated immune cells. In contrast, viral vectors do not induce immunogenicity. Finally, in diabetic wound healing, local delivery of nanoformulations containing regenerative molecules can stimulate tissue repair and thus provide a valuable tool to treat this diabetic complication. Here, we describe these different approaches to diabetes treatment with nanoformulations and their potential for clinical application.

Early Treatment of Acute Stage 0/1 Diabetic Charcot Foot Can Avoid Major Amputations at One Year.

Background: If unrecognized, Charcot neuro-osteoarthropathy (CNO) can be a devastating complication of diabetes. Methods: The aim of this retrospective study was to evaluate the outcomes in a cohort of diabetic patients diagnosed with active CNO managed in a tertiary level diabetic foot clinic (DFC). We included consecutive patients with active CNO, stage 0-1, according to the Eichenholtz-Shibata classification, who were referred from 1 January 2019 to 27 September 2022. Diagnosis of CNO was based on clinical signs and imaging (X-rays and magnetic resonance). All patients were completely offloaded by a total-contact cast (TCC) or removable knee-high device. Each patient was closely monitored monthly until CNO remission or another outcome. At 12 months of follow-up, the following outcomes were analyzed: remission, time to remission, major amputations (any above the ankle), and surgical indication. Results: Forty-three patients were included. The mean age was 57.6 ± 10.8 years; 65% were males and 88.4% had type 2 diabetes, with a mean duration of 20.6 ± 9.9 years. At baseline, 32.6% was affected by peripheral artery disease. Complete remission was recorded in 40/43 patients (93%), with a mean time to remission of 5.6 ± 1.5 months; major amputation and surgical indication occurred, respectively in 1/43 patients (2.3%) and 3/43 patients (7%). Conclusions: Early treatment of active Stage 0/1 CNO leads to high rates of remission and limb salvage.

Does the Relationship of the Autonomic Symptoms Questionnaire COMPASS 31 with Cardiovascular Autonomic Tests Differ between Type 1 and Type 2 Diabetes Mellitus?

Background: The aim was to investigate if autonomic symptoms questionnaire Composite Autonomic Symptom Score (COMPASS) 31 has different association with cardiovascular autonomic neuropathy (CAN) and diagnostic performance between type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). Methods: Seventy-nine participants with T1DM and 140 with T2DM completed COMPASS 31 before cardiovascular reflex tests (CARTs) for CAN, and assessment of symptoms, signs, vibration, and thermal perception thresholds for diabetic polyneuropathy (DPN) diagnosis. Results: COMPASS 31 total weighted score (TWS) was similar in the two groups, but significantly associated with confirmed CAN only in T1DM (P=0.0056) and not T2DM group (P=0.1768) and correlated with CARTs score more strongly in T1DM (rho=0.356, P=0.0016) than in T2DM group (rho=0.084, P=0.3218) (P=0.016). Only in T1DM and not T2DM group, the area under the receiver operating characteristic curve (AUC) reached a fair diagnostic accuracy (>0.7) for confirmed CAN (0.73±0.07 vs. 0.61±0.08) and DPN (0.75±0.06 vs. 0.68±0.05), although without a significant difference. COMPASS 31 TWS (cut-off 16.44) reached acceptable diagnostic performance in T1DM, with sensitivity for confirmed CAN 81.2% and sensitivity and specificity for DPN 76.3% and 78%, compared to T2DM group (all <70%). AUC for DPN of orthostatic intolerance domain was higher in T1DM compared to T2DM group (0.73±0.05 vs. 0.58±0.04, P=0.027). Conclusion: COMPASS 31 is more weakly related to CAN in T2DM than in T1DM, with a fair diagnostic accuracy for confirmed CAN only in T1DM. This difference supports a multifactorial origin of symptoms and should be considered when using COMPASS 31.

Omega-3-Enriched Diet Improves Metabolic Profile in Prdx6-Deficient Mice Exposed to Microgravity.

BACKGROUND: Space travel has always been one of mankind's greatest dreams. Thanks to technological innovation, this dream is becoming more of a reality. Soon, humans (not only astronauts) will travel, live, and work in space. However, a microgravity environment can induce several pathological alterations that should be, at least in part, controlled and alleviated. Among those, glucose homeostasis impairment and insulin resistance occur, which can lead to reduced muscle mass and liver dysfunctions. Thus, it is relevant to shed light on the mechanism underlaying these pathological conditions, also considering a nutritional approach that can mitigate these effects. METHODS: To achieve this goal, we used Prdx6-/- mice exposed to Hindlimb Unloading (HU), a well-established experimental protocol to simulate microgravity, fed with a chow diet or an omega-3-enriched diet. RESULTS: Our results innovatively demonstrated that HU-induced metabolic alterations, mainly related to glucose metabolism, may be mitigated by the administration of omega-3-enriched diet. Specifically, a significant improvement in insulin resistance has been reported. CONCLUSIONS: Although preliminary, our results highlight the importance of specific nutritional approaches that can alleviate microgravity-induced harmful effects. These findings should be considered soon by those planning trips around the earth.

Peripheral Blood Mononuclear Cells: A New Frontier in the Management of Patients with Diabetes and No-Option Critical Limb Ischaemia.

The current study aimed to evaluate the effectiveness of peripheral blood mononuclear cell (PB-MNC) therapy as adjuvant treatment for patients with diabetic foot ulcers (DFUs) and no-option critical limb ischaemia (NO-CLI). The study is a prospective, noncontrolled, observational study including patients with neuro-ischaemic DFUs and NO-CLI who had unsuccessful revascularization below the ankle (BTA) and persistence of foot ischaemia defined by TcPO2 values less than 30 mmHg. All patients received three cycles of PB-MNC therapy administered through a "below-the-ankle approach" in the affected foot along the wound-related artery according to the angiosome theory. The primary outcome measures were healing, major amputation, and survival after 1 year of follow-up. The secondary outcome measures were the evaluation of tissue perfusion by TcPO2 and foot pain defined by the numerical rating scale (NRS). Fifty-five patients were included. They were aged >70 years old and the majority were male and affected by type 2 diabetes with a long diabetes duration (>20 years); the majority of DFUs were infected and nearly 90% were assessed as gangrene. Overall, 69.1% of patients healed and survived, 3.6% healed and deceased, 10.9% did not heal and deceased, and 16.4% had a major amputation. At baseline and after PB-MNC therapy, the TcPO2 values were 17 ± 11 and 41 ± 12 mmHg, respectively (p < 0.0001), while the pain values (NRS) were 6.8 ± 1.7 vs. 2.8 ± 1.7, respectively (p < 0.0001). Any adverse event was recorded during the PB-MNC therapy. Adjuvant PB-MNC therapy seems to promote good outcomes in patients with NO-CLI and neuro-ischaemic DFUs.

Hospital Readmission in Patients With Diabetic Foot Ulcers: Prevalence, Causes, and Outcomes.

The aim of the current study was to evaluate the rate of readmission in patients affected by diabetes and foot ulcers (DFUs), and causes and outcomes of patients requiring a new hospitalization. The current study is a retrospective observational study including patients who have required hospitalization since January 2019 to September 2022 due to a DFU. Once patients were discharged, they were regularly followed as outpatients. Within 6 months of follow-up, the rate of hospital readmission for a diabetic foot problem was recorded. According to the readmission or not, patients were divided into 2 groups, readmitted and not readmitted patients, respectively. Hence, all patients were followed for 6 months more and outcomes of the 2 groups were analyzed and compared. Overall, 310 patients were included. The mean age was 68 ± 12 years, the majority of patients reported type 2 diabetes (>90%), and the mean diabetes duration was approximately 20 years. Sixty-eight (21.9%) patients were readmitted. The main reason for hospital readmission was the presence of critical limb ischemia (CLI) in the contralateral limb (6.1%), the recurrence of CLI in the previous treated limb (4.5%), and the onset of new infected DFU in the contralateral foot (4.5%). Readmitted patients reported lower rate of healing (51.5% vs 89.2%, P < .0001) and higher rate of major amputation (10.3% vs 4.5%, P = .2) in comparison to not readmitted patients. Critical limb ischemia resulted in the only independent predictor of hospital readmission. Hospital readmission is a frequent issue among patients with DFUs, and readmitted patients showed a lower chance of wound healing. Critical limb ischemia resulted in the main cause of new hospitalization.

Prevalence and risk of new-onset diabetes mellitus after COVID-19: a systematic review and meta-analysis.

Aims: After the acute phase of SARS-CoV-2 infection, the onset of glycemic impairment and diabetes have been reported. Nevertheless, the exact burden of glycemic impairment and diabetes after COVID-19 has not been clearly described. Materials and methods: Electronic search was run in Pubmed (MEDLINE), Web of Science, Scopus, and ClinicalTrial.org for reports published from database inception to September 2022. We included observational studies reporting quantitative data on diabetes prevalence or its onset in subjects with a history of SARS-CoV-2 infection from at least 60 days. Risk of bias was assessed by the JBI's critical appraisal checklist. Random effect model was used to calculate pooled data. The review protocol was registered on PROSPERO (CRD42022310722). Results: Among 1,630 records screened, 20 studies were included in the analysis. The mean or median age of participants ranged from ~ 35 to 64 years, with a percentage of males ranging from 28% to 80%. Only two studies were considered at low risk of bias. The estimate of diabetes prevalence, calculated on a total of 320,948 participants pooled with 38,731 cases, was 16% (95%CI: 11-22%). The estimate of proportion of incident cases of diabetes was 1.6% (95%CI: 0.8-2.7%). Subgroup analysis showed that previous hospitalization increased the prevalence of diabetes and the proportion of incident cases. Conclusion: Diabetes is common in individuals who have experienced SARS-CoV-2 infection, especially if they required hospitalization. This data may be helpful to screen for diabetes and manage its complications in individuals who experienced COVID-19. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022310722, identifier CRD42022310722.

A multidisciplinary team reduces in-hospital clinical complications and mortality in patients with diabetic foot ulcers.

AIMS: The current study aims to evaluate the effectiveness of a multidisciplinary diabetic foot team (MDFT) in the management of in-patients affected by diabetic foot problems. MATERIALS AND METHODS: The study was a retrospective observational study. Consecutive patients with a diabetic foot problem requiring hospitalisation were included. All patients were managed by a MDFT led by diabetologists according to the guidance. The rate of in-hospital complications (IHCs), major amputation, and survival were recorded at the end of patient's hospitalisation. IHC was defined as any new infection different from wound infection, cardiovascular events, acute renal injury, severe anaemia requiring blood transfusion, and any other clinical problem not present at the assessment. RESULTS: Overall, 350 patients were included. The mean age was 67.9 ± 12.6 years, 254 (72.6%) were males, 323 (92, 3%) showed Type 2 diabetes with a mean duration of 20.2 ± 9.6 years; 224 (64%) had ischaemic diabetic foot ulcers (DFUs) and 299 (85.4%) had infected DFUs. IHCs were recorded in 30/350 (8.6%) patients. The main reasons for IHCs were anaemia requiring blood transfusion (2.8%), pneumonia (1.7%), acute kidney failure (1.1%). Patients with IHCs showed a higher rate of major amputation (13.3 vs. 3.1%, p = 0.02) and mortality (16.7 vs. 0.6%, p < 0.0001) in comparison to those without. Ischaemic heart disease (IHD) and wound duration at the assessment (>1 month) were independent predictors of IHC, whereas IHCs, heart failure, and dialysis were independent predictors of in-hospital mortality. CONCLUSIONS: The multidisciplinary management of diabetic foot problems leads to an IHC rate of 8%. The risk of IHCs is higher in patients with IHD and long wound duration.